> GRADUATE SCHOOL
>
> U.S. DEPARTMENT OF AGRICULTURE
>
> \* \* \*
>
> FDA FOOD ADVISORY
>
> COMMITTEE MEETING
>
> \* \* \*
>
> FOOD BIOTECHNOLOGY SUBCOMMITTEE
>
> OF THE FOOD ADVISORY COMMITTEE
>
> MOLECULAR CHARACTERIZATION
>
> CENTER FOR FOOD AND APPLIED NUTRITION
>
> Wednesday, September 24, 2003
>
> J.W. Marriott Hotel
>
> 1331 Pennsylvania Avenue, N.W.
>
> Washington, D.C.
>
> The meeting convened, pursuant to notice
>
> at 8:36 a.m., before Acting Chairman Francis F.
>
> Busta.
>
> MEMBERS PRESENT:
>
> JONATHAN ARIAS, Ph.D.
>
> Associate Research Scientist
>
> Department of Biological Sciences
>
> University of Maryland, Baltimore County
>
> 1000 Hilltop Circle
>
> Baltimore, Maryland 21250
>
> Tel: 410-455-3470
>
> Fax: 410-455-3875
>
> Arias@umbi.umd.edu
>
> BOB B. BUCHANAN, Ph.D.
>
> Professor
>
> University of California
>
> Department of Plant and Microbial Biology
>
> 111 Koshland Hall
>
> Berkeley, California 94720
>
> Tel: 510-642-3590
>
> Fax: 510-642-7356
>
> view@nature.berkeley.edu
>
> FRANCIS FREDERICK BUSTA, Ph.D.
>
> Emeritus Professor
>
> University of Minnesota
>
> Department of Food Science and Nutrition
>
> 1334 Eckles Avenue
>
> St. Paul, Minnesota 55108-6099
>
> Tel: 612-624-3086
>
> Fax: 612-625-5272
>
> DOUGLAS GURIAN-SHERMAN, Ph.D.
>
> Science Director, Biotechnology Project
>
> Center for Science in the Public Interest
>
> 1875 Connecticut Avenue, N.W.
>
> Suite 300
>
> Washington, D.C. 20009
>
> Tel: 202-332-9110 Ext. 377
>
> Fax: 202-265-4954
>
> dgurian-sherman@espinet.org
>
> MEMBERS PRESENT (Continued):
>
> ANNE R. KAPUSCINSKI, Ph.D.
>
> Professor, University of Minnesota
>
> Department of Fisheries & Wildlife
>
> 180 McNeal Hall
>
> 1985 Buford Avenue
>
> St. Paul, Minnesota 55108
>
> Tel: 612-624-3019
>
> Fax: 612-625-8153
>
> ark@fw.umn.edu
>
> ABIGAIL A. SALYERS, Ph.D.
>
> Professor of Microbiology
>
> Department of Microbiology
>
> University of Illinois at Urban-Champaign
>
> B103 CLSL
>
> 601 S. Goodwin Avenue
>
> Urbana, Illinois 61801
>
> Tel: 217-333-7378
>
> Fax: 217-244-8485
>
> Temporary Voting Members:
>
> DENNIS GONSALVES, Ph.D.
>
> Center Director
>
> Pacific Basin Agricultural Research Center
>
> 99 Apuni Street, Suite 204
>
> Hilo, Hawaii 96720
>
> Tel: 808-932-2100
>
> Fax: 808-969-6967
>
> Dgonsalkves@pbarc.ars.usda.gov
>
> STEPHEN BENEDICT, Ph.D.
>
> Department of Molecular Biosciences
>
> University of Kansas
>
> 1200 Sunnyside Avenue
>
> Lawrence, Kansas 66045-7534
>
> Tel: 785-864-4007
>
> Fax: 785-864-5294
>
> sbene@ku.edu
>
> MEMBERS PRESENT (Continued):
>
> CALVIN QUALSET, Ph.D.
>
> Genetic Resources Conservation Program
>
> DANR Building, Hopkins Road
>
> University of California
>
> Davis, California 95616
>
> Tel: 530-754-8502
>
> Fax: 530-754-8503
>
> coqualset@ucdavis.edu
>
> NINA FEDOROFF, Ph.D.
>
> 519 Wartik Laboratory
>
> Huck Institute for Life Sciences
>
> Penn State University
>
> University Park, Pennsylvania 16802
>
> Tel: 814-863-5717
>
> Fax: 814-863-1357
>
> Industry Representative:
>
> JAMES ASTWOOD, Ph.D.
>
> Director, Food and Feed Safety Policy
>
> Monsanto
>
> 800 North Lindbergh Boulevard
>
> St. Louis, Missouri 63167
>
> Tel: 314-694-8396
>
> Fax: 314-694-8562
>
> james.d.astwood@monsanto.com
>
> ALSO PRESENT:
>
> MR. BOB LAKE
>
> MS. JEANETTE GLOVER GLEW, CFSAN
>
> MR. MICHAEL HANSON (Public Comment)
>
> DR. JAMES MARYANSKI, CFSAN
>
> DR. THOMAS CEBULA, CFSAN
>
> [C]{.underline} [O]{.underline} [N]{.underline} [T]{.underline}
> [E]{.underline} [N]{.underline} [T]{.underline} [S]{.underline}
>
> [AGENDA ITEM]{.underline} [PAGE]{.underline}
>
> Welcome and Introductions 6
>
> Acting FBS Chair
>
> Conflict of Interest Statement 9
>
> Welcome from FDA 13
>
> Charge and Questions 23
>
> Acting FBS Chair
>
> FDA\'s Biotech Food Safety Assessment 29
>
> Ms. Jeanette Glover Glew, CFSAN
>
> Questions of Clarification 43
>
> FBS Members
>
> Codex Approach 74
>
> Dr. James Maryanski, CFSAN
>
> Questions of Clarification 92
>
> FBS Members
>
> FDA\'s Discussion Paper --- Molecular
>
> Characterization 103
>
> Dr. Thomas Cebula, CFSAN
>
> Questions of Clarification 122
>
> FBS Members
>
> Public Comment 153
>
> Summary and Review of Charge and
>
> Questions 172
>
> FDA
>
> Discussion 179
>
> FBS Members
>
> Response to Questions 194
>
> FBS Members
>
> Concluding Comments 334
>
> Acting FBS Chair
>
> [P]{.underline} [R]{.underline} [O]{.underline} [C]{.underline}
> [E]{.underline} [E]{.underline} [D]{.underline} [I]{.underline}
> [N]{.underline} [G]{.underline} [S]{.underline}
>
> CHAIRMAN BUSTA: The meeting is called to order. And welcome, all of
> the committee members, guests, and the members of FDA to the\--this
> Biotechnology Subcommittee meeting of the Food Advisory Committee.
>
> My name is Frank Busta. I\'m a professor emeritus at the University of
> Minnesota. I\'m a member of the, let\'s see, the term is full
> committee. I\'m\--that is not implied that I\'m full of it, but some
> people would say it. And I\'ve been asked to chair this meeting as an
> acting chair.
>
> In front of you, you have an agenda, and, as you see, in addition to
> welcoming you, we\'d like to have our introductions so that everybody
> knows who everyone is, and we have it on the record.
>
> I believe that we\'re asked always to talk into the microphones
> because it is being recorded, and that gives us a record, as well as
> someone taking notes.
>
> So, if we could start with introductions, telling us basically who you
> are and your\--the
>
> committee. Douglas, would you start?
>
> DR. GURIAN-SHERMAN: Doug Gurian-Sherman. I\'m with Center for Science
> in the Public Interest.
>
> CHAIRMAN BUSTA: And you are a member of the\--the regular member?
>
> DR. GURIAN-SHERMAN: Yes, I\'m a member of the subcommittee.
>
> DR. QUALSET: I\'m Cal Qualset, professor emeritus, University of
> California at Davis. I\'m a member\--a temporary member of the
> subcommittee.
>
> DR. BENEDICT: Steve Benedict, University of Kansas, and I\'m a
> temporary member.
>
> DR. ARIAS: Jonathan Arias, University of Maryland. I\'m a subcommittee
> member.
>
> DR. FEDOROFF: Nina Fedoroff, Penn State University. I guess I\'m a
> temporary member.
>
> CHAIRMAN BUSTA: Abigail?
>
> DR. SALYERS: Abigail Salyers, University of Illinois, and former
> President of the American Society for Microbiology. And I\'m not sure
> what kind of member I am.
>
> CHAIRMAN BUSTA: You are a member of the
>
> subcommittee.
>
> DR. SALYERS: Oh, okay.
>
> DR. BUCHANAN: Bob Buchanan, University of California at Berkeley, and
> I believe I\'m member.
>
> DR. GONSALVES: Dennis Gonsalves. I\'m at Pacific Basin and Agriculture
> Research Center, and I\'m a temporary member.
>
> DR. ASTWOOD: I\'m Jim Astwood. I\'m with Monsanto, and, I\'m the
> industry liaison.
>
> CHAIRMAN BUSTA: And Mike?
>
> DR. WATSON: Mike Watson, the Food and Drug Administration.
>
> CHAIRMAN BUSTA: And Mike does all the work.
>
> All right. To get this organized and straight, I would like you to
> refer to our agenda. You see estimated times to accomplish what we
> need to do today on the agenda.
>
> We hope that we can stay fairly close to that. I will try to be as
> firm a chair as possible so that we do not diminish our opportunities
> for discussion and summaries in the afternoon.
>
> Mike, we\'re five minutes ahead of time, but I\'d like\--I don\'t mind
> that at all.
>
> DR. WATSON: That\'s fine.
>
> CHAIRMAN BUSTA: I will turn over the conflict of interest statement,
> et cetera, to Mike Watson.
>
> DR. WATSON: Good morning, again. I\'m Mike Watson. I\'m the Acting
> Executive Secretary for the Biotechnology Subcommittee of the FDA Food
> Advisory Committee.
>
> First, I would like to read the temporary voting member appointment
> and conflict of interest statements into the record.
>
> By the authority granted under the Food Advisory Charter of July 2002,
> the following individuals have been appointed as temporary voting
> members by Joseph A. Levitt, Director of the Center for Food Safety
> and Applied Nutrition:
>
> Dr. Steven Benedict;
>
> Dr. Nina Fedoroff;
>
> Dr. Dennis Gonsalves; and
>
> Dr. Calvin Qualset.
>
> With regard to the issue of conflict of interest, committee members,
> both permanent and temporary, were screened for interest in
> bioengineered food developers. As a result of this review, in
> accordance with 18 U.S.C., Section 208 (b)(3), Dr. Robert Buchanan and
> Dr. Dennis Gonsalves have been granted a particular matter of general
> applicability waiver that permits them to participate fully in matters
> at issue.
>
> Copies of their waiver statements may be obtained by submitting a
> written request to the Agency\'s Freedom of Information Office, Room
> 12A-30 of the Parklawn Building.
>
> We would also like to note that Dr. James Astwood is participating in
> this meeting as the acting industry representative, and is a
> non-voting participant.
>
> With respect to all other participants, we ask that, in the interest
> of fairness, that they address any current or previous financial
> involvement with any firm that develops or sells bioengineered food
> crops.
>
> Finally, FDA received a letter on Monday this week, September 22,
> 2003, from the Center for Science in the Public Interest, CSPI,
> related to the work of this subcommittee. This letter was signed by
> Dr. Gurian-Sherman, a consumer representative on this subcommittee, on
> behalf of himself and two other subcommittee members, Drs. Arias and
> Kapucinski.
>
> The letter expresses concern about FDA\'s management of the
> subcommittee, selection of agenda topics, and other issues. FDA has
> provided copies of this letter to the subcommittee members, and copies
> are available to the public.
>
> FDA appreciates receiving suggestions for enhancing the work of the
> subcommittee. Since this letter was submitted too late for FDA to
> fully consider its contents and suggestions for changes for this
> meeting, we intend to examine the letter carefully and respond
> following this meeting.
>
> For today, we intend to focus on the agenda that we have prepared. Mr.
> Chairman, we note that one of the issues raised in the CSPI
>
> letter dealt with future agenda items for the subcommittee.
>
> We leave it to your discretion; but, if time permits, FDA will be
> interested to hear any suggestions that subcommittee members may have
> on future agenda items.
>
> I\'ll turn it back over to Dr. Busta.
>
> CHAIRMAN BUSTA: Well, thank you, Mike.
>
> I\'m not sure if we got a copy of that letter by e-mail before this
> meeting. I\'m not sure how many of you are in a position to see your
>
> e-mail en route. The\--we\'ll have an opportunity to look at that in
> case you hadn\'t seen it earlier; and, as Mike indicated, we will do
> our best to get through the agenda. And we will place that at the end
> of the agenda for comment, and we can expand that for other comments
> beyond the letter as for future agenda items.
>
> All right. Now, we\'re going to have a welcome from FDA. And I assume
> that\'s Bob Lake?
>
> MR. LAKE: Yes.
>
> CHAIRMAN BUSTA: They\'re really neglecting
>
> you this morning, Bob. They didn\'t give you a name card.
>
> MR. LAKE: Well, that\'s all right.
>
> Let me\--well, again, I am Bob Lake. I\'m the Director of Regulations
> and Policy at the Center for Food Safety and Applied Nutrition. I
> report directly to Joe Levitt, and one of the things in my portfolio
> is policy issues relating to bioengineered foods. Jim Maryanski, Dr.
> Maryanski, who will be talking to you later, and who I think is\--most
> of you know very well\--has been my technical advisor for probably 15
> years.
>
> He is the biotech coordinator, but we established that position back
> in the late \'80s; and his title and mine have changed a little bit
> over the years. But we have worked very closely together throughout
> that time.
>
> I want to officially, on behalf of SISAM management, welcome you here
> to this meeting. I know everyone has very busy schedules, and it\'s
> certainly hard to find a time where we can get everyone.
>
> But we very much appreciate all of you being here. You are important
> to us. We very much appreciate your time, your consideration; and will
> value whatever advice we get from you.
>
> I thought I would take a little bit of a moment to just sort of update
> you on sort of what\'s been going on, or, in some cases, not going on.
> Just to give you a little bit of a backdrop, I\'m going to try to do
> this very quickly.
>
> As you all I think know, FDA is only one of the agencies in the
> Federal Government that is involved in issues that relate to
> bioengineered foods. The Department of Agriculture, most notably. The
> Animal, Plant, Health and Inspection Service has responsibility for,
> you know, the planning of bioengineered plants. EPA has responsibility
> for genetically engineered pesticides that are genetically engineered
> into new plant varieties. And then FDA, of course, has the
> responsibility for the safety of foods, and, you know, again,
> that\'s\--we\'re talking about what happens to the person who eats the
> food.
>
> Also, we have the responsibility for animal feeds, and so we have a
> concern about that, as well.
>
> Since the StarLink episode of a few years ago, there\'s been a sense
> across the agencies that there has been a need for greater
> interaction. And, indeed, there have been numerous meetings among the
> agencies, these agencies, also others, from time to time, to deal with
> a couple of sort of cross-cutting issues. These, by the way, have
> generally been held under the auspices of the Office of Science and
> Technology Policy, OSTP.
>
> One of these issues that we have grappled with in an interagency
> context has related to the potential for new plant varieties that are
> still in the developmental stage perhaps inadvertently contaminating
> traditional food crops. And the OSTP, after numerous interagency
> discussions, published a document setting out some tentative thoughts
> about that and invited public comment.
>
> Following that, the\--there was a recognition that there\'s a growing
> concern about
>
> the use of food crop plants to produce pharmaceutical, industrial
> chemicals. We generally refer to these as pharm plants, spelled
> P-H-A-R-M, as a convenient shorthand for talking about these kinds of
> crops.
>
> As some of you know, we did have an episode last year. Nothing got
> into food. But it sort of heightened the concerns within the
> government about the potential for contamination of food with non-food
> producing crops, such as corn used to produce pharmaceuticals.
>
> Those discussions are ongoing. They have not come to closure yet. When
> they do, I expect that there will be something similar coming out of
> that to the OSTP publication that I mentioned a moment ago.
>
> Of course, throughout all of these discussions, FDA is going to the
> meetings, participating in the meetings, with the recognition that our
> primary responsibility really is about the safety of the food; and we
> try to stay focused on that as we go through these discussions,
>
> recognizing there are many other issues.
>
> But the one that is primary importance to FDA, and that we like to
> stay primarily focused on is the safety of the food itself.
>
> We\--as you all know, we published a proposal to make our current
> consultation process mandatory. We have not taken final action on
> that. Any of you who read the proposal will know that we raised in
> that proposal an issue about whether we actually had the legal
> authority to make the process mandatory. That has continued to be an
> issue.
>
> The other thing that has come along is the events of September 11th of
> 2001, and a need to focus a lot of attention on bioterrorism. I can
> tell you personally that that issue has largely taken over my life
> since I head the office that is responsible for developing FDA\'s
> regulations to implement that new law that was passed by Congress and
> signed President Bush June a year ago.
>
> The other thing, of course, that we always face is that there are a
> large number of very
>
> important issues before the agency at any given time, and we can\'t
> deal with all of them all at once.
>
> When our Center Director, Joe Levitt, came back in 1998, one of the
> practices he instituted was a process, a priority-setting process,
> that results in something that we normally refer to as the Yellow
> Book, that articulates the Center\'s priorities.
>
> And the A-list things are things we are going to do within the
> current, you know, fiscal year. B-list are things that are being
> worked on, and anything that\'s not on either of those two lists is
> not going to be done for a while.
>
> We have\--again, one of the other things that Mr. Levitt instituted
> was a process of seeking public input on what these priorities are.
> And we can\'t make everybody happy. We can\'t deal at any instant with
> anything\--with everything that is deemed by even us to be important;
> but we do try to have this orderly process for setting priorities. And
> one of the things you will note is that the
>
> mandatory proposal is not an A-list item.
>
> The other thing that we are continuing to work on, but have not come
> to completion on yet, is allergenicity. This subcommittee considered
> some of those issues at your first meeting. We still intend to come
> back to the subcommittee with allergenicity issues, but we have not,
> you know, we were not ready to do that for this meeting.
>
> We generally are trying to keep up with the science, though, we
> certainly see this subcommittee as helping us in that process. And, as
> you will hear more about a little later, we have, over the last four
> years, participated actively in the Codex Alimentarias effort at the
> international level to develop principles and guidelines for the
> assessment of bioengineered plants and also bioengineered
> microorganisms used in food production. And Dr. Maryanski will talk
> about some of that as it relates to the agenda before you today.
>
> In the meantime, FDA is still following the guidance that we issued in
> 1992. We\--it
>
> continues to be our belief that all of the foods that are in the
> marketplace in the United States today have gone through that process;
> and, also, so far as we know, none of the foods that have successfully
> completed that consultation process is presenting any kind of public
> health problems to American citizens.
>
> Nonetheless, we recognize that science changes. We want to assure that
> our guidance remains current. And that is one reason why
>
> this\--in fact the primary reason\--why this subcommittee was created.
>
> We want to use the very best science in all of the work we do, but I
> think particularly in this area where there\'s so much noise that is
> not about science. We want to be sure, and we understand people
> disagreeing on matters of policy et cetera. But we want to be sure
> that we are following the best science possible.
>
> And with that in mind, we will be seeking your advice at this meeting,
> and in future meetings. And today, we\'re asking you to look at
>
> some things on molecular biology\--I can\'t even pronounce it, and I
> can assure you I know nothing about it, so I\'m not going to say
> anything more about that other than to return the meeting back to the
> Chair, who will explain what it is we are asking for advice on today.
>
> So with that, I will close.
>
> Thank you very much. We are looking forward to your deliberations
> today, and to the advice you give us at the end of the day. And, if
> there\'s anything we can do to help, let us know. Thank you.
>
> CHAIRMAN BUSTA: Thank you, Bob.
>
> I know there\--you have a busy schedule, and you\'ll be with us
> for\--until the break at least?
>
> MR. LAKE: Yes. I\'ll be here through the break; though, again, the
> other BT, that is, bioterrorism, as opposed to biotechnology, it
> causes to me leave at the break to go to some other meeting.
>
> CHAIRMAN BUSTA: Okay. So, if we have
>
> some questions or clarification for Bob before\--
>
> MR. LAKE: Yeah, and, in fact, I can stay through the break if anyone
> has anything they want to ask me privately; though, I will take any
> questions other than anybody might have now.
>
> DR. GURIAN-SHERMAN: Dr. Gurian-Sherman. Bob, maybe you could clarify a
> couple of things: one is I think you mentioned that the mandatory
> process is not on the A-list. Is it on the B-list? You mentioned that
> things that are not on the
>
> A-or B-list are probably not going to get looked at very closely.
>
> The other is, do you have any kind of timeline, or rough timeline, on
> your progress on the allergenicity issue, as well?
>
> MR. LAKE: Yes. Yeah, I guess I should have clarified. It not only is
> not on the A-list, but I\'ve been\--okay.
>
> DR. WATSON: It\'s on the B-list for \'03.
>
> MR. LAKE: Okay. Well, it is still on the B-list. The \'04 is still I
> think not finalized.
>
> The\--but there\'s a good chance that simply
>
> because of everything going on, that it may not even be on the B-list
> for the next issue, though we have not yet issued the \'04 plan.
>
> With regard to the allergenicity, I don\'t know that I can give you a
> specific time frame, other than to note that that continues to be
> something that we consider to be very important; and we do, indeed,
> intent to come back to this subcommittee. But I\'m not prepared to
> give you a time frame for that. I just don\'t know.
>
> CHAIRMAN BUSTA: Thank you. We\'ll I\'m on line now to talk about our
> charge, and questions that we have for today.
>
> You all should have received in the mail a discussion paper and a
> draft guidelines of Codex; and this morning, in front of you, you have
> the charge and questions.
>
> I\'d like to go through this slowly and try and paraphrase it
> somewhat, but as you\'ve heard this is an area that is of interest and
> activity with FDA.
>
> And, as it states in the introduction, FDA
>
> believes that it\'s important to the developers of products to
> characterize the genetic modifications introduced in those food
> plants.
>
> Developers using molecular biological data to assess whether these new
> substances, intended or unintended, are likely to be expressed as a
> consequence of the inserted genetic material. There have been many
> advances in the field, as you\'ve heard many times and are well aware.
> And FDA is seeking to determine whether any of these new advances
> would enhance FDA\'s food\--FDA\'s safety assessment of bioengineered
> food plants.
>
> So, our charge, specific charge for today is to consider the current
> FDA approach for the molecular characterization of bioengineered food
> plants, and to provide suggestions regarding additional information
> the FDA subcommittee believes would enhance the safety assessment.
> This is an assessment of the science.
>
> Now, there\'s three items, issues that are listed below, and these are
> some. Our discussion and questions and issues are not limited to
> those,
>
> but they are questions that have been put forth with our charge from
> FDA.
>
> Number one: the molecular biology data provide information that
> assists in identifying new substances. Techniques like Northern or
> Western Blot have been useful in identifying newly expressed
> substances.
>
> The question here is: to what extent does sequencing information
> contribute to the identification of newly expressed substances? And if
> sequencing information is important for the purpose of FDA\'s safety
> assessment, what sequence information should be reviewed? For example,
> the entire sequence of inserted genetic material or the sequence of
> the surrounding region of the plant genome et cetera.
>
> If so, how does this information contribute to the safety assessment?
> The science behind that, and we\'ve got a lot of experts here that
> should be able to give us some insight into that after we hear what
> FDA is doing.
>
> Number two: current approaches to safety
>
> assessment recommend certain kinds of molecular biology data. There
> are four that are listed
>
> here\--the number of insertion sites, number of gene copies inserted
> into each insertion site, the information on the organization of the
> DNA within the inserts, and the potential reading frames that could
> express unintended proteins.
>
> The question here is: are there other data that would be useful to
> safety assessment? And, if so, what data, and how would safety
> assessment be enhanced?
>
> The third item on the issues is: there have been many advances. Are
> there new advances that could be used to enhance the safety
> assessment? And, if so, what and how?
>
> I\'ll open end, as we said, as I said at the beginning, these are some
> of the items. It\'s not limited to these, but these are
> considerations. From my vantage point, it seems like there\'s\--that
> could keep us here for a week and a half. It\'s plenty open-ended. So,
> that is our charge.
>
> The approach that I hope that we\'ll be
>
> able to do is we will listen to the presentations on FDA\'s current
> food safety assessment and the Codex approach, and the discussion
> paper; and we\'ll have questions for clarification at the\--after each
> of those presentations, but not significant debate at that point, or
> extensive discussion; but questions of clarification.
>
> And then, we will have an opportunity for public comment. Has any
> public comment been submitted? One? Okay.
>
> And then, we will, again, look at this issue and have some real
> opportunity for discussion and evaluation, getting into greater depth
> that need from the participants of the experts that are here. And
> then, in the middle of the afternoon, I would like to see us go round,
> one by one, and succinctly\--I love that word\--succinctly summarize
> our thoughts in response to the charge and the issues.
>
> At that point, and, hopefully, we\'re on time or even a little ahead
> of time, we then\--there is a little bit of agenda on the
> back\--concluding
>
> remarks. But then I would like to address the letter and future
> guidance, future agenda items, at that point.
>
> But we will have addressed our charge, and then we can move on to the
> future.
>
> That\'s all right? We\'ll move on.
>
> Well, I\'m quite proud that we\'re running about 10 minutes ahead of
> time, and since no one else has his timing agenda, no one else is sort
> of coming 10 minutes late, so I\'m very pleased.
>
> So, if our next presenter, Jeanette Glover Glew is ready to go, we
> will\--oh, Mike Watson has a statement.
>
> DR. WATSON: I\'d just like to ask if there\'s any questions for Mr.
> Lake, please do them before the break so they can be part of the
> record?
>
> CHAIRMAN BUSTA: Oh. All right. So we have it on\--
>
> DR. WATSON: On the public record.
>
> CHAIRMAN BUSTA: All right. You have copies of the presentation,
> PowerPoint, so that you only have to take notes and not write what\'s
> on the
>
> slides.
>
> MS. GLOVER GLEW: I\'m going to give a little caveat up front, as they
> showed me how to work this device, but I was not very successful in
> the rehearsal earlier. So, we\'ll see how we do right now.
>
> Good morning. As I said, I\'m Jeanette Glover-Glew. I work in the
> Office of Food Additive Safety in the Center for Food Safety and
> Applied Nutrition; and I\'m going to be talking to you, in general
> terms, about our policy for evaluating bioengineered foods. I will
> also touch on parts of our molecular biology review for these types of
> foods. However, I\'ll just do a little foreshadowing here, and let you
> know that Dr. Tom Cebula will be going into some more detail about the
> type of molecular biology evaluation we do, a little bit later this
> morning.
>
> Do I have to point to that? To give you a quick outline of what I\'m
> going to cover in my presentation, I\'ll start out talking about the
> Federal Government\'s regulatory framework, then
>
> talk specifically about FDA\'s policies and procedures. And I\'ll wrap
> up talking about some recent initiatives we\'ve made in light of
> public input we\'ve received.
>
> In 1986, the Federal Government proposed a coordinated framework for
> regulating genetically engineered foods. There were three primary
> players: the U.S. Department of Agriculture, the Environmental
> Protection Agency, and the Food and Drug Administration.
>
> Two of the primary principles based on this coordinated framework were
> that it would be the product that would be evaluated, not the process
> of its development; and that the products would be evaluated under
> existing frameworks. The United States Department of Agriculture
> evaluates agricultural food safety, doing field trials; and EPA
> evaluates the food safety and environmental safety of products that
> have, well,
>
> pesticidal\--insecticides inserted; in other words, if BT proteins
> have been inserted into a crop that is EPA\'s responsibility to
> evaluate.
>
> That brings us to FDA. Our statutory authority derives primarily from
> the Federal Food, Drug, and Cosmetic Act. I\'ll be calling that the
> \"Act\" through the rest of my talk.
>
> Under the Act, we\'re responsible for the food safety and proper
> labeling of all foods and food substances, except for meat and poultry
> products, which are evaluated by USDA.
>
> That means that we have oversight over cereals, fruits, vegetables,
> plant by-products, such as starch and oil, milk, seafood, and other
> substances added to food, such as flavorings and preservatives.
>
> There are two provisions of the Act that are particularly important in
> ensuring food safety. One of them is our post-market adulteration
> provision in Section 402. This is our primary legal tool for
> regulating the safety of whole foods. It means that if a food enters
> the marketplace, and we find it to be adulterated, for example, if it
> had a level of toxicant that was outside of the normal range, or if it
> had an
>
> unlabeled food allergen, then we could take action to remove that
> product from the market using our post-market adulteration authority.
>
> We also have the Section 409 authority, which means that an additive
> that is going to be added to food must undergo pre-market review and
> approval by FDA before it can enter the marketplace, that is, unless
> the product has been demonstrated to be generally recognized as safe.
>
> If we see a product that is not substantially similar to products that
> have been consumed in food, then we could ask that it come in under
> our pre-marked approval authority.
>
> I\'ll next talk to you about FDA\'s policies and procedures.
>
> In 1992, FDA published a policy stating how we believed the foods
> derived from new plant varieties should be regulated. It was developed
> for genetically engineered foods, but it described how we would apply
> our authority under the Act to ensure the safety of all foods under
> our authority.
>
> It was, as I said, derived primarily for
>
> developers who, at that time, were using recombinant DNA technology in
> crop production. And those are primarily the users that have operated
> under that policy statement.
>
> Let me go over some of the basic principles in the policy statement.
>
> First, we consider the nature of the food, not primarily the method of
> development. Any food, including genetically engineered foods that
> enter the market place, must meet the same stringent safety standards
> as convention foods. And those traditional counterparts are the foods
> that we compare the bioengineered food to.
>
> Some other basic principles in the policy statement. We recommended
> guidance on particular scientific and regulatory issues, and we also
> recommended a voluntary consultation with FDA. The purpose of that
> consultation was to make sure that any questions that might arise of a
> scientific or regulatory nature would be resolved before the developer
> went to market.
>
> The core of the guidance document was a
>
> series of flow charts related to the safety and the nutritional values
> of genetically engineered foods. You could see if you were a
> developer, you would walk yourself through this flow chart, and you
> would\--could end up eventually in one of two boxes. The box at the
> bottom says no concerns, and the boxes off to the side say consultant
> FDA. There is also in the flow charts a third box that says basically
> don\'t even think about going in that direction; but that\'s not on
> this particular slide.
>
> What happened, practically speaking, is most developers, when they go
> through the flow charts, end up in the no concerns box. However,
> because of our desire to encourage the voluntary consultation process,
> we believe that all of the people have come in to us to demonstrate
> what they think are the issues that, once they go through our flow
> charts, and to make sure we agree that they fall into the no-concerns
> box.
>
> The frequency and level of consultation that we carry on with the
> developers is really dependent upon the complexity and the novelty of
>
> the crop and the insert.
>
> We encourage them to come in early and often. This is an iterative
> process. We believe that, by coming in early, it benefits both the
> developer and FDA. We\'re aware of what\'s being done in terms of the
> research, and they\'re aware of the kinds of issues that we might find
> of concern.
>
> We\--in our 1990 policy, we did not publish a suite of testing regimes
> that people could go and say, okay, I\'ve got a tomato or I\'ve got
> this type of insert, therefore, I need to do these types of testing.
>
> We wanted this to be done on a
>
> case-by-case basis. And so what happens is the company comes in. They
> say, okay, this is the information we\'ve developed in the lab or in
> the greenhouse or in our field trials. And, we say, okay, well, based
> upon what you\'re demonstrating to us, we have these kinds of
> questions. And the company will use the input FDA gives them to go
> back to their lab or the greenhouse or the field trial, and develop
> the data to answer those
>
> questions.
>
> So we have an iterative process, where FDA has credible input about
> the kind of testing regime. It\'s done on a case-by-case basis.
>
> Prior to commercialization, the notifier will come in to us with a
> final data package that summarizes the information they\'ve developed,
> and FDA will respond to them with a letter saying either we
> have\--still have remaining questions or we have no further questions.
>
> The approach in these consultations is multidisciplinary. We have
> teams of individuals who review these submissions. They include
> molecular biologists, several of which are here today,
> microbiologists, chemists, nutritionists, food scientists of various
> kinds; and we cover a broad spectrum that\'s provided, everything from
> the agronomic characteristics to the compositional characteristics of
> the crop.
>
> In this next slide, I\'ve just presented the information in this way
> to emphasize that we look at both at the intended changes and the
>
> unintended changes to the crop. In the intended changes, of course,
> we\'re going to be looking at information about the trait\--desired
> trait that was inserted and to the kinds of alterations that might
> make. And we look at information about the background of the crop, and
> the exposure.
>
> However, we\'re also looking for unintended changes, because this
> tells us whether or not cryptic pathways have been turned on. We\'ll
> look and see whether or not there\'s been changes in known toxicants
> or nutrients to see if there\'s something that lets us know that a
> genetic pathway has been interrupted by the insertion, and that
> there\'s something that we need to be paying special attention to. And
> another way that we do that is to look at the genetic stability over
> time.
>
> I\'ve added these next four slides just to go over real quickly
> because it gives you the elements of the safety evaluation, including
> what we look at in terms of the molecular biology evaluation. But Dr.
> Cebula is going to be going into some more detail later on; so this is
> a just a
>
> skim to prepare your minds for what we\'re going to be talking about.
>
> In the host plant, we\'ll look at the taxonomy, history of safe use,
> the presence of any naturally occurring harmful constituents, and
> important nutrients. If we were going to be looking at an orange,
> we\'d expect Vitamin C to be there.
>
> In the donor organism, we\'re going to be looking at similar
> characteristics, but we\'re also going to be looking through\--whether
> or not any baggage has been picked up due to passage through microbial
> host. And, of course, most importantly for the donor organism, we\'re
> going to want to know about the identity and function of the
> introduced material.
>
> For that introduced material, we\'re going to look at concentration,
> so we know what dietary exposure is.
>
> We\'re going to look at the potential for it to be an allergen or a
> toxin. I already mentioned that we\'re going to be looking at
>
> similarity to other substances in the food supply. Talked about
> looking for changes in metabolic pathways.
>
> We\'re going to find out if there\'s
>
> post-relational modification, such as glycosylation of a protein. And
> something that I\'ll throw out here. Other countries have been
> concerned about the presence of antibiotic resistance marker genes.
> And we also evaluate those.
>
> And this comes to the information that is more the basis of what
> we\'re going to be talking about and getting input from you on today
> is the inserted genetic material. And here, we\'re going to look at
> the method of transformation, what the regulatory sequences are, the
> promoters, the terminators, how those are working, whether there\'s
> the chance of open reading frames that might read through into the
> indigenous genome, how many inserts they are, where they are, if they,
> you know, flipped or they inserted into a site that may create
> problems; and then we\'re going to be looking at Mendelian
> inheritance, so whether or not it\'s
>
> genetically stable.
>
> I\'m going to switch gears here, and just for a few minutes talk about
> some of the recent initiatives that we\'ve taken as a result of a
> public outreach.
>
> We know that the biotechnology field is rapidly changing. That\'s why
> you\'re here. That\'s why we want your advice. But also, in 1999, we
> decided to hold a series of three public meetings. And we said, we\'re
> going to look at our 1992 policy to see if it needs to be modified in
> any way. And, as a result of soliciting that input, we received over
> 50,000 comments. Excuse me a moment.
>
> We were pleased to find that, as a result of those comments, that we
> really hadn\'t received new data to question the safety of
> bioengineered foods that are on the market today. However, we heard
> concern from public, academics, public policy groups about the future,
> of whether or not the products that were going to be coming down the
> research pipeline were such that we had either the regulatory or
> scientific framework and background
>
> to address the safety of these products.
>
> So, as a result of that solicited input, we have taken several
> initiatives. One of them is you guys. That\'s why we\'re here today.
> We established the Food Biotech Subcommittee, and we hope to be using
> you for this purpose quite a bit in the near future.
>
> We have committed to support research on allergenicity, and we have
> combined with USDA and EPA to support a study by the National Academy
> of Science on potential unintended effects in bioengineered foods.
>
> Before I wind up, I\'m just going to give you a snapshot of the types
> of products we\'ve seen. The corn, cotton, and soybean are the primary
> commodities that we\'ve seen in. We\'ve seen other minor crops. The
> kinds of traits that have been introduced have been primarily
> agronomic traits that are of interest to the farmer, either pest
> resistance or herbicide tolerance. Though we expect, in the second and
> third generation of crops, to see more complex physical traits, such
> as
>
> salinity, tolerance, or drought resistance; and also traits that would
> be of interest to the consumer, such as increased nutritional value.
