2023 UEHIRO-CARNEIGE-OXFORD ETHICS CONFERENCE
PROCEEDINGS OF CONFERENCE REPORT - ETHICS OF CELL AND GENE THERAPY
29 – 30 June 2023
Venue:

NUS Shaw Foundation Alumni House, 11 Kent Ridge Drive, Singapore 119244

Organizers:

Uehiro Foundation on Ethics and Education, Tokyo
Carneige Council for Ethics in International Affairs, New York
Oxford Uehiro Centre for Practical Ethics, Oxford University
Centre for Biomedical Ethics, National University of Singapore

PurposeThe purpose of this conference is to facilitate the exchange of ideas across the Carnegie-Uehiro-Oxford
network in the US, UK, Japan and beyond. The organizers will also use the ideas generated at theconference to shape future programmes at their institutions.

1) The Ethics of Cell and Gene Therapies in a Constantly Shifting Landscape
Dr Henry Greely, Deane F. and Kate Edelman Johnson Professor of Law
Director, Center for Law and the Bioseciences
Stanford University
Basically, what I want to talk about is the ubiquity of change and its implications for the ethical,
legal and social and policy and political implications of biotechnology. I’m talking about changes
beyond the “hype cycle”, where every new technology immediately is heralded as revolutionary,and within a few months plummets to the bottom of everyone’s attention. But then, often, it
comes back up, and goes back down, making the pattern of a sine wave over time.
I also want to talk about changes beyond those occasioned by the long delays that seem to be
inevitable. Although the COVID vaccines are excellent counter-examples, it usually takes several
decades for even successful discoveries to move from the laboratory to the clinic. Monoclonal
antibodies took 20 years to become what they are now—products that include Humira, the bestselling drug in the world. Gene therapy has taken 40 years to get to the point where it's now finallybeginning to be approved. New treatments usually take a very long time to affect the world.
But those really aren't the kinds of changes I want to talk about. Instead, I want to talk about threekinds of changes. First, I want to talk about what happens when the relevant science changes andhow that can upset our ethical, legal, social policy issues. Second, I want to discuss what happens
when changes in other sciences have important indirect effects on the science in question. And
then, third, what happens to technologies when the society goes through relevant changes while
the technology itself is being developed? And I plan to do this in the next 25 minutes or so andthen take questions.

1WHEN THE RELEVANT SCIENCE DOES NOT DEVELOP AS EXPECTEDFirst, what happens when the most relevant science doesn't develop the way it's expected?
Sometimes that's predictable. Sometimes it's not. In January 2015, I had the great good fortune ofbeing invited by Jennifer Doudna to a small workshop in Napa Valley, where the discussion, at her
request focused on issues of human germline genome editing. Jennifer, one of the co-discoverersof the CRISPR technique, was very concerned about the possibilities of human germline genome
editing. She invited a dozen scientists to a meeting of 14 people. My bioethics colleague, Alta Charo,from the University of Wisconsin, and I were the only non-scientists there. We had a fascinating
day's discussion that led surprisingly quickly to a consensus. That consensus led to a joint paperin Science. And that paper was part of what caused the American National Academies of Science,
Engineering, and Medicine to create a special program to look at human genome editing.
I was powerfully struck by the fact that two of the people at the meeting were scientific giants.
Paul Berg and David Baltimore had both won Nobel prizes (so a few years, later, did Jennifer
Doudna), but they were also two of the five organizers of the famous February 1975 Asilomar
meeting, which proclaimed a temporary moratorium on recombinant DNA research. Our meeting
was held almost exactly 40 years after the Asilomar meeting. Both Berg and Baltimore, in talking
about human germline genome editing, said that “we” had said definitively at Asilomar thatscientists would never do germline editing and that it would stay forever. off the table. I asked
them where that was written down or published—was it in the conference’s conclusion statement.
And they said, Well, no, but we were constantly saying it.
One of the truisms about science policy is that it is very easy for scientists to promise not to do
things that they don't know how to do. At the Asilomar meeting, on recombinant DNA, there was
no expectation that human germline genome editing was going to be feasible for many decades,
if ever. So they promised that they wouldn't do it.
In retrospect, it was quite predictable that at some point (it turned out to be four decades later),that human germline genome editing would become feasible. And that is an example of therelevant science changing. A policy was set out by the scientists, in part, for public relations andpolitical purposes, to forswear ever doing something that at that point, they didn’t know how to
do. But then it turned out, they could do it. And so the policies had to be changed and revisited,at least reconsidered.
Human cloning is a second great example. Many of us, who were more than eight years old in 1997,
probably remember the announcement of the birth of Dolly the Cloned Sheep. Dolly was one
sheep, one embryo out of 287 managed to become a living lamb. And yet, as soon as Dolly wasborn, the headlines around the world were filled with stories of armies of cloned warrior slaves.
