**\[DATE\]**

Joyce E. Jones

Executive Secretary

U.S. Department of Health & Human Services

Exchange Visitor Waiver Review Board

200 Independence Avenue, SW

HHS Building, Room 627H

Washington, DC 20201

Re: Request for HHS Waiver on Behalf of Dr. , PhD.

To Whom It May Concern:

I am writing this letter to request that the Department of Health and
Human Services act as an Interested Government Agency in recommending a
waiver of the two year home residency requirement on behalf of Dr. , a
research scientist at .

**[1. Description of Program]{.underline}**

Our research program takes place at the () and is part of the Indiana
University School of Medicine. , located at the , is currently
celebrating its twelfth anniversary. The major goal of the is to foster
cutting-edge basic scientific laboratory research that focuses on the
cellular, biochemical, and molecular biology of cancer. is at the
forefront of maintaining close interactions with cancer clinicians in
order to accelerate the translation of new laboratory findings towards
clinical utility. As such, the Center consistently receives significant
funding from the National Institutes of Health (NIH) in support of our
basic research. One such study currently underway at is a NIH funded
research study focused on the use of certain biologically active
molecules called cytokines to modulate blood cell production during
cancer disease states and treatment with chemotherapy.

Treatment of leukemia and lymphoma includes the use of chemotherapy as
well as stem cell transplantation from bone marrow. Stem cell
transplantation is now the standard therapy for selected patients with
blood cancers such as leukemia and lymphoma. Yet, despite the relative
success of stem cell transplantation, there remains much that is
misunderstood of the genetic and molecular mechanisms of stems cells and
their relation to blood cancers. Consequently, there is clearly a great
need for more effective treatment therapies for these diseases.

Dr. is currently an Assistant Scientist and Principal Investigator at
involved in a number of ongoing studies funded by NIH. One major
research program in which Dr. is engaged focuses on improving the
efficiency of retroviral-mediated gene transfer into hematopoietic stem
and progenitor cells. Retroviral-mediated gene transfer therapy using
human hematopoietic stem cells has great potential because the
hematopoietic stem cells can completely and permanently regenerate to
replace the host hematopoietic and immune systems after bone marrow
transplantation. Hematopoietic stem cells are vital elements in
bone-marrow transplantation, and because they are very rare (\<0.01% in
bone marrow) the ability to genetically reproduce healthy hematopoietic
cells is clinically significant in treating a variety of blood diseases
such as leukemia and lymphoma.

Specifically, Dr. 's research program is working on the use of
retroviral vectors to introduce genes stably and safely into many types
of cells, including primitive hematopoietic cells by integrating them
efficiently into a target cell genome. This is significant because the
introduction of these genes is required to enable the cells to reproduce
by passing the gene onto progeny cells. While it is clear that
transplantable human hematopoietic cells can be transducted with
retroviral vectors, the efficiency levels at which genes can be
transferred into human long term repopulating cells are currently below
the levels necessary to produce any likely therapeutic benefit. Thus,
Dr. 's research is essential to developing new methodologies for
efficiently transferring genes into hematopoietic stem cells to increase
production of these cells, thereby increasing the levels of normal and
healthy cell reproduction.

The research program is experimenting with various methodologies to
improve the efficiency of retroviral-mediated gene transfer into
hematopoietic stem and progenitor cells as well as engraftment of
transduced cells in mice. Our goal is to achieve reproducible gene
transfer to levels that would be adequate for many therapeutic
applications. The objectives of the program are twofold: 1) to
demonstrate that the presence of soluble stromal-derived factor 1
(SDF-1)/CXCL12 during retroviral transduction significantly enhances
efficiency of gene transfer into human and mouse hematopoietic
progenitor cells; and 2) to optimize the retroviral transduction
procedure so that the rates of gene transfer into hematopoietic stem and
progenitor cells using our procedure are higher than those using
conventional therapeutic procedures. In order to fulfill these
objectives, the research program has received significant funding from
the National Institutes of Health, as well as funding from the Core
Centers of Excellence in Molecular Hematology.

The above objectives aim to increase the therapeutic benefit and
effectiveness of retroviral-mediated gene transfer therapy. Already, Dr.
's research has determined that retroviral-mediated gene transfer may
facilitate designing clinical protocols for use in trials and ultimately
lead to reproducible gene transfer levels that would be adequate for
many therapeutic anticancer applications. Having discovered this fact,
Dr. 's research is clearly embarking on a breakthrough discovery
regarding treatments for many diseases including such devastating blood
diseases as leukemia and lymphoma. Needless to say, Dr. is conducting
extremely important work that may help to save the lives of many cancer
patients.