>
> The goal of us at CFSAN and here today in talking with you is to make
> sure that we\'re prepared to meet our scientific and regulatory
> responsibilities in the future. So we\'re really looking forward to
> you looking at the charge and the questions and advising us as to
> where we can to specifically in the arena of molecular biology
> techniques.
>
> And I just wanted to let you know that I\'ve given you our website. If
> you want to look at any of the documents that I\'ve mentioned today,
> either our 1992 policy statement or the proposed rule that Mr. Lake
> mentioned, or a list of the products we\'ve developed, including our
> scientific memos evaluating those products, you can go to the website
> and find that information.
>
> But I think we\'re running ahead of schedule, so I have time to answer
> any questions you might have before we go on to the next speaker
>
> at the break I guess.
>
> DR. GURIAN-SHERMAN: Jeanette, I had two questions, clarification. One
> is concerning the website. That doesn\'t have, as far as I know, any
> of the more detailed aspects of the consultations, in other words, the
> data summaries, which I found very useful to look at to kind to get a
> better idea of what is actually submitted and what you\'re actually
> doing with it.
>
> MS. GLOVER GLEW: That. That\'s a\--
>
> DR. GURIAN-SHERMAN: So one question is: if committee members want to
> see any of those, could they be made available and how could that be
> done?
>
> And the second question is: If you could clarify a little bit kind of
> the case-by-case approach. How do you determine kind of what the
> baseline minimum assessment should be? And to put that in context, for
> instance, when I looked at some of those studies, just as one example,
> two of the BT crops, looked at whether phytate levels and known
> anti-nutrient in the corn had changed, two
>
> did not. You know, so how do you determine what\'s enough? Which
> anti-nutrient should be looked at? Which allergens, you know, et
> cetera, under the current system?
>
> MS. GLOVER GLEW: Okay. Try and remove the first question before I get
> to the second.
>
> The first question has to do with the fact that I mentioned that at
> the end of the consultation process, we receive a data package that
> summarizes the material, and this is what we use when we are
> completing our evaluation.
>
> That information is not currently available on our website. It is
> available by Freedom of Information Act request, which is how Dr.
> Gurian-Sherman got it.
>
> We\--I did not go into all of the efforts that we have committed to
> make as a result of the public meetings. I wanted to focus primarily
> on the scientific nature of some of the concerns that were expressed,
> particularly the ones that you can address today in the molecular
> biology discussion.
>
> However, we have made some commitments to
>
> try and have increased transparency. Those are something that we have
> to balance with our obligations to protect confidential business
> information. But we have\--our ongoing discussions. I honestly don\'t
> know, Doug, whether or not the Food Advisory Committee can get copies
> of those documents outside the FOI process, and perhaps one of the
> people on the FAC Committee can help us with that a little bit later.
>
> The second question: how do we get a baseline? That\'s a good
> question, and the thing is it\'s like mini-targets as it moves. And
> I\'ll use your phytate example; is that when some of the earlier
> consultations, we would talk about the areas of concern\--the
> nutrients, or the toxicants, or the anti-nutrients\--and the company
> would go away; and they would develop that information. And, this is
> in addition to general principles, which we outlined in the 1992
> policy, about looking for allergenicity, examining whether it\'s a
> potential for it to be a toxin.
>
> So we have the general principles, and
>
> then we have some of the more specific give and take on the
> case-by-case basis. And the answer about the phytate is that it
> does\--the target moves.
>
> As we\'ve been involved with Codex, as we\'ve been involved with our
> European counterparts, particularly Dr. William Price, who is in the
> audience today, has been participating in committees that are laying
> out some of the known important nutrients, anti-nutrients, and
> toxicants; and we\'re able to now use these kinds of materials to give
> clearer, better, more particular information.
>
> So, you can look at earlier submissions, and you\'ll find that
> they\'re missing information that perhaps are in more current
> submissions. And that\'s because, as the science advances, as we are
> more aware of the types of information that are important for us to
> look at, we would be
>
> giving\--tailoring our information.
>
> Does that answer your question?
>
> DR. GURIAN-SHERMAN: Yeah, I guess the only follow up I would have is,
> if you\'re
>
> developing some of this internal guidance or guidelines, is there any
> plan on making them publicly available? Are they just still in the
> development stage?
>
> I think in 2000, NAS recommended that you do that with, you know, come
> up with a database of known toxicants and anti-nutrients. So, you
> know, is that something that\'s going to be made public?
>
> MS. GLOVER GLEW: We\'re working internally on guidance. It suffers
> from the same resource problems that Mr. Lake referred to earlier, but
> one of the things that, if everything works out in terms of our
> resources, and how productive we think this would be for industry, we
> might use the information that we develop today for a molecular
> biology guidance.
>
> The compositional guidance we have held off a little bit on because
> we\'re waiting to see what the NAS says about the unintended effects.
> So, guidance documents are something that we constantly have it in the
> back of our head in order to give guidance to industry.
>
> But, as we\'ve just talked about the phytate issue, we weren\'t\--we
> didn\'t know that that was something that we probably be asking for
> perhaps early in the process. We know now. So, if we have guidance and
> it\'s hard and fast, that leaves us a little less flexibility in order
> to look at these on a case-by-case basis. So there\'s advantages and
> disadvantages to having written guidance.
>
> CHAIRMAN BUSTA: Abigail.
>
> DR. SALYERS: I have a question for you, and for Mr. Lake, both. It has
> to do with priorities.
>
> If I were prioritizing issues on your A-, B-, C-lists, I would put
> bioengineered foods on the E-list, and I\'d put bioterrorism on the
> F-list. You know, as in forget it, you know.
>
> And I would put on the A-list things like probiotics and functional
> foods that have been largely un\--not looked at; and also just good
> old early detection of microbial, unintentional microbial
> contamination of foods. And so that we don\'t have to pull things back
> after they\'ve
>
> appeared on grocery shelves.
>
> And so my question is, and I understand why you\'ve had to put
> bioengineered foods and bioterrorism on the A-list, but so I\'m going
> to
>
> be\--this question is kind of pessimistic. I know you\'re stuck with
> that because of political considerations, but are you thinking about
> ways that you might use whatever money you\'re pouring into those
> areas to also address some of these other issues, the real, which in
> my opinion, the real public health issues, the things that sicken and
> kill people at still somewhat horrifying level; that there are ways to
> divert some of this attention and finances into doing something in
> those areas.
>
> MS. GLOVER GLEW: I\'m going to let Mr. Lake answer the part about
> dealing with substances that might kill people.
>
> DR. SALYERS: I\'m not, I\'m not\--this is not a hostile question.
>
> MS. GLOVER GLEW: I\'ll answer something that perhaps is underlying
> your question, and you
>
> may not have intended this to underlie your question, is that we have
> for bioengineered foods a process that is working, and that we believe
> is protective of the public health.
>
> So, there are many ways that we would like to expand our abilities to
> be responsive to industry in giving them guidance about molecular
> biology. That\'s why we\'re here. That\'s why we\'re interacting with
> the National Academy of Science. There are things that we would like
> to do to make certain that our regulatory framework and our scientific
> background is what we need in order to evaluate these things. And I
> think that we have that, and we\'ll continue to have that in terms of
> Center priorities.
>
> DR. SALYERS: Well, let me just give you an example. This is one of
> these things that happens to me accidentally. It makes me even more
> unpopular than I am already.
>
> But I happen to think probiotics is a good idea, but I found out, sort
> of accidentally, that most of the strains of bacteria that are used
> for
>
> probiotics are resistant to vancomycin, which is one of our less
> antibiotics for treatment of certain types of diseases.
>
> And so I said to them, to these people, I said, have you\--now are you
> talking about markered antibiotic resistance genes in transgenic
> plants, which are for, you know, effective against antibiotics that
> basically are not a problem any more; but here\'s some vancomycin
> resistance in these probiotic strains.
>
> And so I got this storm of anger out of that. And I said, but you
> really ought to ask yourself is this just some metabolic thing or
> some, you know, could possibly pose a public health risk. And that, as
> far as I could tell, was not under investigation anywhere.
>
> And I just wonder how many more examples of that kind are out there in
> the probiotics, the functional foods area; and then, of course, we
> have the problem of is there some way that we could try to detect
> contamination of foods before the food actually gets on the grocery
> shelves. So that\'s
>
> the reason I was asking this question.
>
> CHAIRMAN BUSTA: And I\'m being very good on chairing this, and letting
> you ask these questions before we lose Bob. But that wasn\'t a
> terribly expansive question on clarification. Bob.
>
> MR. LAKE: Nonetheless, I think it was a good question, so let me
> comment to the extent that I can.
>
> Though we try to do priorities in a way that we think is rational from
> our perspective, you know, there are a lot of forces out there,
> including congressional mandates that are, you know, in the case of
> bioterrorism, very explicit.
>
> And one of the things that\'s driving my life now is that Congress,
> and the law that I mentioned earlier, the new bioterrorism law has a
> couple of regulations, a couple of requirements, that will go into
> effect on December 12th of this year\--one on registration and one on
> prior notification on imported foods\--that will go into effect
> whether FDA has regulations on the street or not. However, we have
> been mandated to write
>
> regulations, and it is our strong belief, and I think the belief of
> everybody we\'re hearing from in other governments and the industry
> and whatnot, that, if we fail to have regulations on the street, that
> there will be chaos; that everybody needs those regulations in order
> to implement this law in an orderly way.
>
> So, whether we or anyone else, you know, necessarily would have chosen
> those as being a top priority, it is certainly clear that the events
> of September 11, 2001 have altered the state of play in a very
> significant way for FDA and for, frankly, all of the Federal
> Government.
>
> But also, I think aside from the very real issues, which I personally
> believe need to be addressed in the area of bioterrorism, I think
> we\'re facing a situation with the registration and prior notice
> activities, and I will be going
>
> here\--from here to a meeting about those because we really need to
> publish those by October the 10th if we are to have an adequate lead
> time. And we\'ve had a huge effort ongoing, and hopefully we\'ll meet
>
> that date.
>
> So that\'s one thing that\'s kind of out of our control. But also,
> it\'s just one of the realities that, you know, the world sometimes
> gives us things that we didn\'t expect.
>
> With regard to\--when you talk about probiotics, I assume you\'re
> tying that back to genetic engineering. And I guess my general comment
> about that is that we try to keep up with products that are actually
> entering the marketplace. And that, of necessity, I think sometimes
> means maybe we\'re lagging a bit on things that are under development
> that are not quite close to being marketed.
>
> I should, however, note a couple of other things with regard to
> genetic engineering. We do have, you know, on the pharmaceutical side
> of the house, a lot of activity that has been ongoing for a number of
> years. And I\'m not, you know, qualified to speak about all of that.
> But just keep in mind that bioengineered products are not just about
> foods; they\'re about other things. And
>
> the Agency has people heavily involved in many of those areas.
>
> The other thing is, just to comment on your issue of methodology. That
> is something that is receiving attention here and internationally, as
> well. But, you know, what we are really focusing on here is our job of
> evaluating the safety of in particular new plant varieties, and being
> sure that we\'re doing that in the right way. And that\'s why we\'re
> seeking the advice that we\'re seeking here.
>
> DR. SALYERS: Well, the reason I asked that question, which our
> esteemed Chairman obviously thinks is not germane to the issue at
> hand, and I think you sort of don\'t either.
>
> But my point is that, if we\'re going to talk about technology for
> evaluating safety, fortunately because of the new types of technology
> that are available, many of the things that we would talk about here
> today have broader implications; and maybe we should be aware of those
> possible broader implications; that there are broader uses. And that
> was the only reason I
>
> raised the issue.
>
> MR. LAKE: Well, no, I think, you know, I mean you\'re raising an
> important point, and the Chair has added to the agenda, if I\'m
> understanding it, the issue of what are topics that this subcommittee
> perhaps might address in the future; and maybe, at that time, you
> could, you know, put some of those thoughts on the table. And we\'re
> certainly anxious to hear from all of you on your thoughts, and we\'ll
> certainly consider them.
>
> By the way, in my thing earlier, I did fail to mention the one thing
> that Jeanette did briefly touch on. And after I\'m gone, if you have
> any further questions, Dr. Maryanski can address them; and that\'s the
> National Academy of Sciences study on unintended or unexpected
> effects. And, as Jeanette pointed out, that is being co-sponsored by
> USDA and EPA, as well. And we are certainly looking forward to that
> input. Thank you.
>
> CHAIRMAN BUSTA: Anne?
>
> DR. KAPUSCINSKI: Thank you. Thank you, Jeanette. That was a really
> nice, clear overview
>
> presentation.
>
> My question has to do with when you talk about that you are using the
> language we look at, for example, when you were showing the slide
> about intended modifications and unintended modifications, I\'d like
> to just get a better sense of how the look at process really works.
> When\--if you\'re going into a consultation with a developer, are you
> primarily going to look at what that developer on their own has though
> is necessary to do to look for both the effects of the intended
> modifications and possible unintended modifications? Or, to what
> extent are you\--and are you going to basically look at what they
> provide to you as they think is the information and the issues they
> should be asking about. Or, to what extent are you going in with a set
> of things that you think should be asked about, given their specific
> case. And then, I guess, as a follow up to that question, how do you
> envision that might change after the National Academy report on
> unintended modifications comes out? And I\'m sort of focusing
>
> on the unintended modifications, because that\'s clearly, I mean, from
> my perspective, that\'s sort of the main bug-a-boo in this area. And,
> personally, I\'m interested in, you know, helping the agency come up a
> way that those unintended modification issues can be addressed in a
> way that\'s not going to completely paralyze the Agency. I don\'t
> think it\'s realistic for the Agency to be the one that actually
> carries out the risk studies and all the assessments. I think the
> burden of that has to be on the developers. But I\'m interested in
> helping the Agency figure out what\'s a good balance so that, you
> know, there is some kind of independent\--if it\'s not a standard
> checklist, which may not be always useful, at least some kind of
> independent process of sort of going through, an eliciting of, you
> know, have we thought of this. Have we thought of A, B, C, and D to
> make sure that the developer has done an adequately thorough job.
>
> MS. GLOVER GLEW: Okay. Excellent. For a while there, I was going, yes,
> yes, no, yes, to
>
> your various questions. But since I\'ve lost track of which are yes
> and nos, I\'ll try to answer it in a more global sense.
>
> As I mentioned earlier, there are specific principles and flow charts
> in our 1992 guidance document that walk the developer through the
> types of considerations they should be evaluating toxicity,
> allergenicity, is there a marker gene, is the marker gene expressed
> for an antibiotic that, you know, is valuable clinically. So we have
> principles in general in our 1992 policy.
>
> Then, when the company comes in for the early part of their
> consultation, this iterative process, we develop collaboratively what
> they\'re going to be doing. They usually will bring us some early
> data, and we\'ll look at it. And in terms of unintended effects, we
> may be looking at a Western Blot, and see that there\'s a protein
> that, you know, doesn\'t belong. It\'s the wrong shape, size, and
> it\'s showing up on\--and then we\'ll be going, what\'s that? And why
> is it there? And what\'s your explanation for that?
>
> And so, they\'ll go, okay, well, we, you know, sequenced this little
> piece, and we found out that this happened. So\--it\--we have\--so
> what
>
> I\'m\--I guess I\'m trying to say, we have principles that people
> follow using our 1992 policy, and our 1996 consultation procedures,
> which are also on the web. Then we have an iterative case-by-case
> discussion; it\'s a chat that we have with these people. They tell us
> what they\'re doing. We tell them the kinds of regulatory and
> scientific questions we think arise based upon what they\'re doing.
> And they will go out and develop the data that answer those questions,
> come back to us with a data package, and we\'ll say, okay, these are
> the questions we asked. Did they address them? Are more questions
> raised by the information that they developed? Do we need to go back
> again?
>
> And so it\'s a collaborative, iterative process based upon established
> principles, plus a case-by-case interaction.
>
> And\--has that answered at least a piece of your question?
>
> DR. KAPUSCINSKI: Yeah, the second piece I guess is I was just
> wondering how you envision the, you know, the recommendations you get
> from the NAS? Do you envision that, at this point, changing this
> process in some ways and?
>
> MS. GLOVER GLEW: I just don\'t have a good picture in my crystal ball
> about that. We\'re real excited about the potentialities for what we
> can get, and how we might use that. We\'re hoping that they will do
> something similar to what you\'re doing today, and say, okay, the
> technology has changed enough that we can recommend that you ask for
> this type of information or that they develop this type of data,
> because this will provide valuable information. But I\'m not sure
> what\'s going to happen with that. But we\'re looking forward to it.
>
> CHAIRMAN BUSTA: Nina?
>
> DR. FEDOROFF: My question is partly historical and partly
> contemporary. It has always puzzled me that the EPA was approving or
> not approving StarLink corn based on the potential for allergenicity
> of the cryonide seed. That seems to
>
> be your bailiwick, because it\'s environmental.
>
> MS. GLOVER GLEW: Your confusion is understandable. I didn\'t spend a
> lot of time at the very beginning talking about the regulatory
> framework because I wanted to speed through into FDA\'s part. EPA is
> responsible for evaluating both the environmental and the human food
> safety for pesticidal proteins, for plant incorporated protectants.
> And so this is mostly BT products. It\'s the way the framework of the
> law is divided up. We will look at the product and see if there are
> any considerations in terms of compositional changes that might
> require, like, different labeling. So we do evaluate the product from
> FDA\'s perspective, only we love the fact that on StarLink, we can do
> this huge burden shift. It wasn\'t our responsibility.
>
> DR. FEDOROFF: Pardon?
>
> MS. GLOVER GLEW: It wasn\'t our responsibility.
>
> DR. FEDOROFF: Yeah, I noticed, though\--on the other hand.
>
> MS. GLOVER GLEW: Because of---
>
> DR. FEDOROFF: On the other hand, is there any effort to make the
> criteria uniform? Is there any effort to reconcile your criteria and
> theirs?
>
> MS. GLOVER GLEW: Absolutely. Mr. Lake mentioned the fact that we have
> collaborative efforts that are ongoing. We are right in the middle of
> discussions with EPA and USDA about what our requirements\--I say
> requirements loosely since it\'s a voluntary program\--but what types
> of information we look at in the data packages that we get. Mr.
> Watson, Dr. Watson is working on that right. He developed this table,
> and we pay very close attention to the kinds of information that EPA
> developed in terms of allergenicity detection for the StarLink,
> because that\'s something that\'s real pertinent to us. Those of you
> who were on the previous meetings, subcommittee meeting, you know,
> heard about what we\'re doing about allergenicity, and the kinds of
> considerations we\'re taking. A lot of that came from our interaction
> with our counterparts at EPA and their experience with
>
> StarLink.
>
> CHAIRMAN BUSTA: Bob?
>
> DR. BUCHANAN: A general question: how many new conventional foods and
> genetically engineered foods do you approve per year approximately?
>
> MS. GLOVER GLEW: I\'m sorry. I didn\'t.
>
> DR. BUCHANAN: How many new conventional foods, for example, a new type
> of nut that existed somewhere, and it\'s sought to have approval in
> the U.S., and how many genetically engineered foods do you approve per
> year?
>
> MS. GLOVER GLEW: Per year. Okay. We have since 1994, when we first
> started receiving these biotech notification files, or BNFs, evaluate
> a little over than 50. If you\'re talking about do we have some brand
> new novel, never-before-seen food on the marketplace, I don\'t think
> that you could characterize it that way. It\'s mostly people who have
> taken maize, soybean, cotton, and they have added an herbicide
> tolerant, or a pest-resistant chain to it. So it\'s something that, if
>
> you drove by the field at 55 miles an hour, you\'d look out there and
> say, that\'s cotton.
>
> So\--just\--an entirely novel crop isn\'t something that we see. We
> see mostly modifications to existing commodity crops.
>
> DR. BUCHANAN: So there\'s no new macadamia nut or something like that?
>
> MS. GLOVER GLEW: No, not at this point in time.
>
> DR. BUCHANAN: Thanks.
>
> MS. GLOVER GLEW: That could be coming down the research pipeline. Who
> knows?
>
> DR. FEDOROFF: I think your question was whether your approve, when
> someone brings in a new whole food from a different part of the world
> that has not been marketed here before, wasn\'t that the nature of
> your question?
>
> DR. BUCHANAN: Right. Yes, right.
>
> MS. GLOVER GLEW: Okay, so it\'s like\--
>
> DR. FEDOROFF: I misunderstood your question. Do a kiwi fruit\--
>
> MS. GLOVER GLEW: \--If I showed up from
>
> New Zealand.
>
> DR. BUCHANAN: Yeah, kiwi is a great example.
>
> MS. GLOVER GLEW: Okay. If\--I mentioned that our post-market
> adulteration provisions were the primary legal tool for evaluating
> whole foods. If something came on the market today, and we didn\'t
> have any information indicating that it
>
> was\--had toxicant, or wasn\'t allergic, we probably would have no
> need to take action; and so we would not utilize our post-market
> authority to take action against that crop. However, if something came
> on the marketplace that was just totally novel for the American food
> supply, we have our authority under the Act, totally aside from the
> bioengineered food process.
>
> DR. BUCHANAN: Yeah, that was the\--
>
> CHAIRMAN BUSTA: That\'s separate from the biotechnology activity. So
> I\'m not sure that\--
>
> MS. GLOVER GLEW: Yes.
>
> CHAIRMAN BUSTA: I\'m trying to keep us obviously focused\--
>
> MS. GLOVER GLEW: Well, I\'m trying to explain is that we still use our
> authority under the Act for bioengineered foods. If we needed to see
> something that was adulterated or, you know, if we saw that something
> needed to come through the petition process, we would do that for a
> bioengineered food. So the Act applies uniformly. We have the same
> safety standards for all foods the FDA evaluates.
>
> CHAIRMAN BUSTA: First of all, before I call on Doug again, are there
> others who have not asked a question that want to\--clarification
> questions?
>
> Or, last call for Bob Lake.
>
> Doug?
>
> DR. GURIAN-SHERMAN: Yeah, I want to make two points of clarification.
> They\'re not actually questions, but they\'re both points of
> clarification. In terms of new foods, I know of at least one that\'s
> come on the market in the last few years in the U.S. It\'s called
> Kworn. It\'s made with fusarium finatum. It\'s a soil fusarium. It
>
> was never the food supply before; was marked in Europe, and did go
> through the grasp process at FDA that did have some toxicity studies,
> animal studies, et cetera that that was subjected to. That was, again,
> grasp studies, voluntary.
>
> To Anne\' question, I would just like to venture, and I know the
> committee isn\'t really privy to this, but when we did our study
> looking at FDA, we FOIAed not only the actual data packages that FDA
> looks at, but also the communications between the developers and FDA.
> And I won\'t say that it\'s impossible that I missed anything, but
> only found about six examples where FDA, on record, asked the company,
> let\'s say for more data or for clarifications. And three of those
> went unanswered or were not, we felt, adequately answered. So, there
> certainly is give and take. Maybe some of it isn\'t on the record. It
> should be. But there\'s not, from our perspective of what we saw, a
> lot of information to indicate that FDA is pushing the companies for
> more data.
>
> CHAIRMAN BUSTA: Doug, to keep us\--
>
> DR. GURIAN-SHERMAN: So that\'s---
>
> CHAIRMAN BUSTA: On line that\'s good discussion comment, but not in
> the presentations. We have this afternoon to get into discussion.
> We\'re still in the clarification\--questions for clarification.
> Dennis?
>
> DR. GONSALVES: Well, I just was going to add, you know, the question
> on the whether FDA asked questions that had an impact. Well, when we
> were deregulating the transgenic papaya, we actually were moving two
> lines through the process. And when we hit the FDA, another line had
> some other inserts in it, and because of the questioning that we
> needed more data, basically we withdrew that line, because we did not
> have enough information. So the point here is that\--the experience
> that I had was that the questions that FDA did ask had an impact on
> our actions to withdraw one of the papaya lines.
>
> MS. GLOVER GLEW: Just a quick remark. I\'m sorry to interrupt. I just
> want to say that FDA, along with all the other regulatory agencies,
>
> occasionally struggles with the do we want to know this or do we need
> to know this. And occasionally, we do err on the want to know, but
> primarily believe that when we ask questions, it\'s in the need to
> know area. And if a company or developer did not provide us with the
> information that we needed to know to evaluate the safety of that
> product, we would not give them a letter saying that we had no more
> questions.
>
> CHAIRMAN BUSTA: Any more clarification. James?
>
> DR. ASTWOOD: Thank you. I have one question, and it kind of relates to
> Dr. Fedoroff\'s earlier question. Would you agree that, although it
> appears complex that both the EPA and the FDA share jurisdiction over
> plant incorporate protectants, or BTs in particular, that when you
> look at the history of the regulation of pesticides and the experience
> that the EPA has with food-feed environmental safety of chemical
> pesticides, and then the subsequent history that they have had
> regulating and evaluating the safety of microbial
>
> pesticides, including BTs, that it makes sense, in fact, for the FDA
> and the EPA to collaborate and share responsibility for the evaluation
> of those kinds of products.
>
> MS. GLOVER GLEW: Yes, I think the way the roles are laid out right now
> has been working very successfully.
>
> CHAIRMAN BUSTA: I have one last question. If the use of biotechnology
> has developed to, let\'s say, double a specific nutrient\--
>
> MS. GLOVER GLEW: I\'m sorry. I\'m not hearing you.
>
> CHAIRMAN BUSTA: If one uses a biotechnology to double a nutrient, a
> given vitamin or whatever, this is arbitrary, would that be in the
> same consideration?
>
> MS. GLOVER GLEW: As I just mentioned briefly is we believe that some
> of the products that are going to be coming down the research pipeline
> are going to be products that are targeted to consumers who want to
> have increased levels of, you know, a fancy nutrient or something. And
>
> certainly a product that was bioengineered and had an alteration in
> its nutrients would\--we would request that they come to FDA during
> our\--are part of our consultation process. And if there was a
> substantial change in nutrients, we would probably have to consider
> whether or not the product would need different labeling or a
> different common unusual name.
>
> CHAIRMAN BUSTA: We\'re at break time. I just would like to\--before we
> come back say that what I\'m trying to do is keep us on focus. Our
> charge is to consider the current FDA approach to the molecular
> characterization of bioengineered foods and make suggestions for
> additional information that will be needed. We\'ll try to stay with
> questions of clarification for the next three presenters. And then we
> can get, and after public comment, get into depth of discussion and
> where we want to\--what we want to tear apart and put together. Let\'s
> take 15 minutes. Let\'s start promptly at 10:14 on my watch.
>
> \[Whereupon, the meeting went back on the
>
> record at 10:15 a.m.\]
>
> CHAIRMAN BUSTA: May we reconvene, please. The next presentation is on
> the Codex Approach, by Dr. James Maryanski. I have been negligent in
> my chairing to remind you all\--I\'ve just been calling you by your
> first name, and it\'s appropriate that individuals give their name
> before you make your comments or you ask your questions so that it\'s
> in the official record. I think the stenographer, being that no one
> has the same first name, we\'re all right. But if would be appropriate
> that everyone give their name as they speak. And with my voice, I
> rarely have to do that. Most people, whenever I talk, people know who
> I am. I\'m\--I guess I\'ve stalled long enough. We\'re about ready
> to\--
>
> DR. FEDOROFF: Almost everyone\'s back.
>
> CHAIRMAN BUSTA: Almost everybody\'s back.
>
> DR. FEDOROFF: Not quite. She\'s still getting coffee.
>
> CHAIRMAN BUSTA: Yeah, and we will have Dr. Anne Kapuscinski read her
> name into the record
>
> when she returns, because she wasn\'t here on our initial round. But
> she is here for the record.
>
> Dr. Maryanski?
>
> DR. MARYANSKI: Okay. Thank you, Mr. Chairman. Good morning, ladies and
> gentlemen.
>
> I have the pleasure to tell you a real success story in biotechnology
> this morning. You know, we hear so much discussion that\'s often seems
> either difficult or even contentious; and you often hear of
> differences between our country and other countries around the world
> on biotechnology.
>
> I want to tell you a really different story, a story where everybody
> actually came to agreement at the end of the day. So this is really a
> pleasure to be able to tell you about the new guidelines that have
> been developed on the\--in the international community for assessing
> the safety of foods developed by biotechnology, and one which we at
> the Food and Drug Administration have participated in.
>
> But let me first tell you who Codex is. Many of you, I\'m sure, know,
> but, in case you don\'t
>
> know, the Codex Alimentarias Commission is the body that has been
> established under the U.N. system by the parent organizations\--the
> World Health Organization, the Food and Agriculture Organization.
> Codex Alimentarias is Latin. It means food code. And, as such, it is a
> collection of internationally adopted food standards and guidelines,
> and those are intended to ensure consumers\' health, as well as to
> facilitate free trade. And, so, this is a body that has been in
> existence since 1962. There are about 169 member countries, so this
> organization has global representation around the world in both
> developed and developing countries, as well as NGO representatives
> that include public interest groups, as well as industry. And so it\'s
> a very broad organization.
>
> Woops. Wrong way. Sorry. In 1999, the Codex decided that it would take
> on some work in the area of food biotechnology, and it established a
> temporary committee. Codex has lots of committees that work on various
> things. But it
>
> also occasionally establishes temporary committees for specific
> purposes; and these are often called ad hoc task forces; and, in this
> case, with the long title of the Ad Hoc Intergovernmental Task Forces
> on Foods Derived from Modern Biotechnology was established by the
> Commission in 1999. It was given a four-year charter, and Japan was
> selected as the host country to facilitate this committee. And the
> Japanese Ministry of Health, Labor, and Welfare was the part of the
> Japanese government that ran the secretariat, essentially helped
> organize the meetings for this.
>
> The task force was chaired by Dr. Ushikora, who is world renowned
> virologist, and is fluent in both English and French, and Japanese, of
> course; and did a superb job of negotiating through various complex
> issues during discussions. And I think everyone involved recognized
> that the Government of Japan deserves a great deal of credit for the
> success of this work.
>
> Japan did host four meetings of the Task Force that just concluded
> this past March in
>
> Yokohama. And the recommendations that came out of that work then were
> presented to the Commission at its meeting this summer.
>
> The Task Force was given, in terms of reference by the Commission,
> which you see here, very general terms, consideration for the
> elaboration of standards, guidelines, or other principles for foods
> from biotechnology. So a very broad mandate. The Task Force, at its
> first meeting, in looking at this mandate, felt that there are many
> things in the word of food biotechnology, and it would have to somehow
> identify work that it could accomplish within four years so that it
> would have something finished at the end of that time; and do that in
> a way\--on a priority basis. And they felt that since foods derived
> from crops were already in the marketplace that that should be the top
> priority; and that they would focus their work on developing
> guidelines for assessing the safety of those foods for human
> consumption.
>
> They also felt that foods developed using
>
> organisms modified using recombinant DNA, using microorganisms
> modified with recombinant DNA techniques, would also be on the
> frontier and of a priority.
>
> Animals, of course, were well understood to be in research, but they
> felt they were not quite ready to discuss animals yet at this time.
>
> So that was the order of work that was set out by the Task Force.
>
> And the work that was accomplished I\'m really showing you here the
> final product, and then I\'ll tell you what it means. But the Task
> Force, within its four years of work, developed three documents.
>
> One was a\--the principles for risk analysis you see here. That\'s
> really an umbrella document that talks about how risk assessment and
> risk analysis can be carried out within the existing framework of the
> Codex. And it\'s thought to be sort of an umbrella for the guideline
> documents, but the real crux of the matter, the important work, are
> the two guideline documents.
>
> The guideline on foods derived from plants, and the guideline on foods
> derived from microorganisms. Both of these guidelines have an appendix
> to them as well that deals with assessing the possibility for
> allergenicity for new proteins that would be in the foods derived from
> the plants or microorganisms. And so those also are important
> documents that go with and are part of these guidelines documents.
>
> These documents were presented to the Codex full body at its meeting
> this summer, and were adopted unchanged. And they are available, at
> least in their draft form, on the Codex website. They will be
> published simply taking off the draft. So they are the texts that\--I
> believe we have given you the texts for the guidelines for foods
> derived from plants, because that\'s the one we\'ll be focusing on for
> the discussion today.
>
> Now, I want to talk about one of the principles that the Codex felt
> was important. The Codex system has a number of defined terms\--risk
> analysis, risk assessment, risk management, and so
>
> forth\--that are all well understood withing the food safety system
> and Codex to deal with things like pesticides and food additives and
> contaminants in food, essentially single chemical substances. And
> often times, certain of those substances will have some hazard
> associated with them and how to manage that in terms of tolerance
> setting, for example, for pesticides. But it was recognized early in
> the discussion that we\'re dealing with food crops when we\'re talking
> about foods derived from crops, and trying to establish guidelines for
> safety assessment. But these are crops we\'re well familiar
> with\--corn, potatoes, soybeans, and so forth\--that are modified in
> some way, using recombinant DNA techniques; and that often when we go
> through the process of evaluating these, we don\'t find a hazard. In
> fact, that has been in the case in the 50-some varieties has looked
> at.
>
> And so we felt that there really was a new term that was important
> here. And so we established the term \"safety assessment\" as a way of
> having something to focus on that really takes
>
> the emphasis on making sure that this food is as safe as other foods,
> but doesn\'t necessarily find a hazard or a risk. So, if a hazard is
> identified, and, of course, there\'s always the possibility that that
> could be the case, then that hazard, then, would be treated as it is
> in the Codex system. You wold have to decide does this food have to be
> removed from the marketplace, or are there conditions by which the
> food can be marketed, recognizing the nature of the hazard; for
> example, establishing a tolerance for a pesticide as a way to manage a
> risk. And so, if there\'s a hazard identified, then the system would
> work just the Codex systems normally operates. But the focus that
> we\'re going to talk about is really on safety assessment.
>
> So safety assessment, then, is something that the Task Force felt was
> important, recognizing that it does fit within the Codex framework.
> But it\'s\--this safety assessment process is really a comparative
> process. It is one we recognize that the standard that we have are the
> crops that are
>
> already out there. The foods that we have accepted in the marketplace
> are the gold standard. That\'s what we consider to be safe,
> recognizing that no food is perfectly safe or necessarily safe for all
> individuals all of the time. But, in fact, the process, then, is to
> compare the new food with what has gone before, with its counterpart.
> And the purpose of that is to try to identify whether there are any
> differences in the new food derived from this newly modified plant
> that would have any effect on health; and where those differences are
> identified, to make sure that those differences are also safe for the
> consumer.
>
> So the idea is to look at what\'s new; make sure that that\'s safe for
> the consumer; make sure that the food is still what it\'s expected to
> be, because this is food that we have consumed and have a history of
> consuming. And this comparison should take into account both the
> intended changes that have been made in the plant, as well as, to the
> best that one can, to look for any unintended changes that may have
> occurred; and make sure that
>
> if they have occurred and can be identified, that they are also safe.
>
> This is what we call substantial equivalence, a big, long term that is
> often confusing, but a very simple concept. We don\'t decide at the
> end of the day that the food is substantially equivalent. That\'s not
> the decision. This is the tool at the beginning of comparing what\'s
> new; what\'s different about this new product, if anything, and making
> sure those differences are safe. That\'s what we mean by substantial
> equivalence.
>
> The Codex has adopted a number of definitions so that they would have
> terms to use in the documents that would be understood by all the
> countries. Modern biotechnology was adopted as the general term, and
> that was adopted because it had already been defined in the Cartagena
> Biosafety Protocol, so there was a large agreement on the definition
> by many countries, and so it was felt that there was no need to create
> a different definition and that would work for the purpose of
>
> this work of elaborating food safety guidelines.
>
> The Codex also did something that I think was very useful. They
> avoided all the terms that cause everybody a great deal of angst, such
> as genetic engineering, genetic modification, GMOs, and other kinds of
> terms that would be difficult to get consensus. And, so, they simply
> referred to recombinant DNA plant or recombinant DNA microorganism
> where they needed to refer to the modified plant.
>
> And then they did, of course, design\--or define conventional
> counterpart because we have a comparator, they wanted to make clear
> what we mean by the comparator. The comparator is a food or a
> component of food for which there is a safe history of use. And the
> Task Force recognized that, in some case, there might have to be more
> than comparator used in a particular assessment.
>
> But those are the definitions. I don\'t want to spend much time on
> those, just to make you aware of them.