The hysteria that was triggered by the cloning of Dolly was, in my experience, unprecedented, as
well as inappropriate. But it triggered lots of legislation. 27 American states introduced and about
15 passed laws relating to human cloning. Many other jurisdictions around the world hurriedly did
so. The Council of Europe’s Oviedo Convention was amended, immediately after it was adopted,
to include a ban on human cloning.
But our British friends, taking what some might consider a typically British attitude said “Oh, notto worry, we've already banned human cloning.” I was a little surprised by that, so I looked it up.
2And in fact, in the 1990 Human Fertilisation and Embryology Act, a section forbade the Human
Fertilisation and Embryology Authority the Act create from granting licenses for human cloning.
So the British were right, they had banned human cloning seven years before Dolly. The problem
was, they defined human cloning in that act as replacing the nucleus of a cell of an embryo with anucleus taken from the cell of another person or embryo. That was not the process used to create
Dolly. That process involves removing the nucleus from an egg, not an embryo, and replacing thatwith the nucleus from another cell and then triggering it to develop. The British legislation had
tried to foresee the future in order to prohibit a scientific advance that they didn't like. But thescience took a turn on them that the law didn't anticipate and their ban was ineffective.
Dolly the Sheep not only prompted a great deal of hysteria and legislation, but provided nearly full
employment for bioethicists for about five years. Because debates about cloning, particularly
about cloning humans went on for a long, long time. (There was a lot less concern about cloning
sheep.) At the time, many people said, “I'm going to clone humans.” Some of you may remember
Dr. Richard Seed, a physicist who announced he was going to clone himself. He looked like a cloneof a mad scientist from a movie—perhaps Doc Brown from the movie, Back to the Future. Then
there was a religious cult called the Raelians, founded when a French race driver was visited by aUFO. They announced that the aliens had told them it was their religious duty to clone humans.
They actually announced that they had cloned a human being, a baby was born around Christmas
Day, 2002. They named her “Eve”. But out of respect for her privacy, they never let anyone examine
her to see if she was actually a clone. Except for card carrying Raelians no one don't believe thatthey actually cloned anyone.
We ended up with six or seven years of fervent debate about human reproductive cloning, cloning
to make human babies. In late 2004, Hwang Woo Suk, a South Korean researcher, published papers
in Science claiming that, about seven years after the birth of Dolly, he had become the first person
to successfully clone human embryos. And over the space of the next year, that claim was revealed
as a blatant fraud. Hwang was eventually charged with crimes by South Korea and convicted.
And so the world spent a lot of time thinking that human cloning was really close. We discussed it,lots of countries passed laws on it, but then, after Hwang’s fraud was revealed, the conventional
wisdom became that it was impossible. Many kinds of mammals could be cloned, but not primates,
including humans. And so all that effort to guide the ethical regulation of the technology seemed,in some sense, wasted—the science had not developed the way the scientists, legislators, or
ethicists had expected.
This story has an ironic footnote. In 2013 Shoukhrat Mitalipov, a researcher at the Oregon Health
Sciences University, proved that one could clone human embryos. One of the major “secret
ingredients” to his success, he assured me when we once chatted, was adding caffeine to theculture medium. So if you drink a lot of coffee or tea this morning, be careful—you may be setting
up some of your cells to be cloned. Mitalipov’s feat was replicated in numerous labs very quickly,
but, interesting, no hysteria or ethical discussions have followed. I published a short piece in 2020
wondering where was Dr. Seed? Where were the Raelians? Since cloning human embryos has now
been possible for over a decade, why haven't we heard of people trying to clone themselves? My
guess is that cloning was just old news.

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So human cloning still stands as an example of where we guessed wrong about the relevant science.
We thought the science was going to make human cloning easy. We spent a lot of time in policy
discussions, but then it turned out to be, we thought, impossible. Now it's turned out to bepossible again, but no one's talking about it.
My last example here is one that I know is going to be talked about a lot in this meeting—embryo
research. Similarly to Berg and Baltimore in 1975 forswearing any possibility of doing humangermline editing, it was very easy for the Warnock commission and an earlier NIH commission to
propose the so-called 14 day rule: that human embryos should not be the subjects of research
past 14 days of development. It was easy because, at that point, no one knew how to keep them
alive ex vivo for more than a very few days of development. It was another case of promising not
to do something that they didn't know how to do—and did not know would, or would not, bepossible. As with germline editing, I think it was foreseeable that, at some point, people would
probably discover how to keep human embryos alive in a lab (not a uterus) for more than 14 days.
would learn how to do it. But the 14-day rule bought a truce of almost 40 years. And I know that
Professors Hyun and Lysaght are both going to talk about the embryo research and embryo models,but, in my view, this is another example of science announcing a policy position that, with thencurrent knowledge, is easy to take because it forecloses no research. The policy decision, however,doesn't say “until the science changes.” But the science does change. And when the sciencechanges, the policies have to be reconsidered.