**[2. Exchange Visitor's Essentiality to Program and His Unique
Capabilities]{.underline}**

Dr. was recruited to the research program at the as an expert scientist
with an extensive multidisciplinary background in cell and molecular
biology, biochemistry, immunology, and specific expertise in
intercellular signaling and gene transfer technologies, and as such has
brought unique knowledge and skills to our molecular hematology, and
retroviral mediated gene transfer research projects. Since joining our
research team, Dr. has become more than just an additional competent
researcher; indeed Dr. is now a major contributor to the success of our
program. Dr. has exhibited extraordinary capacity in solving many
problems in experiments. In short, Dr. is a brilliant research scientist
with extensive experience in molecular and genetic level research.

Given his extensive multidisciplinary background, Dr. is playing a
leading role in a number of important research studies in our program.
For instance, as noted above Dr. is an essential member to our team of
scientists working on our research to improve retroviral-mediated gene
transfer. Indeed, Dr. is directly responsible for directing, designing,
and planning our research experiments. Dr. directs the course of our
study and assists in determining our objectives and goals. In fact, Dr.
is also responsible for interpreting the results of our experiments, as
well as providing the literature related to our research programs
objectives, experiments, and discoveries. Furthermore, Dr. has the added
responsibility of overseeing and guiding several M.D./Ph.D. and Ph.D.
graduate students and postdoctoral fellows in our laboratory. Dr. plays
such a leading role in our program because he has contributed greatly to
many of the discoveries we have made since beginning our study.

In addition to his research on retroviral mediated gene transfer, Dr.
has made a major contribution to our research investigation on cell
survival/anti-apoptosis regulation in stem and progenitor cells. Dr. 's
leadership goes to the very heart of our research program for Dr. is
critical to conducting vital research at designed to elucidate the role
of cell survival and apoptosis in connection to the development of
therapeutic treatments for several diseases including Alzheimer's
disease and cancer. There is a serious need for researchers like Dr. who
because of his unique qualifications in cell and molecular biology is
not only essential to our goal of understanding the molecular events
that contribute to cell survival and drug-induced apoptosis, but is also
vital to realizing the impact such research can have on the development
of more rational approaches to therapeutic design and pharmaceutical
treatments.

Specifically, Dr. is evaluating and identifying how apoptosis-related
genes in hematopoietic stem and progenitor cells are regulated in
response to apoptosis induced by a widely used chemotherapeutic drug,
etoposide. Dr. is performing this aspect of the study using the most
cutting edge cDNA gene array technology available. This allows for the
efficient and simultaneous monitoring of the expression profiles of a
large number of genes. Dr. has also used a technique, known as
quantitative real-time RT-PCR (polymerase chain reaction) to identify
alterations in gene expression during response to etoposide-induced
apoptosis in primary human CD34+ cord blood cells and highly enriched
hematopoietic and progenitor cells. The aim of this study is to identify
the basic molecular and genetic components, as well as the main cellular
pathways that govern and mediate the cellular response within
hematopoietic stem and progenitor cells during etoposide-induced
apoptosis.

The results of Dr. 's research project already suggested that TRAIL
(TNF-related apoptosis-inducing ligand) molecules may be used to
directly and selectively induce apoptosis of malignant cells. This
finding enables the potential for their use in the development of more
rational and effective approaches to blood cancer therapeutics.
Furthermore, because the TRAIL molecule, unlike most traditional
chemotherapies, is a naturally occurring immune system protein, Dr. 's
research suggests that TRAIL's use as an anticancer therapy should
reduce the toxic side-effects of most existing chemotherapeutic drugs.
Thus, the identification of those genes that are involved in causing
undesirable side effects associated with most chemotherapy drugs can be
eliminated through the design of screening strategies that would enable
the development of a new generation of anticancer drugs with minimal, if
any, side effects.

Dr. recently submitted an article entitled "*Profiling of Differentially
Expressed Apoptosis-related Genes by cDNA Arrays in Human Cord Blood
CD34^+^ Cells Treated with Etoposide,*" which is currently *in press*,
and is to be published in 2003 by the prestigious scientific journal
[Experimental Hematology]{.underline}. It should be noted that Dr. is
the primary author of this article and that this research is current and
hits the target of our research focus. Moreover, Dr. has also received
recognition as evidenced by his selection for an impressive grant award
from the Core Centers of Excellence in Molecular Hematology (CCEMH) to
fund our retroviral-mediated gene transfer study.

The CCEMH is an NIH funded center dedicated to understanding the
molecular and genetic levels of disease. CCEMH awards very limited,
competitive, peer-reviewed grants to research projects that have
demonstrated great achievements in hematology research. CCEMH recognizes
a great need for research in the areas of translational hematology and
the development of gene transfer technology, and as such recognized the
important contributions Dr. has made to blood-related disease and cancer
research.