>
> And I\'ll quickly just go through some of
>
> the elements of food safety assessment that are laid out in the Codex
> guidelines. These will be no surprise to you, but it is, of course,
> asking what the plant is. What\'s known about the plant in terms of
> its use for producing food? How has it been modified? What are the new
> techniques that have been used?
>
> The Codex guidelines use a method of first describing what the
> developer intends to do, and then going on to characterize what was
> actually done. So you will see paragraphs that start description of
> molecular characterization, for example, or genetic modification
> rather; and then characterization of the same thing. That\'s the
> reason for the difference. The idea is, well, they intended to do
> this. This is what they started to do. Now, what did they actually do?
> What do you find actually occurred. So that\'s how the document is set
> up.
>
> In terms of safety assessment, of course, use for substances that
> would be in the food are really one of the major keys to safety
> assessment,
>
> and are those substances likely to have any impact on public health,
> including toxicity or allergenicity. As I\'ve said, there is a
> separate guidance that deals with allergenicity. I think that today
> that annex represents the best consensus that there is internationally
> on how to approach the question, is a new protein likely to be an
> allergen.
>
> The compositional analyses are part of addressing unintended effects,
> a part of answering the question, is the food still what we expect it
> to be?
>
> Evaluation of metabolites: if there are new substances of food that
> break down into other metabolites, obviously one wants to be sure that
> any other substances are also safe.
>
> Effects on food processing may be taken into account. In some cases,
> of course, such as a refined oil, there may be no protein in the food.
> Or there may be other cases where the processing may concentrate
> things in the processing of the food.
>
> Nutritional modifications. Obviously, if the food is modified in a
> nutritional sense, it has to be looked at in terms of the overall diet
> of what people eat, not necessarily just the modification of this
> particular food, but how does that affect the diet and what are its
> implications; and other considerations, such as the use of selectable
> marker genes and so forth.
>
> Now, to get more to the topic of today, the guidelines do set out, in
> a number of paragraphs, first, as I said, describing what the
> developer has done in terms of a genetic modification, what is the
> host plant that\'s being modified, what are all the materials that are
> contributing to that modification, in terms of the source of the
> organism; the genetic material that\'s obtained from those organisms
> and how that\'s combined and introduced into the plant; what is
> introduced; what its size is; what its function is and so forth; and
> then going to what actually happened in the plant, characterizing the
> plant in terms of\--at the molecular level, what are the
>
> genes that have been inserted; how many sites; how many copies.
>
> Using sequence data to identify open reading frames, for example, so
> that one can get a sense of what likely substances are\--can be
> expected, and will those be present in the food.
>
> The Codex discuss the sequencing of the inserted region and the border
> sequences, as well. And they also recognize that there are other ways
> to get at the question of expressed substances, looking at transcripts
> and expression products as a way of keying in to what might be new
> substances that would be present in the food.
>
> So I think in terms of looking at new substances, the molecular data
> being used to both establish what is the function of this substance;
> what\'s the phenotype of the plant; what is the level of expression.
> In other words, one of the common food safety questions is always how
> much do we eat. So are these metabolic enzymes or are these substances
> that are seed-storage proteins. What will this mean in terms of actual
> consumption.
>
> In some cases, we can think back to the old flavor saver tomato. We
> may be actually not adding genes, but modifying the genes.
>
> \[Reporter notes that main tape deck stopped here due to a sticky
> tape.\]
>
> inclined to modification. So that is here in the guidelines, as well.
> And there are other things that are taken into account when this
> genetic material has been inserted. Have there been rearrangements in
> the DNA, and is there any consequence of those in terms of safety for
> health.
>
> Post-translational modifications of the proteins that may have
> occurred as a result of changes in protein sequencing and so forth.
> And is this material inserted in a way that it will be heritable,
> stable, over several generations.
>
> So I think that these are things that are not of any surprise to you.
>
> So what is the goal of these guidelines? First of all, that the food
> should be safe; that it should not, when it\'s used as it\'s intended
> to use, it should be as safe as other foods on the market.
>
> And that\'s important. We\'re not trying to show that this food is
> absolutely safe or guarantee that the food is safe. We\'re comparing
> it to foods that are already on the market. We\'re not accepting foods
> that would be of a lower standard with respect to safety, so they
> should be as safe as their conventional counterparts, taking into
> account any changes in dietary patterns that may occur, if there have
> been nutritional modifications. And the idea of these safety standards
> within the Codex system is then to allow risk managers to have
> information that if there are hazards identified or other
> considerations that have to be taken into account, that they have this
> information that is based on sound science that they can use then to
> make their decisions about allowing these products to enter the
> marketplace.
>
> So this is\--these are the new guidelines that have been adopted in
> the Codex system, and represent an international guideline and,
> basically, yardstick for countries to look at to see whether a food
> has been evaluated in a manner
>
> that has been accepted in the international community. One of the
> things that these guidelines do note is that while this is all focused
> on recombinant DNA and was designed to answer questions about
> recombinant DNA, no one knows any other way to evaluate the safety of
> a whole food if we were asked to do so. So if someone came to FDA and
> said, well, we didn\'t use recombinant DNA, we used some other method,
> how should we go about evaluating the safety of this food.
>
> We would point to similar guidelines. Our own or these guidelines,
> because we don\'t know any different way. Some of the questions might
> be different, just as some of the questions might be different for
> recombinant DNA product that might present different characteristics
> than have been laid out in this general framework. But while this
> focus is on our DNA, you should really think of this as way to
> evaluate the safety of a whole food using a scientific approach.
>
> Thank you very much.
>
> CHAIRMAN BUSTA: Thank you. Abigail?
>
> Abigail Salyers. Say your name, and then we\'ll have it in the record.
>
> DR. SALYERS: Abigail Salyers. Okay. So my question is I don\'t know if
> any industries are getting ready to do this, but, in theory at least,
> one could produce foods that are safer. Take the peanut, for example,
> if you could produce a peanut that didn\'t make peanut allergic people
> sick, and you used recombinant DNA to do that, would proving that that
> is a\--I mean, how would you evaluate something like that?
>
> DR. MARYANSKI: I would actually\--
>
> DR. SALYERS: Casava also has been brought up as a possible case\--
>
> DR. MARYANSKI: Right.
>
> DR. SALYERS: Where they might use recombinant DNA to\--
>
> DR. MARYANSKI: No, and actually, of course, the Japanese did some
> early work using antiscents, trying to suppress the allergenic
> proteins in rice, and, you know, it was partially successful. The
> problem with allergenicity is that
>
> there are a number of proteins within any given food that are
> allergens, and some are more allergenic to some individuals than
> others. Dr. Astwood is much more of an expert in this, and Dr. Jones,
> who works with me, is also much more knowledgeable about this. But I
> think the potential is there for\--
>
> DR. SALYERS: I\'m just asking in terms of the Codex, do you think that
> the basic principles there would apply to cases\--
>
> DR. MARYANSKI: Well, I think that one of the things that Codex
> recognized is that these guidelines were set up to assess the safety
> of food. They\--we\--they can\'t really address that question in the
> sense that you would have to look at clinically, probably, whether the
> food still can cause clinical reactions. In other words, have you
> eliminated all of the allergenic potential, or at least sufficient
> allergenic potential that that food is going to be safe for consumers.
> That\'s going to be a difficult standard to meet, at least as far as
> we know technically now. No reason not
>
> to try, of course.
>
> CHAIRMAN BUSTA: Dr. Benedict?
>
> DR. BENEDICT: Steve Benedict. The previous question actually raised
> another thing. Isn\'t it true, though\--this isn\'t my question.
> Isn\'t it true, though, that if someone did attempt to eliminate an
> allergen, it would still have to go, the product would still have to
> go through the Codex for changes in safety and unintended effects and
> other sorts of things? Exclusive of what you talk about proving no
> longer allergenicity, you still have to take it through all the
> recombinant questions; would you not?
>
> DR. MARYANSKI: Yes. I think if you\'re asking would\--for the product
> to be acceptable in various countries, and it\'s, you know, modified
> using these techniques, I think that today at least most countries
> would expect that it would also
>
> be\--you know, these other issues would also be taken into account.
>
> DR. BENEDICT: Yes. So actually my question is fairly trivial; and that
> is at the
>
> meeting, did anyone discuss the range of sequence, border sequences up
> and downstream? How many KB that people thought should be sequenced in
> order to determine that you\'re really not near an opening reading
> frame you could influence?
>
> DR. MARYANSKI: I think that certainly one of the questions that was
> raised was whether there could be any fusion proteins. In other words,
> is the insert done in a way that there\'s not
>
> read-through into the plant DNA; and if there is, then can you
> identify that. But there certainly wasn\'t any boundaries given in
> terms of how far out one should look. And, quite honestly, some
> countries were interested in that more for methods of detection than
> actual, you know, safety considerations. So there were various reasons
> why people are interested in border sequences. So, but our focus here,
> of course, is on the safety assessments. So, but the issue of whether
> that insert leads to any fusion proteins or read-through into the
> plant genome that would express different proteins than what the plant
> normally expresses, I
>
> think is the sort of fundamental question about the region surrounding
> the insert.
>
> DR. BENEDICT: Yeah, one of the things I recall that we sort of
> discussed in 1994 was insertion into a gene, which you would pick up
> with just a short distance, inactivation of a host gene. But the other
> possibility is that if you\'re bringing in regulatory sequences, the
> possibility of some sort of downstream promotion, having not so much
> to do with fusion, but just is there an opening reading frame nearby
> that, for some esoteric and maybe unpredicted reason, you can, in
> fact, activate or inactivate an adjacent gene. And so that was why I
> asking how many KB downstream you should go to say, well, there\'s a
> low probability we\'re going to influence a host gene in its
> expression.
>
> DR. MARYANSKI: Well, I think that\'s a very good question for you to
> come back with after Dr. Cebula gives his talk.
>
> CHAIRMAN BUSTA: Other questions of clarification?
>
> DR. ARIAS: Jonathan Arias. James, I\'m\--
>
> CHAIRMAN BUSTA: Could you? Why don\'t you pull the mike in front of
> you?
>
> DR. ARIAS: Is that better? Okay. I\'m concerned about the issue of
> substantial equivalence in regard to characterizing the meat food as
> being no more unsafe perhaps than conventional derivatives. Does this
> include
>
> long-term studies, or just acute, sort of toxicology biochemistry?
>
> DR. MARYANSKI: No, we have taken
>
> long-term effects into account at FDA, and in the Codex, because
> long-term effects are, of course, a question and a difficult one. But
> we know a lot about the foods that we eat. There are also a lot of
> things about foods we don\'t know. I don\'t know what consuming
> carrots over my life time does for me, other than my mother told me it
> was good for my eyesight. But whether it has any other effect on my
> health over consuming that, or any food does, we know very little
> about long-term effects of most of the foods that we consume beyond
> the nutritional
>
> kinds of things that are, you know, we know about saturated fat and so
> forth. But we don\'t really know much about consuming foods to begin
> with.
>
> What we do know about foods is that they do contain certain nutrients,
> certain toxicants, and so forth, and that we have accepted the foods
> that we have in spite of the toxicants that certain crops have; that
> at the levels those occur, we\'ve accepted those as safe. What we
> believe about the foods that we\'ve seen so far with bioengineering is
> that the modifications that we see are fairly small modifications of
> the genome. And most of these, of course, produce metabolic proteins
> in the case of the proteins that FDA looks at or the BT proteins or
> viral proteins that EPA has been seeing. And we know a lot about
> protein toxicity, and we know that the proteins that we\'re seeing do
> not lead to
>
> long-term effects. So we know at least the introduced proteins do not
> lead to long-term effects. And we\'re not aware of any reason why
> these foods would produce long-term effects any differently than foods
> developed by other methods
>
> of plant breeding.
>
> DR. ARIAS: Thank you.
>
> CHAIRMAN BUSTA: Are there other questions. Dr. Benedict?
>
> DR. BENEDICT: Since there\'s open air\--
>
> CHAIRMAN BUSTA: It\'s Steven Benedict.
>
> DR. BENEDICT: Steve Benedict, again. One of the things that, as I read
> through this, clearly, you\'re dealing heavily with allergenicity, and
> the thing that came to mind, and I\'m an immunologist, and I\'m not
> sure I have the definition correct, even though I am an immunologist;
> but, as we all know, there are billions of epitopes going through the
> system daily, and their toleringenized \[ph\]. And so we\'ve been
> tolerant, immunologically speaking, to all of those. And the lack of
> tolerance may lead to an allergenic response. But lack of tolerance
> might not necessarily be allergenic, but it might, in fact, lead to
> something that was immunogenic, and I\'m not sure that there\--this is
> where I\'m not sure that there\'s a distinction between the two,
> because
>
> I haven\'t thought it through for more than five minutes. But the
> possibility seems to me that that checking for immunogenicity
> exclusive of allerogenicity \[sic\] might be something that someone
> should think about other than me. And I\'m wondering whether that came
> up at the Codex discussions.
>
> DR. MARYANSKI: Yeah. I would say yes that it did in the sense that
> there was certainly a recognition that there is more to allergenicity
> and immunogenicity than IGE responses. I think that what was felt to
> be important is that we do our best to address the issue of the IGE
> kind of response because we know that certain proteins are allergens
> through that mechanism, and that the idea of transferring genes from
> one source to another, and obviously the expression of those proteins,
> raises the question of whether there could be an IGE-type response.
>
> I think that your question is one that\'s much more appropriate when
> we get to the issue of allergenicity as opposed to the molecular
> subject
>
> today. But I just want to recognize that, yes, there is\--we don\'t
> just simply put blinders on; that we only look at IGE. But these
> guidelines are focused on IGE because of the need to address the
> safety of the new proteins.
>
> DR. SALYERS: Just a brief question. Abigail Salyers. The\--we have
> people who are today who are living a lot longer than in the past, and
> we also have people who are alive today, like cystic fibrosis
> patients, who were not alive in the past, and so did the Codex
> consider the fact that we\'ve got these new populations of people,
> especially I\'m thinking especially about the geriatric population,
> where our previous experience may not be as good a guide as we tend to
> think it is as to effects that foods, even conventionally used foods,
> might have.
>
> DR. MARYANSKI: Yeah. I\'m becoming much more interested in the
> geriatric population.
>
> \[Laughter.\]
>
> DR. SALYERS: So am I.
>
> DR. MARYANSKI: Actually, the Codex didn\'t
>
> address the geriatric population specifically, but it did discuss the
> fact that there are basically subgroups within the population that one
> needs to take into account, including the elderly, pregnant women,
> infants and so forth. And so, yes, while not addressing that in
> detail, the guidelines do generally recognize that in thinking about
> the safety of a new product, you do have to think about subgroups in
> the population as well as the population as a whole.
>
> CHAIRMAN BUSTA: Thank you very much.
>
> DR. MARYANSKI: Thank you.
>
> CHAIRMAN BUSTA: We\'ll continue on. Dr. Thomas Cebula on FDA\'s
> approach.
>
> DR. CEBULA: Thank you. I\'m Tom Cebula. I\'m the director of the
> Office of Applied Research and Safety Assessment. I\'m also the lead
> scientist for molecular biology for the Center, and those that know me
> in the room know that I never give a scripted talk. I\'m taking out a
> crib sheet because I was taking notes.
>
> The first thing I\'d really like to say
>
> about the process that FDA uses is that it\'s an evolutionary one.
> And, since joining the Center, I\'ve interacted with Jim Maryanski,
> Bob Lake, others in this room since about 1987, so, like Jim, I\'m
> also worried about the geriatric population.
>
> In that process, we saw a number of people come to us with a lot of
> ideas about what they were going to do, and I think Dennis made a very
> valuable point when, early in a consult, some advice might be given,
> the company goes back, and we don\'t hear anything more about it. So
> there is a lot of oral history perhaps that should have been captured,
> and I\--the point that you make earlier about how do we see those
> numbers. Early in the process, it was an evolutionary one. I think
> Jeanette made a very good point about after a series of discussions,
> clearly, we\'re trying to make that a very much more transparent
> process to really capture how many times the sort of advice that\'s
> given from this side out has influenced.
>
> The other point I\'d like to make before going into my talk: I think
> Abigail Salyers made a
>
> very credible point about connecting dots in the scientific community.
> All science is interconnected and interwoven. Jim Maryanski talked
> about R-DNA and the subject for transgenic plants. Clearly, we\'ve
> taken cues from R-DNA in microorganisms. I serve as one of the experts
> for WHO for the microorganisms in R-DNA. But Abigail\'s point about
> probiotics. I\'d just like to extend probiotics, counter terrorism,
> and our budgetary process called OMB. I do believe that what we have
> heard is that there is a real need to really take some of the counter
> terrorism dollars and move them into other areas of food safety.
>
> I believe something that FDA is doing, and our laboratories within
> CFSAN are actively engaged in. My office, for example, has the mission
> to ensure, to do research that ensures food
>
> safety\--microbiological food safety\--and we also have a team of
> toxicologists.
>
> Post 9-11, that mission changed somewhat, and it became food security
> and food safety. It\'s a very valuable point, because the research
> that
>
> we\'re doing for food safety could be immediately applied to food
> security. And, of course, those dollars that are coming in, we\'re
> using as a twofer. So if we\'re developing methods for the intentional
> contamination, those serve for methodologies for accidental. So,
> again, we\'re trying to be very proactive, recognizing that it\'s a
> zero-sum game. There\'s only a certain number of budgetary dollars out
> there; and if it\'s applied to counter terrorism, we have to get the
> most bang for the buck.
>
> The point about Vancomycin is a very important one. And I\'m just
> going to say that probiotics in the genomic era, as people have looked
> to sequence total genomes, people have looked at probiotic organisms;
> FDA, in contributing to the genomics project, has often emphasized it
> is nice to know that a bacillus cereus that is being used a probiotic,
> we can know the entire genome. But isn\'t it more important to know
> about a bacillus cereus that causes disease. So, again, FDA is trying
> to move in the direction of saying if
>
> we\'re going to use those dollars, let\'s get some information about
> food safety from that.
>
> I just want to make sure that I\'ve covered some of those points.
>
> The final thing I would say is that since 1987, we have served in a
> way as internal consultants for some of the process that you\'ve been
> hearing. We are primarily the laboratory portion of the Center, and
> since our hands are the wettest on the techniques, we\'re often called
> in to say how would you evaluate this. So there\'s a very responsible
> team, and we interact with that responsible team to offer some advice
> and also do the consult\--also do a review, as well. So there is, if
> you might say, there is some partial duplication, but it\'s a very
> important duplication, I believe.
>
> With that said, I\'m really going to take some of the slides that
> Jeanette gave and Jim gave and kind of put our wrinkle on it.
>
> Jeanette pointed out that really we\'re asking for companies to come
> in to provide the
>
> documentation that assures us that there\'s a reasonable certainty of
> no harm. But I think the important caveat is this is the real
> opportunity to find out what\'s in the pipeline and what\'s coming
> down in the future so that we can be proactive rather than reactive.
>
> We neither prescribe or proscribe specific tests up front. We\'re
> there to hear what industry has to offer, and somebody said, well, how
> much input do we have. Clearly, the input is we are going to offer
> advice, but we\'re going to be focused on the characteristics of the
> food product, as you heard Jim say, as you heard Jeanette say.
>
> We are there for scientific evaluation. Our intent is really obviously
> the food safety question. But, as scientists in this room, as you
> heard around the room, often we get off on a tangent. We talk about
> the strengths, and that should say limits of a particular technique
> that might be used, because this helps us in future deliberations. But
> our primary focus is food safety, and that\'s the important thing to
> remember
>
> for our evaluation here.
>
> Again, borrowed from Jeanette, we do take a multidisciplinary
> approach, but I want to point out that the duplication is very
> important, because we\'re going to be really focused on the molecular
> analysis and really talking about the genetics of a particular
> manipulation or a particular plant.
>
> We often get clues from the chemical and nutritional analysis about
> stability and genetic stability, so we\'re looking at pretty much the
> same thing that a chemist might be looking at, a nutritionist, but
> perhaps from a different slant.
>
> Clearly, as you\'ve heard, we want to know about the identity and
> source of introduced genetic materials because that will tell us a lot
> about what are the potential food safety concerns. For example, in a
> sidebar during the break, we were talking about transferring genetic
> material from one microorganism to another. I point out that the
> nomenclature has changed over the years, and something that is
> streptococcus a few years ago and may have been considered commensal
> is now
>
> enterococcus and is a pathogen. So we definitely ask people to
> identify the organism, but to trace the nomenclature of that organism
> to ensure that we have taken into consideration that nomenclature
> changes haven\'t affected our assessment.
>
> And, again, the intended changes of the composition of the
> food\--clearly, we\'re always concerned about the intended effect,
> but, as you heard from all of the discussions, clearly, in evaluating
> food safety, it is often the unintended effects\--allergenicity,
> toxins, and I should add the toxicants that Jeanette
> mentioned\--because in a manipulation, as you heard, if you happen to
> insert and get downstream expression, you might get the expression of
> a toxicant. We want to know that.
>
> The allergenicity, as you\'ve heard, will be a separate discussion,
> but I would point out in our evaluation, since we are seeing sequenced
> data, the bioinformatics tools are there to say what sites could be
> potentially glycosylated; and these days, with the glycosylation kits,
> we\'re often seeing the data for whether those sites are,
>
> indeed, glycosylated.
>
> The nutrient levels. Again, you\'ve heard why we look at that, but I
> would just like to take a digression, and say when we talk about
> natural foods, and we\'re looking at a nutritional status of anything
> be it a nutrient and this is also true for a toxicant, you would
> expect a normal distribution from the natural varieties over time.
> When you\'re looking at a R-DNA plant, since the manipulations are
> among one variety, we would expect that distribution to be much
> tighter, and the sort of data that we see says that. And so, if we\'re
> looking for toxicant values, which might also be this value, where
> this is low to high, clearly the data that we have been seeing up
> until now is that can fall on the low side of the toxicant. So, when
> we\'re considering an R-DNA plant versus a natural variety, we find
> that all of the data, thus far, seems to follow the strength; that
> you\'re getting nutrients that you expect, with a narrow distribution,
> and lower toxicant values. And I would say that\'s a fairly general
> way of stating
>
> the sort of data that we have been looking at.
>
> And finally, something I neglected to say that our laboratories are
> very interested in DNA repair and effects on the emergence of
> antibiotic resistance, and the penetrants of virulent straits. We are
> very interested in evaluating antibiotic resistance. And, again, from
> an evolutionary perspective of the process, as you are all aware, the
> primary marker that was used early was antibiotic resistance, and we
> now see a drift away from antibiotic resistance.
>
> Now stealing some of Jim Maryanski\'s slides and the Codex slides, I
> would really like to emphasize some points, but I\'m not going to
> reiterate all the points. When we\'re describing the genetic
> modification, the sort of data that we have been seeing is people are
> showing you the nucleotide sequence of the material that they\'re
> starting with.
>
> They\'re telling you about the promoter set they\'re using. They\'re
> telling you about the terminator set they\'re using. That\'s a very
>
> important piece of data, because that\'s direct information, and now
> you can use indirect methods; and there\'s a host of indirect methods
> that could be used to evaluate the construct once it\'s inside the
> plant. And that\'s a very important point as we consider do we need
> sequence data and how much sequence data do we need.
>
> What I\'m establishing here\--if you know the sequence, you then can
> do a restriction map and ask does\--is the restriction map consistent
> with the sequence that was delivered to the plant. You can look at
> restriction maps. You can look at expression. Northerns. We
> actually\--or expressions of the protein, Westerns. Now, clearly,
> there\'s a distinguishing factor here. If you look at expression,
> Western analysis of the protein, you\'re usually looking at the
> intended effect. The Northerns, however, give you a lot of
> information, because, if there are other transcripts made, that\'s
> something that we would be looking for as an unintended effect. So
> unless it is stated that the intended effect is, any Northern
>
> expression that would be aberrant, we would be questioning what is the
> significance of this RNA, this extra RNA.
>
> Again, I\'ve already made the point about marker genes and the
> nutritional modification, so I\'m just going to skip this slide and
> talk about the transformation process that Jim alluded to.
>
> Again, when you are talking about a ballistic method of random
> insertion, we might have a number of things that we\'re looking at.
> You know, how many sites does this randomly insert. If we\'re talking
> about site-specific recombination, if it is a site-specific
> recombination, it\'s a more tailored type of mechanism. So, again, in
> making the point that it is a case-by-case analysis, it\'s important
> that if you prescribe the tests too soon, scientifically some of those
> tests would not make sense or some of the questions would not make
> sense. So we\'re very interested in the DNA to be introduced\--the
> genes, the markers, the regulatory sequences. But Steve Benedict
> mentioned a point about regulatory sequences and sequencing, and I
>
> really would like to make the following points right here.
>
> We are consistent, I think, with Codex, we\'re talking about size,
> identity, and location. If we\'re saying we know that there is
> material inserted into a genome, say, the tomato genome. We are also
> consistent in saying we would like to know orientation of that insert.
> However, the location down to the nucleotide is something that we
> personally don\'t ask for. And the reason is, and I should state it up
> front: all of the effects that we\'re looking at are SIS proximal
> because you can sequence 10 KB, 20 KB versus a trans effect from
> another chromosome, you\'re going to miss it anyway. So I would really
> view them as a\--up until now, we have said that we are looking at SIS
> proximal effects and the integrity of the genome in the intended and
> unintended effects the researcher has inserted into a gene.
>
> As far as the data that we\'ve been seeing, basically, there have been
> times over the years, I can remember where people have provided
> inside-out
>
> PCRs as to tell us some conference. Okay so I will leave it at that to
> say that the location to us is that it is inserted and that it is
> stably inserted.
>
> The number of sites and organization. Clearly, we all know that when
> the material goes in, that you have duplication. Okay, so at the same
> site, you can have many inserts lined up or you can have many inserts
> lined up at different sites in the chromosome. One is more important
> in our evaluation than another. If you have multiple copies at
> different locations, the chance for recombination, reassortment,
> rearrangement, and ultimately effects on genetic stability are much
> more of a concern than if you have a single insert. So that\'s why
> talk about wanting to know how many inserts and how are they located.
> And, of course, as Jim emphasized, we are definitely interested in any
> open reading frame and insertions the possibility of fusion proteins.
>
> The important thing here I wanted to emphasize un-translated RNA. Jim
> mentioned one possibility. If the intent is to make antiscents
>
> RNA, it\'s not going be translated. We want to know about that. But
> there\'s another\--it seems every journal you pick up at least there
> are two articles in each of the journals talking about un-translated
> small RNAs. That is not our intent. We\'re not asking for people to
> tell us about every small RNA that\'s produced in the plant, because I
> don\'t know what those data would tell us. But I leave that to you.
> That is a very burgeoning field right now, the un-translated small
> RNAs that act as regulatory molecules.
>
> And, again, the intended effect and heritable stability. I\'ve
> mentioned a couple of ways we measure genetic stability or we assess
> genetic stability. One of them is the Mendelian inheritance. Clearly,
> if the insert is unstable and is hopping, the mosaicism rather than
> the Mendelian inheritance pattern would be seen. So that\'s a very
> important thing. But some of the other data that we\'ve been talking
> about, the expression data et cetera, are also measures of stability
> also.
>
> And, again, these should read strengths and limits rather than
> limitations, because from the perspective of an R-DNA, it\'s important
> to realize that one or only a few genes are being incorporated into
> the plant. There\'s a limited number of manipulations. One can talk
> about unintended effects, and we\'ll get to that in a moment.
>
> But it\'s also important to remember that, as genes have been
> introduced by R-DNA techniques, those genes will become the docking
> points for traditional breeding, and those sites, then, will be now
> the conventional traditional breeding that we\'re all used to. So,
> again, as people talk about propagation of R-DNA, the R-DNA will be
> propagated by traditional breeding also.
>
> So the questions that I took from this were what tests are necessary
> and are there tests that should be required. I think those are all the
> questions in your minds, and you will be discussing this afternoon.
>
> I\'d really like to point out that Mendel
>
> did a nice experiment many, many years ago, talking about round and
> wrinkled peas. And that experiment was reproduced in the molecular era
> about a decade ago or so. And basically, if you do traditional
> breeding, and you get round or wrinkled peas, and then subject it to
> some proteomics, you find that 62 of the 636 protein spots are
> qualitatively different. The R-locus, of course, now we know affects
> sugar content, lipid content, storage protein composition. But the
> round pea is safe to eat, and so is the wrinkled pea. Okay.
>
> The way I would like to look at this is as we were musing about this
> in Paris at a meeting, I went off to the Monet exhibit at the Musee
> Marmite, and there\'s some wonderful water lilies, canvases that just
> dominate. For those that have seen, this is definitely Monet.
> Everybody knows the blues, the greens, the purples. This one happens
> to be the blues and the greens and the whites, but this is also Monet.
> It looks more like a Jackson Pollard. And this is about 1917. The
> other one was 1880. Okay. But they\'re Monet, and I submit
>
> to you that they\'re safe to consume.
>
> \[Laughter.\]
>
> It\'s also important that Gottlieb and de Vienne in \'88 did an
> experiment also that found that if you take the AF mutants, you\'ll
> see that tendrils can replace the leaflets. So it\'s something that
> you wouldn\'t want to see in a plant. Weeding this is not a good
> characteristic, but, basically, the protein profiles were absolutely
> identical. So, again, the tests would not reveal a difference, whether
> it was a food safety issue or not. I\'d leave that for discussion.
>
> I said I\'d return to unintended effects, because, again, I think we
> have to recognize that, as the techniques get better and better,
> pleiotropy will be a universal trait of any mutation. We know how much
> cross-talk is going on in the cell, and within an organ, and within an
> organism so that there will be always cross-talk anytime a mutation is
> introduced; and now I\'m talking about a point mutation, be it an
> insert of a couple of genes or a point mutation, a base substitution.
>
> So, again, not to argue that pattern recognition can\'t work, okay. We
> are believers and users of technologies like genomics, like DNA
> arrays, like proteomics. But, again, I\'ll borrow from the
> impressionists and say that pattern recognition works Seurat proved
> that points of paint on a canvas can be recognized. It can look like a
> lighthouse, or it can look like an afternoon on the island of the
> Grand Jatte.
>
> However, in a regulatory setting, I want you to concentrate on the
> dog, because that dog is very docile, at least captured at this
> moment. So when we are doing expression profiles, if that dog changes
> to green, red, polka dot but remains docile, it is not a food safety
> question. If that dog happens to bit that individual in front, it
> becomes a food safety question.
>
> I submit to you that we\'re at a stage to recognize that expression
> arrays do, indeed, work, but it\'s not at a point where we can find
> and isolate the genes that define safety. And so, as people are
> talking, I would suggest that we talk
>
> about the new technologies as they relate to food safety. And with
> that, I\'ll stop.
>
> CHAIRMAN BUSTA: I just want to make a comment. You didn\'t need your
> entire 55 minutes.
>
> DR. CEBULA: That was intentional. I really wanted this to be a
> conversation, and, as I had pointed out, I would\--
>
> CHAIRMAN BUSTA: Dr. Salyers.
>
> DR. SALYERS: I have a question.
>
> CHAIRMAN BUSTA: Please identify yourself.
>
> DR. SALYERS: Oh, Abigail\--Abigail Salyers. I have a question about
> the extent to which or how you see your group\'s position vis a vis
> advising industry about what it should do. I\'m struck, as I talk to
> various, especially the small biotech companies, but even the
> bigger\--people at the bigger companies like Monsanto is the extent to
> which they have a very narrow range of expertise. And even in the big
> companies, where they might have a broader range of expertise, the
> components don\'t necessarily communicate freely with each other.
>
> You\'re a world renowned scientist with a lot of contacts, and I\'m
> sure that you\'ve\--so you\'re the sort of person I wish we had more
> of in industry, but we don\'t. And I\'m sure you\'ve assembled a group
> that is\--has outstanding representation of the various sciences; and
> that you are probably more like to the many people in industry to
> become aware of changes in the basic science technology. So my
> question is one would hope that the FDA somehow could serve in an
> advisory capacity to industry; and yet, of course, you see the other
> side of it, which is the conflict of interest side I guess. But how do
> you see your role as an advisor of people in industry?
>
> DR. CEBULA: I believe the\--when I said that we were serving a
> consulting role, I meant within the context of FDA.
>
> DR. SALYERS: No, I understand that.
>
> DR. CEBULA: Oh, okay.
>
> DR. SALYERS: So I\'m just asking you to expand on the outreach part of
> it.
>
> DR. CEBULA: In the outreach, I believe,
>
> as I said since \'87 or thereabouts, everybody time somebody has
> decided to talk to Jim or Bob Lake, Jim Maryanski has graciously said,
> well, why don\'t we get Tom involved. He may have some ideas. When
> we\'re out at meetings, we are scientists; and, clearly, if there\'s a
> technique out there, you know, we\'re doing that right with
> pyrosequencing. Pyrosequencing is a very valuable technique. Some
> people haven\'t heard about it. We\'re using it. We\'re saying how
> about this. So it is scientist to scientist. We\'re trying to exchange
> information and the technologies as we see it, and we\'re welcoming
> the input the opposite way. We\'re getting fantastic input from
> academia and from industry; and we\'re working collegially I
> think\--is the important thing. And if I might say something about the
> whole process, again, over time, let\'s start when we first consulted,
> if we said, do you have data. The first response was why. I believe
> now it is, you know, developed to a point where people are saying,
> well, these are the sort of data, and this is\--there\'s scientific
> reasons for
>
> the data. So, I believe there is a trust in its finest sense of the
> word, a mutual trust, that questions aren\'t being asked for it would
> be nice to know, but as was stressed in the two talks here, there is a
> need to know because it may impact a safety decision.
>
> And so I think there\'s been a good rapport built up over time.
>
> DR. FEDOROFF: Nina Fedoroff. I was very struck by your cogently
> pointing out that you can have many differences, and the foods are
> still safe. I think if people had suggested that we would knock out
> starch genes and get sweet corn, somebody would haven\'t objected to
> the religious grounds or ideologically grounds.
>
> In any event, the other point that you made that I\'m struck by, and
> that leads to my question, is that, so far, your assessments have
> indicated that the distributions are narrower and that none of these
> unintended effects have surfaced. My question is: how many instances
> do you have to assess before you can evolve your
>
> guidelines to say, okay, this is not a major problem, we don\'t have
> to collect all of these data.
>
> DR. CEBULA: Well, I think one thing you\'ve heard from the two
> speakers before me, we are clearly waiting to hear what the National
> Academy has to say. We\'re awaiting what the input of your group will
> say. But, clearly, I wanted to point out there will be unintended
> effects. The question is, will those unintended effects affect the
> quality or food safety of\--
>
> DR. FEDOROFF: Sure.
>
> DR. CEBULA: Okay.
>
> DR. FEDOROFF: But the other thing is that there are\--in\--in-those of
> us who work on little experimental plants have been making insertions
> left, right, sideways, hundreds of thousands of them. And the
> information that comes back is that plenty few of them make a huge
> difference. In fact, people struggle to identify insertions that
> change how the plant grows, flowers, reproduces. It\'s a very small
> fraction of them. And the
>
> ability of insertion\--even when people set out to activate genes by
> pointing a promoter out, that doesn\'t even work much of the time. It
> does work occasionally, but not\--certainly not as frequently as
> you\'d expect. And it seems to me that there\'s a large volume of
> information, not just new techniques, but accumulating information
> from actually insertions done for mutagenic purposes that one could
> bring to bear to increase the amount of information that you have
> available to you in making judgments about how frequently there are
> unintended consequences.
>
> DR. CEBULA: Those data, indeed, would be very helpful. I think when we
> were talking about CalGene, I think that you were on the committee
> then, and I was giving a talk. And I\--you said the problem is that
> the negative experiments are seldom, or can\'t be published, and
> we\'re saying that we need that database, whether that database is in
> the published literature or available, we would like to see the number
> of cases so that that can really help us.
>
> DR. FEDOROFF: That\'s a real challenge because people frequently
> don\'t\--you know, they put a lot of effort into identifying mutants.
> They don\'t put a lot of effort into quantifying the frequency of
> those mutants.
>
> CHAIRMAN BUSTA: Doug.
>
> DR. GURIAN-SHERMAN: Doug Gurian-Sherman. I think that whole issue
> brings up a discussion that we should, you know, probably take up at
> some point. But, with time limited, I wanted to focus on a whole other
> issue.