Another issue that I know both Julian and Professor Lysaght are going to talk about is embryomodels. I really wish I were going to be there for that because I find that topic fascinating. In justthe last few weeks, many different groups have announced that they've come up with new anddifferent kinds of embryo models. This is another place where unexpected science raises new
problems. The 14 day rule and other laws, regulations, and guidelines about human embryo
research were created to govern “human embryos, presumably those made by the fusion of egg
and sperm,. (Some of the more careful policies also include the possibility of cloned embryos
being involved.) Nobody regulated thinking about the possibility of models that look like and act
like human embryos but did not involve, directly at least, any eggs or sperm. Are embryo models
governed by regulations and guidelines about embryos? We don’t know. Changes in the relevantscience can force us to revisit policy decisions.
WHEN OTHER SCIENCE DEVELOPS IN UNEXPECTED WAYS THAT AFFECT THE REGULATED SCIENCE
Second, other areas of science may change in ways that have effects on the science you're
concerned with. An example may come from another reason why I'm sorry that I'm not in
Singapore—I wanted to eat the chicken nuggets produced in a vat by chicken muscle stem cells,
which I understand has been legal and sold in Singapore for some time. Two companies just had it
approved in the United States; it’s not yet available to eat, but it should be soon. I wanted to try
it just to see what it was like. I have been interested in cell-line based meat for over a decade,although I've written only a little bit about it.
But in the last few years, I've become less optimistic that it's going to be an important part of
future diets. Part of that is because the techniques have proven—as is always the case inbioscience—to be more complicated than we expected. The one great truth of moving research toclinical use or to the marketplace is that it's always more complicated than we expect. But, for4stem cell meat, the bigger issue is another area of technology that's gotten much better—plantbased meat substitutes. These have gotten to be quite good. I now cook “Impossible burgers”
made from plants rather than beef hamburgers. I don't think I'm going to live long enough to beable to eat an excellent “Impossible ribeye steak” but most beef is used less demanding forms.
And it’s going to be a long time before anyone will make a nicely marbled stem cell ribeye steak
either. The change hasn’t been in the science of stem-cell derived meat, but changes plant-based
meat substitutes now seems to me likely to preempt stem-cell meat.
Another example of this goes back to the cloning fights. I was the main author of a California
commission's report on human cloning, written in the early 2000s. And at that point, there was ahuge fight, both on our commission, but more importantly, between political parties, about what
was called reproductive cloning—using cloning to make an identical twin to somebody—and what
was then called either research cloning or therapeutic cloning. The idea behind the therapeuticcloning was to produce immune compatible cells or tissues for a patient. Let’s say Julian has hada heart attack. The good news is he survives. But the bad news is his heart muscle has been scarredand his marathon time has gone from two hours and 20 minutes to two hours and 40 minutes. (Ihope Julian is chuckling at that idea, especially if the marathon is in the heat and humidity ofSingapore!) But he wants his 20 minutes back.
In theory, we could take human embryonic stem cells, turn them into heart muscle cells, put theminto Julian, have them fit in place, and then his heart would work perfectly. And that's actually
been done in some rodents. It hasn't worked out in humans, yet, but even if it did, the heart muscle
cells derived from embryonic stem cells would likely trigger an attack by Julian's immune system.
And so that concern led to a clever idea: Let's not take just any human embryonic stem cells but
let's make an embryonic clone of Julian, not so it could grow up to be a bioethicist but for its
embryonic stem cells. We want to destroy that embryo at about six days, harvest the inner cellmass cells, turn those into human embryonic stem cells, turn those into heart muscle cells, andput those cells in Julian. And since they have his DNA, his immune system will be perfectly happy
with them.
That was the fascinating idea behind therapeutic cloning. What happened to it? Shinya Yamanaka
did. This Japanese scientist figured out, in 2006 with mice and in 2007 with humans, how to makeinduced pluripotent stem cells. These cells seem, like human embryonic stem cells, to be able tobecome all human cell types but they do not require destroying an embryonic clone of Julian. Now
we don't have to make an embryo of Julian and destroy it; we just have to take a few of Julian's
skin cells, grow them up into a cell line, feed them the right factors, turn them into induced
pluripotent stem cells, turn those into the heart muscle cells, and put those in Julian. Voila! His
marathon time miraculously gets shorter. The idea of therapeutic cloning disappeared because thescience changed—not the science of human embryonic stem cells, but the science of induced
pluripotent stem cells.
I will talk about a few more examples, some of which are going to be talked about later in thisconference. Professor Gyngell is going to talk about the genetic disease, spinal muscular atrophy(“SMA”). A long time ago I had a law student with SMA, who had to use a wheelchair. There has
been a lot of interest in gene therapy to correct the flaws that cause SMA. But the last decade has
seen great progress with drugs to treat SMA. Professor Gyngell’s talk is about choosing between
treating the disease after birth, using genetic selection to avoid the birth of babies would have the5disease, curing the disease in an embryo by genetic editing? The long hoped for “traditional genetherapy” for SMA may not be the common treatment.