Dr. 's grant represents an important contribution to the funding of our
gene transfer study. This is an extremely significant fact because it
means that if Dr. were to return to his home country for two years,
would lose this important portion of funding since the grant is, in
essence Dr. 's. Consequently, the research program would be greatly
diminished without Dr. . Moreover, Dr. is essential to our program
because his abilities and expertise are critical to the development of
new therapeutics for various blood cancers such as leukemia and
lymphoma. Dr. 's work is essential to the further advancement of our
research and the design and development of more effective anticancer
therapies. Moreover, Dr. 's extensive multidisciplinary background in
molecular hematology and gene therapy is important to this research
study. This is because conducting molecular and genetic level research
requires knowledge of cell and molecular biology, intracellular
signaling, the development of retroviral vectors, and gene transfer
technologies. Indeed, Dr. is one of the few researchers who have the
requisite knowledge and experience to grasp the sophisticated issues
that arise in evaluating such complicated research. Thus, the continued
presence of Dr. in this country and the continued progress of his
research are in the direct interest of the United States.

**[3. Information Regarding Current Personnel]{.underline}**

In addition to Dr. , and myself as Principal Investigator and Program
Director at , there currently are a number of key personnel that work
under Dr. 's supervision. The employees include Dr. , M.D., Ph.D., Dr. ,
B.S., and Dr. , D.V.M., each of who participate in the scientific
development of the our projects, and as such are key to Dr. 's research.
These three key personnel are dependent on Dr. , who as a lead scientist
on our projects has spearheaded our research.

**[4. Recruitment Efforts]{.underline}**

While Dr. is indispensable to this nationally important research, we
were greatly concerned that he may be required to return to Peoples'
Republic of China for two years, as required by his current J-1 visa. In
order to avoid a significant loss in the progress of our work, we placed
advertisements for the position: [Science]{.underline} and at the
*American Society for Microbiology* website. The language of the
advertisement indicated that we needed an assistant scientist with
experience in cell and molecular biology, gene transfer and expression.
The advertisement was sufficiently broad enough so as to attract many
applicants, while still tailored to fit our requirements. Unfortunately,
the advertisement failed to yield applicants possessing the requisite
experience and leadership qualifications necessary to carry on these
studies.

**[5. Future of Program if Waiver is Not Granted]{.underline}**

As noted above, Dr. has a unique multidisciplinary expertise in cell and
molecular biology, biochemistry, immunology, as well as immense
knowledge and expertise in molecular hematology, and retroviral mediated
gene transfer therapies. Perhaps even more importantly, he is the
recipient of a grant that is critical to funding our research, which
also evidences his significant contributions to our research. We have
had great difficulty recruiting qualified scientists with such rare
talents, and I find it very unlikely that I will be able to recruit a
research scientist possessing the same qualifications as Dr. .
Therefore, if the waiver is not granted, this aspect of our program will
be significantly compromised by Dr. 's departure. It will be a pity to
have this research program compromised because its successful completion
will have a major impact on the development of new treatments for
cancer.

**[6. Long Range Plans for Exchange Visitor]{.underline}**

With respect to the future of Dr. 's research, the research strategy is
to continue our present research projects with the aim to facilitate the
design of clinical protocols to improve therapeutic efficiencies of such
important treatment regimes as gene therapy. The ultimate goal is to
develop novel therapeutic treatments for several blood-related diseases
such as leukemia and lymphoma. As Dr. is indispensable to our research
program, if the waiver is granted, we would propose to retain Dr. as an
Assistant Scientist, with the possibility of promotion to Associate
Scientist and then to Scientist within the Department of Microbiology
and Immunology at Indiana University School of Medicine, .

**[7. Exchange Visitor's Qualifications]{.underline}**

Dr. has an extensive background in cell biology, biochemistry, and
immunology, as well as specialized skill in molecular hematology and
genetic therapy. Dr. earned a Ph.D. degree from the ), considered to be
one of the top biological sciences graduate programs in the country. Dr.
completed his specialty studies and training in the Department of
Development and Cell Biology, and at the Beckman Laser Institute and
Medical Clinic. Under the guidance of Dr. Michael W. Bern, Ph.D., Dr.
conducted groundbreaking biological research demonstrating that
exogenous genes can be transferred directly into cultured human cells.
In fact, Dr. 's article entitled "*Direct gene transfer into human
cultured cells facilitated by laser micropuncture of the cell membrane*"
is published in the prestigious scientific journal [Proceedings of the
National Academy of Sciences of the United States of
America]{.underline}. While at UCI, Dr. 's research was also published
in the [Journal of Cell Biology]{.underline}. Following this training at
UCI, Dr. was awarded a Postdoctoral Research Associate position in the
Department of Biology at Yale University. During this time, Dr.
concentrated his research on flagellar regeneration, and the results of
his research were chronicled in his article entitled "*Flagellar radical
spoke assembly in Chlamydomona"* published in [Journal of Cell
Biology]{.underline}, and presented at the *Annual Meeting of The
American Society for Cell Biology*.