>
> You mentioned several instances of types of data that you look for, so
> you\--you know, you talked about stability, and, you know, differences
> in nutrient levels, and all that kind of stuff. One concern that I
> have that maybe you could address is, what the level or type of
> analysis that you consider to be acceptable, because, again, and I
> have to put this in context of the studies that I looked at that you
> folks looked at, and often found there was limited methodology
> described, limited statistical analysis. You know, stability is one
>
> thing brought up. Half the cases we looked at\--a lot of them did look
> at Mendelian analysis. Probably half of them didn\'t do any
> statistical, like the chi square analysis to tell you\--I mean,
> you\'re not going to get a perfect four to one ratio in most cases, so
> you have to have some kind of analysis that tells you how much of a
> deviation you get, and then try to figure out what that means.
>
> So, I mean, I think a whole other issue the quality of the data, and
> the expected level of analysis, and how\--I mean, you know, one
> standard could be comparable to what goes into a peer review journal.
> To be frank, I don\'t think that, on average, that was the case. So
> how do you decide what the quality is that\'s acceptable?
>
> DR. CEBULA: I think it\'s very important to recognize that I said
> several times that one way of measuring genetic stability is Mendelian
> inheritance. As I said, if it weren\'t Mendelian inheritance, there
> would be a large deviation. However, if those were the sole data that
> we were looking at, I would say yes, you would have to do a
>
> very sophisticated statistical treatment to unequivocally say it\'s
> Mendelian inheritance. But there\'s a body of other evidence that
> says, the material is still where it is because on the second
> generation, we\'ve done, you know, a map that has provided us other
> data that supports it\'s sitting in the same site that it started out
> with. It\'s also being inherited at almost, or, I mean, I\'m taking
> your word. You know, I don\'t know which data you are speaking to. But
> if it\'s almost Mendelian, and it\'s sitting at the same place, it\'s
> likely to be Mendelian rather than some runaway jumping gene. And
> that\'s so\--you use the different techniques. I would rather see the
> company offer three different techniques to verify it rather than
> working on the statistics to come up unequivocally to come up with a
> Mendelian inheritance.
>
> DR. GURIAN-SHERMAN: I think that\'s a good point, but, again, you
> know, addressing that issue: you know, when we looked at this, some
> companies did do things like expression analysis for a bunch of plants
> that, you know, the F-3 generation or F-4
>
> generation, but many of them didn\'t. And similarly, you know, some
> companies did bioassays, but at levels of expression that might be,
> you know, 20 times over the lethal dose, so variations that could be
> fairly substantial wouldn\'t even necessarily show up.
>
> So, I think, you know, what it comes down to often is a lot of times
> the devil is in the details, as we\'d all expect, you know, in
> empirical science. And I\'ll just raise it and leave it as a concern
> that there need to be sufficient analytic standards, redundancy if you
> want in tests, but then they need to be there. And I didn\'t find that
> that kind of redundancy was there in many cases.
>
> CHAIRMAN BUSTA: Jim.
>
> DR. ASTWOOD: This is Jim Astwood. Dr. Cebula, thank you for the
> thoughtful presentation and interesting art. In thinking about it, I
> was wondering if you could comment on, what seems to be in this
> presentation, an analysis at the genotype level, you know,
> fundamentally, if you think about it as a geneticist. What importance
> should be
>
> placed on the phenotype, the agronomic evaluations, the compositional
> analyses, which can be thought of as biochemical sampling\--these
> other factors. How do you, as a molecular biologist, how do you sort
> of think about the weight of those different aspects?
>
> DR. CEBULA: Well, the agronomic issue I believe is away from my
> bailiwick. I\'m expecting a company to make a decision if there\'s, I
> hate to say it, but there\'s a different bottom line. If it\'s going
> to be developed and marketed, there has to be one bottom line.
>
> The molecular analysis, by the time somebody has made the decision
> that they\'re going to bring something forward, I believe they\'ve
> already done some of the routine analysis that impinges upon molecular
> biology; and that is the genetic stability, the ease of manipulation,
> and when I say stability, I mean it on two different levels: the
> internal rearrangements that could occur, the possibility of
> methylation and silencing\--all of those have been done by the time
>
> they came in. So, in that sense, by the agronomic consideration that a
> company might do, I feel that a lot of experiments have been done that
> we haven\'t seen the data for. But, again, the data that we\'re
> analyzing supports the notion that you have a stable insert; and it
> supports the notion that it is constantly being expressed.
>
> I presume, again as Nina Fedoroff said, those data are to come by, but
> within the notebooks, they are probably a lot of failures to come
> forth simply because a methylation pattern decided to silence a gene
> or something. But those are the data that we don\'t see, so we can\'t
> give statistics on those. But, by the time we\'re seeing the data\--
>
> DR. KAPUSCINSKI: Thank you, Dr. Cebula.
>
> CHAIRMAN BUSTA: Identify yourself.
>
> DR. KAPUSCINSKI: Anne Kapuscinski. I also appreciate your
> presentation, and, by the way, I\'m a lover of that art, and I was
> born in Paris, so it kind of got under my skin a little bit.
>
> But I have a question. It seems to me
>
> that the question about these genomic and proteomic methods for the
> committee should really be, and I assume, therefore, for the FDA,
> should really be how could using those help to improve sort of
> strategic searching for the few cases where something unanticipated
> might cause a real food safety problem, rather than asking about those
> techniques alone.
>
> So, I would like to get your feedback on that. What I\'m really
> getting at is I think I want to ask sort of what Dr. Astwood asked but
> a little bit differently. Isn\'t it better for us to think about how
> can we direct the use of these techniques in combination with
> information at the level of biochemistry, and then at the level of the
> whole plant, phenotype, et cetera, rather than ask to only look at
> those techniques alone. I think if we just look at those techniques
> alone, we\'re kind of barking up the wrong tree. And I fully
> appreciate, you know, your concern that the status of the technology
> right now is you could generate tons of data about transcripts and
> expressed proteins and
>
> not really know what it means. But I think it seems to me what we need
> to do is figure out how can we, knowing that there\'s that limit, how
> can we direct the Agency, and maybe even direct recommendations for
> research, to improve the use of that technology in a very strategic,
> focused way so that it could add to the toolbox that you have right
> now. Because it seems like the bottom line challenge in this area is
> that, yes, the large majority of the time, there isn\'t going to be a
> problem. We just want to make sure that that doesn\'t make us
> complacent so that it becomes hard to proactively detect the few cases
> where there will be problem. And we all know that coming down in the
> future, this technology is becoming more and more powerful, and
> there\'s going to be chances to make much larger scale changes as we
> get into gene stacking and genes that we know will have major effects
> on composition because you actually want them to have major effects.
> So, that definitely raises the question that they might also have some
> major unanticipated effects. So, we have to be
>
> looking at the future. So, what\'s your reaction to what I\'m saying?
>
> DR. CEBULA: I think these technologies are wonderful technologies to
> do just what you said, search and discovery. If I could read into your
> question and say, what could you do to help, the first message that I
> would do\--ask you to send is to ensure that any of the technologies
> being used have been validated, because there are a number of these
> expression chips out there, and you read the same literature that I
> do. Recently, one of the major manufacturers of a particular chip,
> there was an article in Nature, called \"When the Chips are Down.\"
> The company in their quality control missed the fact that they put the
> wrong strand, and, even then, 30 percent of their sequences were
> aberrant sequences. And this was sent out, and people are using them,
> and flooding the literature with array papers.
>
> DR. KAPUSCINSKI: Trash.
>
> DR. CEBULA: The rush to public a new technique has often showed us
> that there are lot of
>
> holes in the technique. So, I would say that what you could do is make
> sure that we don\'t damn a technology because we got started with the
> technology prematurely.
>
> So, for expression, there are some very good examples. David Bottstein
> teamed up with Stanford to come up with a lymphoma chip, very
> predictive. But to get to using a lymphoma chip, they had to go back
> and show that the repository for the sequences were cluttered with
> about 24 percent of the sequences that had the wrong sequence.
>
> So, everybody\'s using these chips, and it takes a couple of
> scientists to say, well, let\'s not rush to publish. We\'ll just go
> ahead and find out what\'s going on first.
>
> So, my first message would be could you carry back and say, let\'s go
> slowly but very together on making sure that the chips we\'re going to
> use to evaluate biotechnology, natural foods, or any other is the best
> chip to make sure that it\'s right. We don\'t repeat mistakes. I mean,
> we saw
>
> the same thing with the emerging PCR technology. Everything gets
> exponential the first few years, and that\'s where the mistakes are
> buried. I\'m sorry.
>
> CHAIRMAN BUSTA: Dr. Fedoroff.
>
> DR. FEDOROFF: But I think that\'s missing the point. In order to make
> a lymphoma, and you\'ve made the point earlier, in order to make a
> lymphomas chip, it\'s not only important to have accurate sequences,
> but it\'s important to have the lymphomas.
>
> DR. CEBULA: That\'s right.
>
> DR. FEDOROFF: Okay. And that\'s really the whole point\--is that
> we\'re\--we need to avoid focusing on the technology when we don\'t
> know what we\'re measuring. There is a huge range of permissible
> compositions that are perfectly good foods, okay? We seem to slip off
> that over and over and over again. And I think it\'s extremely
> important because some of the notorious incidents that have hit the
> press worldwide have been based on the lack of recognition that the
> very processes
>
> of transformation, the culturing of cells, which has been used to
> generate variation, does generate variation. And, so, people attribute
> variation to somehow this terrible recombinant DNA when it has to do
> with tissue culture.
>
> But it\'s not an unexplored territory. And so the question is one of
> connecting the limits of variation with permissible\--and I think that
> we\'re going about it the wrong way. Instead of saying what
> is\--characterizing the entire range of variation for every component
> of foods, we need to collect the information on what has proven to be
> problematic health wise\--glycoalkaloids in potatoes, sugar binding
> proteins, which are lectins, which are under characterized as yet in
> both plants and animals.
>
> But it\'s not an infinite variety. One doesn\'t have to look at
> everything.
>
> DR. KAPUSCINSKI: That was why I was asking about, to kind to get your
> input, on how your thinking about potentially directing the use of
> these new technologies for strategic searching
>
> for the things that might go wrong, sort of playing off of what Nina
> is saying. So, I just wanted to get a sense of whether you, as a
> molecular biologist, are thinking in those terms and whether you
> realize that or to what extent you\'re thinking on drawing on
> information from the biochemistry and other levels of the phenotype to
> guide, then, how you would use, for example, a DNA chip.
>
> CHAIRMAN BUSTA: That the first comment there was Dr. Fedoroff. The
> second one was Dr. Kapuscinski.
>
> DR. KAPUSCINSKI: Sorry.
>
> CHAIRMAN BUSTA: We\'ll let you respond, and then we\'ve got two more
> over here.
>
> DR. CEBULA: I apologize. Nina, thank you for bringing me back. You\'re
> absolutely right. That is the major point.
>
> The one thing that I think would be very helpful, and this is
> something that we\'ve discussed internally, is that narrow
> distribution versus the broad distribution is, in a way, comparing
> apples and oranges, because that is the gamut of varieties
>
> versus one variety.
>
> DR. FEDOROFF: But only for one component.
>
> DR. CEBULA: No, I know. And no, no. And what I meant to imply is if we
> are going to use the new technologies, it might be important to really
> do counterpart, the natural counterpart to, the variety from whence it
> came compared to the transgenic and then ask, because I\'ve looked at
> some data where clearly there are differences in expression, but I
> don\'t know what it means; because I don\'t know what the variety
> used, how that compared to the manipulated variety.
>
> So I think first of all we have to do some fundamental genetics. If
> you\'re going to approach it, approach the new technology, take the
> new technology and combine it with some good genetics. That\'s all
> I\'m saying. And, there, I would say that we would like to see, you
> know, again,
>
> data\--if you\'re doing it strategically, as you\'re suggestion, I
> would say that any gene that you see from an array would be verified
> by another technique, a more sensitive technique.
>
> To say, if you have a knockout, do you get the expression that you
> expect or the
>
> non-expression. It\'s what\'s going on in the field right now in array
> technology everywhere else. So, if it\'s going to be applied, and I\'m
> not saying I\'m recommending it, I\'m saying if it\'s going to be
> applied, it should be applied in a very structured way to follow the
> sound scientific principles.
>
> CHAIRMAN BUSTA: First Jonathan, then Calvin.
>
> DR. ARIAS: Jonathan Arias. Thank you for the very interesting and
> informative presentation. I had two points, or questions, actually, to
> address. One is in regards to the overall view of risk assessment and
> safety.
>
> And it seems to me that one of the difficulties intrinsic in these
> more computational biological approaches of genomics and such is
> ultimately how to interpret all of this data. Genes will go up. Genes
> will go down. And are those changes in ways\--or confer changes in the
> plant that would be significant in terms of health.
>
> And I think that\'s a real challenge, that maybe the answer isn\'t
> quite known at present.
>
> The second point is related to more global issues, and that is, the
> input of safety analysis. You mentioned that, and I commend, that the
> FDA has a consultative process with developers, and, as part of that,
> wants to get heads up about new products in the pipeline. Likewise,
> does the FDA also communicate what they would perceive as
> recommendations to minimize risk intrinsic in the state-of-the-art
> technologies, for example, the use of strong viral promoters that can
> activate genes at distances might be, for instance, less preferred
> than using more tissue of targeted promoter systems. Obviously, if a
> product is expressed in non-food components, it may be less of a
> concern than if it\'s generically expressed in the plant, including in
> the food component. So, is that dialogue also two ways?
>
> DR. CEBULA: I\'ll answer the second first. I believe it is. I think
> over the years, there have been a number of times when, in a very
>
> interactive discussion, FDA scientists have made some suggestions, and
> that has led to a shift in the thinking of what was going to be used.
> There have been cases where we suggested an experiment, and I keep on
> saying it was an evolutionary process; so these are earlier times,
> where the very technique, there was a concern that there may be
> read-through through a border sequence, and we suggested some
> experiments that ultimately turned out to be a very nice publication
> for the company. I noticed that in the acknowledgment that FDA
> scientists weren\'t acknowledged.
>
> \[Laughter.\]
>
> You know those things happen, but it was a good experiment. It was a
> nice experiment. So, I mean, I think it happens, but again it\'s part
> of that consultative nature: that somebody comes forward and shows you
> the data. I think I said in the sidebar, I almost treated it as an
> academic, you know, show me what you\'ve done in the lab lately. And
> over the first few consultations, it was why do you want to know this.
> And, over time,
>
> people said, I did this experiment but. And, you know, that\'s how you
> find how people are thinking. You know, we really\--it was more
> collegial, and people were opening up to say we were trying this. It
> didn\'t work. We were trying this. It did work. That\'s the process
> that I\'m trying to define, and I\'m probably not doing a good job of
> it. But it is a learning process on both parts.
>
> DR. ARIAS: I think we recognize that in very few cases are we going to
> find clearly demonstrable risks associated with a particular
> transgenic plant. I mean, those would be probably be quite evident in
> the range of studies that are done to date. And it\'s the more subtle
> ones that we would obviously be\--considered as problematic. Thus,
> using new to change the overall level of risk or probability of risk
> would seem to be also intrinsic in this process. And I gather that\'s
> what I\'m hearing, as well.
>
> DR. CEBULA: I would just like to return to your first question of
> combinatorial. I actually should have put a slide in here, because I
>
> usually keep the yeast genetics\--the yeast array up there. Brown, out
> at Stanford, now has looked at 20 different strains of yeast, using a
> chip that has about 2,000 pieces of DNA down there, so 2,000 reporting
> groups for each experiment. And he\'s done it under seven different
> environmental conditions. So, you have 2,000 to the 20 times 7, 2,000
> to the 140th power, bits of information coming in. And so that\'s why
> I\'m saying, let\'s be careful what we ask for because that
> information cannot be sorted through. And we will always see genes go
> up and genes go down, but the question, again, remains is it a food
> safety concern.
>
> CHAIRMAN BUSTA: Dr. Qualset. You\'ve been very patient. I appreciate
> that.
>
> DR. QUALSET: This is Cal Qualset. I\'ve sort of forgotten what I was
> going to talk about\--
>
> \[Laughter.\]
>
> Because I\'m intrigued with this discussion. I\'m a old-fashioned
> plant breeder. And I see us drifting quite a ways from the 1992
> policy; that is, product versus process issue.
>
> What I understand is that FDA will receive a product\--is that not on?
>
> DR. FEDOROFF: I think it\'s not close enough to you.
>
> DR. QUALSET: Okay. Anyway, I think that we are drifting away from the
> discussion of approval of a product versus discussion of all the
> academic issues of process. So, I think we need to, as a committee or
> a group, needs to slow down on this and decide what is important to
> know about a product. And it\'s a\--the developer is already obligated
> to product a product that is stable; that demonstrates the
> functionality of a gene or segments being introduced; and to show how
> they established the stability, the genetic stability as well as the
> performance stability, over environments in which a plant will be
> grown.
>
> So I think it will be nice to know about these various kinds of
> molecular things that can happen with genes jumping around and all
> that. But the issue is, is the product produced and is it stable. We
> cannot understand every genetic thing
>
> that could happen. But if the product is as advertised, and it does
> not have any risks with human food safety as a whole food or as a
> processed food, I think that we are thinking steps further than are
> necessary for the evaluation process. So that\'s just my comment. I\'m
> throwing that out as a point for detailed discussion I think by the
> people who understand both product marketing, development; and they
> understand whether they\'re on the right track.
>
> So, I like the idea that there\'s consultative process with FDA, so
> they can kind of get a clue of where the product\--what the targets
> are for a new product. But the developers really have to provide the
> information to support the claims. So, I hope we can discuss that
> further.
>
> CHAIRMAN BUSTA: Bob. Identify yourself.
>
> DR. BUCHANAN: Bob Buchanan. I was intrigued by your discussion of
> Mendel and the proteomic analysis. Of the 62 proteins that differ, did
> any, would any raise eyebrows as to whether the product might be a
> problem? We know
>
> the peas are safe. Do any of the protein changes look suspicious?
>
> DR. CEBULA: Well, I gave you some classes. Some affected sugar
> content. Some affected sugar storage. But none of those changes said,
> you know, there\'s an unknown toxicant, cryptic toxicant peas that
> came up. That answer is\--yeah.
>
> DR. BUCHANAN: That\'s good to know.
>
> DR. CEBULA: Right.
>
> DR. GURIAN-SHERMAN: Just\--did they actually look for\--
>
> CHAIRMAN BUSTA: Ah, yeah---
>
> DR. GURIAN-SHERMAN: Doug Gurian Sherman. I\'m sorry. Just for
> clarification in that study, did they look for those kinds of changes?
> I mean, we assume they\'re safe, and they\'re probably safe, you know.
> But in terms of specific new anti-nutrients, you know, toxicants, were
> those looked at in that study or they looked at just general classes,
> like protein, starches, et cetera?
>
> DR. CEBULA: What they did was they
>
> resolved over 600 proteins on a two-D gel, found approximately 10
> percent changed, and then went about to characterize all 10 percent
> qualitative changes, and showed that, you know, it was sugar storage.
> It was lipid storage. So, they would have\--if there were a toxicant,
> they would have had an unknown protein, but it didn\'t show up in
> their analysis. Sixty-two of them were fully characterized. So.
>
> DR. GURIAN-SHERMAN: Well that\'s\--just again to follow up. Doug
> Gurian-Sherman. I mean, most\--many products, especially legumes do
> have toxicants and anti-nutrients, and they\'re often removed through
> the process, and through cooking, they\'re not\--for instance,
> they\'re not heat stable. So, you know, if there\'s a change in
> levels, some of them could theoretically have been, you know,
> toxicants and anti-nutrients. I guess what I was getting at was were
> they trying to identify whether those proteins were, you know,
> trypsin-inhibitors, or amylase-inhibitors, or, you know, whatever
> things that\--maybe it wouldn\'t be problematic
>
> anyway, because they may be removed through processing; but others
> that if the level was increased\--I mean, some allergens are also, you
> know, some of these types of proteins that might have an effect, and
> that\'s what I was getting at.
>
> DR. CEBULA: I really don\'t know if the wrinkled peas in that
> experiment were consumed by the investigators. I am sure they went a
> lot of blood, sweat, and tears to get it published in Genetics, but
> that was the standard.
>
> DR. FEDOROFF: What does conventional alleles work? That wasn\'t
> recombinant DNA anything.
>
> DR. CEBULA: It wasn\'t. No, no.
>
> DR. FEDOROFF: It was just round peas and wrinkled peas.
>
> DR. CEBULA: It was a natural. Right.
>
> CHAIRMAN BUSTA: You know the conversation is rolling toward lunch. Any
> other questions for clarification? The speakers will be around this
> afternoon, correct, as we go to discussion for additional expansion if
> we need it?
>
> DR. CEBULA: I will be on a conference call, but I said I would be
> available.
>
> CHAIRMAN BUSTA: Okay.
>
> DR. CEBULA: I will be on a conference\--
>
> CHAIRMAN BUSTA: But, if we have to, we can drag you in; right?
>
> DR. CEBULA: Okay.
>
> CHAIRMAN BUSTA: Any\--immediately after lunch, we will have the public
> comment. Is that one? Is that correct? And we will have that public
> comment\--it\'s generally set for 10 minutes, and then we will go
> directly into the summary and discussion. Anne?
>
> DR. KAPUSCINSKI: I was reminded that you need to read my name.
>
> CHAIRMAN BUSTA: I was going to do that right after lunch, but do it
> right now. We have the time.
>
> DR. KAPUSCINSKI: Okay. So, my name is Anne Kapuscinski, and I\'m from
> the University of Minnesota; and I\'m on the subcommittee, and I\'m
> really here.
>
> CHAIRMAN BUSTA: And she showed up immediately after we went through
> that activity this morning.
>
> DR. KAPUSCINSKI: Twice.
>
> CHAIRMAN BUSTA: Twice.
>
> DR. KAPUSCINSKI: That\'s because I have to get some good coffee. It\'s
> my one weakness. One of my weaknesses.
>
> CHAIRMAN BUSTA: Thank you all. I\'d like to thank all the speakers
> this morning\--and for your tenacity and the group. I look forward to
> an exciting discussion after the public comment this afternoon.
>
> \[Whereupon, the meeting went back on the record at 1:05 p.m.\]
>
> CHAIRMAN BUSTA: We have one public comment, and Mike Watson will
> introduce it.
>
> UNIDENTIFIED SPEAKER: We have one public comment from Dr. Michael
> Hanson, from Consumers\' Union, and he asked for 10 minutes to present
> to the committee.
>
> CHAIRMAN BUSTA: Yes, please. Use the
>
> microphone, so it\'s recorded.
>
> DR. HANSON: Thank you. My name is Dr. Michael Hanson. I work for
> Consumers\' Union. They\'re the people that publish Consumer Reports
> magazine. And we\'ve been very interested in genetic engineering
> issues; have actually been commenting on all the\--ever since 1992, on
> the FDA\'s various bio tech proposals. And I should also point out
> that Consumers\' Union is part of the international network called
> Consumers International, which is composed of 270 consumer
> organizations in 117 countries. And we have observer status at the
> U.N., and we\'ve also been very actively involved in the whole Codex
> process. We went to all the meetings of the Task Force on
> Biotechnology. And we would actually agree with Dr. Maryanski that
> that was a very positive process.
>
> What I\'d like to do here today is very quickly just make a few
> comments about molecular characterization. And these are the few
> points that I want to make.
>
> First, we think that it\'s a very good idea that the FDA is now
> talking about requiring a lot of molecular characterization data, as
> is laid in these Codex documents. But we have a basic question, and
> that is, whether this will be mandatory and not voluntary, and also to
> what extent data is going to be required post transformation. Because,
> in what you were told earlier today, it made it seem like the FDA has
> sort of been requiring this data all along. But that\'s not really
> true. That was a new requirement that came in with this 2001 policy.
> And I\'ll tell you about three years ago, I was on a State Department
> Committee, this Trans Atlantic Policy Project, and it was focusing on
> biotechnology; and the idea was to try to get the U.S. and Canada and
> the European Union to work toward harmonization. There was a lot of
> debate within the subcommittee, because, first, they wanted to look at
> full biotechnology, like a\--and they argued about should we require,
> should we look at a human data package or environmental issues. And
> they couldn\'t decide
>
> on anything, so the one thing that they decided on in this working
> group was to focus just on molecular characterization. And what
> happened, this was I think in 2000, late \'99, early 2000; when we
> finally met, data had come in from both the U.S. and Canada saying
> here is the molecular characterization data that\'s required. And the
> European Union, because I guess the data is different in different
> countries, they actually never submitted anything. So, this
> subcommittee has only met twice. We still haven\'t gotten any data
> from the European Union. But it should be pointed out that the data
> that was submitted by the U.S. and Canada, the molecular
> characterization that they said they were requiring, was functionally
> complete maps of the vectors and plasmids and what you were going to
> insert. But post insertion, it was just information to show that the
> transformation had been complete; that is, that the gene was in there
> and was active. But there was no requirement in terms of the data that
> they were showing us to do this\--these nice maps of
>
> how many insertion sites, what the structure is at each insertion
> site. So, that\'s what caused us some concern, and we really think
> that all that information needs to be in there. I would also point out
> that, in the 2001 pre-market biotech notification proposed rule, it
> says in this paper that was handed out today that it\'s just an
> extension of the 1992 policy. But it really isn\'t because there\'s,
> in the Federal Register Notice, they said for the first time they will
> be requiring data, and the data that they\--part of the reason that
> they said that they were going to be requiring data is they said that
> the unintended effects that come from the random insertion, they
> called it insertional mutagenesis, because that can differ between
> different transformation events, the Agency said that they would
> require data on each separate transformation event, even if the
> vectors and plasmids used were the same, and the genetic background
> used was the same; that they would require separate data.
>
> We think this is a very positive thing,
>
> but we wonder whether the FDA is actually going to move forward with
> those rules, because I should point out that the molecular
> characterization data, for example, for the BT crops that EPA used in
> their safety assessment, they actually bridged, they allowed companies
> to use data from separate transformation events and have it go
> collectively.
>
> And\--so, we think that the data that should be required is that there
> should be complete molecular characterization of each line with
> respect to identity, stability, and unintended positional and
> pleiotropic effects. And the agency\--the components of a complete
> molecular characterization should, for molecular identity, would
> include for each transgenic or transformed line the total number of
> inserts; the location of each insert, whether organelle, chloroplast,
> mitochondria, et cetera, or chromosomal; the exact chromosomal
> position of each insert; the structure of each insert, whether
> duplicated, deleted, rearranged, et cetera; the complete genetic map
> of each insert, including all the elements\--the coding
>
> region, non-coding regions, marker gene, promoters, enhancers,
> enterons, leader sequences, terminators, T-DNA borders, plasmid
> sequences, linkers, et cetera, including any truncated incomplete
> sequences; also the complete nucleotide base sequence of each insert.
> And we also suggested that the base sequence of at least 10 kilobase
> pairs of flanking post-genomic DNA on either side o the insert,
> including changes in methylation patterns. The reason for this is
> because the prominent use of hyper-promoters, such as the CAMV-35S
> promoter.
>
> And the other main point I wanted to make is for determining molecular
> stability, we think there needs to be data on both functional and
> structural stability. And the functional stability should be the level
> of expression remains constant over time and over successive
> generations. And I would point out that just requiring Mendelian data
> is not good enough. For example, with the BT crops, there\'s a high
> dose strategy, and the high dose is defined as 25 times the LD-99. And
> so, if all you\'re doing, in some of the data that was submitted to
> the EPA, they would just say to show that something\'s stable, you
> just had to show that the trait still worked; that is, that it still
> had activity against these insects. Well, if you\'re talking about a
> high does being 25 times the LD-99, you could have variability, and
> one trait could be 20 times lower and only have 5 times the LD-99 of
> the cryoprotein in there. But if you did a simple bioassay with
> caterpillars, you would find that 99 percent of them still die. That
> is, you couldn\'t see the variability there.
>
> So, that\'s why we think that for structural stability that the FDA
> would need data on the physical location of the insert in the genome,
> as well as on the structure of the insert throughout the lifetime of
> the plant and over successive generations, say, three to five
> generations. And, particularly, to look at that structural stability,
> we think there needs to be data on the flanking sequences, so you can
> see whether it\'s moving around inside the plant or not,
>
> because we noticed that those kind of data were not submitted for the
> majority of crops that have gone through this process. Of the 54 crops
> that\--54 things that have gone through the FDA\'s process, I believe
> only two of them have gone through since 2001.
>
> And finally, for the other form of stability, we think that the
> FDA\--I\'m sorry\--to look at the tests for unintended positional
> effects, we believe the FDA could carefully look at methylation
> patterns of genes in the flanking host genome DNA. And that\'s, again,
> 10,000 or 10 kilobase pairs upstream and downstream of the insertion
> site.
>
> So, in sum, we think this is a very positive movement that the FDA is
> proposing, but we do have the question of whether these data, which
> they say are going to be required through the PBN, since we hear that
> that\'s going to fall off the radar screen, not be on category list A
> or B, whether the FDA will be requiring all these data that they said
> they will in the future. Thank you.
>
> CHAIRMAN BUSTA: Thank you. Any burning questions? Just one.
>
> DR. SALYERS: I just want to make a comment about this. Monsanto must
> love you, because if that grocery list is actually enacted as
> obligatory, it\'s going to make it even harder for small companies to
> get into the biotech; and for developing countries who follow our
> lead, even though they\'re not bound by our requirements to develop
> their own products.
>
> So, I just think that we need to be careful about\--it\'s always
> appealing to add on another item to the long list of existing ones.
> But the question is, is there a reason to do it? And are we doing
> anything but further increasing the power of the big companies in this
> area?
>
> DR. HANSON: Well, my response to that is I think that all we\'re
> asking for is the kind of data that has now been agreed upon
> internationally; that are actually\--it\'s in paragraphs 30 to 33 of
> this Codex document that was agreed upon. And the reason that this is
> important is, written into the
>
> GAT agreement, which set up the World Trade Organizations, if there is
> disputes between countries, they\'ll look, written into the GAT
> agreement is, indeed, Codex Alimentarias is considered the neutral,
> scientific standard. So the concern we have is that some other
> countries could pass laws saying that they require all the data that
> is mentioned in here, and then they could turn around, and since this
> data is not required in the U.S., they could exclude products coming
> from the U.S., saying that they don\'t meet this standard.
>
> So, we\'re not suggesting that further data should be added. We\'re
> asking that the FDA require the level of data that has now been agreed
> upon internationally so that there is not a problem with trade,
> potential trade impacts with products that come from the U.S. Because
> you should know, most of the world did agree that these safety
> assessments should be required. The U.S. does not require that at this
> point. So, that\'s why\--we\'re not asking for extra data that will
> overly burden
>
> developing countries. It\'s just the data that has been agreed upon
> globally.
>
> CHAIRMAN BUSTA: Now, it\'s Dr. Salyers.
>
> DR. SALYERS: Abigail Salyers. Sorry, I didn\'t hear\--
>
> CHAIRMAN BUSTA: Dr. Qualset. Go ahead.
>
> DR. QUALSET: Okay, it\'s Cal Qualset speaking. It seems that if the
> developers are developing a product for U.S. markets, then why would
> they be required to get data that isn\'t essential to the evaluation
> of the efficacy of the product in terms of food safety? If the
> developers want to go to international markets, they can follow the
> international standards. But why make everybody fall into this,
> whether it\'s a small university, a small company, or large company? I
> think it should be clear that we have to evaluate for the product
> safety, and not necessarily all the ins and outs of its development.
>
> DR. HANSON: Well, but I think a response to that is the main crops are
> engineered right now, corn and soybeans and cotton, are actually used
> a
>
> lot in international commerce and are submitted\--if this is only
> something used within the U.S., then that could be a different story.
>
> DR. QUALSET: What I\'m thinking is that there are people considering
> doing modifications to minor crops that may not ever get into the
> export stream, and they can\'t afford to go through all of this for a
> crop that will be sold to small farmers, for example.
>
> CHAIRMAN BUSTA: Dr. Fedoroff.
>
> DR. FEDOROFF: Nina Fedoroff. I guess my question is, could you say
> there\'s data from the literature that would suggest that this
> information that you think should be made mandatory is predictive
> of\--is useful in predicting unintended consequences that affect food
> quality?
>
> DR. HANSON: I can get back to you on that. There is\--all I can say is
> that there was a lot of data that was talked about at these Codex
> meetings, and part of the problem is you have to know what you\'re
> dealing with before you can start to figure out what the safety
> implications are,
>
> right? And so, with the unintended effects, since that\'s actually a
> new field, and there was a huge discussion at Codex. There\'s quite a
> number of paragraphs on that. They\'re talking about these
> metabolomics and the use of genome arrays. And I think that\'s useful,
> but I agree with the other scientists here. The basic problem is how
> do you take, once you\'ve identified all those differences, how do you
> then figure out what the safety implications of them are. But before
> you can figure them out, you have to know what they are.
>
> CHAIRMAN BUSTA: Dr.
>
> DR. FEDOROFF: Yeah, but my question to you was how does accumulating
> all of these sequences and methylation patterns help you identify what
> the safety\--that the food quality implications are?
>
> DR. HANSON: Well, I can point to studies in the scientific literature
> with yeast and actually with tobacco where there have been unexpected
> effects that have led to toxins that were not previously present in
> the plants or to
>
> things that have an\--would have an adverse effect on DNA or other
> things, I mean.
>
> DR. FEDOROFF: That\'s what I\'m asking for. Could you cite those
> references?
>
> DR. HANSON: Yeah, I can get those. One of them is Enos and Eurata. I
> mean, we can talk afterwards. I mean, I do have a list of those
> various studies that I can get to you\--
>
> DR. FEDOROFF: Please do.
>
> DR. HANSON: And I will submit them.
>
> CHAIRMAN BUSTA: Dr. Gurian?
>
> DR. GURIAN-SHERMAN: Yeah, I guess one issue in terms of\--
>
> CHAIRMAN BUSTA: Introduce yourself. No, introduce yourself.
>
> DR. GURIAN-SHERMAN: Oh, I\'m sorry. Doug Gurian-Sherman. I think the
> economic issues kind of go beyond, you know, what we\'re supposed to
> be talking about here, and I don\'t think we\'re qualified to really
> even talk about them, because there\'s\--you know, we could get into
> all kinds of sidetracking to discuss those. For instance, you
>
> know, for pesticides, where there\'s a minor crop issue to getting
> pesticides for minor crops comparable to this with biotech, there\'s a
> set-up system that is not as effective as it could be but could be
> stronger called IO4 that probably a lot of your are familiar with to
> help small companies and minor crops get through the system. So I
> think we\'re just getting into areas that are way beyond what we need
> to be talking about here, which is the safety issue.
>
> CHAIRMAN BUSTA: We\'ll take one more question. Go ahead.
>
> DR. KAPUSCINSKI: I\'d like to ask a question.
>
> CHAIRMAN BUSTA: Would you give your name?
>
> DR. KAPUSCINSKI: Anne Kapuscinski. It might be actually be better to
> ask this of Dr. Maryanski and of Dr. Hanson. I\'m assuming when I got
> this Codex document that these guidelines on paper here are the
> outcome of a very rigorous and intensive scientific discussion, and
> that there is science backing these up. So I\'d just like to get
>
> a sense of whether that\'s a reasonable assumption.
>
> In other words, when I read, you know, Item 30 in this, \"in order to
> provide clear understanding of the impact on the composition and
> safety of foods derived from recombinant DNA plants, a comprehensive
> molecular and biochemical characterization of the genetic modification
> be carried out.\" And then when I read the stuff below it, I mean it
> looked to me like a lot of thought had gone into figuring out what
> should be considered and what is not that crucial to consider. And I
> think it would be useful if our committee doesn\'t try to second guess
> another scientific process that was, you know, broadly viewed as being
> scientifically based. So I\'d just like to get a sense from Dr. Hanson
> and Dr. Maryanski about that.
>
> DR. HANSON: Yeah, I\'ll point out first and Dr. Maryanski say anything
> else he wants. But as part of the Codex process, what they did is the
> first year there was a request for five questions on safety. And they
> asked that an expert
>
> consultation be set up, and one was set up and happened in June of
> 2000. And so, a big technical report came out of that. They then at
> the end of that technical report said, well, there\'s actually the
> question of allergenicity. There is new data which suggest that the
> present methods aren\'t good enough. And so they suggested holding
> another expert consultation on allergenicity. That was held in January
> of 2001, and came up with an excellent report and recommendations. And
> then there was a third joint expert consultation that happened in
> October of 2001 that looked at safety assessment for foods
> derived\--produced using recombinant DNA microorganisms. And those you
>
> can\--all of those expert consultations, the papers that fed into
> them, and the reports, they\'re all up on Codex\'s and FAO\'s and
> WHO\'s website. And yes, there was a huge amount of scientific
> consultation that went into those, and that ultimately is showing up
> in this Codex document. So I would say look at the results of those
> three expert consultations.