This may turn out to be true of a lot of gene therapy because other therapies or interventions will
replace it. My personal favorite example is Cystic Fibrosis. When human germline genome editing
became an issue, I argued was I didn't think it was going to be very important, because almost
everything you'd want to use it for could be achieved through embryo selection by preimplantation
genetic diagnosis. But I always noted an exception. Imagine two people who have the sameautosomal recessive disease. They live long enough, and they're healthy enough, that they wantto have children, but they don't want their children to have their disease. Because each of themhas two copies of the pathogenic variant of the gene, their children would have to get two
pathogenic copies and have the disease. The example I used was cystic fibrosis. People with thatdisease, who used to rarely live to become teenagers, are living into their thirties, forties, andbeyond and doing well. In just the last four or five years, cystic fibrosis treatment has been
revolutionized by old fashioned small molecule drugs. has undergone an old fashioned small
molecule chemical revolution. Miraculous drugs have allowed people with cystic fibrosis (and good
health coverage) to live long and healthy lives.
I had a student this year, a healthy looking young man about 185 cm tall and weighing about 90
kilograms who told me he had cystic fibrosis. At first, I couldn't believe him. He told me that until
he got the drugs three years ago, he weighed 80 pounds less, had almost no muscle, and had tospend many hours a day trying to keep his lungs clear. That's another situation where an expectedscience, gene therapy for cystic fibrosis, may have been preempted by great improvements inalternative approaches.
This kind of unanticipated change will happen in many cases. Just today Stat News had a shortarticle about how the bariatric surgery for obesity might disappear because of new anti-obesity
medications, with effects on the surgeons and the firms that make the medical devices used forthat bariatric surgery.
It is an amazing time in bioscience right now because of all the different plausible approaches todisease. Consider failing kidneys. We can plausibly think about fixing kidneys with drugs or with
devices, including possibly implantable mechanical kidneys. We might be able to increase theavailability of human kidneys for transplant by changes in transplant rules. Or perhaps we willtransplant pig kidneys into humans, but pig kidneys that have been genetically edited so thatpatient’s immune system doesn’t reject them. Or maybe we will use actual human kidneys thatwere grown in pigs. And, ultimately, we could transplant human kidneys that are grown from thepatient’s own cells in the laboratory. We don’t know how to do any of these technical solutions
yet and we probably will never be able to do all of them. Almost certainly, though, we will to beable to do one or more of them. It's a time of almost infinite possibilities, which means many
challenges for who specialize in one approach, whether they are pharmaceutical companies,
medical device companies, surgeons, or regulators. And if you have become specialized in using
the genetically modified pig organs and somebody else is able to do a better treatment using
human kidneys made in the laboratories, your field may disappear. And, if you are a regulator,
your rules and guidelines can become obsolete.

6WHEN THE WORLD CHANGES IN UNEXPECTED WAYS THAT AFFECT THE REGULATED SCIENCE
The last of my three big issues is when the world changes. This can happen in a variety of ways.
I'm sure most, if not all, of you are familiar with the Collingridge dilemma. This states that thetime when it is politically easiest to regulate it a new technology is at its beginning, but at thatpoint you don't know enough about it to regulate it well. After a few years, the problems thatneed regulation become clearer, but by that time, vested interests that built up around thetechnology that make regulation very, very difficult. So that’s the regulatory dilemma: You can try
to regulate early when it's politically possible but you don’t know enough or try to regulate later
when you know better what to do but it's politically hard. That's one example of the societychanging.
Another from my own country, is how various prenatal genetic interventions took on a different
meaning in 2022, one year ago, when our Supreme Court abolished the federal constitutional rightto abortion. Since then, over 20 states have greatly limited or banned abortion, which makes issuesof prenatal genetic diagnosis or of embryonic genome editing much more salient than they werewhen abortions were easily available for everyone as one way to deal with fetuses with genetic
diseases.
Another consequences is that now that abortion is illegal in many states, some advocates forembryos are attacking in vitro fertilization (”IVF”) because it leads to many human embryos being
created but never transferred into a uterus to get a chance at becoming a baby That might haveworked forty-five years ago, but now about 10 million people, all around the world, are alive only
because of IVF. Those people, their parents, their siblings, other people who know them and careabout them constitute a change in the culture that changes what kinds of regulation of thetechnology are possible.