Dr. has also established himself with distinction in Canada, having held
several important research positions at a top Canadian universities,
including the University of Toronto, the University of Western Ontario,
and the University of British Columbia. It was during his tenure at the
University of British Columbia that Dr. conducted a groundbreaking study
on congenital fibrosarcoma. Congenital fibrosarcoma is a malignant tumor
of fibroblasts that occurs in patients ages two years or younger. Dr. 's
research group was the first to identify a novel recurrent t(12;15)
chromosome rearrangement that fuses the *ETV6* gene from chromosome 12
with *NTRK3* neurotrophin-3 receptor gene from chromosome 15. In fact,
Dr. was directly responsible for cloning the novel t(12;15) chromosome
translocation breakpoint (*ETV6-NTRK3*) in two cases of childhood
fibrosarcoma. This remarkable finding not only reveals a molecular
mechanism that may underlie the distinctive biological properties of
congenital fibrosarcoma, but also provides a potential diagnostic marker
for this tumor. These findings were published in one of science's top
journals, [Nature Genetics]{.underline}. Dr. 's research while at the
University of British Columbia also generated a number of additional
publications appearing in such important scientific literature as the
[Journal of Experimental Medicine]{.underline}, [Blood]{.underline}, and
[Molecular and Cellular Biology]{.underline}.

After his success in Canada, Dr. returned to this country where he held
critical positions as a Ph.D. Level Research Associate at Indiana
University School of Medicine, and as Research Specialist II at the
Herman B. Wells Center for Pediatric Research, Howard Hughes Medical
Institute. In his position as a Research Specialist, Dr. conducted
extensive research in the area of intracellular signal transduction
pathways, making several findings including the characterization of the
molecular, biochemical, and biological defects in a patient with
phagocyte immunodeficiency. Specifically, Dr. investigated how the
regulatory molecules (RHO GTPases) function in hematopoietic cells, and
has identified and characterized a mutation of Rho GTPase, Rac2 that is
associated with human phagocyte immunodeficiency. The results of this
study were published as a very important plenary paper entitled
"*Dominant negative mutation of the hematopoietic-specific rho GTPase,
rac2, is associated with a human phagocyte immunodeficiency*" in the
scientific journal [Blood]{.underline}.

Thus, prior to joining our program, it is clear that Dr. had established
himself for his significant research in the fields of molecular biology
and genetics research. The major impact of Dr. 's work is clearly
reflected in his numerous important papers that have appeared in major
peer-reviewed medical and scientific journals over the past years. These
include a number of first and co-authored publications in the [Journal
of Cell Biology]{.underline}, [Proceedings of the National Academy of
Sciences of the United States of America]{.underline}, [Molecular Cell
Biology]{.underline}, [Journal of Experimental Medicine]{.underline},
[Cancer Research]{.underline}, [Blood]{.underline},
[Immunity]{.underline}, and [Nature Genetics]{.underline}. In addition
to his important publications, Dr. has also presented his research
before a number of professional societies. These include the *Phagocyte
Gordon Research Conference*, and several presentations before the
*Annual Meetings of the American Society of Hematology*.

In addition, the impressive list of high impact journals in which
citations to Dr. 's work have appeared is further evidence of the
widespread impact of his work. This list includes: [Nature]{.underline},
[Biochemical and Biophysical Research Communications]{.underline},
[Journal of Biological Chemistry]{.underline}, [International Journal of
Hematology]{.underline}, [Journal of Immunology]{.underline},
[International Journal of Oncology]{.underline}, [Oncogene]{.underline},
[Pediatric and Developmental Pathology]{.underline}, [International
Immunology,]{.underline} and [Analytical Chemistry]{.underline}, to name
but a very few. In fact, Dr. 's work has been cited over *350* times.
Indeed, such numerous citations in several prestigious journals reflect
the strong foundation Dr. created upon which other researchers in the
field have built their own investigations.

Moreover, the recognition that Dr. has received also comes in the form
of prestigious honors and awards, as well as membership in prominent
medical and scientific societies. For example, Dr. 's research has
attracted the attention of such prestigious granting institutes as the
National Institutes of Health and the Core Centers of Excellence in
Molecular Hematology for his cancer research in the area of
retroviral-mediated gene transfer. Dr. has also received a number of
competitive fellowships, including a research fellowship form the
National Cancer Institute of Canada. In addition, based on
recommendations and his vital contributions to the field, Dr. was
granted membership in the *American Society for Cell Biology*, the
*American Association for the Advancement of Science*, and the *American
Society of Hematology*. Dr. has gained this impressive recognition based
on his extensive history of excellence.

Thank you for your time and attention to this matter.

Sincerely,

**\[Name\]**

**\[Position\]**