>
> CHAIRMAN BUSTA: Dr. Maryanski, anything to add to that?
>
> Dr. Maryanski will respond when he gets to the summary statement.
>
> DR. ASTWOOD: Thank you. This is Jim Astwood. I have a question for
> Michael. When I read the discussion paper from the FDA, they basically
> concluded that, in the FDA\'s opinion, that their proposals and
> guidelines were\--and practices\--were consistent with the Codex
> guidelines. And listening to your list of suggestions, it was not
> completely clear to me which suggestions you had that were above and
> beyond the FDA practice. I did detect two, and I wanted to be sure I
> had those two correct. And if there are others, I\'d like to know
> them. The one I detected was your suggestion that the methylation
> pattern should be determined. And the second was you suggested that
> there should be 10 KB of flanking sequence determined. Were there
> others?
>
> DR. HANSON: No, those are basically the two. Although I have a basic
> question. Since a few
>
> months ago, Dr. Lester Crawford got up on the Hill and basically said
> that they thought that the old, the 1992 policy, is fine, and they
> don\'t really need this new one. So I don\'t know what the status of
> this 2001 PBN is. If this is now going to be the new thing at the FDA,
> and all these data will be required, then those are the only two
> modifications that we would have to that. But I think it\'s still an
> open question since that hasn\'t been finalized, and we had heard 12
> months ago that it was going to be finalized in 18 months, and now it
> appears to have moved off, and who knows if it\'s going to be
> finalized. So I don\'t know what the FDA is going to be actually
> whether they\'re going to be requiring this. If it\'s true, then we
> applaud that, and, if it\'s consistent with Codex, then that\'s fine.
> But that\'s the one question I have to the FDA.
>
> CHAIRMAN BUSTA: I think, or it sounds like we\'re moving right into
> the discussion ahead of the discussion. So thank you, Dr. Hanson.
>
> DR. HANSON: Thank you.
>
> CHAIRMAN BUSTA: And we will now have the summary and review of the
> charges and questions by Dr. Maryanski.
>
> DR. MARYANSKI: Oh, I\'m sorry. Just a moment. Mike just needs to make
> a statement.
>
> DR. WATSON: Dr. Hanson was the only person who asked for public
> comment in time either before the meeting or on a sign-up sheet
> outside. So we\'re just going to move to the next agenda item at this
> point.
>
> DR. MARYANSKI: Jim Maryanski from FDA. Thank you. I just will take a
> couple of minutes here to provide a little bit of clarification. And I
> would like to thank Dr. Kapuscinski for raising that question about
> the information in the Codex, and what supported it, and Dr. Hanson\'s
> response because I realize that\'s something I need to add to my
> presentation are the expert consultations that FAO and WHO conducted
> that were\--that served as background material for the consultations.
> And those were very important; and, as Dr. Hanson pointed out, there
> were a number of them. There
>
> was one in 2000 that dealt with the question of overall safety
> assessment and the application of substantial equivalence. And then
> there was a session on allergenicity. And there was a session on the
> use of microorganisms to produce foods that Dr. Cebula and I actually
> did by video conference from Washington in the middle of the night for
> a week because of 9-11. But those consultations were part of the
> information. Now countries also brought forward information on their
> own part, based on their own experience, so they were not the only
> information that was behind the Codex guidelines.
>
> But the basic answer to your question is, at least from my perspective
> is I do believe that those guidelines are based on what the Codex
> member countries that participated in developing, understand, were the
> best science available at the time.
>
> I would also like to point out that the Codex guidelines are just
> that. They are guidelines. The Codex guidelines are not binding
>
> on any country, so they\'re not requirements. And they\'re guidelines
> in the sense that you should use them as they\'re appropriate. If
> certain information is applicable, it should be used. If, in some
> particular case, it\'s not, it would not. I mean, that\'s
> how\--that\'s the intent of guidelines. It\'s to provide a framework,
> to provide a general direction, always recognizing that some questions
> may be applicable and sometimes there may be questions that aren\'t
> within the guidelines that need to be added because there\'s some
> difference about the question at hand. So we always want to think of
> these not as a checklist that you go down, but as a tool that you use
> in the process.
>
> And in terms of requirements, whether the data is required or not, in
> our view at FDA, is not the question for this subcommittee, because
> what we\'re asking you to think about is if we\'re assessing the
> safety of a food, and, in this case, we\'re looking at specifically
> the use of molecular biology data, what data can contribute to
> answering the question about safety. So whether it\'s
>
> required by FDA or somebody else, or not required, is not the
> question. What scientifically will help us do our job. That is the
> question that we\'re asking you to think about in the context of how
> one can use molecular data to support safety assessment.
>
> Now, the question was raised earlier of how much is enough, which, of
> course, we\'re always asked. How much is enough, which is a difficult
> question. But that\'s why we\'ve established this safety standard that
> we\'re not trying to prove absolute safety. We\'re trying to get at
> the question is this new variety as safe as what went before it. Now,
> we don\'t expect the molecular biology piece of the safety assessment
> that you\'re talking about today to fully resolve that, because we\'re
> going to be taking into account all of the information that we have in
> front of us in reaching that final decision. But in thinking about how
> much is enough, how is this going to help put the pieces of the puzzle
> together so that ultimately you have that level of standard is I think
> what
>
> we\'re asking you to think about.
>
> The other thing we take into account, and it goes to some of the
> discussion this morning about the wrinkled pea, and the fact that you
> can see all kinds of changes in the plant, in the food, and they\'re
> not always relevant to safety. We, of course, ask companies to compare
> the new, modified variety with its parent or some comparable
> counterpart in terms of doing the analysis at various steps. But
> that\'s not the end of the game, because they often see differences
> between the modified and the parent plant at what the statistician
> would tell you is the 95 percent confidence limit.
>
> What we do ask, though, what\'s important is are those changes within
> the range that\'s typically of that plant, when that plant is produced
> commercially, has been accepted as a commercial food product. That\'s
> what\'s important, because we\'ve recognized that genetic background
> and differences in weather patterns and growth and stages of growth,
> and all of these things affect
>
> the composition of the food in different ways. So we have to ask the
> question is there a change that\'s outside the pattern that\'s been
> accepted as safe. So that\'s how we really look at the data in terms
> of food composition, which, of course, again is not the question
> we\'re posing for you today, which brings me to the study of the
> Academy.
>
> DR. FEDOROFF: You can start singing.
>
> \[Laughter.\]
>
> DR. MARYANSKI: Which brings me to the study of\--yes, I\'m sorry I
> don\'t have that kind of voice at all. But we have a study with the
> Academy on unintended effects, and that\'s a much broader study than
> what we\'re asking you to think about today. They are there thinking
> about the overall question of long-term effects and unintended effects
> on human health as a result of genetic modification. So today, to come
> back to what we\'re asking you to think about is this part of the
> safety assessment that deals with the molecular biology data, and how
> that data can help us better understand questions related to the
> safety of the
>
> food as part of the overall safety assessment process. And that would
> include, for example, how can this data be used to generate\--to
> identify new substances that may be in the food, because one of the
> questions we\'ll ask is if there are new substances in the food, are
> they safe. The obvious question. But you may also be thinking about
> the fact of gene insertion in the genome, and at the molecular level.
> Is there data that will help us understand? To what extent can we get
> at the question of other effects in addition to the introduced
> substances that may be important to safety assessment.
>
> So, we\'re not asking you to take on the whole issue of unintended
> effects, but really it is how can molecular biology help in this
> process. That\'s what we\'ve asked you to do today. I\'m just looking
> at the Chairman.
>
> CHAIRMAN BUSTA: Dr. Fedoroff.
>
> DR. FEDOROFF: You could help us.
>
> CHAIRMAN BUSTA: Dr. Nina Fedoroff.
>
> DR. FEDOROFF: Nina Fedoroff. Sorry. You
>
> could help us a lot by telling us how these different kinds of data
> have helped you so far, if they have helped you. In other words,
> you\'ve collected, if not all of this\--these different flavors of
> data, some of them; right?
>
> DR. MARYANSKI: Mm-hmm.
>
> DR. FEDOROFF: Have, in any case, they helped you assess the food
> safety?
>
> DR. MARYANSKI: Well, I think I can give you an example I think that
> Dr. Cebula referred to this morning. Early on, you know, that\--there
> was a basic mantra that what you used the TI insertion process; that
> the information\--the region between the borders is what goes into the
> plant, and the region outside does not. And when we actually asked
> CalGene to look closer\--you may recall from the flavor-saver meeting,
> when they actually did the PCR outside the region, where there is an
> antibiotic resistant marker on the backbone of the plasma, they found
> that actually an insignificant proportion of transformation events
> that material from the backbone\--in other words, the biology was
>
> not as precise as just the borders. It was\--were occasions when that
> material would be transferred. And, so, then, companies then did begin
> to look at the inserted material to be sure that it was introducing
> the material that was intended.
>
> So this information can be very helpful in that sense, because that
> allowed us then to eliminate the question of having to look at that
> other antibiotic resistant marker; and, you know, did that need to be
> considered.
>
> And, so, there are certainly examples where this helps. We found it
> very helpful, for example, using some of the blotting techniques to
> identify the presence of transcripts, as you heard this morning, to
> find out are they the transcripts that are expected or are we also
> seeing other transcripts, and then have to sort of ask the question of
> are those meaningful or not. Or Westerns to get at the question of how
> much protein or what proteins are being produced.
>
> So, there certainly is information at the molecular level. And one of
> the things I have told
>
> people in many talks around the world is that, you know, we often hear
> about plants being developed by R-DNA as new plants, a new technology,
> and these new things are coming. But, in fact, it\'s the molecular
> biology techniques that have given us much more powerful tools in
> terms of safety assessment. In other words, being able to understand
> the changes that have been made at the molecular level so that we can
> identify the new substances in the food, so we can decided whether or
> not they pose any safety problem.
>
> I think, and certainly if any our other colleagues here, you know,
> feel there\'s another point, they can put up their hand. But I think
> that\'s the crux of, you know, what we\'ve been seeing in the
> molecular biology data.
>
> Now, I would add to that we have also asked companies to look at the
> stability. And the stability, as I understand it has been to address
> the question of unintended effects down the line, as these plants
> are\--you know, will be bred, of course, by conventional means and
> further
>
> developing the cult of ours, the idea being if the initial insertion
> event has been done in a way that that\'s stable in the chromosome,
> that once that plant then is put into the normal breeding process and,
> as breeders do, and bred into a number of different lines, that any
> changes that will then take place afterwards will not be due to that
> insertion event, but will be the normal kinds of changes that take
> place through the other methods of plant breeding.
>
> I\'d suppose one of the other things we\'ve looked for is how many
> insertion sites there are, just to get at the question of what\'s the
> likelihood of recombination events occurring, as well.
>
> So, that\'s\--so, yes, we have found some of this. We felt some of
> this information has been useful. But, again, you know, we\'re not
> here to tell you what\'s useful. We\'re really asking you, from your
> perspective, what do you think will continue to help us.
>
> DR. FEDOROFF: I guess what I\'m hearing is
>
> that you found that the T-DNA transformation or whatever
> transformation is messier than you thought it was. But what I didn\'t
> hear you say is how any of those things have actually helped you
> identify a food hazard, a problem. Okay? A real problem that you said,
> okay, like the potatoes with\--high
>
> glyco\--high solanine potatoes. Okay, that\'s a real problem. You
> don\'t want it to get out in the marketplace. And I guess what I\'m
> asking is, in all of the cases that you have analyzed, did this
> information allow you to identify some such problem coming up the
> pike?
>
> DR. MARYANSKI: It kind of gets to the question we\'re often asked of
> how many times did we say no to a company. How many times did we, you
> know, reject a submission because there was some problem with it.
>
> DR. FEDOROFF: Well, there\'s probably\--
>
> DR. MARYANSKI: And we really haven\'t done that, and the reason is
> because the guidelines and these questions that we set out really help
> the companies to, you know, basically make sure that
>
> the products that they have don\'t raise any of these questions.
>
> So, I think it\'s not so much a matter of FDA finding the problem, but
> everyone now understanding what the questions are so that the problems
> can be avoided, and generally are avoided. I mean, we did have the one
> example of the Brazil nut in soybean that, of course, turned out to be
> an allergen. But, otherwise, no, I don\'t know of any cases where we
> have identified a problem.
>
> DR. FEDOROFF: A problem.
>
> DR. MARYANSKI: Yes.
>
> DR. FEDOROFF: By using those particular molecular markers.
>
> DR. MARYANSKI: Right.
>
> DR. FEDOROFF: Okay.
>
> CHAIRMAN BUSTA: Dr. Arias.
>
> DR. ARIAS: Jonathan Arias. I think perhaps the answer to that question
> was given earlier by the number of applications that have been
> submitted so far to the Agency, which I believe were about 50 over the
> last several years
>
> for safety assessments of transgenic plants. Most likely, there are
> just too few examples to get a sense of the probabilistic issues of
> safety, and I assume companies and developers as good stewards are
> already screening those that show potential problems in terms of
> agronomic traits right off the board. So, you wouldn\'t likely see
> examples of those.
>
> I do want to also point out there is, of course, one highly
> contentious example in the public and the scientific literature in
> regards to the safety of genetically modified foods that would, I
> think, impact our discussion: that is, of course, the study by I think
> it\'s Rowers and Hustive in the Lancet a number of years ago. The
> conclusions of that study, of course, have been highly debated, and
> I\'m not going to redress them here. But they do raise the potential
> issue, and I think that\'s what we\'re really dealing with
>
> today\--is the potentialities for risk, given that certain processes
> may be mutagenic or altered the metabolic profiles of plants. And
> there are
>
> also\--the other fact is that there\'s clearly an end point to this,
> which is predicated on time, money, and other issues in relationship
> to the public safety concern.
>
> And, so, I think those have to be factored into this, as well; that
> the discussion hopefully will focus on the fact that what are the
> potential risks that might be likely given certain circumstances
> implicit in genetic engineering.
>
> CHAIRMAN BUSTA: Dr. Gurian.
>
> DR. GURIAN-SHERMAN: Doug Gurian-Sherman. I guess I\'d have to ask a
> further question in terms of the kind of data that we\'re being asked
> to look at today, and further on Nina\'s question is, of the
> submissions that you\'ve actually looked at, what percentage of them
> actually looked at the
>
> specific\--some of the specific kinds of data that, let\'s say,
> Michael Hanson mentioned or that are mentioned in the Codex, such as
> potential for fusion proteins, potential insertion mutagenesis into an
> open reading frame\--that kind of thing. Because, again, my awareness
> is that, at most, a
>
> very small minority of the submissions actually had that kind of data.
> So, I\'m not sure that there\'s a very\--much of a data set on those
> specific questions. And I think, you know, to go a little further, I
> think the general potential issues are just that\--are we inserting
> something into a gene that may have an effect. And, again, it\'s a
> potential risk, and I think part of what we have to think about is
> what, you know, what kind of potential risk is there from an insertion
> mutagenesis, or for activating several upstream or downstream genes.
> It\'s a, you know, that\'s the potential risk that I think we have to
> address is how much should be done; how much is it worth, you know,
> pursuing.
>
> CHAIRMAN BUSTA: Jim.
>
> DR. ASTWOOD: Jim Astwood. I have a comment or an observation based on
> Dr. Maryanski\'s response that of the 50 or so petitions that have
> been reviewed by the FDA, certainly there have been no cases of safety
> issues being raised on the basis of molecular information. And he
> indicated that
>
> that\'s not surprising because there are a lot of screening activities
> done by companies, and surely that\'s the case.
>
> But as a matter of safety, I would say that, as a practical matter,
> the molecular characterization has led to very few decisions, at least
> in my company, about moving a product forward or not forward to the
> FDA. And the reason for that is that those unexpected effects, those
> pleiotropic effects that Dr. Gurian has mentioned are readily apparent
> when you do agronomic evaluations and compositional analyses by
> chemical evaluations, nutritional studies in animals. That is the way
> you pick up the unexpected effects. And so, it\'s not surprising that
> nothing has come to the FDA. Likewise, companies really are not using
> that as a criteria from a safety assessment point of view. And
> that\'s\--that gets to a comment about whether we need\--whether
> we\'re operating at a phenotype level or a genotype level, and is the
> characterization of the insert a matter of responsible information or
> is it truly a decisive study in terms of is the
>
> product safe or not safe. I think it can be decisive, but it\'s\--so
> far, it has not been our general experience that it has been a
> decisive study or a pivotal study.
>
> CHAIRMAN BUSTA: Dr. Kapuscinski.
>
> DR. KAPUSCINSKI: Yeah. Dr. Maryanski, I have a question that I
> think\--
>
> CHAIRMAN BUSTA: This is Anne Kapuscinski.
>
> DR. KAPUSCINSKI: Anne Kapuscinski. We have a\--I think actually will
> follow from what Dr. Astwood was just saying. I wanted to ask a really
> elementary question. When you\'re asking us in our charge about
> molecular biology data, are you using molecular biology in the
> narrowest sense to just asking us for data at the level of DNA and
> RNA? Or are you including the expression, expressed protein? Because I
> guess the way I\'m looking at this is that I would want to start with
> some level of the phenotype of the organism, ideally, knowing what\'s
> useful about the proteins expressed, and then higher level organismal
> traits, people often refer to those as agronomic traits; and then
> maybe
>
> use that to guide me. If I see something that raises a red flag, to
> guide me and to try and figure out if I need to get more information
> to figure out if it\'s really a risk. And maybe, at that point, some
> of the DNA- and RNA-level information might be useful. And I\'m saying
> might because in some cases, it might not be that useful. I seems like
> down the road, if we got the point that we knew that every time we
> noticed a certain class of proteins being expressed, that it gave us a
> certain kind of signal on a DNA chip, then, in the future, you could
> maybe just rely on the DNA chip data early on in your production of a
> engineered plant to quickly identify that. But we\'re not really at
> that point yet, because we haven\'t yet been able to do those kinds of
> correlations. So, I\'m trying to get a better sense of really what
> you\'re charging us to do, because I feel that it\'s not going to be
> very useful for us to limit our discussion only to DNA and RNA
> information. It feels to me like that\'s just looking at that stuff in
> a vacuum. When, really,
>
> what\'s going to drive whether the thing is safe or not is the actual
> phenotypic consequence of changes in the DNA that\'s being transcribed
> and actually then what happens with those RNA transcripts.
>
> So, how narrow or broad would you like our discussion to be of your
> charge?
>
> DR. MARYANSKI: Well, I think we don\'t want to\--
>
> DR. KAPUSCINSKI: You see what I\'m getting at?
>
> DR. MARYANSKI: Well, we\--what we would like to do is have you focus
> on the part of the safety assessment that can be gleaned from
> molecular data. So, in other words, we\'re not asking you to take on
> all the pieces of safety assessment and evaluation. For example,
> we\'re certainly interested in what happens at the gene level and the
> expression of message in protein. We feel confident about evaluating
> the safety of substances once we know they\'re components of food. If
> a protein is identified as it\'s going to be in food, then we feel
> that we have the capability
>
> today to do that. That\'s not the question that we\'re posing to you
> of how do you ultimately, then, determine if that protein is safe, for
> example.
>
> So, yes, the expression of the message, the expression of the protein,
> there\'s certainly some things that we would hope that you would talk
> about. But, you know, I don\'t want to place limits on what you, this
> subcommittee, might decide are issues that you think are important for
> FDA to think about from data that can be gleaned at the molecular
> level. I would prefer to leave that to your deliberations.
>
> We\'ve put down a set of questions as a way of giving you some of the
> things we\'ve been thinking about. They are not intended to be things
> that we absolutely need answers to or the only things that you should
> think about. But this is intended to be guidance so as to get you
> started at least in an area that we have some question about.
>
> CHAIRMAN BUSTA: You know we could keep you up there for the next two
> hours, and see how\--
>
> DR. MARYANSKI: No. No.
>
> CHAIRMAN BUSTA: To see how resilient you are.
>
> DR. MARYANSKI: I appreciate the opportunity, Mr. Chairman. I think
> I\'m done. Thank you.
>
> CHAIRMAN BUSTA: But what I\'d like to propose is that we go around the
> entire group\--it\'s been a normal group technique of each one
> expressing some of their thoughts. This is not the final discussion,
> but limiting it to no more than maybe about five minutes of where you
> see us at this point. How you would suggest we address our charge, and
> your thoughts on some of the issues that we\'ve been given.
> That\--knowing how time slips, that will probably take us to at least
> a bio break. And then we can come back and do a conclusion-type
> discussion of one-by-one, sometimes called the vote, of where you see
> the committee\'s comments should be going. If it appears that there\'s
> a significant consensus, at that point, we can try and summarize then.
> If it looks like it\'s a number of individual comments, they will go
> in as
>
> that.
>
> Is that acceptable for an approach?
>
> All right. I\'ve always had a problem. Those of you that know
> Meyers-Briggs, I\'m at the
>
> E-level, at about 99 percentile on E. And, so if you lose me every
> once and while because of the laughter next store, these external
> inputs really distract me. I\'m trying to focus real hard, but I just
> want to go over to see what\'s funny.
>
> \[Laughter.\]
>
> We can start in one way. I\'ve started one there, one time there. Jim,
> would you like to start?
>
> DR. ASTWOOD: Gosh. I can start. I mean, I\'ve made a couple of
> comments. I think that in reacting to the issues that\'s presented in
> the charge from the FDA, I would say that certainly I would agree that
> the FDA\'s proposals and practices are consistent with the Codex
> guidelines. One of the things that I continue to struggle with in the
> safety assessment realm is really this question of how impactful
> molecular characterization is to the
>
> safety assessment. We can talk about theoretical fusion proteins. We
> can talk about theoretical rogue transcripts, a lot of things. What I
> tend to come back to is the overall risk assessment and all the other
> tools that we bring to bear. And whether or not that we lose sight of
> those tools when we are thinking about molecular characterization. I
> mean, specifically, Dr. Arias brought up the Pustai example. And for
> those who aren\'t too familiar with the Pustai example, Dr. Pustai and
> colleagues in Scotland evaluated a number of transgenic potato lines
> that were transgenic for lectins. And they showed, and there\'s some
> debate about this, but superficially they showed that these potatoes
> were, in fact, toxic to rats. Toxicologists debate that point, but
> let\'s accept that as a fact; that they were, for the sake of
> argument.
>
> Can one predict on the basis of the molecular characterization of
> those potatoes that those potatoes would have been toxic? Probably
> not. Except to say that a lectin was expressed in potatoes, and
> lectins are known to regulate gene
>
> expression of plants; and, so, perhaps it could have affected other
> genes. It turns out, in that case, that those potatoes were not
> compositionally equivalent to traditional potatoes. And, so, in this
> case, those potatoes would have failed a key test in the Codex
> guidelines or the FDA process, which is that those potatoes fall
> outside the range that one would expect for the composition and
> nutritional profile for potatoes. And that would raise concerns that
> would have to be addressed in the FDA process or in the Codex process.
> You could not have predicted that knowing the molecular arrangement of
> the lectin gene in the potato plants. And, so, for examples that we
> know about from the literature and from our own experience as
> producers of this technology, those tend to be highly pivotal studies
> versus the molecular characterizations.
>
> So, when we think about the broader debate, there\'s probably no end
> to the amount of characterization one can do. One has to make a
> decision about how much risk you leave on the table
>
> in terms of the compositional analytes you measure. How much molecular
> characterization you do. How many animal feeding studies you do. How
> many toxicology studies you do. You\'re always leaving a little bit of
> risk on the table; and the key question, therefore, is when do you
> meet the standard of reasonable certainty of no harm for the FDA. And
> I think the FDA has done a very good job of describing scientifically
> backed internationally supported lists of criteria for molecular
> characterization that I think is rational. But someone needs to
> articulate exactly I think, or in some more precise ways, when you
> will need to do actually more than that. It\'s not clear to me that
> you do.
>
> And, so, it\'s a question to ponder. It\'s probably bigger than this
> one meeting, but I\'m sure as we move forward, we\'ll have
> opportunities to ponder it in the future.
>
> CHAIRMAN BUSTA: Dr. Gonsalves.
>
> DR. GONSALVES: In analyzing the papaya, we actually maybe have some
> unique experience in
>
> that we went to the FDA guidelines back in 1996; and we actually have
> also\--are moving through the guidelines for Japan, which, more or
> less, follows these Codex rules. And so, we\'ve had to analyze in much
> more detail the papaya than we\--now than we did in 1996. And my
> general conclusion is that more or less what we knew about\--what we
> knew in 1996 based on previous history of viral coat protein and so
> forth\--what we analyzed in getting more data did really not add much
> more to what we knew back in 1996. And it\'s not surprising to me.
> Like either the question of allergenicity, I know there was a report
> saying that this papaya ring spot may be allergenic and so forth. But
> with all the history of eating virus-infected papaya for years, and we
> deliberately instantly inoculated millions of trees with a mild strain
> of the virus and sold those papaya commercially with no impact on
> allergenicity. I was almost certain that our transgenic papaya was not
> going to be allergenic.
>
> Now, should I have, at that time back in 1996, sequenced
> the\--analyzed the amino acids and
>
> then checked the susceptibility of the co-protein to pepsin or other
> stuff. Well, that remains debatable. We did not do it. But I think the
> preponderance of data was such that we really did not have to do it.
>
> Now, getting back to another tack, I think there\'s obvious areas in
> which we have to pay attention to alkaloids and so forth. But I also
> think that sufficient data have come forth that there are areas in
> transgenic plants\--for example, viral coat protein resistance. Well,
> that is a major thing to many people that produce crops. It appears to
> me that in that kind of case, it might be a lot of the data that have
> been accumulated, we may be able to recommend just a few maybe key
> tests or analysis of the protein that might suffice so that you don\'t
> have to go through a lot of all of these other tests.
>
> Now, with a lot of the other stuff, I would think you definitely want
> to go through that, because they are definitive, well-documented
> things that could happen.
>
> CHAIRMAN BUSTA: A compliment. Two people have automatic timers. They
> were in four minutes, four minutes apiece. I\'m impressed.
>
> Dr. Kapuscinski.
>
> DR. KAPUSCINSKI: Thank you. I would actually. I would appreciate
> having more time to reflect on this, like, you know, and speak again
> after hearing everyone. But my thoughts right now are the following:
> first of all, when resources and time are limited I guess I\'d rather
> see more effort into characterizing the proteins than in to the DNA
> and the RNA, because I think that alone is not\--if we focus only on
> that level, I\'m just really worried about losing the forest for the
> trees, if we focus only on that level.
>
> And it seems like the big challenge is looking for pleiotropic
> effects. That\'s where our level of understanding, whether you\'re a
> quantitative geneticist and have done traditional breeding or a
> molecular geneticist, that\'s where our level of understanding is
> really very poor. And I don\'t see right now how only doing stuff at
>
> the DNA level is going to really increase our chances of detecting
> pleiotropic effects. So, if someone comes up with a way that combining
> those methods with some protein-level analysis and even higher level
> phenotype analysis that might hint at a pleiotropic effect, if they
> find that using DNA methods could help in screening for that, then
> that would be great. But I\'m personally not aware of some kind of
> screening like that right now that\'s helpful. So, and I don\'t have a
> really detailed advice about what FDA could do to do a better job of
> looking for pleiotropic effects, but I think that would be a really
> good topic for this committee to maybe examine in more detail. And,
> again, you don\'t want to look for pleiotropic effects just ad
> infinitum and for ever. You would want to be very targeted and
> strategic in searching for that by using the kinds of ideas that Dr.
> Gonsalves just talked about. There are clearly certain kinds of
> organisms, such as potatoes and tomatoes, or we know already there are
> some metabolic pathways that might cause some problems
>
> if they get upregulated, for example. So, especially if a developer is
> using a construct that does not have tissue-specific expression, you
> know, then that might raise the desire to look more proactively for
> pleiotropic effects. And, if they\'re putting it in a kind of plant
> that there is some history of knowing that there are some chemicals,
> biochemicals in that plant that might cause a health risk. So, in
> other words, you\'d want to combine things like that. So I guess I\'m
> more interested in taking a more integrated approach to it.
>
> My final thought, just to reemphasize something I said earlier in the
> question-and-answer period, is I could see that maybe five years from
> now if there\'s some well targeted research that\'s conducted to help
> this, that you might reach a point where you could find some DNA
> signals that would be strongly positively correlated with evidence of
> something at the protein level that is a problem. So then it\--maybe
> five years from now, you could use the DNA-level screening as a first
>
> cut kind of early on way of testing. So it wouldn\'t be if a DNA
> itself is the problem, but it\'s positively correlated with some
> levels of changes in protein expression or even secondary, no probably
> not secondary metabolites, but changes in the levels of expression or
> certain genes getting turned on that, you know, turn out to pose
> problems. But I don\'t have a sense that we\'re at that point today.
>
> CHAIRMAN BUSTA: Three out of three. Timing is great. Dr. Buchanan.
>
> DR. BUCHANAN: Yes, I\'m willing to follow that perhaps in a little
> different way. First of all, there are far greater experts in DNA, the
> area of DNA stability than I am, and DNA rearrangements. But I have,
> in the past few years, our group has embarked on studies with
> proteomics, and I\'m very impressed with the power of proteomics. I
> hope we\'re not in the formative stage that half of what we\'ve found
> turn out to be artifacts, as referred to earlier.
>
> But we\'ve discovered things that would
>
> have taken years before the advent of proteomics. That\'s why I was
> interested in the Mendel, the pea experiment, with proteomics.
>
> And, I think as time goes on, we will have maps of major crops called
> proteome, as we now have for arabidopsis. There\'s a group in France
> that\'s developed that, and it\'s a very nice website with many of the
> proteins. We are developing the same in collaboration with the USDA
> laboratory in Albany for the endosperm, the wheat endosperm. And one
> can see with great precision when a protein is different. And I think
> with time, whether the time is right for this now, whether the
> technology is at that stage, but one can compare the genetically
> engineered plant with the null segregant, the protein content of the
> organ or tissue of question.
>
> And I think one can see the differences, as we\'ve seen with the
> Mendel peas. And 62 proteins is not a great number now to identify
> with the common methods.
>
> And I think one might pick up interesting candidates, and it\'s not a
> great expense for most
>
> companies, either, or will not be.
>
> And then one, I would have to think it about it more, but one could go
> further and look at subsets of proteins like gylcosylated proteins,
> populations within the null segregant and within the genotype of
> interest. And I think with this, it would be reassuring without undue
> labor and undue costs to convince one of the safety of the particular
> product. But, as I say, I think with the\--in the future, this is
> going to become very common, and we\'re going to have proteome maps of
> certainly the major food crops.
>
> CHAIRMAN BUSTA: Dr. Salyers.
>
> DR. SALYERS: Well, basically, I don\'t have to take much time because
> I\'m going to\--this is Abigail Salyers. I\'m going to underscore what
> Dr. Kapuscinski said. I think that it\'s important to\--at least as I
> interpret\--as interpreted through me, I think it\'s very important
> that there is some flexibility in this, in the FDA\'s response to new
> products that come through the pipeline. I think it\'s a very bad idea
> to have a shopping list that
>
> is applied uniformly to everyone for the simple reason that there are
> some cases in which there are problems that might be missed that way.
> And, for example, we know the cases\--all of these come from
> traditional practices, where we have seen people produce foods that
> actually made it to the supermarket that were toxic at some
> level\--have been. The alkaloids have been the problem.
>
> So, it makes sense in certain foods where we know that that is a
> potential problem to look at the alkaloid levels in anything that
> people mess around with genetically. And, so, I try\--I guess there
> are those of us who trust the FDA, and those of us who don\'t.
>
> I trust the FDA, their intentions and the abilities of their
> scientists; and, therefore, I\'m willing to accord them a certain
> amount of flexibility. I think it\'s a big mistake to\--I think we\'re
> fooling ourselves if we talk about taking DNA sequence information at
> our current level of understanding and extrapolating too far from
> that, because I don\'t think that we right now
>
> have the information that would allow us to do that. And, so, you get
> yourself the illusion of safety when actually it\'s not there.
>
> So, I argue for an approach that is one that has a certain amount of
> commonsense, based on knowledge about the individual type of plant and
> the way it will be consumed, the uses of which it will be produced;
> and structures a regulatory program for that particular areas. And I
> wish we could build that kind of flexibility into anything that is
> done rather than having certain set lists of things that are applied
> uniformly to every example.
>
> CHAIRMAN BUSTA: Thank you. Dr.
>
> Gurian-Sherman.
>
> DR. GURIAN-SHERMAN: Yeah, I\'d like to build on a couple of the
> comments here. I think the comment that Jim Astwood made was a good
> one that, you know, these things all have to be looked at in a broader
> context of the overall risk assessment, and I think Dennis also
> addressed that. There\'s differences between types of genetically
>
> engineered organisms and probably the inherent risk in them.
>
> And I guess I would also agree with Abigail that there needs to be
> some flexibility to address those differences.
>
> I guess the concern I have is that, in part, that I\'d like to see
> more of a system that does both, that tries to, where possible, and
> where there is an issue with the types of tests and the protocols,
> that there is some guidance, some specific guidance given, but in the
> context of broader assessment of the risk of the plant. I mean we
> certainly do know that some of the protocols\--there\'s been
> experimental data, and I don\'t think the characterization issue is
> necessarily the best one to address this\--but where differences in
> protocols make differences\--result in differences, practical
> differences in the result, and probably in genetic engineering the
> best one, at this point, is with pepsin digestion, which is part of
> the allergenicity assessment, where an FDA scientist varied the
> conditions of the
>
> experimental protocols, and came up with very different results in
> terms of how you might interpret the allergenicity of a GE protein
> based on its stability.
>
> So, I think it is important that there\'s some\--in some cases, some
> uniformity.
>
> On the specific issue here, I guess I\'m going to go back a little bit
> on what I said before in terms of economics. The\--there\'s a lot we
> don\'t know, and it\'s not predictive about sequence data. But, on the
> other hand, we\'re developing more and more, through genomics,
> databases of proteins that have, to some extent, known functions. And
> I think that has to be weighed with the, again, in part how difficult
> is it to get this data, and I guess I agree, although on a slightly
> different issue, with Bob that some of this data is not that difficult
> to get. The sequence\--DNA sequence, which then can be translated in
> the protein sequence of the inserted DNA in the plant is not very
> difficult or expensive to acquire. Now, is it going to tell us
> everything? No. There\'s a lot of things it\'s not
>
> going to tell us, and there\'s always the risk that when somebody sees
> a difference, that they\'re\--you know, that they\'re going to
> interpret that as being a significant difference in terms of safety,
> which will often not be the case. I think we have to have a little
> more confidence that when we have that kind of data, that we get what
> we can out of it in terms of looking at homologies with allergen
> epitopes or looking at homology in toxin databases or allergy
> databases to see if potential changes through the transformation of
> that or insertional mutagenesis or fusion proteins do, you know, tell
> us anything. But again, I think that has to be weighed with, against,
> you know, how difficult is it to get this data. And I do share the
> concern that, you know, this kind of analysis could go on forever, ad
> infinitum, and I\'m certainly not pushing that. But I think in this
> particular case, you know, some of the types of data we\'re talking
> about\--getting Northern blots, you know, to look at expression of
> flanking sequences, that kind of thing is not, you know, that
> difficult; and may,
>
> may, in some cases, reveal some useful information.
>
> So, again, I think, you know, the point that\'s been brought up
> before. You have\--it does make sense to weigh how difficult is this
> data, and then how useful is it.
>
> I guess the final point I\'d want to make is that, you know, Nina had
> a good point earlier I think that, you know, there is often a lot of
> data floating out there that can be useful if we try to gather it
> together. I haven\'t seen enough. I\'d like to see more of what we
> might be able to find out with some of this data. In other words, how
> predictive are secondary protein structure models. Or, you know, that
> if you see a difference in the structure of\--the sequence and
> structure of the protein how much can we, you know, derive from that.
>
> So, I think we\'re also, you know, working a little bit blind here,
> and working at the last minute trying to digest a lot. And I think it
> would be useful to try to pull together some of that data before we
> make any kind of substantive
>
> decision on this, or recommendation.