Another important social change has been increased interest in disability issues, particularly, but
not exclusively, those around neurodiversity. The ethical debate about genetic selection, or genetic
editing, or prenatal testing, with respect to Down syndrome, has changed dramatically in the last
20 or 30 years as advocates for Down syndrome, including, occasionally, people with Down
syndrome, have made the case that they aren’t disabled, they're just different. They're
neurodiverse. And we also hear that from people on the autism spectrum, that they don't have adisability, they have a different way of thinking. That sort of social change then feeds back andaffects the policy issues on science.
My last example was important to my own career. Thirty-two years ago I made a choice whether
to focus my career on energy law or health law. I sometimes wonder if I made the wrong decision,as it seems increasingly clear to me that climate change is the most important issue of this century.
But , climate change is not just an energy issue, it's also a biological issue. The urgent need to deal
with climate change is going to change the regulation of some biosciences. For example, I predictthat in a decade or two or less, Europe will no longer ban genetically modified food, because it will
prove much easier to change the genes of wheat, maize, rice (or wine grapes) to let them tolerateheat better than to move all that agriculture 500 kilometers north. Climate change force changes
in how we think about the ethical, legal, social and policy implications of some of the biosciences.

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CONCLUSION
So, what does all this mean? There is a line often attributed to Niels Bohr, although it appears tohave been said first by other Danes: “It's always hard to predict things, especially the future.” Thoseof us who work on the ethical, legal, social, policy, and political implications of advances in thebiosciences need to take that to heart. We have to make predictions about the future in order tomake ethical conclusions or policy recommendations about new technologies. But the future
we're predicting is not only hard to see, but it's hard to see in ways that are changing every minute.
Every time a new paper comes out in a journal someplace, it may change the future of thetechnology you're trying to influence, or to regulate.
So what should we do? We need to be open-minded. We need to be open-eyed. We need to pay
attention. We need to put even more caveats in our papers about assuming that the technology
develops in this direction. We need to be better at monitoring events, paying attention to what's
happening and to make needed adjustments nimbly.
The last thing I will urge may seem an ironic comment to make to a roomful of people working inbioethics areas. Some people might even say that it’s a particularly ironic comment coming fromme. We need to be humble. We need to realize the important limits of our knowledge and of ourability to predict the future and the consequences those limit can have for the ethical, policy, andlegal analysis we make with respect to these new technologies.
Thank you for your time and attention.

82) Unproven Stem Cell Interventions in Japan under the Act on the Safety of Regenerative
Medicine
Dr Misao Fujita, Professor
Uehiro Research Division for iPS Cell Ethics
Kyoto University
My name is Misao Fujita from Kyoto University. I'm so grateful to the Uehiro Foundation on Ethics
and Education, Julian, and the organizers for giving me the opportunity to speak at this prestigious
event today. My talk is about unproven stem cell-based interventions in Japan under the Act on
the Safety of the Regenerative Medicine.
Unproven stem cell-based interventions are now globally acknowledged as the serious problem.
And in this slide, the color-coded map indicates the number of website advertising unproven stem
cell-based interventions by country. The country with the highest number of such websites is theUnited States, with 187 websites.
Moreover, administration of unproven stem cell-based interventions can cause acute or chronic
complications, even deaths in extreme cases. A review article published in 2018 detailed 35
adverse events in 14 countries, including Japan, where one Korean patient died after receiving an
unproven stem cell-based intervention. I will talk a little bit about this case later. Also, this review
paper had cited our previous study on the Japanese court case of a patient who experienced
numbness and became wheelchair-bound after receiving an allogeneic adipose-derived
mesenchymal stem cell infusion. At that time, such interventions were not regulated in Japan
except for research and clinical trial.
This is our empirical data. Before the Act on the Safety of Regenerative Medicine (ASRM) was
enacted, we identified 74 private clinics administering 247 interventions using stem cells or
somatic cells. These interventions were used to treat various diseases, such as cancer,
cardiovascular diseases, gastrointestinal diseases, and for other purposes, such as cosmetic/antiaging treatment and breast/buttock argumentation. However, this was the situation before theimplementation of the ASRM, which regulate private practices, as well as research involving theadministration of human cells.
Yet, even five years after the implantation of ASRM, a Nature article published in 2019, criticized
the Japanese policies as the policies might give people false hope about how effective thetherapies are. However, in order to accurately evaluate the policy, we should identify the situationof Japan with regards to cell-based interventions after the ASRM was enforced.
This is the outline of my talk. First, I will briefly describe the ASRM, which regulates all cell-based
interventions in Japan. Next, I will present our data about the current situation in Japan after theenactment of ASRM. Then, I will discuss various studies on the quality of review by Certified Special
Committees for Regenerative Medicine, which is a sort of ethics committee under the ASRM. And
finally, I will summarize the outreach activities. I'm not sure if I could call it public engagement, but
at least we can call them the outreach activities conducted by us thus far to educate the public onsuch issues. So let me move on to the first topic.