>
> CHAIRMAN BUSTA: Dr. Qualset.
>
> DR. QUALSET: Yeah, I\'m Cal Qualset, the token plant writer, to
> emphasize my point.
>
> The issue I am hearing is what I would call mostly dealing with
> development stage information. It\'s molecular data that\'s useful in
> the development of the product, and maybe not so useful after it\'s
> into the evaluation stage for FDA.
>
> That doesn\'t mean it\'s not important, because I believe it\'s useful
> in developing the guidelines and the protocols that the developers are
> using to know that they should be looking for certain inserts and that
> sort of thing. So
>
> that\--what I am hearing is that I\'m not sure that that information
> can be translated into safety and risk.
>
> Now, Bob talks about proteomics, and once we know what a protein does
> and structurally, that it might be related to some undesirable effect,
> then we can use that information. But we need that
>
> kind of trait-based linkage to the molecular structure.
>
> So, what is safe and what is not safe? What do you know about that
> question when you are doing molecular characterization. So that\'s a
> question.
>
> I\'d like to think we are talking about consumer oriented evaluation
> of safety, food safety, and that we should be looking at, very
> carefully, the ways the product can be used, whether it\'s in
> traditional food preparations or unusual food preparations. And some
> of the products may be targeted to specific components of the
> population.
>
> If that\'s the case, then we need some post-release identity issues,
> and there may be, Bill, some molecular characterizations there that
> can be very quick and prove that you, in fact, are looking at the
> variety as it was released. Labeling it comes up in that context,
> however.
>
> So, those are the issues I think we have to think about if we\'re
> talking about molecular,
>
> value molecular characterization in evaluation of food safety. I think
> the connection is tenuous in many respects, I think.
>
> CHAIRMAN BUSTA: Thank you. Dr. Benedict.
>
> DR. BENEDICT: Steve Benedict. I have sort of in front of me some
> fairly hastily scribbled airplane notes that, as I was reading the
> documents on the way out here, and they turn out to be for me, anyway.
> And I want to agree with almost everybody\--what they said. It seems
> to me that genomic evaluation has a couple of values, but they\'re
> fairly limited. And one thing I don\'t think can help us is any kind
> of array technology. I really can\'t see how the effort and expense we
> have to go through to get that analysis is going to tell us anything
> at this point. And what everyone has said is, yeah, ten years from
> now, we might be able to know some things.
>
> I also agree that the real relevance here with respect to safety is
> something a toxin. Is something an allergen, or is something doing
> something odd that we can\'t predict. And, as a
>
> couple of people have said, except for things that I don\'t
> understand, like, non-proteinaceous materials, which have to be done
> by compositional analysis. The proteins that we\'re putting in, we\'re
> going to know going in, based on databases is this an allergen, is
> this a toxin, or is it related to them, and so that will require
> considerations. But if it doesn\'t do any of those things, then we
> have to ask questions about changes in the proteome. And I agree with
> Dr. Buchanan, this is a powerful way to go.
>
> And, so, I think that we could end up with an iterative process, a
> decision tree where FDA asks before the projects begins even, is your
> gene of interest an allergen or a toxin or a related sequence, 80 base
> pairs or 80 amino acids, whatever that thing is. If it isn\'t, well,
> go thou forth because you don\'t have a problem yet.
>
> And, so, then we ask questions based on the proteome. If you put your
> protein into a cell, a tissue culture cell just to find out will the
> presence of that protein change the proteome in any
>
> way. And, again, you\'re only talking\--you\'re not talking about
> looking at wrinkled versus turgid peas. You\'re really
> asking\--you\'ve got an organism. You\'re changing one protein in it.
> So, does that have secondary effects on other proteins. You can ask
> that quickly with a two-D gel, and if you don\'t see anything, okay,
> now you go engineer your organism. And, so, you ask these questions
> back and forth, and none of this, I think, is particularly expensive
> with the possible exception of tissue culture, which I don\'t
> understand in plants. And, so, looking\--following the changes in the
> protein seems to me the place to go, and there are always places to
> bail out.
>
> Then when you get to the point of analyzing the vector, that\'s
> already been said. The real question for me there is how strong is
> your promoter, and are you doing, as Dr. Arias said, have you selected
> some tissue-specific promoters like we do in animals. And if you can
> do that, then that helps you also. And so, this can be part of a list.
> And then, once you\'re
>
> transfecting\--I\'m one of the early 1994 proponents of learning about
> upstream and downstream sequences. But that was before we could look
> at proteomes and determine what\'s going on. And so, again, if you
> have no problems, then we don\'t need to I think ask many of the
> questions. The relevant question with the genome to me is, how many
> insertion sites are there, because that gives you the chance of
> homologous cross-over, and that could mess up your plant, big time, I
> guess.
>
> So, if you ask that question, and the answer is you don\'t have that,
> then again, you could go forward. It seems to me that we don\'t to
> apply everything all at once. We can apply them at the stepwise,
> logical fashion, but always based on what proteins are being
> expressed, not necessarily what data we can get. But what\'s possibly
> going to cause the problem.
>
> And I think I have one other point. Give me a second. How am I doing?
>
> CHAIRMAN BUSTA: You\'re doing fine.
>
> DR. BENEDICT: Oh, you\'re so gracious.
>
> CHAIRMAN BUSTA: Everybody\'s doing so fine, I can hardly stand it.
>
> \[Laughter.\]
>
> DR. BENEDICT: So to sum it up, I think we have to concentrate on the
> proteins or some compositional analysis that tells us that something
> has been changed; and if, as we go through the steps nothing has been
> changed, and if FDA works with the producers all along, then it could
> be a very painless process. And Dr. Gonsalves brought up a question at
> lunch, and that is what about the small guy who maybe can\'t afford to
> do this. There can be a cut-off, an economic cut-off, the size of your
> company, and why not have FDA, as he suggests, do a simple two-D gel
> and analyze it with\--I can\'t use a company name\--with a series of
> database, and send it back to them. Help them out.
>
> I think you can do it, and I don\'t think it\'s such a big deal.
>
> CHAIRMAN BUSTA: Okay. Dr. Arias.
>
> DR. ARIAS: Jonathan Arias. It\'s wonderful being at the end of a long
> line of
>
> distinguished speakers because I can be truly brief and say I concur.
> I just will add a few additional points.
>
> I think, really, all of the comments that have been made are right on
> the mark, and, in particular, we need to recognize a couple of things
> that is that the state of the art is intrinsically flawed. Most of the
> techniques, even in measuring changes in gene expression, may not
> predict deleterious effects for human health. That\'s the state of the
> art.
>
> Yet, we still have to deal with the risk management aspects of that.
> And so it to be prudent, clearly some of the specifics that have been
> outlined in the draft guidelines that we\'ve received for this
> subcommittee make good sense.
>
> Looking at changes in the gene itself, the transgene, its insertion
> site, and any attendant effects, like translocations of the genome in
> which it\'s inserted, would be prudent, because, clearly, we want to
> avoid any untoward effects that are not anticipated.
>
> And, so, I would say that the state of the art still precludes many
> advanced analytical techniques, which have been raised by various
> members of this subcommittee, such as functional proteomics, which I
> do believe, in the future, will probably provide enormous insight, yet
> currently lack the predictive power to tell us about what, again, are
> the risks that changes in protein expression would engender to the
> consumer.
>
> Given that, I would like to propose a slightly different tact in this,
> and that is, a proactive one taken by the FDA and the developers. And
> some of my points, perhaps my thunder has already been stolen by
> various subcommittee members, and I welcome that; but I think some of
> the points that I\'m about to make seem very prudent indeed.
>
> As we know, in certain cases, expression of the recombinant protein in
> the food or edible portion of the plant raises red flags in and of
> itself. As the state of the art in plant gene expression has advanced
> enormously over the years,
>
> as evidenced by numerous publications, the use of tissue-specific
> promoters, as Dr. Benedict mentioned, would seem a very good prospect
> for redirecting expression in those cases where it can be done of a
> recombinant protein to those tissues that it needs to be targeted to,
> preferably those that may be outside of the human food chain.
>
> However, we also recognize that coming through the pipeline, no doubt,
> are modifications which will affect the sort of nutriceutical portion
> of the plant, the edible portion of the plant. And, in those cases,
> clearly a different level of analysis may have to be done. So, we
> could see a decision tree that would readily distinguish, just on the
> basis of the promoters that drive expression of the product, different
> types of decision trees. And, so, that would give a different type of
> balance entirely.
>
> The second point is related, in a sense, to the first, or as a
> consequence of that; and that is that most of the promoters that are
> currently used to drive expression of recombinant proteins
>
> inplants are strain viral enhancers, which drive very high expression
> often of the recombinant protein and do so typically in a somewhat
> constitutive manner throughout the plant. Again, more targeted
> approaches I think would be prudent for the future, would alleviate
> concerns by consumers, as well as scientists to review the expression
> patterns of these, and would at least take up, perhaps in many cases,
> the problem out of the food chain, which is the strict focus of this
> committee.
>
> So, I would also encourage us to think proactively in terms of what
> types of technologies are in hand now that could be recommended to
> developers in the future to help them in creating a better, safer
> product that would conceivably raise less problems and less red flags.
> Thank you.
>
> CHAIRMAN BUSTA: Dr. Fedoroff.
>
> DR. FEDOROFF: Last, but not least. I am an expert in genome
> rearrangements, having worked on transposed lines. T-DNAs don\'t move.
> And some of the problems we\'re taking, we\'re suggesting are
>
> the purview of FDA are really the problem of the developer. It\'s a
> problem for the developer if there are genomic rearrangements and
> recombination events, which, by the way, are quite rare in plants;
> that is, ectopic recombination events between homologous sequences
> located on different chromosomes. If that messes up the chromosomes,
> the developer will see that and throw that away long before that
> plants gets to the point at which it\'s ready to come here.
>
> So, I think that already the amount of information that is being
> required about the inserts is probably more than we really need given
> that they have so little predictive value. I can tell you\--I probably
> couldn\'t quantify it. I could quantify it, more or less, from people
> who have put together insertional databases in arabidopsis. But the
> bottom line there is that rather few of the insertions affect the way
> the plant develops and reproduces, which is what plants do.
>
> So, the probability that there will be a huge accumulation of
> insertions that happen to
>
> affect just that part that we use as food is very low. I think there
> are other places we should be looking. I think at the biochemical
> level, we know what the problem compounds, whether they\'re proteins,
> alkaloids, lipids, or secondary metabolites, we know a lot about that
> for different kinds of foods. That\'s where we should be looking.
> Sometimes it\'s at the\--at the level of proteins, but it certainly
> isn\'t always at the level of proteins. So, the tests should be
> relevant to what\'s known about the history of toxic compounds or
> allergenic compounds in the food.
>
> Okay. Something that Dr. Gonsalves I thought would bring up but
> didn\'t bring up is asking for information that\'s relevant to the
> particular modification. The RNA-based inactivation processes minimize
> the effect of the protein. So, if you have a viral coat protein gene,
> basically what you\'re doing is shutting down the translation of that
> gene, because you\'re destroying the RNA. We didn\'t know that 10
> years ago. We know that today. You will see on the web
>
> lots of commentaries about how terribly allergenic the\--what is
> it\--the papaya ring spot viral coat protein is. But the fact of the
> matter is that the mechanism by which the coat protein gene confers
> immunity to the papaya minimizes the production of that coat protein
> gene. And, by the way, the evidence that it\'s allergenic is so thin.
> I\'ve just been reviewing some of those papers, and it\'s simply
> approximally \[sic\] eight amino acid homology between it and another
> coat protein. And someone was commenting, I think it was James at
> lunch, that we now have a very large database of allergenic proteins,
> and the probability that two
>
> homologous\--two proteins will cross react that are not homologous,
> with the same IGE, is pretty small at this point.
>
> So, those are the kinds of data we should be incorporating into our
> assessments. But I think at the level of DNA characterization, there
> maybe isn\'t much to be gained. There\'s not any indication that I\'ve
> heard from anybody that you can even point to one instance where the
> particular
>
> site of insertion passed through all of the tests that the developers
> put the plant through, whether it\'s back crossing or simply growing
> out, and then suddenly a problem was revealed when one looked at the
> food.
>
> The probability that you will uncover food issues at the DNA level is
> much smaller, it seems to me, than looking at either specific proteins
> or the biochemical composition of the food.
>
> So, I would strongly urge us not to extent the amount of molecular
> evidence that we\'re asking for at the moment, but to ask that the
> kinds of data that the FDA requires be relevant to the kinds of
> compounds that have proven problematic in those foods.
>
> And my final comment-I\'m probably way over my time\--
>
> CHAIRMAN BUSTA: That\'s all right. But you\'re doing a nice job of
> summarizing. Keep going.
>
> DR. FEDOROFF: Okay, the one thing that I wanted to add to Dr.
> Astwood\'s summary of the
>
> Pustai problem is that it\'s really important for people who have an
> animal background and a plant background to come together on these
> issues. I think that\'s what went wrong in that case, because what he
> saw was nutritionally different potatoes, never mind that rats didn\'t
> like them, but. And he concluded that it was something about the
> recombinant DNA that was different because his control was potato plus
> lectin, okay. And that was the wrong
> conclusion\--what\--that\--but\--probably. I mean, you wouldn\'t know
> that unless you went back and did the experiments, which are hard
> experiments. And that is, to ask why kind of variability comes out of
> tissue culture. And that\'s something that many animal biologists
> don\'t know. But in plants, most of the processes that we use
> currently, not all of them, but most of them for introducing genes,
> involve a de-differentiation of the plant tissue into something that
> doesn\'t even look like a plant, and then regeneration of that. Now,
> that changes methylation patterns. That changes things, both
> transiently and stably.
>
> All the different kinds of stable genetic mutations\--single-base
> changes, insertions, deletions, translocations\--have all surfaced in
> those regenerated cells. That\'s one of the first things that happens
> in a breeding program. You throw them\--and that\'s actually been
> used. It\'s called somaclonal variation. It has been used to evoke
> more variability, but then you have to sort through the garbage and
> throw away the garbage.
>
> So, the point is that you can\'t simply transform a gene into a tissue
> culture cell, analyze the protein composition, because that isn\'t
> necessarily what you\'re going to get out of it.
>
> One, and the plant that you get out to begin with, if you begin to
> backcross it, you will get rid of the other junk you\'ve accumulated,
> which we\'ve actually never worried about when we used radiation to
> induce variation. That is very much more less specific, and introduces
> a lot more damage. And, yet, the whole breeding process, and its
> multiple generation\--I don\'t think it\'s
>
> been\--it\'s probably reduced to\--how
>
> many generations do you typically do now?
>
> DR. ASTWOOD: I\'m sorry.
>
> DR. FEDOROFF: In your breeding programs?
>
> DR. ASTWOOD: Before going to the marketplace?
>
> DR. FEDOROFF: Correct.
>
> DR. ASTWOOD: It could be as many as 10.
>
> DR. FEDOROFF: Okay. So, it\'s not really much less than was
> classically used.
>
> There\'s\--there\'s ten generations of backcrossing, which gets rid of
> other junk, okay, that might have happened.
>
> And, finally, rearrangements, is the basic stuff of plant change. Even
> closely related varieties differ from each other by insertions,
> deletions, rearrangements. That\'s a constant process. So, the notion
> that we have a genome that can\'t be disturbed is an illusion. It\'s
> an illusion in people. It\'s an illusion in plants. The phenotype is
> what\'s important, whether you\'re looking at the biochemistry or the
> way the plant grows and reproduces.
>
> End of lecture.
>
> CHAIRMAN BUSTA: As the ultimate novice here, compared to the rest of
> this panel, in
>
> my\--not sufficiently alert or listening to the singing next door,
> I\'m not sure what it was. But there seems like there\'s a great deal
> of consistency here, a great deal of agreement. Did I miss something?
>
> Gee, it\'s going to be sort of dull.
>
> \[Laughter.\]
>
> DR. FEDOROFF: You can make a difference.
>
> CHAIRMAN BUSTA: As I was listening through this, I\'m hearing that as
> we looked at our charge, and as some of the things have, saying
> scientifically what will help FDA do their job, what I\'m hearing is
> that they shouldn\'t put a lot more effort into the genetic
> assessments sequencing, et cetera, than currently going on. And what I
> heard was that no changes in the genetics may not really
> indicate\--may not identify a possible food safety issue if it might
> exist, but that an awful lot of food safety issues that might occur in
> the biotechnology never get very far
>
> because they disappear in the development; that the development takes
> care\--rules out essentially all of that.
>
> DR. FEDOROFF: It depends on the plant.
>
> CHAIRMAN BUSTA: Depends on the plant.
>
> DR. FEDOROFF: Some are crossed, and some are not.
>
> CHAIRMAN BUSTA: Okay. The changes in proteins, and I heard proteomics
> a lot, and these new techniques get awfully exciting. Now, I heard
> that we\'re on the edge of that yet, and we still got a lot to learn.
> We may not\--don\'t want to get the chip upside down.
>
> DR. BUCHANAN: That hasn\'t happened.
>
> CHAIRMAN BUSTA: That hasn\'t happened yet. But did I hear that if you
> detected a change in the proteins in some way, it wouldn\'t
> necessarily be allergenic; it wouldn\'t necessarily be a food safety
> issue. But if there weren\'t any changes in the protein array, if you
> would, that we\'re fairly sure that there isn\'t a potential food
> safety issue.
>
> DR. KAPUSCINSKI: Oh, I think we need to talk about that a little more.
>
> DR. ARIAS: Are we talking about the complement of plant proteins
> encoated by the genome, in addition to changes in the recombinant
> protein or apart from?
>
> DR. KAPUSCINSKI: I think in addition to. I mean, and that\'s part of
> why I was stressing pleiotropic effects. You know, or things such as
> the promoter ending up driving the expression of another gene that\'s
> somewhere downstream. And, you know, rather than trying to deal with
> that by figuring out how to look at it at the DNA level, which is
> fraught with problems. My understanding is that through the kinds of
> techniques you\'re using, if it really did drive the expression of a
> protein that either is not expressed otherwise or at much lower levels
> that your methodologies have the potential to reveal that.
>
> CHAIRMAN BUSTA: In sequence that was
>
> Arias\--
>
> DR. ARIAS: Arias, again. My concern is
>
> there isn\'t enough information yet, except in a well few well
> characterized conditions or states to identify a change in the
> expression of an endogenous protein with a specific effect. In fact,
> you know the metabolomics of plants is still in its infancy, even in
> the model plant arabidopsis has a lot to go before a full
> characterization occurs. So, perhaps that\'s something that when we
> get to that level, it can be done.
>
> But I\'m concerned about the issue of
>
> post-translation changes in the plant of the recombinant protein as a
> more significant issue; and that this is something I think that can
> and should be perhaps be readily addressed by developers because of
> the potential for changes in plant due to post-translation
> modifications that might conceivably alter the biochemical properties
> of the recombinant protein. So, in most cases, when recombinant
> proteins are expressed and tested, they\'re done so in heterologous
> systems, like yeast or in bacteria, frequently.
>
> And, in that sense, their bioactivity
>
> might differ significantly from that expressed in the plant because of
> intrinsically different metabolic reactions that lead to
> post-translational modifications in different plant cells and tissues.
>
> So, I think a complete characterization at the biochemical level of
> the recombinant protein in plant is probably just as important as
> looking at changes in gene insertion and mutagenesis events, because
> those changes in post-translational effects could, at least, act as a
> red flag for thinking about what the bioactivity properties might be.
> And this is certainly not beyond the realm of current technology, such
> as mass spectroscopy, where proteins that have been purified can be
> completely sequenced in many cases, and their
>
> post-translational modifications can be analyzed.
>
> So, I think that it would behoove us to think specifically as well
> about those effects as they relate to bioactivity.
>
> CHAIRMAN BUSTA: Dr. Astwood.
>
> DR. ASTWOOD: This is Jim Astwood. I wanted to reinforce and agree
> completely with what
>
> Dr. Arias just said about the importance of full characterization of
> the protein as it\'s expressed and manifested in the plant. Although
> it\'s basically out of the scope from the questions we ask here,
> conventionally what developers do is, in fact, a complete
> characterization of the protein as produced in plants. They typically
> purify from the plants, sequence it, look for post-translational
> modifications, the good glycosylation, if present, look at
> bioactivity, if it\'s an insecticidal protein, look at enzyme activity
> and enzyme kinetics, if it\'s an enzyme, and carefully compare that to
> the e-coli material, which is typically used in safety studies. So
> there\'s usually a significant investment in the characterization of
> the actual transgenic protein. And so I think that\'s an extremely
> important point. But I also think that is what we are doing.
>
> DR. ARIAS: I\'m sorry just one additional comment. I believe that is
> true, but I think that the realm of analysis still needs to go that
> extra step. I know glycosylation is looked. I don\'t
>
> believe phosphorylation, for example, is typically done so, although I
> may be wrong on this. And there are other post-translational
> modification states, as well as proteins, that may be equally
> relevant. Given the high analytical capabilities of mass spec these
> days, it seems like this would be a technology that is already
> available for applications for these types of things. And it\'s also
> highly sensitive.
>
> CHAIRMAN BUSTA: One, two, three.
>
> DR. BUCHANAN: Bob Buchanan. Yes, I just wanted to add one minor point,
> and that is I think proteomics has the capability to pinpoint
> unintended effects. For example, if we see new proteins, we don\'t
> know what all of them are, we don\'t know what all of the secondary
> products, or natural product pathways are, which might form toxicants.
> We know many of them, and, with time, we\'ll know most of them.
>
> But I think we can identify potential problems. I think it\'s very
> unlikely that they\'ll arise. But the capability to identify them is
>
> present or soon will be.
>
> CHAIRMAN BUSTA: Dr. Gurian?
>
> DR. GURIAN-SHERMAN: Doug Gurian-Sherman. Yeah, I wanted to reiterate
> Dr. Arias\' point about the importance of post-translational
> modifications. I think his laying out the testing kind of protocols
> and using bacterial surrogates is very accurate. And, but I\'m not,
> again, you know, I hate to keep harping on this point, but I have
> looked at a number of the actual studies. And there\'s a lot of
> variation in the extent of analysis of post-translational effects. And
> that was one of the issues that came up, for instance, with StarLink,
> which was a major protein, and the committee of allergists and
> immunologists and others that looked at StarLink concluded that they
> were uncomfortable about Aventis is the company that produced that
> crop. Their analysis of the glycosylation state or the cryo 9 C
> protein. So, there\'s an example where, you know, there as a group of
> scientific experts that have a lot of experience with that, and
> glycosylation can be
>
> importance for a number of reasons, especially immunological reasons.
> It has, you know, there is some association between glycosylation and
> allergenicity, among other things.
>
> So, again, you know, I think all the specific points about the issues
> that we\'re dealing with and discussing are important. But, again, you
> know, I have to come back to the point about how studies are actually
> done; what\'s actually looked at in practice; or what\'s at least
> what\'s submitted to the agencies\--maybe, you know, companies are
> doing more than what they submit\--and the bearing that that has on
> the rigor of the results.
>
> So, it\'s a little bit different issue. But I\--you know, I think
> it\'s still very important that that be considered more carefully.
>
> CHAIRMAN BUSTA: Dr. Benedict?
>
> DR. BENEDICT: Steve Benedict. Just a couple of loose comments. One is
> that with a properly done two-D gel, and other associated things, you
> can pick up post-translational modifications pretty readily. And I
> come back to
>
> this. It\'s not that I would advocate that the
>
> two-D gel could tell us everything that\'s going on. They could pick
> up the difference between the parent plant and the progeny plant. And
> that\'s all I was sort of suggesting, which was to echo what Dr.
> Buchanan said; and, that is, if you find the difference, then you go
> to mass spec, you find out what that protein is, and you ask yourself,
> is this likely to be a problem. It will be a problem either because
> it\'s a toxin or an allergen, or it will be a problem because it\'s
> misdirecting some metabolic pathway that you can now learn about
> because you know what the protein is. And so that\'s why I\'m pounding
> on this a little harder.
>
> We can tell phosphorylation differences with a Western blot and the
> right antibody. That\'s trivial almost.
>
> The other thing for Dr. Fedoroff is, when I mention plant tissue
> culture, the sort of statement I didn\'t make clearly was that my
> argument was that if you have a tissue culture, and you put a protein
> in there, if there is a change in
>
> the proteome there\--admittedly, you can\'t predict anything about the
> plant, you can\'t predict anything else, but you can ask the question
> whether that protein that you\'ve introduced can alter gene expression
> levels, can alter the pathway of some expression pathway. And if the
> answer is no, then you have good information that that protein itself
> introduced into the plant that it\'s going to be in is not by some way
> likely to soak up some metabolic pathway protein and cause a shift in
> gene expression. That was sort of the question that I was trying to
> address.
>
> CHAIRMAN BUSTA: Dr. Fedoroff.
>
> DR. FEDOROFF: That\'s actually a harder question to answer than you
> might think because it\'s not impossible, but, basically, it\'s a
> given that different tissue culture lines have different
> modifications. It\'ll shut down genes methylation at exchange. Lots of
> junk happens, okay? So, in order to ask whether it\'s that protein
> that you introduced that\'s doing whatever it is that you picked up
> with your proteomics, you really have to
>
> use one of these site-specific recombination systems so you can excise
> the particular gene and say, okay, is it still there.
>
> So, that\'s doable, but, again, the criterion of the plant growing it
> back, and then asking the questions after you\'ve cleaned up your
> background, which is basically what breeders have always done, is more
> relevant to the food safety issues than asking whether tissue culture
> messes up stuff.
>
> DR. BENEDICT: But I think I\'m still not being clear. I really didn\'t
> care, in my question, what happened to the plant at that point. The
> question is, is the introduced protein, all by itself, regardless of
> future phenotypic changes, is that protein capable of doing something
> to the metabolic milieu that causes a rearrangement of gene
> expression.
>
> DR. FEDOROFF: And what I\'m trying to tell you is that it\'s harder to
> tell, to distinguish that from random changes that happen as a result
> of tissue cultures, than you might think, because the
>
> tissue culture itself is evolving. So, if you culture cells for long
> enough, you can\'t even regenerate plants from them.
>
> DR. BENEDICT: Really, we\'re only talking about a few hours, you know.
>
> DR. FEDOROFF: Well, no.
>
> DR. BENEDICT: A day or so.
>
> DR. FEDOROFF: We\'re not talking about a few hours. This is getting
> very technical, but we\'re not talking about a few hours.
>
> CHAIRMAN BUSTA: I\'m going to take two more, and then we\'re going to
> take a
>
> biological\--three more\--and then we\'ll take a biological break.
>
> DR. ASTWOOD: Jim Astwood. I wanted to pick up on the proteomics
> conversation, because it\'s a fascinating one, and share with you a
> bit of my own experience. I have a Ph.D. student who actually is at a
> proteomics conference tomorrow presenting data from arabidopsis,
> Twelve Different Varieties of Arabidopsis, with a View to Can You
> Detect Differences from One Variety to the Other. And, of course, you
> can. Of the 850 proteins
>
> identified, over 300 vary from one accession really of arabidopsis to
> another. And, so you start getting a sense of the variability in the
> proteome. And that really gets to Dr. Maryanski\'s comment early. When
> we do compositional analyses, it\'s actually insufficient in a risk
> assessment context to do a head to head comparison between the
>
> so-called isoline and the actual transgenic product precisely for the
> reasons that Dr. Fedoroff mentioned, which is that, because of
> somaclonal variation and the actual underlying genetics of most crops,
> you can very rarely find a true genetically thing to do the
> comparisons from. So, you actually have to do a comparison to a
> population, and so you have to understand what\'s the range in the
> population before you can actually do these kinds of experiments. And
> so, at a technical level, I think we\'re at the frontier, and that
> there\'s some opportunity that proteomics could be of value. I\'m not
> sure when that will be, but, as we talk about applying proteomics, it
> seems to that before we apply such technology, in addition
>
> to all the ground work we got to lay in terms of understanding it, we
> also need to ask ourselves, what incremental public health protection
> are we actually achieving by the application of that technology or a
> different technology or a new kind of toxicology study. Usually, in a
> regulatory context when you apply a new methodology, it\'s because
> you\'re attempting to address a risk that your current assessment does
> not address. So, as we contemplate those technologies, I think we need
> to understand what risks we are not currently addressing by the range
> of studies that we\'re already using. Until we know what those are, I
> think it\'s premature to really talk seriously about applying
> proteomics or any other kind of technology until we understand that
> safety context. So, it is two things. There\'s when is the technology
> really ready to use, and then what is the public health benefit of
> using the technology. And for me, proteomics isn\'t there yet, but I
> think it\'s an attractive area to work, as Bob mentioned and others.
> And, in fact, we\'re working on it, and I
>
> know others are.
>
> So, it\'s a tough area.
>
> CHAIRMAN BUSTA: Dr. Gurian-Sherman.
>
> DR. GURIAN-SHERMAN: Yeah, I think getting back to\--those are some
> good points that Jim makes that, you know, may be something that
> requires further development to be able\--and I think there\'s
> been\--this point has been made a number of times to interpret changes
> that are very likely to be seen. I think addressing both, you know,
> Nina\--Nina\'s point and Dr. Benedict\'s point that it seems to me
> that what we\'re concerned about is the risk of the plant, you know,
> both the genetic material, its products, and the overall\--the whole
> plant.
>
> And there would probably be\--certainly be more appropriate to look at
> it after whatever backcrossing has been done for the last, you know,
> maybe whatever is typical\--one centimorgan of DNA, flanking DNA, that
> will remain after backcrossing. But, be that as it may, it\'s still,
> even at that point, whatever risk still remains from both the insert,
> any linked mutations that might still be
>
> there is really, you know, ultimately the point. And can we get at
> that, and how much marginal risk is there. And that, I think, goes to
> Jim\'s point about what is the purpose or what would be the value of
> that. And I think, again, it goes back to the whole issue of
> pleiotropic effects and how much we do and don\'t know or what is
> predictable and not predictable about the safety of the plant and
> changes that can occur in the plant that may have deleterious effects.
> I think, again, you know, echoing what Ann said earlier, that\'s where
> there\'s a certain amount of lack of understanding. You know,
> without\--I\'m reluctant to even say this because I don\'t want to
> sound like I\'m looking for that infinite risk, which is really not
> the point I want to make. But, certainly, if we can improve the safety
> of the crop, looking at a genetically engineered crop, by new
> knowledge, and I go back to what Jim said earlier, you know, he\--we
> eat carrots all our life and maybe there\'s some incremental risk from
> eating carrots. We don\'t want to be paranoid about eating carrots.
> But, as we do find
>
> out new issues that can improve the safety of crops, I think, you
> know, even if we did not know them before, it\'s relevant to consider
> them, and there may be, you know, issues that we learn about
> pleiotropic effects that can have relevance.
>
> And I\'ll just bring up two, and there punitive cases, so, you know,
> again, I\'m bringing this up in the context of, you know, not real
> well established science. But there have been recent examples with
> corn, for instance, where some studies have been done with rodents,
> and I think it was ovarian, human ovarian cells, that discovered a new
> compound; and I don\'t remember the chemical compound. But it seems to
> have some estrogenic effect. Well, that wasn\'t known five years ago.
> How important is it? I don\'t know. It may be very irrelevant.
>
> There have been some recent compounds in wheat proteins that have been
> associated with the development of Type-II diabetes.
>
> The point I\'m getting at is there\'s still a lot we don\'t know, and
> that by, you know,
>
> improving our analysis of pleiotropic effects, we may be able to
> improve the safety of these crops, because there are compounds that
> may be expressed at very low levels now that we don\'t know much about
> that could\--that we shouldn\'t. I\'m not suggesting that we should be
> paranoid about those or not\--or overly concerned about those. But
> those are the kinds of things that proteomic analysis, you know, can
> ultimately get it. So, what I\'m trying to do is answer Jim\'s
> question. I don\'t think we\'re quite there yet. But there are, you
> know, questions that this technology could be relevant for. And, so,
> you know, I think it is something that needs to go forward and
> continue to be developed.
>
> CHAIRMAN BUSTA: Dr. Buchanan. You can conclude this portion of the\--
>
> DR. BUCHANAN: Oh, that\'s a rare opportunity. Yes, I just wanted to
> add one point to what Jim, and when I described what we were doing, I
> said we had compared the nulsegregant with the transgenic; and I think
> that\'s the best
>
> control. That\'s the\--it\'s gone through all the tissue culture
> treatment. It\'s just that the gene at point has segregated out.
>
> And when we have compared our plants in that way, we\'ve looked at
> seeds, we don\'t see differences other than the gene of interest, not
> great differences, anyway. We see very interesting developmental
> differences because of the protein we\'re looking at. But if we look
> at the chromosomal product, it\'s kind of like the twins. It\'s hard
> to tell one from the other. Go for it. Identical twin.
>
> CHAIRMAN BUSTA: A true geneticist. Yes. Dr. Fedoroff.
>
> DR. FEDOROFF: This came up at lunch, and I think it\'s a point worth
> making. Corn breeders look at agronomic traits. They never worried
> about the corn and the edibility of the corn. They never analyzed it,
> never looked at it. And as far as I know, they didn\'t do much damage.
>
> UNIDENTIFIED SPEAKER: They didn\'t eat it.
>
> DR. FEDOROFF: Huh?
>
> UNIDENTIFIED SPEAKER: They didn\'t eat it.
>
> CHAIRMAN BUSTA: I\--we will take a
>
> 15-minute break, and then we\'re going to come back, and we\'re going
> to try and come up with some conclusions and recommendations of this
> discussion. And then we will, after that summary, look at some of the
> future and the letter that Trudy generated, and look at other
> recommendations and future agenda items.
>
> \[Whereupon, the meeting went back on the record at 3:23 p.m.\]
>
> CHAIRMAN BUSTA: Our next challenge of the afternoon is to come up with
> a summary of what we\'ve discussed and what we feel we want to
> conclude on our charge.
>
> And I think as I was listening to this apparent consensus to me, that
> when we\'re talking about the molecular characterization of
> bioengineered food plants, and suggestions regarding additional
> information, I tended to hear that the genetic characterization
> that\'s being done right now is sufficient; that it\'s\--for the
>
> purposes of specifically food safety and our charge of scientifically
> how can we help FDA scientifically do their job, that identifying any
> more genetic information, any more sequencing, any more information
> than is already there would not enhance the assessment of food safety.
> Okay, I\'ve got two hands. So, that\--at least we started the
> conclusion.
>
> DR. GURIAN-SHERMAN: Okay. Doug
>
> Gurian-Sherman. I\'m not entirely clear on what we may have consensus
> about, but I think I dissent from that. And so, I just want to be
> clear about what I\'m dissenting from. I basically would agree with
> the Codex analysis. I certainly would also agree that, you know,
> potential unintended effects, such as changes in known toxicants,
> allergens, anti-nutrients, are probably, you know, more important on a
> risk assessment basis than the characterization of the gene. But I
> also have to put that in the context of, again, how difficult it is to
> acquire the sequence of the transgene and possibly some of the
> flanking sequences, at least
>
> whether there\'s an open reading frame that\'s been interrupted.
> So\--and I think while, you know, there are certainly a lot of limits
> in terms of how valuable that data is or can be, it can be of value.
> And, again, I just want to give one potential example. Small changes
> in\--we know\--most changes that may occur with the insertion of a
> gene are going to be deleterious. They are probably more likely than
> not to significantly reduce the effect, the intended effect, of the
> gene and gene product. And it\'s going to be the minority of the cases
> where there\'s going to be some change that causes some safety issue.
> But I think that has to be weighed against, again, the cost and the
> ease of getting that data and some of the kinds of things that can
> happen. We do know there\'s consensus sequences for, at least for
> M-glycosylation. I don\'t know if we know enough about
> O-glycosylation, the sequences involved.
>
> But some of these sequences are fairly small. Allergen epitopes can
> be, you know, four to five, six amino acids. So, sometimes small
> changes
>
> can be meaningful. Most of the time, these changes are not. But if we
> have the data, we can eliminate those issues where they\'re
> non-issues. If there seems to be an issue, then there can be further
> exploration. So, I guess what I\'m saying is I agree with the Codex
> assessment, and I think that has to be, again, put in the context of
> what FDA is actually getting. And, from what I\'ve seen, they rarely,
> if ever, get the sequence of the inserted gene in the plant or
> expression analysis of surrounding flanking regions, open reading
> frames or a sequence of those flanking regions. They may get it
> sometimes, but that\'s not the norm from what I have seen. So I think
> I need to be more clear on what there may or may not be consensus
> about.
>
> CHAIRMAN BUSTA: Thank. Kapuscinski.
>
> DR. KAPUSCINSKI: Yeah, I, during the break, looked again at the
> specific points on
>
> our\--in our questions and realized that one of the bullets under
> number two I wasn\'t sure I understood clearly. And that was a bullet
> about information on the organization of the DNA within the inserts.
>
> So, I was assuming that that meant that FDA is currently recommending,
> when a developer comes to them, that the developer provide information
> on the sequence, the complete sequence of the inserted construct. And,
> during the break, I ask Jim, and he seemed to indicate, Jim Maryanski
> seemed to indicate that they haven\'t specifically asked that from the
> past. So, if that\'s really true, then the one thing I would recommend
> is that that information would be useful because it seems like, today,
> it\'s fairly easy to get that data; and it\'s at least a first cut. If
> you think about taking the kind of iterative approach that Dr.
> Benedict was recommending earlier, and I really endorse that kind of
> approach, the sequence data would be a first cut at whether there are
> any predicted amino acid changes could then raise a flag or they might
> not raise a flag. You do have to then ask the next question: are any
> of those amino acid changes problematic? But this gives you at least a
> first cut at knowing whether you need to even ask that.
>
> So, I want to make sure that the people
>
> realize that the comments I made earlier when we went around the
> table, I was focusing my comments on the issue of should FDA go beyond
> this list to, you know, go into that whole universe of all this DNA
> array stuff and genomic stuff; and that\'s what I was sort of wanting,
> suggesting we sort of hold back on, and place the effort more at the
> biochemical and protein level. But that was with my assuming that
> they\'re presently encouraging developers to present complete data on
> the sequence of the inserted constructs.
>
> CHAIRMAN BUSTA: And how does\--without me looking, what is Codex say
> on that?
>
> DR. KAPUSCINSKI: I think Codex recommends doing that.
>
> UNIDENTIFIED SPEAKER: They recommend the sequence.
>
> CHAIRMAN BUSTA: The full sequence?
>
> DR. BENEDICT: I think so.
>
> DR. KAPUSCINSKI: Let\'s see\--
>
> DR. BENEDICT: I shouldn\'t say that, nodding because I think so, no,
> because I know so.
>
> DR. KAPUSCINSKI: Well, it says the characterization\--item 31 big
> \"A\" says the characterization and description of the inserted
> genetic materials. It\'s not really clear about\--
>
> DR. GURIAN-SHERMAN: \"C\" says the organization of the inserted
> genetic\--this is Doug Gurian-Sherman. The organization of the
> inserted genetic material, at the insertion site, including copy
> number and sequence data\--
>
> DR. KAPUSCINSKI: And sequence data.
>
> DR. GURIAN-SHERMAN: And sequence data of the inserted material and the
> surrounding regions sufficiently to identify, but then it also says or
> where more appropriate other information, such as analysis of
> transcripts, expression products, to identify any new substances that
> may be in the food. And then it goes on to \"D.\" So, yeah, and I
> would agree. If you have expression data that\'s more appropriate or
> can be shown to be more appropriate\--but it seems to encourage the
> sequence data of the insert.
>
> CHAIRMAN BUSTA: But what I also heard was
>
> that there was a lot of agreement with the decision tree approach of
> looking at a number of other things as well as the genetic
> composition.
>
> DR. KAPUSCINSKI: Yeah, my sense is that everyone\'s agreeing.
>
> CHAIRMAN BUSTA: Right. Yeah. Right. I guess I should have started with
> that, but, to me, that results in not really expanding what FDA is
> currently doing on the gene work.
>
> DR. KAPUSCINSKI: Well, but I think the devil is in the details. It
> would depend on what kind of information they\'re actually requesting
> or encouraging on the organization of the DNA within the inserts. If
> it\'s compatible with what\'s laid out here in the Codex guidelines,
> then fine. And if that is one of the steps on the decision tree,
> that\'s great. But if it\'s not compatible with what\'s in the Codex,
> then that\'s\--then I\'m not sure I would agree.
>
> CHAIRMAN BUSTA: What would you like to say there? I\'m just\--
>
> DR. SALYERS: Abigail Salyers. Just very,
>
> very brief. What I heard, and what I think is something that is very
> strongly to be recommended is that the full characterization of the
> gene product\--I mean, I think the sequence data may be nice, but I
> think it\'s an illusion to think that\'s going to give you the
> information you really want. And, so, that\'s\--Steve, you may have
> been the person who brought that up or Bob, I\'ve forgotten who. But
> that the protein product, if there is a protein product of the gene,
> needs to be very thoroughly characterized. I think that\'s being done
> or my assumption is that\'s being done already. Because that\'s where
> you\'ll see the glycosylation, phosphorylation and other, you know,
> any abnormalities that might have occurred during the cloning process.
>
> CHAIRMAN BUSTA: Dr. Arias.
>
> DR. ARIAS: To add on to the scope of the discussion relevant to the
> Codex document, I wanted to just get some clarification on the
> statement about\--under 31 C, where sequence data of the inserted
> material and of the surrounding region
>
> sufficient to identify any substances expressed as a consequence of
> the inserted material. There\'s another issue that is also relevant to
> the flanking region of the insertion of T-DNA, and I discovered that
> doing a literature search last week in preparation for this meeting,
> in which I found several papers that imply that T-DNA insertion
> itself, in addition to potentially being mutagenic by inserting into
> intergenic promoter regions or coding sequences can also induce fairly
> large, in this case up to 40 kilobase region, translocations between
> chromosomes. And, in the particular example cited here in Plant
> Physiology 2001, by Tax and Vernon, they show, using arabidopsis
> daliana as the model, that a significant region of one chromosome,
> five, was induced to translocate next to the transgene in response to
> the insertional event on a different chromosome. So, my question
> is\--I have no idea about the frequency of these events. This is a
> deported case. They were a couple of other papers that have suggested
> also translocation events may occur in response to T-DNA
>
> insertion. So, I\'m wondering whether or not it would be prudent to
> consider at least having some marker genes that are comparative in
> terms of their chromosomal distribution in the progenitor lines versus
> the transgenic lines to at least confirm that, you know, large scale
> translocation events may have occurred as an untoward consequence of
> the T-DNA insertion. I have no idea whether this specific case or
> others might pose a risk for safety or health. But it certainly would
> be a concern if large regions of chromosomes are relocating to new
> sites, which may result, as we all know, in a number of cases that
> have been document in animal and plant literature in dramatic changes
> in phenotype.
>
> So, I just raise for discussion, and I have no particular suggestion,
> whether or not it would be advantageous to consider including some
> marker analysis to show that genes that are identified flanking the
> T-DNA insertion events are in the appropriate chromosomal location.
>
> CHAIRMAN BUSTA: Dr. Fedoroff.
>
> DR. FEDOROFF: This is a problem with T-DNAs that\'s been known for a
> long time. Not only do they insert in multiple places, but they can
> induce translocations.
>
> But, again, is it a food safety issue? Or are we just disturbed by it,
> and, therefore, asking for data? If you want to know that the same
> sequences\--that the sequences that were originally together are at
> each end of the T-DNA, all you have to do is amplify and sequence the
> two flanking sequences. They should be together in the original DNA
> and not.
>
> But that\'s a problem for the developer. Unless you can point to a
> case where it\'s a food safety issue, I think it\'s going to be more
> of a problem. It\'s not the case that translocations and various
> rearrangements don\'t affect plant growth and development, but if they
> have a major effect, you\'re going to throw it out in the field. Or
> it\'s going to mess up your backcrosses.
>
> CHAIRMAN BUSTA: Dr. Gonsalves. Gurian and three\--one, two, three.
>
> DR. GONSALVES: Yeah, it\'s Dennis Gonsalves. As I listen to a lot of
> this, I think we\'re in danger of becoming too academic. You know,
> it\'s easy to say, if you put markers, and you\'re going to change the
> non-antibiotic resistance markers, but you know to go through, and
> I\'ve been through this, so I know, to go through the process of
> deregulation and AVIS, EPA, and FDA, and all what we have to go
> through is not a trivial thing. And it takes time.
>
> So, I think that the decisions that we make could theoretically have
> tremendous impact on whether products even go through. And this is why
> I really think we have to look at food safety issues, and I heard, I
> thought I heard, that Dr. Fedoroff said that in many of all the things
> that have been studied, very few insertion events make a difference.
> And I see, Dr. Sherman\'s concern about, you know, he want more
> systematic information; and I really think we might want to come back
> and just look at the charges and questions that were asked here and
> maybe just try
>
> to answer some of these questions; that one was: to what extent does
> sequencing information contribute to the identification of newly
> expressed substances? If sequence information is important for the
> purpose of FDA assessment, what sequence information, should be
> reviewed, for example, border sequences?
>
> You know, I think if we address some of these things more
> specifically, we might be able to address some of these charges, but,
> you know, we can go on and on and talk about all these possibilities
> that might happen.
>
> DR. ARIAS: I\'d like to interject and say this would fall under the
> domain of information on the organization of the DNA within the
> inserts. This is an organizational issue at the chromosomal level. And
> I\'m not saying that this has any implications for food safety, but
> this is a mutagenic event. It will also result in altered junctions,
> presumably between the translocated chromosome into the new site. Does
> this engender concern? That\'s my question.
>
> DR. GONSALVES: Yeah, for food safety.
>
> DR. ARIAS: For food safety, exactly.
>
> DR. GONSALVES: Right. Yeah.
>
> CHAIRMAN BUSTA: Dr. Gurian-Sherman.
>
> DR. GURIAN-SHERMAN: Doug Gurian-Sherman. I guess there\'s a couple of
> points, and I definitely with Abigail\'s point that the protein is
> ultimately, and the phenotype after that, is more important than the
> gene. But I think a thorough characterization of the protein would
> include the protein sequence. And, again, I have to go back to the\--a
> few examples that we do have where there\'s been characterization of
> the protein. I think some of these points have been brought up. There
> have been problems that have been identified with the characterization
> of the bacterial surrogate compared to the inserted DNA or inserted
> consequent protein, where there\'s a protein involved. And I think we
> just have to be careful about what a thorough characterization of the
> protein really is, and certainly sequence is a good part, I think, a
> good part of that. I mean, either, you know,
>
> certainly the protein sequence would ultimately be probably better
> than the DNA sequence, the mature protein sequence. But you can also
> obviously translate the DNA sequence, with some caveats.
>
> So, you know, again I think that that\'s right, but\--and, again, I
> think the devil\'s in the details about what\'s actually done, and how
> it\'s done, and how effective it is. You know, the point was made
> several times before: bioassays are sometimes done. But how those
> bioassays are done are going to determine the sensitivity of the
> expression data that you\'re looking at.
>
> So, I think that really, again, whether it\'s the protein or the DNA,
> it\'s not that big a deal and the data can be useful in terms of
> getting at some of the structure and function relationships of the
> protein and the plant.
>
> CHAIRMAN BUSTA: Dr. Astwood.
>
> DR. ASTWOOD: This is Jim Astwood. Back to the question of consensus,
> Anne and others have suggested that we may have consensus that the FDA
> approach is consistent with Codex. And the one
>
> sort of unresolved issue was whether that also implied that the DNA
> insert itself was sequenced. It\'s conceivable that you can have
> enough information without the sequence, but certainly the general
> interpretation internationally would likely be that you need to have
> the DNA sequence of the insert.
>
> From a U.S. perspective, what you would need to judge is whether you
> need to meet that international standard for all products. I can
> envision that, for a small academic project, that might not be
> necessary at all to establish the safety of the product. And I\'m not
> sure that the FDA is explicitly suggesting that you have the DNA
> insert sequence or not. From the organization that I represent, we
> always do. For a large corporation, this is routine, because it meets
> international standards. But you may need a different standard locally
> to meet the local needs, and, so, I kind of put that on the table.
>
> As for the suggestion that we need to also characterize and fully
> understand the extent, if
>
> any, of potential chromosomal rearrangements, that is actually a
> fairly large question. And going back to first principles, does the
> knowledge that there is a chromosomal rearrangement in and of itself
> become criteria for the safety, or do we have this battery of other
> tests that really gets at that question through finitive compositional
> analysis and other things. If that
>
> rearrangement\--it\'s not that a rearrangement is a priority, a
> concern. It is rearrangements that cause the phenotype to be
> different. And we have a lot of ways of measuring the phenotypic
> properties with respect to food safety. So, I would be reluctant to
> support a criteria that said you couldn\'t have rearrangements. In
> fact, we know most inserts do create rearrangements.
>
> So, it\'s not clear that the knowledge and the specific knowledge of
> how large it is, and what genes were deleted actually informs you
> about the safety of the product.
>
> And that has been a question mark, a question that has been raised and
> debated
>
> internationally many, many times. And you\'ll see that\'s actually not
> in the Codex document.
>
> What is also suggested in the Codex document is the need to have some
> sort of flanking sequence DNA, DNA sequence from the flanks, which
> kind of gets at the question of did you create that novel fusion
> protein at the junction of the insert. So, I\'m not sure if the FDA
> intended that also to be implicit in what they\'re proposing, and in
> their argument that the discussion paper is consistent with Codex, but
> if it is, I suspect we would have consensus there, too. But if it\'s
> not, then we probably need to have more discussion about why.
>
> Sorry, I missed three topics into that. I apologize, Mr. Chairman.
>
> CHAIRMAN BUSTA: Very good. That moves us along.
>
> DR. ARIAS: May I make comment. Jonathan Arias, again. It seems that
> the differences I noted between the committee members can fall into
> sort of two categories: the obvious differences in the transgenic
> coded product itself, such as
>
> splicing and untoward effects, and the unintentional, more speculative
> nature, of what insertion does, and I can well appreciate how a number
> of us have different levels of concern for this. I think, at least
> from my standpoint, it\'s only to raise these issues as perhaps
> preliminary devices by which developers might consider ways of
> reducing their own risk. I would think it would be in the developers
> best interest, when they make 200\--thank you, Nina\--independent
> transgenic lines of the particular recombinant DNA that they would do
> some preliminary screening to look at things like large-scale
> translocations, insertional events that obviously result in changes in
> the plant phenotype, et cetera, et cetera. And so these are more, from
> my standpoint, perhaps suggestions by which the developers should
> start thinking about how to minimize the ultimate risk so that when
> they come down to their application to the FDA, they\'ve already
> assumed that many of these things are no longer an issue; that we\'re
> not looking at a plant whose genetics are not characterized or are
> really
>
> up in the air. And I do think, though, however, that chromosomal
> translocation should be looked at rather carefully by developers in
> their process, because we know that they can result in significant
> potential for mutagenesis that may or may not result in obvious or
> perhaps subtle effects that we can\'t currently characterize, but
> that, nonetheless, would represent a potential risk.
>
> So, I, again, mention I brought this up only to help advance the
> issues of risk safety and for no other reason.
>
> CHAIRMAN BUSTA: I, as Chair, I like Dr. Gonsalves\' suggestion that to
> try in the next half hour to wrap this up; that we look at the issues
> and get some, you know, objective\--it\'s like the objective quiz at
> the end of the lecture. Get some consensus, if we can, to these
> issues. And I see number three as a place where the\--one of the
> recommendations on proteomics, ischemics, and come in. Yes, Dr.
> Fedoroff.
>
> DR. FEDOROFF: I think one of the most important things to add is the
> one that I added
>
> based on the recent work on the mechanism of inactivation of viral
> coat proteins; and that is that the advancement that has happened in
> the last 10 years is the recognition that viral coat protein genes
> work at a post-transcriptional level. So that kind of data really
> should be collected, because the implication is immediately that the
> protein level is very low, and that means you have to worry less about
> allergenicity of the protein, if you have a mechanism that doesn\'t
> increase, but massively decreases the expression level.
>
> CHAIRMAN BUSTA: Did everybody follow what she said?
>
> DR. ARIAS: Yeah, I think that is a very good point, and there\'s other
> mitigating parts to the risk analysis that deal with these issues; so,
> you know, if you have a protein that\'s being expressed in food and
> being consumed in the level of the transgene, it is expressed at a
> similar level or lower. That\'s a mitigating issue to FDA. So, again,
> you know, we\'re not looking at these things in a vacuum. And I think
> that\'s a very good
>
> point. If there\'s no protein being expressed, then that\'s a whole
> risk issue that is basically eliminated.
>
> DR. FEDOROFF: Right.
>
> CHAIRMAN BUSTA: Dr. Gonsalves. And I think that\'s a good point. I
> didn\'t bring it up about, you know, the mechanism, but for viral
> resistance, which there\'s many cases of that, it essentially come
> down to post-transcriptional gene silencing. And even now, we can
> induce resistance with a
>
> 200-base pair segment of the coat protein that is
>
> non-translatable. Well, do we have to go through all of these other
> aspects on the food safety issue. That\'s a point I was getting at,
> where, you know, there\'s certain kinds of things that you do that you
> probably don\'t need to look into detail in that aspect. But there\'s
> other aspects of alkaloids and other things that you have to look into
> much more detail because the dangers are much more evident than,
> let\'s say, a non-transmittable viral coat protein.
>
> DR. ARIAS: Jonathan Arias. That\'s a very good point, Dr. Gonsalves,
> and it reminds me of a comment made by Dr. Fedoroff earlier about
> looking at the various metabolites, the proteins that are expressed in
> the plant as really an indicator of potential risk and safety. But one
> of the limitations that I see with that approach is that we really
> don\'t what a lot of the proteins and metabolites are of many
> agronomic plants. Certainly, some of the cereal grain crops have been
> well studied, but I think FDA envisions that there\'ll be many new
> plants. In using transgenic technologies, I think saw a slide earlier
> today that suggested that there, in fact, is quite a wide range in the
> pipeline than these highly studied crops. And their metabolic and
> biochemical properties, I surmise, are probably much lesser well
> known.
>
> So, our ability to predict risk is only going to be as good as our
> knowledge base, which is rather poor in the case, I suspect, of
> cantaloupe, for instance, or kiwi in terms of what could be
>
> potential secondary metabolites.
>
> So, just one point, and then I\'d like to just add my two cents on
> number three about new technological advances. As I indicated earlier,
> I\'d like to really look at this as a proactive process for
> recommendations for developers in the future to enhance their safety
> of their products.
>
> I mentioned earlier several examples. Using tissue-specific promoters
> is one. Another, which I\'d like to also put on the record, is to use
> homologous recombination, either through a variety of constructs, such
> as the Creelocks system that\'s been developed, which might minimize
> some of the potential risk associated with the random mutagenesis or
> insertional events that are engendered by use of T-DNA itself. And so,
> as the technologies are evolving, and have matured, I think the
> developers should certainly be encouraged to try to integrate these to
> lower the potential risks of the products that will ultimately be seen
> by FDA.
>
> CHAIRMAN BUSTA: As long as we\'re on
>
> number three. Let\'s deal with it. We\'ve gotten one on the viral
> coat, and we\'ve gotten this one that I wouldn\'t try to reiterate,
> anyway. And we will keep talking\--
>
> DR. ARIAS: Targeted gene expression.
>
> CHAIRMAN BUSTA: Yeah, targeted gene expression.
>
> DR. KAPUSCINSKI: And I think that the discussion before the\--this is
> Anne
>
> Kapuscinski\--the discussion before the break that especially Dr.
> Buchanan was saying about proteomics and the fact that it\'s\--we\'re
> getting close to being able to use that well would also fit in\--
>
> CHAIRMAN BUSTA: Number three.
>
> DR. KAPUSCINSKI: Number three.
>
> CHAIRMAN BUSTA: That the proteomics and the\--that the decision tree
> aspect seems like it\'s appropriate for number three to rethink that
> approach of looking at the whole variety of situations that Dr.
> Benedict talked about. I think you\'re the one who\'s had the decision
> tree; right?
>
> DR. BENEDICT: Yeah. Excuse me. Yeah,
>
> I\--what I was hoping to convey is that we don\'t have to apply
> everything to every situation, and that if we invoke the decision
> tree, there will times when we\'ll need genetic information. There
> will be times when we\--most times we won\'t. But what we most likely
> might need would be the proteomics information. And, although I\'m
> sensitive to whatever has said, that we\'re not ready, I don\'t care
> in the sense that we weren\'t ready to do the genome sequence based on
> sequencing 300 bases a day, and then money came, and now we can
> sequence a lot more. And my point would be that if we as a group say
> the way you need to go is proteomics, find a way to do it, then that
> gives strength to FDA to go somewhere and say, look, we got all these
> people telling us we\'ve got to ramp up proteomics. That was all I
> wanted to say.
>
> CHAIRMAN BUSTA: And number three\--
>
> DR. BENEDICT: That\'s number three.
>
> CHAIRMAN BUSTA: Yeah. And did\--do we have agreement with that
> statement?
>
> UNIDENTIFIED SPEAKER 1: Yes.
>
> UNIDENTIFIED SPEAKER 2: No.
>
> UNIDENTIFIED SPEAKER 3: No.
>
> UNIDENTIFIED SPEAKER 4: No.
>
> DR. FEDOROFF: I agree with that statement.
>
> DR. ARIAS: Eventually, the statement is whether research and
> development should be done in the field of proteomics to facilitate it
> in the future; is that correct?
>
> DR. FEDOROFF: Yeah, I agree with that.
>
> DR. SALYERS: We\'re talking about food safety.
>
> DR. FEDOROFF: Well, for food safety purposes.
>
> DR. ARIAS: Yeah, I don\'t think it\'s\--
>
> DR. FEDOROFF: I mean, I assume that\'s what she meant as an additional
> tool to help identify food safety issues. I mean, it seems to me like
> that is possibly one of the most useful ways to be able to anticipate
> ideally pretty early on in the development process pleiotropic effects
> that you really didn\'t have any way of predicting
>
> otherwise. And I think the more we can encourage this kind of
> searching and also proactive approach to design transgenic plants that
> won\'t raise safety problems upstream, the better everybody is off.
> And I think it\'s appropriate for our subcommittee to be thinking
> about that, not only thinking about the point at which the developer
> comes to the FDA. The ideal is by the time they come to the FDA,
> they\'ve actually resolved those safety issues. And it seems like
> proteomics, encouraging research and development in proteomics, would
> be extremely helpful for that. So, I strongly support that, with the
> understanding that it\'s to help guide food safety assessment, not
> just proteomics for the sake of proteomics.
>
> CHAIRMAN BUSTA: Is that all right?
>
> DR. SALYERS: No, it\'s not all right with me, but he had his hand up.
>
> DR. ASTWOOD: Well\--this is Jim Astwood. I don\'t disagree that
> there\'s a high degree of value in exploring the potential utility of
> proteomics as it could apply to safety assessment,
>
> food safety of genetically modified foods. In fact, I have a research
> program in that, so I\'m very interested in it and support that.
>
> It is a different thing to recommend back to the FDA that they should
> be looking for proteomics data in dossiers that we submit today. So,
> as long as we\'re very clear about what it is that we\'re
> recommending, my comfort level goes up.
>
> DR. SALYERS: I agree with that.
>
> DR. BENEDICT: I thought this one was\--
>
> DR. ASTWOOD: I understand that, and\--
>
> DR. QUALSET: I think you said the future. That was\--
>
> DR. ASTWOOD: But I\--you might not even pin it to proteomics. It could
> be\--it could turn out that after a couple years of research, we find
> out that metabolomics is really the business end of pleiotropy, and
> that\'s a much more powerful and sensitive to detect things that
> we\'re missing today. So, so\--
>
> CHAIRMAN BUSTA: Is it all right to expand that?
>
> DR. ASTWOOD: So, you need to be a
>
> little\--if you\'re going to be prospective and create some
> language\-- and I suspect the Chairman is tasked with creating that
> language\--but create language that induces that flexibility and that
> prospective nature. And all the suggestions that Professor Arias has
> made are very good suggestions as things for us to evaluate and
> consider, et cetera.
>
> CHAIRMAN BUSTA: So we\'re talking about future being prepared.
>
> DR. FEDOROFF: Right. But we\'re asking what new advances could be used
> to enhance the safety assessment. And I think the issues is that the
> connections between changes in protein composition have not been
> correlated with food safety today. Nor is the variability that\'s
> tolerable in perfectly safe foods known. So, as long as
> there\'s\--it\'s a little bit, again, looking, you know, using the
> technique that you have in hand, but I would not support its
> invocation today. I would support a recommendation that says that
>
> linkages between food safety and protein constitution should be
> explored with the most contemporary tools. But I would also include
> other metabolites, not just proteins.
>
> CHAIRMAN BUSTA: Is that\--are we restoring the role? Is that all
> right?
>
> DR. KAPUSCINSKI: This is Anne Kapuscinski. I\'m okay with that, and I
> think really I understood Dr. Benedict, and what I was supporting is
> encouraging research and development in this area so that we\'re at a
> better position maybe two years from now or five years from now to,
> you know, maybe revisit this and see if there are certain aspects of
> those technologies, the proteomics and the metabolomics, that, you
> know, would be particularly useful. But if we don\'t start encouraging
> that that work be done as research and development; it can be done in
> academia; the research and development can be done in industry, but
> for it to be useful, it\'s got to end up in the public scientific
> literature somewhere. And I agree with Nina, research needs
>
> to be done to link that kind of data to food safety data. But we have
> to get going on that; otherwise, we\'ll be having the same discussion
> five years from now.
>
> DR. FEDOROFF: Actually, I think there\'s more activity in that area
> than you can give either companies or researchers credit. There\'s
> a\--
>
> DR. KAPUSCINSKI: Yeah, and I realize that, but I\'m trying to respond
> to as subcommittee member how\--what we should say about item three.
>
> CHAIRMAN BUSTA: Are you doing anything in FDA right now in that area?
>
> DR. CEBULA: They don\'t do research.
>
> \[Laughter.\]
>
> DR. KAPUSCINSKI: Let\'s ask doctor, let\'s ask the\--what the\--lab
> guy.
>
> CHAIRMAN BUSTA: He\'s back.
>
> DR. CEBULA: Within FDA, we do not have an active program in proteomics
> directed at this.
>
> CHAIRMAN BUSTA: Okay. The answer was
>
> that\--it\'s right now there\'s not an active program in the areas
> that we are talking about. So, the
>
> recommendation would not be redundant or what they might be doing.
> Finally, you are the most patient person\--
>
> DR. QUALSET: I don\'t have that much to say. I think a consensus we
> could come to is that we have already is the decision tree framework
> that\'s in the 1992 thing, and we saw it again this morning. But that
> leads to the specificity of the recommendations for food safety. For
> example, if you knock out the allergenicity of peanuts, it would be a
> very bad thing if that was a repressed gene that got de-repressed, and
> people were eating it, and they were having reactions. So, what is
> your protocol? The developer could use, the evaluators could use, to
> ensure that that is a stable action, that the repression if that what
> is it or whatever the mechanism is, that that is a stable one that we
> can confidently put it on the shelf. So, as we go through the series,
> the
>
> co-proteins and virus resistance in the flavor enhancement, vitamin
> enhancement, amino acid enhancement, all those\--if you have an
> enhanced
>
> lysine, for example, and that character is lost, nobody gets sick,
> probably. So there\'s different levels of risk based on the trait and
> the gene. And I think that\'s where I think we should come to some
> organizational sense of how would FDA proceed. What are the potential
> types of genes and traits, and then develop the assessment based on
> this framework for our decision tree.
>
> CHAIRMAN BUSTA: That was Dr. Qualset.
>
> DR. QUALSET: I\'m sorry.
>
> CHAIRMAN BUSTA: No, I should have called that at the beginning.
>
> Could that statement be added as something that FDA should be doing,
> is putting that sequence of assessment together?
>
> DR. QUALSET: Well, it follows to me that it\'s just a restatement of
> their decision tree idea. So I just think that maybe put some flesh on
> it, and illustrate with some ideas of potential value-added traits,
> and toxicities and that sort of thing.
>
> CHAIRMAN BUSTA: Are there\--as long as
>
> we\'re trying to beat number three, are there other items in number
> three that should be recapped from our earlier comments?
>
> It doesn\'t stop us from adding. Let\'s back up to number one, and if
> we ask the question, to what extent does sequencing information
> contribute to the identification of newly expressed substances. I\'m
> going to get beat down on this, but what I heard was when it comes to
> the food safety issue, and if I could add in there newly expressed
> substances that influence food safety, I heard that it doesn\'t do us
> much good. Is that correct? Is that what I heard?
>
> DR. KAPUSCINSKI: If you stop only at that, it doesn\'t do much good.
>
> CHAIRMAN BUSTA: Right.
>
> DR. KAPUSCINSKI: This is Anne Kapuscinski, again. But if you\'re going
> to follow the iterative decision tree approach that Dr. Benedict
> talked about and that I understand FDA espouses its using, it only
> makes sense that this would be a starting point. Now, you don\'t
>
> necessarily have to require everybody to do this. If some parties want
> to immediately go to the detailed compositional analysis, let them do
> that, and that would be another way to get at it. But some people
> might decide it\'s more strategic and perhaps even more cost effective
> to start with sequencing the inserted DNA construct, and if they find
> some dramatic changes in the sequence due to rearrangement or
> whatever, that then gives them a hint as to whether they should do
> some additional looking. If they don\'t find something, it also tells
> them maybe that there\'s a bunch of further testing that they don\'t
> need to do.
>
> So, I don\'t see any reason to discount that, and I think, in some
> cases, it might very useful. But with the understanding that none of
> these techniques is very useful standing by itself. That\'s why you do
> need a decision tree kind of approach to any kind of risk assessment,
> and it\'s also why you want it to be iterative. What you want to try
> to do is gather information from different sources, but do that in a
> smart,
>
> strategic way. So that\'s where the decision tree comes in, because
> you don\'t want to have everybody to do all of them. You want to start
> with a couple leading questions, as Dr. Qualset was saying, then use
> that to guide you\--and okay, I\'m going to gather this type of info.
> Based on what you learned from that, then decide if you should gather
> another type of info. Then you look at the two types of info, and you
> decide if you have to revisit something or not.
>
> CHAIRMAN BUSTA: Is that a satisfactory answer to number one\'s last,
> the remainder of that question\--if sequencing information is
> important for the purpose of FDA\'s food safety assessment, what
> sequence information should be reviewed, and, if so, how does this
> information contribute to the safety assessment. What you\'re saying
> is, if you see something, well, it\'s a starting point\--
>
> DR. KAPUSCINSKI: That\'s basically what I\'m saying.
>
> DR. BENEDICT: Yeah, Steve Benedict. If circumstances warrant it, based
> on the decision
>
> tree, you may need to know flanking sequences. You may need to know
> the sequence of the input series of genes. There will be occasions
> where it won\'t be necessary, so the answer to this is not a yes or
> no. It\'s a when. And the\--
>
> DR. ARIAS: Jonathan Arias. It\'s clear that because of our relative
> ignorance about events that affect gene expression is fairly profound,
> we\'re not going to be able to predict in many cases what the sequence
> information that we derive from an insert is going to entail in terms
> of risk and safety assessments. As far as I know, there are no
> quantitative indices for those. But, again, to err on the side of
> prudence, it would seem to me that because this is a mutational event,
> the insertion of T-DNA, that at least knowing where it is would be a
> good potential for identifying the subsequent probability of any risk.
> Not asking that question and addressing it is only opening us up to
> the potential errors of ignorance, when we didn\'t have to be
> ignorant. And, so, knowing the identity of the gene and its insertion
> would at least give us a
>
> level of comfort as to whether any additional information needs to be
> derived. And, so, I would agree with Anne that it\'s a preliminary
> device to determine whether there is the potential for any further
> risk in a risk assessment tree.
>
> CHAIRMAN BUSTA: So we\'re really answering number two here; right?
>
> DR. ARIAS: My sense it\'s number one, because there is no answer to
> that question, because there isn\'t enough data as far as I know\--
>
> CHAIRMAN BUSTA: For number one.
>
> DR. ARIAS: For number one.
>
> DR. ASTWOOD: Well, except for the parenthetical question, which
> is\--this is Jim Astwood. The parenthetical question was do you need
> to have the entire sequence of the inserted genetic material, and
> it\'s almost a yes/no question. And I daresay it seems to be yes most
> of the time. And Anne\'s suggestion that perhaps
>
> or\--no I think Dr. Benedict is suggesting there may be times when you
> might not need it, but it\'s hard to define when they might be.
>
> DR. GURIAN-SHERMAN: Doug Gurian-Sherman. I would, you know, basically
> agree with Jim that it should be part of the analysis, unless there\'s
> some good reason not to; and there may be in specific cases good
> reasons not to.
>
> The way it\'s used, I mean, typically what\'s done now, my
> understanding is the sequences of the gene, and usually now before the
> insertion of them, is used to search databases, allergen databases,
> toxin databases to look for matches, for homology.
>
> Clearly, if there\'s a change during the insertion, a small, you know,
> percent, you know, the chances are fairly small, but that change may
> show you some homology that you wouldn\'t see prior to the insertion
> event, where there\'s no change in the gene. So, again, you know,
> I\'ve got to go back to the point that the chances probably in any
> given case that there\'s going to be a change, that the change is
> going to have a health effect are pretty small. But it\'s pretty easy
> to do these informatics, and it\'s pretty easy to do the
>
> sequencing; and why leave ourselves, as Dr. Arias put it, in that
> state of ignorance, when it\'s fairly easy to do.
>
> There may be a change, and you may not see any change in, you know, in
> your database searches or anything else that raises a red flag, and
> then you say that these changes are\--don\'t apparently have any
> meaning. But that\'s how they\'re generally used now. I mean, that\'s
> how the sequences are generally used is to do homology searches.
>
> CHAIRMAN BUSTA: Dr. Fedoroff.
>
> DR. FEDOROFF: I think maybe we could bring this discussion to a close
> by acknowledging that if we strictly answer the question, the answer
> is no. But we should do it anyway? Just in case.
>
> DR. KAPUSCINSKI: I don\'t totally agree with that. This is Anne
> Kapuscinski. I think the challenge we have in this food safety of
> recombinant DNA products is that we\'re primarily going to be dealing
> with rare events that could have big consequences; and that\'s the
> most tricky aspect of the universe of risk assessment. But the
>
> very nature of risk assessment is that it\'s very hard to have total
> yes or no answers. So, I\'d rather word it sort of in the way that
> other commentors were wording, which is that, in some cases, this
> information could be very useful. It\'s fairly easy now to get that
> information, so unless there\'s a good reason for your specific case
> to argue that it\'s not useful information, it\'s probably a good idea
> to get this information, and then go on from there.
>
> CHAIRMAN BUSTA: Okay. I do want to close up in a couple or few minutes
> so that we can discuss the comments and the letter with review, and
> also future agenda items; and guaranteed at five o\'clock, we are
> done, because that was guaranteed to adjourn at five because some of
> you are\--have to get the METRO or something. Some of us are catching
> planes.
>
> Let\'s go to number two, and see if we can conclude that one.
>
> Current approaches. This is\--now, what I was hearing before was that
> if we do what Codex
>
> says we should do, everything is copasetic.
>
> DR. KAPUSCINSKI: We should do everything that\'s what?
>
> CHAIRMAN BUSTA: If we follow the Codex operation, everything is fine.
> Is that what I heard before?
>
> DR. ARIAS: Yeah. Jonathan Arias, again. Yeah, I agree. I just want to
> again raise the issue of whether or not under the subheading of
> information on the organization of the DNA within the inserts, whether
> any mapping data on potential translocation events should be included
> as part of that characterization. I would welcome other comments if
> anyone feels one way or the other about it.
>
> CHAIRMAN BUSTA: Let\'s make sure\--here, again, and presumably Codex
> is food safety. That\'s\--and you keep saying that. And the\--and that
> this is addressed at food safety.
>
> DR. GURIAN-SHERMAN: Can I venture something on Jonathan\'s point? You
> know, I think he makes a very good point. I think it also points
>
> up part of the problem of trying in this forum kind of on the spur of
> the moment to consider fairly complicated issues, new issues and come
> to some conclusion about it without time to consider and look at it.
> And I would suggest that on that issue\--I mean, I\'m not prepared to
> say how important it is. I would follow, you know, Dr. Arias\' lead on
> that.
>
> But as a matter of kind of procedure, maybe it\'s something that we
> should consider further as an addendum on to this at more length,
> where we have more time to consider how important it is to the risk
> assessment, what\'s the
>
> frequency\--you know those kinds of things, which we, I mean, I have
> not had a chance to think about before this meeting. And, again, I
> think it gets to the point of having time prior to the meeting to be
> able to consider these issues thoroughly, which we haven\'t done.