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As some of you may know, in 2010, a Korean patient died of pulmonary embolism after receivinga stem cell-based intervention by the Korean company, RNLBio, at private clinic in Kyoto. Duringthat period, there were three ways of providing cell-based interventions in Japan. The first was
through clinical trials aimed at developing commercial products. All clinical trials were strictly
regulated by the Pharmaceutical Affairs Act. The second was through research conducted atuniversities or hospitals. Research had to be performed in accordance with national guidelines.
The last was in private practices through medical treatments not covered by public insurance andpaid out of pocket by the patient. And at that time, Japan had no regulations regarding theadministration of cell-based interventions in private practice. Therefore, such unsafe and unprovencell-based interventions, which are prohibited in many countries, including Korea, could be easily
administered in Japan.
However, the situation had changed in 2014. The Act Concerning the Advancement ofComprehensive Measures for Citizens to Promptly and Safety Receive Regenerative Medicine wasproposed in April 2013. Based on this act, two more acts were proposed: the Pharmaceutical
Medical Devices and Other Therapeutic Products Act and the ASRM. All these acts took effect in2014, which was called as the “New Year of Regenerative Medicine.”
So, let me explain a little more about these regulations. When companies develop and sell cellular
products, the process is classified as a clinical trial and is subject to the Pharmaceutical Medical
Devices and Other Therapeutic Products. And both research and private practice regulated by the
ASRM. Thus, any cell-based intervention needs approval and must be reported to the Ministry of
Health, Labour and Welfare (MHLW) prior to initiation of the intervention. In addition, more
stringent regulations are placed on cell-based interventions with greater risk, and the penalties
are imposed for violation. I will now explain about this point in more detail.
The ASRM classifies all cell-based interventions into three types of regenerative medicines. For
example, for Class I Regenerative Medicine, the use of ES or iPS cells and gene therapies is
considered to be a high-risk procedure. In this case, a Certified Special Committee for Regenerative
Medicine examines the provision plan and that provision plan is submitted to the MHLW. And aftera recommendation by the Health Science Council, research or therapy can be initiated. For Class II
Regenerative Medicine, the use of somatic stem cells is considered to be a medium-risk procedure.
These differ from Class I Regenerative Medicine, in that no recommendation by the Health Science
Council is required. For Class III Regenerative Medicine, the use of somatic cells is considered to
be a low-risk procedure. These differ from the other two approaches in that research or therapy
can be started after the provision plant is examined by a Certified Committee for Regenerative
Medicine and submitted to the MHLW. The Certified Committee has more lenient competition
requirements than the Certified Special Committee. In this manner, cell-based interventions
administered in private clinics seem to be successfully regulated by the ASRM.
However, unlike many countries, the ASRM does not prohibit the administration of suchinterventions for therapy, which I think is very problematic. So, to illustrate this point, I will show
you a little data from our empirical study on the situation after the enforcement of the ASRM.
First, our research team investigated the type of cell-based interventions administered by private
clinics in Japan. We use the public documents available on the MHLW website since 2017, when
the Regulation for Enforcement of the ASRM was partially amended. We analyze the more than10

3,000 informed consent documents submitted by more than 2,000 medical institutions. We foundthat cell-based interventions were offered for various diseases and conditions. The most common
interventions were the use of platelets for dental treatment, administration of autologous immune
cells to cancer patients, and cosmetic medicine. Several treatments targeted diseases of themusculoskeletal system. You can see that hair loss and menopause are also targeted.
However, some medical societies are against the administration of stem cell “therapies” based on
their literature reviews. For example, the Australasian College of Sport and Exercise Physicians said
that there is still little evidence of mesenchymal stem cell-based interventions for musculoskeletal
conditions such as osteoarthritis, tendinopathy, and osteochondral defects. Similarly, theAmerican Society for Aesthetic Plastic Surgery and the American Society of Plastic Surgeonsreviewed more than 9,000 papers and concluded that scientific evidence is very limited in termsof the safety and efficacy of stem cell-based interventions in aesthetic purposes. However, as
shown in the previous slide, stem cell-based interventions for musculoskeletal diseases and forcosmetic purposes were widely and legally available in Japan.
Furthermore, we found several websites of private clinics in Japan that included sales messages
explaining that cell-based interventions were eligible for “medical expense deductions.” Medical
expense deductions are a tax system in which the government pays a refund to compensate forthe tax burden of people who must pay large amount of the cost of treatment. Therefore, weestimated the total annual amount of refund that the government could pay for cell-based
interventions by private clinics. And as a result, estimated by the “number of patients” whoreceived the interventions, the refund ranged from 94,000 US dollar to 73 million US dollar in fiscal
year 2017, and from 1.7 million US dollar to 135 million US dollar in fiscal year in 2018. Also,
estimated by the “number of the injections” of cell-based interventions, the amount was 1.8
million US dollar to 140 million US dollar in fiscal year in 2017 and 3 million US dollar to 2.2 billion
US dollar in fiscal year in 2018. Of course, this amount does not represent the actual amount ofrefunds paid, as not all patients who receive interventions undergo the process of receiving
refunds. However, these data suggest that there are fiscal risks to society as a whole, in addition
to health and financial risks to individual patients.
But all the cell-based interventions that I presented have been reviewed and approved by the
Certified special Committees and/or Certified Committees for Regenerative Medicine, which arereview committees complying with the ASRM. So next, to examine the quality of the committee's
review, we conducted the following studies as part of the Ministry’s commissioned research.
To assess the quality of the committee reviews, which is quite difficult to define, we first examined
whether the provision plan approved by the committees were reviewed on the scientific basis.
Under the ASRM physicians are required to indicate in the provision plans, including scientificreferences, why they believe that the intervention is safe and applicable. On August 1, 2019, we
obtained 351 provision plans for Class II therapies with more than 2000 references, such as articles,
books, and websites. The results showed that the 20 provision plans did not cite any references,
15 provision plans cited references but were not academic studies or did not have clearer
bibliographic information, 8 provision plans cited articles published in so-called predatory journals,
and 45 provision plans did not cite clinical research articles that confirmed safety. This means that
one-quarter of the provision plan did not have a clear safety rationale. But all these plans wereapproved by the Special Certified Committee for Regenerative Medicine.
11

Next, we examined whether the committees reviewed the qualification of physicians, which areessential for the safe and appropriate implementation of the interventions described in theprovision plans. We reviewed each provision plan to determine if the target disease and theexpertise of the physician implementing the interventions matched. In July 2019, 391 plans were
examined, with 15.9% of all plants having a presumption of a mismatch between the diseases
covered and physician expertise, and 14.1% of plans having a strong presumption of a mismatch
between the diseases covered and physician expertise. In other words, about 30% of the provisionplans have results that raise doubts regarding the expertise of the physicians who will implement
the interventions. Specific examples include a neurosurgeon treating atopic dermatitis; anophthalmologist and an industrial physician treating liver disorders; an obstetrician/gynaecologist
treating myocardial infarction, spinal injury, cerebrovascular diseases, and osteoarthritis.
We were very curious about the reasons behind the committee's approval of such provision plans
and scrutinized the informed consent documents for patients available on the MHLW website. We
found that more than 60% of the provision plans had other plans with provision plans with exactly
the same title, and the contents of the documents were identical among provision plans with thesame title. These findings suggest that many private clinics that provide cell-based interventions
use duplicate plans and informed consent documents. These duplicate documents were reviewed
by a subset of committees.
So next, we investigated these subsets of committee in terms of the addresses, members andminutes. We searched the internet for information, and it was confirmed in four cases that there
was a Company X. They were different companies in each four cases, but a Company X connectedprivate clinics and the Certified Special Committees for Regenerative Medicine that reviewed theirprovision plans. For example, a Company X sells its cells to private clinics and provides the services
to create prohibition plans. At the same time, the company operates a committee to review theplans submitted by the clinics. With such a tripartite relationship, there was a concern that theindependent and fair review required by the ASRM could not be expected.
Finally, we examined 254 private clinic websites that provided Class II therapies. As a result, morethan a half of the clinic websites could fall under the category of exaggerated advertisingprohibited by the Medical Care Act. These websites included such expressions as “strict adherence
to the ASRM procedures,” “approved by the MHLW,” or “reviewed by a nationally certified
committee.” All private clinics performing cell-based interventions must comply with theserequirements. Therefore, labelling them as if they had a special authorization is legally consideredhype.
In Japan, cell-based interventions offered at private clinics are often provided without proper
scientific verification and advertised as special treatments. Moreover, in fiscal year in 2021 alone,according to the MHLW, more than 60,000 patients received such interventions in Japan. Therefore,
outreach activities are very important to educate the public about these issues. We made aJapanese translation of the “Informed Consent Standard for Stem Cell-Based Interventions Offered
Outside of Formal Clinical Trials” issued by the International Society for Stem Cell Research in 2019.
This document outlines the information that must be provided to patients to make an informed
decision regarding such interventions. We have also provided lectures to the general public,
training for local bar associations, and study sessions to the media. We will continue to raiseawareness regarding these issues in the future.
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This is my last slide. We conducted these studies with the cooperation of many individuals. In
particular, I would like to say thank you to Dr. Hatta, a former lab member and now at the Shizuoka
Graduate University of Public Health, who has made great efforts to collect and analyze data withgreat patience. I would also like to thank Dr. Ikka at the National Cancer Center who led some ofthe studies discussed today. Thank you very much for your time and attention.