>
> CHAIRMAN BUSTA: Dr. Benedict.
>
> DR. BENEDICT: Steve Benedict. Jonathan, doesn\'t number four address
> your question a bit,
>
> because if you\'re going to look at potential reading frames, you\'ll
> sequence around, and you\'ll know essentially what the environment of
> the gene is?
>
> DR. ARIAS: Perhaps. Actually, it depends on how the translocation
> event occurs, and what distance from the actual T-DNA insertion event
> it has brought in. I don\'t know specific examples cited, but the
> allogenic recombination event that was characterized appeared to imply
> that a large region of one chromosome was brought into a region
> adjacent to I think it was a hundred base pairs from the T-DNA left
> border. So, again, if you sequenced, for instance, both directions,
> you might be expected to pick that up. That\'s correct.
>
> CHAIRMAN BUSTA: Dr. Fedoroff.
>
> DR. FEDOROFF: Again, I will tend to resist this. There are lots and
> lots of rearrangements that distinguish even closely related
> organisms, be they animals or plants, and that make no difference in
> the phenotype. So, I think the phenotype has to be the primary focus
> of
>
> your examination. If it\'s a plant that is genetically propagated,
> it\'s going to be backcrossed. If it doesn\'t, if it\'s selfed and the
> arrangement is highly deleterious, it\'s not going to survive in the
> breeding program. If it\'s somatically propagated, some of our most
> valuable food plants, are somatic sports that are carefully
> maintained, and if you propagate them genetically, they fall apart.
> So, I think it has to be the food safety issue that has to be primary.
> The genetic rearrangement underlying it is not a good indicator of
> either the benefit, the upsides or the downsides. It\'s\--the whole
> evolution of plant genomes is one of scrambling.
>
> DR. ARIAS: I\'ll have my say on this. Jonathan Arias, again. I agree
> entirely with Dr. Fedoroff that mutations can be both, you know,
> beneficial to human agriculture, but we also know examples where
> they\'re not. I think one of them was cited earlier about traditional
> genetics resulting I think it was in higher psoralen content of
> celery, which went to market, I\'d point out,
>
> before it was recalled.
>
> So, we do know that there are examples that are both beneficial and
> not. Again, here, not having any quantitative indices for risk
> assessment of any of these parameters, I think it behooves us to err
> on the side of prudence and conservation.
>
> CHAIRMAN BUSTA: Dr. Benedict.
>
> DR. BENEDICT: Steve Benedict. When, Dr. Fedoroff, when you talk about
> the backcrossing and stuff weeding out the bad ones, I fully
> understand that. But is it a circumstance where the insertion merely
> activates expression of an allergen, and you could learn that by
> sequencing a little bit. Would your process of genetics and
> backcrossing point this out?
>
> DR. FEDOROFF: If I were worried about an allergen, I would look for
> the allergen, not look at the DNA. The insertional activation\--okay,
> so that in arabidopsis, we have special T-DNA constructs that are
> designed for activation. The general T-DNA constructs don\'t activate
> genes. The activation constructs rarely activate genes. But looking
> for ancillary rearrangements, which is what the conversation is about,
> is\--seems to me to have a much, much lower probability of
> identifying, for example, a change in psoralen level than looking at
> psoralen levels. I\--what I keep trying to come back to is
> that\--is\--we keep shifting to say let\'s do this because this is
> what we can do right now. Okay. And there are lots of things that we
> can do biochemically and looking for specific allergens using serum
> from allergic patients that are much more relevant to diagnosing the
> presence of allergens than looking at rearrangements that move whole
> pieces of chromosomes that, in fact, are bloody difficult to even
> identify sometimes. So, the question is using the tool that is most
> likely to identify the problem that you want to identify.
>
> DR. GURIAN-SHERMAN: I think to kind of rephrase\--this is Doug
> Gurian-Sherman\--rephrase that issue, and it has been brought up
> before, is where the uncertainties lie in terms of unintended effects
> and how much we do and don\'t know about potential deleterious, you
> know, genes and their products in the plant. And, so, where we have a
> targeted means of addressing one of those issues, such as where we
> have serum banks for known allergens, that does make, you know, often
> more sense, although not a trivial issue. We don\'t have those serum
> banks right now. They should be developed. But the problem is where we
> don\'t know and how much effort should be put into those areas where
> we don\'t know what the changes are or what their importance are. So,
> I mean, I would agree with Dr. Fedoroff that where we do know to look
> for something, it makes more sense to look at the specifics. But that
> still leaves open the question of, if you have a large change in the
> genome that might affect many genes, doesn\'t it make some sense to
> have some awareness of that.
>
> And I just want to add one thing: you know, it\'s certainly the
> agronomic traits that might be affected are\--may, you know, screen
> that out before. But one question that was brought up in at least one
> of the FDA studies that was never answered was\--where agronomic
> traits were looked at\--and FDA asked this themselves in one of the BT
> cases: can you correlate the agronomic traits with health safety
> traits? And that was never answered. And, so I mean I think looking at
> agronomic traits by themselves is not necessarily going to get at some
> of the changes in the plants that might have health effects. So, you
> know, again, the problem I\'m having with this particular is not
> having a lot\--had a lot of time to consider it, but it certainly
> seems like something that we should consider further, because I see
> the potential there for, you know, fairly large rearrangements to
> affect the number of genes, you know, at once.
>
> CHAIRMAN BUSTA: Dr. Salyers.
>
> DR. SALYERS: Abigail Salyers.
>
> The\--something about this that bothers me is\--and, I\--ordinarily, I
> would say, you know, more information is better than less information.
> But, in this case, suppose you did sequencing out at the ends. Now, if
> you sequence within the gene, and you saw that there had been changes
> in that gene, then that would motivate you to take a really close look
> at the gene product. If you see, if you get DNA sequence to go to the
> trouble to get DNA sequence from the sides, and you see that there
> might have been a rearrangement, what are you going to do with that
> information? Does that mean you\'re going\--you\'re not going to go
> forward with the product? I don\'t think so. I just think it\'s
> information that if any\--that you\--there will be time spent to get
> it. And then there would be a temptation to say, oh, well, there\'s a
> rearrangement, and so, you know, we don\'t want you to go forward with
> that product. And I just think it\'s kind of useless information for
> purposes of food safety.
>
> DR. ARIAS: Jonathan Arias. I\'d just like to respond to that.
>
> It\'s an excellent question, and I think the answer is embedded in the
> discussion that we were having before; and that, typically, a large
> number of independent transgenic lines are generated containing the
> recombinant DNA of interest. And those are then, we know, down to a
> few that are going to be fully characterized. I sort of envision this
> as a very early analytical tool for the developers to use, to
> determine which of those several hundred perhaps\--perhaps Dr. Astwood
> could tell exactly how many lines might be generated. It\'s a secret.
> Thousands perhaps. But the point is that it is not a final analytical
> tool of when the product is developed. This is something that would be
> done to screen out potential risk very upstream in the process, at
> fairly low cost, I would surmise.
>
> CHAIRMAN BUSTA: Dr. Astwood.
>
> DR. ASTWOOD: I mean, think that\'s an attractive concept, too. This is
> Jim Astwood. How do you codify that in a recommendation back to the
> FDA, who wants to give us specific guidance in terms of what they
> require in a dossier? That\'s the struggle. I mean, you can imagine
> that that might be useful a lot of times or not. But to acquire it in
> every single case is a matter of the data requirements for the food
> safety assessment, I tend to agree with Dr. Salyers, that as a\--it\'s
> not clear to me how a risk assessor would use that information.
> That\'s the bottom line.
>
> CHAIRMAN BUSTA: Doctor.
>
> DR. SALYERS: Abigail Salyers.
>
> I\'m beginning to realize that we\'re talking about two kinds of food
> safety. There\'s safety of the food producer from lawsuits, and
> there\'s safety of the consumer. And, so, this probably goes in the
> first\--as the first kind of food safety rather than safety of the
> consumer. And so I think that our charge here\--
>
> DR. FEDOROFF: Consumer\--
>
> DR. SALYERS: Safety of the consumer. And let the companies worry
> about\--
>
> DR. FEDOROFF: They have to sell it the second, you know\--
>
> CHAIRMAN BUSTA: Dr. Gonsalves.
>
> DR. GONSALVES: You know, I\'m glad I developed the papaya back when I
> did.
>
> \[Laughter.\]
>
> Because, you know, all these discussions about developers, you\'re
> acing out these academic people that, you know, everybody say, you got
> to do this, this, this right, really organized. Well, you know, a lot
> of the best things that come out came out because you\'re doing some
> experiment. And I think the big lack in products in coming out is
> because it has almost become the purview of big companies. You know,
> it\'s easy to talk about this and this, but some labs are just not
> suited to do that. And if they need to do that, then they probably
> won\'t pursue it. And I think if you make it\--if you only think about
> these developers, these big people who got specialized, they\'re going
> to do this and this and that, I think you\'re tending to miss these
> innovations that really make a difference. And I can tell you the
> papaya is one of them. We had only 15 transgenic lines, because during
> those days, that\'s all we could do to transform. And I would think
> we\'re unusual. I think some of the best innovations to really help
> agriculture comes from these things that are not well planned; and if
> you make it such that
>
> if\--because of lack of foresight, where you didn\'t follow these
> protocols; and, therefore, your product is out the window. I really
> think we may miss something.
>
> CHAIRMAN BUSTA: Dr. Qualset.
>
> DR. QUALSET: Yeah, I just thinking we\'re talking about two sides
> here: the development and the evaluation for the consumers. And we\'ve
> written a helluva of a textbook for the development side of things,
> about how to\--what you need to measure and what kind of information
> will be to have, and all this. But let\'s get back to the issue of how
> do you judge whether a product is safe to\--for the farmers to grow
> and the processors and the consumers to buy it and cook it up. So I
> think we\'ve got to get back on track with the\--what are the things
> you can measure and ask about in the stability issue, for example.
> There\'s stability in the\--of the gene. There\'s stability of
> performance, and all those. I think that we can put all this
> nice-to-know stuff on the table, because it will help you understand,
> as a developer, what has happened, what does your thing look like. But
> if there\'s two inserts instead of one, does that affect the
> phenotype. If it does affect the phenotype, what happens if one is
> lost? Have you lost a significant amount of the phenotype.
>
> So, those are issues. I think we need to structure this looking from
> the backside a little bit as to what the consumers might see when this
> product goes to market, if it does, and why would you not let it go.
> And I think the issue that Dennis has raised is outstanding. I think
> that a lot of developments can be done relatively simply. They might
> need to do a little clean up analysis toward the end, but if the
> stable\--if the product is stable and useful, you can go from there.
>
> CHAIRMAN BUSTA: How would you like to answer number two?
>
> DR. KAPUSCINSKI: I think we\'ve answered it. I mean, the only thing
> we\'ve really debated was the chromosome translocations. That\'s what
> generated the debate.
>
> CHAIRMAN BUSTA: Okay.
>
> DR. KAPUSCINSKI: So\--
>
> CHAIRMAN BUSTA: We\'re happy---
>
> DR. KAPUSCINSKI: You know, people were agreement on the other stuff.
> And, you know, I\'ve been fairly silent on this particular debate
> because I don\'t know much about this, and I guess I feel the same as
> Dr. Gurian-Sherman: I\'d like to have a little more time to think
> about it.
>
> CHAIRMAN BUSTA: On the last\--on the issue.
>
> DR. KAPUSCINSKI: Yeah, and to read up on it. Because, you know, I
> appreciate all the different points that have been made\--
>
> CHAIRMAN BUSTA: Not the remainder of this, but this last issue is what
> we\'re talking about?
>
> DR. KAPUSCINSKI: Right.
>
> CHAIRMAN BUSTA: Okay, I\'m just trying
>
> to\--as you see, I\'m trying to close, get a little bit of closure
> here.
>
> DR. KAPUSCINSKI: Right. I would support that.
>
> CHAIRMAN BUSTA: Dr. Fedoroff.
>
> DR. FEDOROFF: Yeah, Nina Fedoroff. I think that trying to revise one
> through four is a losing proposition. I think that\'s in the Codex,
> and that\'s pretty much whether people eventually change that and back
> of it or not is not for us to decide. But I think that I would
> strongly resist adding great characterization of rearrangements for
> all the reasons that I discussed before.
>
> DR. ARIAS: Jonathan Arias. I\'m sorry. I just think that this falls
> within the domain of the particular one through four comments as I
> mentioned earlier. And it\'s not really a separate issue. It\'s a
> definitional one, on information on the organization of the DNA within
> the inserts.
>
> DR. FEDOROFF: Within the inserts.
>
> DR. ARIAS: That\'s\--that\'s\--well, within the inserts; that\'s
> right.
>
> And I think that this extends in terms of the analysis of the
> insertional site.
>
> DR. GURIAN-SHERMAN: I have a question. Jonathan, would you be content
> if we consider this further? I mean, do you feel like we need to come
> to a decision about this in an hour?
>
> DR. ARIAS: No, I don\'t. No, I just feel that this is something that
> should be considered at some point. It does need to be done today.
>
> DR. GURIAN-SHERMAN: I mean, I would absolute support that there should
> be on the\--I\'m just making a suggestion\--
>
> DR. ARIAS: But this must\--that this should be on the agenda.
>
> CHAIRMAN BUSTA: To try to tie this up\--
>
> DR. KAPUSCINSKI: Yeah, and I would support that.
>
> CHAIRMAN BUSTA: I got\--to try and tie this up then, we feel that this
> characterization that is consistent with the Codex description is
> something that is going to be done, if I can sum\--
>
> DR. FEDOROFF: The train has left the station.
>
> CHAIRMAN BUSTA: Yeah. And what that other data that might be useful to
> safety assessment that is something that we need some time to think
> about, like the topic resistance\--
>
> DR. ARIAS: Mapping the chromosomal positions.
>
> CHAIRMAN BUSTA: Right. Or maybe some others. So the last part of other
> data is still an outstanding question that we\'re probably not in a
> position to answer at this moment. Does that really\--
>
> DR. GURIAN-SHERMAN: Can I\--I would just like to make one point about
> the whole context of this that we really haven\'t considered, which is
> on page 50, paragraphs 20 and 21. There\'s two parts of that that I
> think, you know, are important and reflect on the specifics, which,
> you know, one that the design of the experiments, the assessment is
> done in accordance with sound and scientific concepts and principles.
> That\'s kind of vague, but I think, you know, hopefully we know what
> they\'re getting at. But then, in the next paragraph, \"in light of
> the best available scientific knowledge,\" and I think that kind of
> goes to what Abigail was saying about, you know, for instance, the
> protein, you know, the best characterization of at least the protein
> that\'s inserted needs to be done. And it\'s the best
> characterization, and part of that is the sequence of the protein. I
> mean, that\'s\--so I think that this gives some important context that
> yeah, there may be some flexibility built into this, but it needs to
> reflect back on what\'s the state of the science now that can give us
> answers that are, again, reflect on risk assessment and safety. So, I
> think that language is helpful.
>
> DR. ASTWOOD: Yeah. I got a quick question, and it relates to that is
> in terms of our answer to other data, I\'m not sure if it was under
> two or three, did we chose to include, Mr. Chairman, the concept of a
> robust characterization of the protein as expressed in the plant?
> Would that be an add-on? It\'s very closely related to insert
> characterization. Anyway, is that something\--I think everyone is
> agreeing that that\'s what we should we do, but it seems out of scope,
> but even though it\'s out of scope, we could chose to have it in
> scope.
>
> DR. FEDOROFF: Maybe that goes up as three?
>
> CHAIRMAN BUSTA: Yeah, I thought that was in three.
>
> DR. FEDOROFF: Yeah, I think we talked about number three.
>
> DR. ASTWOOD: Yeah.
>
> DR. FEDOROFF: And it seemed like that was something we all did agree
> upon.
>
> DR. ASTWOOD: I agree. Exactly.
>
> CHAIRMAN BUSTA: Yeah.
>
> DR. ASTWOOD: Okay.
>
> CHAIRMAN BUSTA: I thought that was in number three. I\--I\--Dr.
> Fedoroff.
>
> DR. FEDOROFF: Well, I didn\'t want to\--I was going to jump to three,
> but you think you want to close out two.
>
> CHAIRMAN BUSTA: If you are\--
>
> DR. ASTWOOD: Three\'s down.
>
> DR. FEDOROFF: At the beginning.
>
> CHAIRMAN BUSTA: Okay. We got number two is closed. Number three,
> we\'ve put down a number of issues that I hope they are recorded,
> because I didn\'t write them down.
>
> DR. FEDOROFF: But did somebody? I mean\--
>
> DR. KAPUSCINSKI: Yeah, I mean, we\--if I remember correctly.
>
> CHAIRMAN BUSTA: Right we had three or four issues that we named off in
> number three.
>
> DR. FEDOROFF: I think that the major ways that you can expand the
> decision tree are to increase the characterization. We now know what
> we didn\'t know ten years ago that some genes, some from the processes
> that are used while they protect plants against disease and pests
> are\--work at the level of RNA, destroying the RNA, that should
> increase the safety assessment\--the probability that it\'s a safe
> food because and decrease the need for allergenicity assessment. If
> the process knocks down the amount of protein, you don\'t have to
> worry so much about it. Do you see what I\'m saying?
>
> DR. GURIAN-SHERMAN: Mm-hmm.
>
> DR. FEDOROFF: In other words, it\'s a mechanism that destroys the RNA,
> messenger RNA, so it doesn\'t get translated, so when you overexpress
> that coat protein gene, you\'re not actually overexpressing the coat
> protein, you are triggering a mechanism that destroys the messenger.
>
> CHAIRMAN BUSTA: And what are we to do with that?
>
> DR. GURIAN-SHERMAN: Well, Mr. Chairman, I have perhaps that may help.
> If you look at the decision trees in the \'92 policy, there are
> sections in there that directly relate to exposure of the protein in
> terms of aggregate human consumption. And, so, I believe what Dr.
> Fedoroff is saying that if you have a gene for which you can show that
> consumption is actually lower as a result of the expression of that
> transgene, then that can be taken into account in your risk
> assessment, and it would be a positive risk assessment.
>
> DR. ASTWOOD: I have one comment.
>
> DR. FEDOROFF: And the flip side. Excuse me, let me just finish. And
> the flip side of that is if your target, if what you\'re trying to
> accomplish is to inactivate the gene, then you have to show, in a
> sense, in other words, the required data would be that it is a
> stable\--it is genetically stable, that ability to inactivate,
> particularly in the case of a known allergen, for example. If you\'re
> going to sell the food as a allergen free food, then the need to show
> that as a food safety issue is much, much greater than the need to
> show stability of a trait if it\'s an add-on trait. That\'s a problem
> for the company, in a sense. But when it\'s\--when the objective is to
> decrease the production of a known allergen or toxin, then it becomes
> more important to show that stability, that genetic stability.
>
> DR. GURIAN-SHERMAN: I had one relevant comment, I think, to this,
> which\--I think the concept is a good concept. There are some
> exceptions where we\'re in a little bit of trouble, and allergenicity
> is one of them, because, and this we went through ad nauseam on the
> StarLink issue, where the amount of protein needed to sensitize
> someone, nobody can agree on what that is at this point. So, it\'s
> hard to set that low limit. I mean, I agree with it in principle, but
> we can\'t say that 20 parts per million is okay. You know, 10 parts
> per million\--I mean parts per million is okay. Twenty parts per
> million is not. So, unfortunately, with allergenicity, I mean, I think
> you can say that if there\'s no expression of the protein, we\'re all
> right. But with that particular issue, with allergenicity, we\'re in a
> little bit of a hole.
>
> CHAIRMAN BUSTA: Right. But it is a consideration in that, and
> allergenicity is a different session.
>
> DR. ASTWOOD: This is Jim Astwood. You could actually genericize the
> concept to say that for some categories of products, or for some
> straits, demonstration of expression stability of the transgene is
> much more relevant to the risk assessment than for others; and that
> will be on a case-by-case basis.
>
> CHAIRMAN BUSTA: I see shaking heads.
>
> DR. GURIAN-SHERMAN: I\'m sorry, Jim. Could you say that\--say it one
> more time.
>
> CHAIRMAN BUSTA: Dr. Kapuscinski.
>
> DR. KAPUSCINSKI: Anne Kapuscinski. I just want to make sure we
> remembered what we\'d agree on about three earlier, because we
> actually did\--addressing that question first, and then we went to one
> and two.
>
> CHAIRMAN BUSTA: I think some of these are\--
>
> DR. KAPUSCINSKI: So, I want to make sure we haven\'t erased any of
> that.
>
> CHAIRMAN BUSTA: No, and it shouldn\'t be.
>
> DR. KAPUSCINSKI: Okay.
>
> CHAIRMAN BUSTA: And hopefully in the minutes, under number three, when
> we said we were at number three, and it should be taped\--
>
> DR. KAPUSCINSKI: Okay, because to\--my recollection was we all agreed
> that it\'s a good idea to encourage research and development on
> proteomics and metabolomics, and we\'re still doing that; so
> that\--and especially on the correlation of the data from that with
> food safety\--
>
> CHAIRMAN BUSTA: Right. In relation to food safety.
>
> DR. KAPUSCINSKI: Questions. And really encourage that because that
> would help\--
>
> CHAIRMAN BUSTA: Down the road.
>
> DR. KAPUSCINSKI: So, just\--as separate from the conversation we\'re
> having right now, but I want to make sure that it didn\'t get
> eclipsed.
>
> CHAIRMAN BUSTA: Right. It\'s a
>
> different\--it was a different issue.
>
> I am going to move on to the issue of the letter that three of you
> sent in. There were some items there that we can take now. We only
> have about I would say 10 to 15 minutes to discuss items that you have
> in that letter by the whole committee. I\'d like to keep comments to a
> couple minutes per person so everyone has a chance to comment, and
> include in this discussion of future agenda items. But before we do
> that, I\'d like an idea of just your quick feel of a one-day meeting,
> which this is a first experience, with a one-day meeting. We\'ve had
> day and a half or day and
>
> two-thirds meetings, finishing at 3:00 p.m. for a two-day meeting. Do
> you have a quick opinion on the tolerance to this one-day meeting, or
> do you like a day and a half, or do you like a couple of days. Any
> feelings or opinions?
>
> DR. GURIAN-SHERMAN: I think there\'s a couple qualifiers that make a
> difference here. You know, I think we accomplished a lot in the end.
> It\'s a pretty limited, a fairly limited topic in the whole spectrum
> of risk assessment. So if you have a very limited topic, it may be
> enough.
>
> The other piece of that is to have, you know, which is one of the
> points in the letter, to have adequate time prior to the meeting to,
> for any of us to consider the issues. You know, do whatever of
> background reading research we need to do, so when we come to the
> meeting, you know, we\'re more prepared. And the third point is the
> length of an individual meeting versus the frequency of meetings,
> because, obviously, you know, that\'s going to influence it. So, you
> know, a one-day meeting may be sufficient for a small topic where we
> have adequate\--
>
> CHAIRMAN BUSTA: Focus. As long as we
>
> can\--and it takes a great deal of effort\--
>
> DR. GURIAN-SHERMAN: And adequate time\--
>
> CHAIRMAN BUSTA: To stay on the focus.
>
> DR. GURIAN-SHERMAN: Right. And adequate time. And if we are meeting
> frequently enough to address the issues that the committee needs to
> address.
>
> CHAIRMAN BUSTA: Anne.
>
> DR. KAPUSCINSKI: You know, I would just add to that sometimes we
> don\'t have\--I think for me one of the key issues is to have a little
> more regular communication. And, you know, I\'m overworked, so it\'s
> not necessarily that I\'m looking for more work. But it\'s easy\--if
> we have a little more frequent communication, even if it just means
> that there\'s some sort of update via e-mail to us, once every three
> months of sort of where things stand, update can be just a couple
> paragraphs, that just helps to kind of know where we are, and that
> would also make more effective when we do meet. And it might turn out
> that in some cases, we can have a teleconference meeting, depending on
> the subject at hand. We don\'t necessarily have to always meet in
> person. So more frequent communication might be able to be done
> without the extra cost of always bringing us together, face-to-face. I
> wouldn\'t want teleconferences to replace face-to-face meetings in
> totality, but it could be a useful add-on. I\'ve served on several
> other committees, especially NRC committees, National Research Council
> Committees, where that\'s been used very effectively.
>
> CHAIRMAN BUSTA: No, I don\'t know the mechanics of the official FDA
> advisory committees. You know, as you see, everything was recorded.
> Everything is very, very official, and so I\'m\--and we can look into
> that. We may be able to do that, but I don\'t know if there are
> constraints that other places, like NRC or whatever, would not have.
>
> DR. KAPUSCINSKI: I mean, there could still be speaker phones in a
> public room, where anyone else could come in and listen, and we could
> even hear people give public comment to us.
>
> DR. BENEDICT: The experience that I\'ve had from\--with this committee
> was that if it was a meeting of this nature, it must be public, and
> people have to have a right to come and speak. When we had
> teleconferences, they were with working groups that were subsets of
> the food advisory committee. And we could\--we had a charge to do
> significant scientific agreement of a lot of data dealing with
> particular approval, and then we could have essentially a
> out-of-public session. But then we had to report it publicly. So there
> are a lot of really strange, not strange, there some quite well
> prescribed reasons.
>
> CHAIRMAN BUSTA: What I\'ve heard is number one, the length of the
> meeting is very dependent upon the topic and the breadth in the amount
> of time. It\'s not a matter of whether you need the evening to think
> through the meeting; it\'s more the breadth of the topic; is that
> correct? Is that what I\'m hearing?
>
> DR. KAPUSCINSKI: But add on to that, that we would really appreciate
> getting the briefing materials as far in advance as possible.
>
> CHAIRMAN BUSTA: Yeah. Yeah, I was just trying to dispatch the length
> of the meeting. We\'ll get back. Yes, Dr. Qualset.
>
> DR. QUALSET: This is Cal Qualset speaking. Today we\'ve gone through
> some stuff that nominally will be in a report form. If we were here
> tomorrow morning for two hours, we could edit that, work through it,
> and decide if that\'s what we\--that\'s the product of our meeting.
> That\'s the advantage of the overnight that you can get some thinking
> about it and then consensus when you\--if we\'re asked to do a report.
> And I would favor a couple hours in the next day. And that, from
> coming from the West Coast, it\'s just a little easier to get home on
> the same day.
>
> CHAIRMAN BUSTA: I think you can get home by midnight on your time.
> Okay on the time. That\'s good enough. Now how about the comments in
> the letter? There were three items there that I highlighted but other
> comments.
>
> DR. GURIAN-SHERMAN: Well, I think, you know this goes again to
> something, you know, Abigail had mentioned earlier about the
> flexibility versus specifics. And so the first issue was on guidance
> and guidelines.
>
> I think, you know, the rigidity is a downside, but you can build in
> still flexibility into guidelines and still have some specifics by
> giving caveats and saying, if, you know, other methods can be
> justified, then go ahead.
>
> But the reason that, you know, that that specific was in there was
> because we were starting to consider some specific protocols, or if
> not protocols at least performance standards, such as should we have
> the sequence of the insert. And when were considering allergenicity,
> we were talking about specific at least kind of performance standards.
> How should those tests, you know, be done for allergenicity. And I
> think there\'s two benefits to that if you can build in some
> flexibility as well. One it gives some of the predictability that
> Dennis is talking about having a problem with: that if a researcher
> doesn\'t know what to expect or if the ground going to be constantly
> changing, and that\'s a very
>
> difficult\--if you know what you\'re up against ahead of time, and if
> it\'s reasonable, you can take that into account.
>
> But it\'s the same for the companies as well, I would think; that to
> have some independently determined either performance standards or
> specific, you know, testing standards where they can be developed
> would be useful to everybody to know what, you know, the ground, the
> foundation and the ground, the playing field is. So that was kind of
> the first point that I think needs to be considered. And part of that,
> again, is attached to the second point that, you know, again this goes
> to a study that, you know, that we did that probably most people here,
> or a number of the people, may haven\'t seen. But the concern that I
> have is that we can set up what we consider to be reasonable
> parameters to be looked at in risk assessment. But I don\'t think that
> it\'s a good idea to leave it there and not consider if those are
> being done according to good scientific practice and that the data
> that the Agency is looking at are good.
>
> And, so, that kind of goes to both one and two; and what I would
> suggest, and I don\'t\--you know whether we look at my report of not,
> I don\'t really care. But I think two things that I found very useful
> in doing that report that\--you know, that I think it could be very
> useful for the committee is one, well, the main thing is to actually
> look at what FDA evaluates in some cases and how they made their
> decisions and how they acted on them, because, again, you can come up
> with all the kind of general suggestions or not, but if the process
> for evaluating those is not adequate, then you\'re going to end with a
> product that\'s not great. And I think, you know, there was a fair
> amount of some discussion between, you know, myself and some of the
> FDA people, where we just kind of disagreed about the kind of data
> that they\'re seeing and what they are seeing, what they\'re asking
> for.
>
> So, I\'m kind of just throwing that out as a possibility. I have 14 of
> these studies. They have been cleared through the Freedom of
> Information Act, so they can be made available.
>
> That\'s one possibility, and then the third one goes to some of these
> procedural things that we\'ve talking about: you know, getting
> information, meeting adequately enough, and I think we\'ve already
> discussed.
>
> CHAIRMAN BUSTA: Other comments now on these topics by other members of
> the committee. Anne?
>
> DR. KAPUSCINSKI: Well, just a minor one regarding the third topic
> about process. You know, I think one of the things that had frustrated
> me was just not knowing what the outcome was of the last meeting that
> the committee had; and, you know, I just want to make sure that when I
> put effort into this, that its\' useful so it\'s constructive. And,
> you know, just hearing from Bob Lake today that, yes, they\'re still
> going to do something about allergenicity. They do plan to come back
> to us with recommended guidance, but they just haven\'t gotten to
> that. Even that helped, because without having had any communication
> at all about it in the last year, I just didn\'t know if maybe it had
> fallen into a Black Hole. Maybe it would something we recommended that
> they didn\'t really want to deal with or what. So, that\'s part of why
> I was suggesting earlier, even if the staff could once every three
> months briefly check in with us, and just tell us, this is where
> we\'re at. That would, at least, give me the sense that our
> subcommittee is actually of some value.
>
> CHAIRMAN BUSTA: So major and ongoing communications.
>
> DR. KAPUSCINSKI: And it doesn\'t have to be onerous. I can brief, but
> just to let us know what\'s going on.
>
> CHAIRMAN BUSTA: The format of the
>
> meeting\--these meetings generally, I guess all of them that I\'ve
> been at, have been a presentation sort of bringing the committee or
> subcommittee up to speed on FEA is doing, the various specialists; it
> depends on what topic it is. Presentations. Essentially a
> show-and-tell, and then a discussion. Is the format useful or would
> you rather just get the write-ups and come in and go right, brute
> force, into discussion\--discussion questions?
>
> DR. ARIAS: I just have a suggestion here. It would be nice to know in
> sufficient advance the topic of the subcommittee meeting so that
> perhaps we, as subcommittee members, could provide input to the FDA on
> potential technical expertise that could be presented at the meeting
> as part of the process of discussion that would incorporate, you know,
> sort of an education as well as a point of discussion. The discussions
> today were very useful, but, for instance, I don\'t think at the two
> meetings that I\'ve been involved, we\'ve had a detailed presentation
> by expertise, for instance, in genetic engineering of plants about,
> you know, the molecular basis of the process and sort of a summary of
> the literature to get a sense of the potential risks or not. Most of
> these have been brought, I would say, relatively ad hoc to the
> committee or through our experiences.
>
> I think it would be useful, just for input purposes, if the FDA would
> like to hear about potential topics for discussion and presenters,
> that\--this might be a good opportunity.
>
> CHAIRMAN BUSTA: Other comments on\--
>
> DR. FEDOROFF: There\'s a recent report released in July. Can you get
> the latest report? The big\--
>
> DR. KAPUSCINSKI: Big U.K.\--the GM
>
> plants\--
>
> DR. FEDOROFF: That\'s available on the web, and it\'s a very up to
> date assessment of the procedures, the data on horizontal transfer,
> everything\--
>
> CHAIRMAN BUSTA: So what you would be recommending there, consistent
> here, is that we would be alerted to that ahead of the meetings, so
> you could go into it or, even to the point of bringing in someone to
> summarize for the people who aren\'t up to speed.
>
> DR. FEDOROFF: Yeah. People have summarized. There\'s lots out there
> that you can use to catch up on.
>
> DR. ARIAS: I think particularly the risk aspects of this\--safety risk
> assessment.
>
> DR. FEDOROFF: It\'s a British report is very, very comprehensive\--
>
> CHAIRMAN BUSTA: Anne.
>
> DR. KAPUSCINSKI: Anne Kapuscinski. I think the generic point is that
> it\'s hard for us to feel prepared as best as possible if we get the
> charge very late in the game. So, and I can appreciate that the staff
> is really busy, and they got a lot of pressure on them. And I can see
> why they would be trying to refine the charge at the, you know, right
> up to the day before. But even if they could send us a draft charge so
> that we have a sense of what they\'re thinking about, you know, a
> couple weeks ahead of time. I mean, ideally, it would be about a month
> ahead of time. But at least a couple weeks ahead of time. Then, and if
> they\'ve got suggestions of things that we could read. That\--we,
> obviously, don\'t them to necessarily to photocopy all the relevant
> materials, but if they want to recommend five or six things that we
> look up, great. And plus, if we get that charge ahead of time, each of
> us is reading different aspects of the literature isn\'t on top of
> different things, and we can go and, you know, collate the information
> that we think will help us refresh our minds and sort of prepare us
> for the meeting. Kind of get our head around what the key issue is
> going to be. So, if we can get it earlier, even if it\'s draft form
> and subject to change, that, at least, gets us a sense of what the
> Agency is thinking about, and what it is they would like us to talk
> about at the meeting.
>
> CHAIRMAN BUSTA: I don\'t know some of the official mechanics. You
> know, I\'m a academic. We\'re not very regulated, especially when
> you\'re an emeritus\--then you\'re really not regulated. So I\'m not
> sure of the mechanics. Whether there\'s a problem with sending out a
> draft that then it\'s official, even though it\'s a draft. You know,
> it can go to the news media, and even though it didn\'t surface, and
> it was a draft, it might still
>
> be\--then, I don\'t know those situations.
>
> DR. KAPUSCINSKI: Well, I mean if that is a problem, then at least get
> the final one to us, you know, at a minimum two weeks beforehand.
>
> CHAIRMAN BUSTA: Last call for any comments.
>
> DR. GONSALVES: My brief comment is that, from a format, your prior
> question was the format of this meeting today. I thought it was very
> productive. It was extremely helpful to hear from Bob Lake and what
> the FDA activities are, priorities are, and, of course, the other
> presenters I thought laid the context and landscape of the issues for
> us very nicely. So I\'m very appreciative to the FDA for that.
>
> DR. ASTWOOD: Yes, I\'d say the updates are very important.
>
> CHAIRMAN BUSTA: Well, I would like to thank all of the committee,
> subcommittee, and appreciate all your effort, your intensity, your
> putting up with me as the ultimate, whatever, acting, the acting FBS
> Chair. I would like to thank the staff who are sitting back there, the
> FDA group, for all the preparation, and we appreciate all that you\'ve
> done, and you\'ve heard the comments. We appreciated that
> presentations. Have a good trip home.
>
> \[Whereupon, at 5:05 p.m., the meeting
>
> adjourned.\]
>
> POST-ADJOURNMENT DISCUSSION
>
> DR. GURIAN-SHERMAN: I would just I guess like to say in closing, what
> were trying to get at with this letter, I mean, and entering into the
> public record was a consideration of the issues we were bringing up.
>
> So, I don\'t want to belabor it now. I mean, we\'re running out of
> time. We\'re out of time.
>
> But I think, you know, what I would suggest is that a couple of those
> issues be considered further, and I don\'t know how we would get at
> that or whether there\'s any consensus about that.
>
> But maybe, you know, one way to get at that is if there\'s further
> thought or discussion about the points made in the letter that somehow
> we could consider that as a committee. We\'d be able to dismiss it and
> say, those, as a committee, we don\'t agree with those points, or if
> maybe we should pursue them further.
>
> But I didn\'t want to let it just die here with just making a couple
> of points, and then forgetting about it forever.
>
> CHAIRMAN BUSTA: Well, I think Bob Lake said, you know, FDA does not
> have enough.
>
> \[End of tape recording.\]