133) Regulatory Dynamics of Gene and Cell Therapies in JapanDr Jusaku Minari, Associate Professor
Uehiro Research Division for iPS Cell Ethics, Center of iPS Cell Research and Application
Kyoto University
Thank you very much for giving me this great opportunity. I also appreciate all the staff and theorganizations that prepare and support this wonderful conference. My name is Jusaku Minari, andI am from Kyoto University. Today, I offer a presentation entitled “Regulatory Dynamics of Geneand Cell Therapies in Japan.” Along with other countries, Japan has considered and enacted various
ethical and legal regulations for medical research and clinical care. In this conference, I would liketo share some of the key characteristics and lessons of these regulations, which we have learnedin Japan. I hope this talk will be useful for you.
In today’s presentation, I have three topics. First, I will touch on the current international landscapeof cell and gene therapies. This is very important because we must grasp the specific context when
considering appropriate regulations and institutions. Second, I will discuss a previous historicalanalysis of regulations in Japan using an example of genome research. In this section, using thelens of the regulations surrounding genome research, I try to show some specific challenges
regarding the handling of regulations. Finally, I will present a recent analysis of regulations on
regenerative medicine and genome editing therapy. Let’s start with the first topic.
I am very interested in the initiatives of the ISCT, the International Society for Cell and Gene
Therapy. The ISCT published a global regulatory report on cell and gene therapy on June 22, 2023.
This report shows not only representative developing and approved drugs related to cell and genetherapy, but also some of the regulatory issues, including the current situation of the Good Clinical
Practice (GCP) and EU pharmaceutical legislation.
This slide shows the number of gene therapies, genetically modified cell therapies, andnongenetically modified cell therapies by phase. As of June 1, 2023, the majority of therapies werein preclinical development. Eighty percent of gene therapies, totalling 739 therapies, are inpreclinical development, and 23 therapies are in preregistration or Phase 3. Genetically modified
cell therapies stand at 70%, or 804 therapies, in preclinical development, and 14 therapies inpreregistration or Phase 3. A total of 44 nongenetically modified cell therapies are in Phase 3 orpreregistration. The slide indicates that most of the therapies are under review, while some havealready been reviewed at preregistration or Phase 3.
This slide shows an overview of the approved products of these three therapies. As of June 1, 2023,
87 products have been approved globally. Sixty-two nongenetically modified cell therapies, 11
genetically modified cell therapies, and 14 gene products were approved. That is, while themajority of the approved products are nongenetically modified cell therapies, 25 geneticallymodified cells and gene products have already been approved.
This is the list of genetically modified cell products approved over the past ten years. One of therepresentative products is Kymriah, which was first approved in 2017 and is currently approved in
the US, the EU, the UK, Japan, Australia, Switzerland, Canada, and South Korea. Indeed, many ofthese cell products are autologous CAR-T, chimeric antigen receptor T cells, like Kymriah.
This is the list of gene products that have been approved over the past 10 years. One of therepresentative products is Zolgensma, which was first approved in 2019 and is currently approvedin the US, the EU, the UK, Japan, Australia, Canada, Brazil, Israel, Taiwan, and South Korea. Like
Kymriah, which I referred to on the previous slide, many countries have approved this product. In
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Japan, much attention was paid to this drug in 2020. This is because Japan’s health ministry set
the price of Zolgensma at about 167 million yen, or 1.17 million dollars, making it the mostexpensive medication funded by the public system. Such a relationship between emerging drugs
and medical fees will be increasingly discussed in the future.
Regarding the regulations of these therapies and drugs, a revision of the GCP, Good Clinical Practice,is planned. This revision will occur due to the development of designs and technologies of clinical
trials and may provide innovators with additional benefits. The scope and application of therevision will address the incorporation of diverse trial types and data sources in clinical trials.
On the other hand, EU pharmaceutical legislation will also change, representing the largest reformin over 20 years. The aim of this revision will be to make medicines more available, accessible, andaffordable through supporting innovation. The revision includes proposals for a new directive andnew regulations. Currently, six key elements of the proposal are shown. The intention of theseelements includes facilitating better access to new drugs and establishing a more simplified
regulatory framework. From these regulatory changes in GCP and EU pharmaceutical legislation,
it can be said that conventional regulatory systems must come to a turning point to be significantly
reconsidered and revised.
Here, I want to revisit the meaning and significance of regulations. There are various types, suchas legal regulations and nonlegal binding regulations, such as governmental and professional
ethical guidelines. Regulations also include both fundamental concepts and specific procedures. If
these characteristics of regulations are used, appropriate regulations are established andimplemented, and the regulations can contribute to the promotion of science and technology andthe creation of social benefits while avoiding negative risks and side effects. This, by somemeasures, indicates that regulations can be regarded as social constructions. In this case, it ispossible to have various relevant perspectives on regulations, such as the structure of regulations,
regulatory architecture, and the engineering of regulations.
In addition, when regulations are shaped and formed, various philosophies, social values, andconcepts, including equality, diversity, respect, justice, and tolerance, are considered, andincorporated into the regulations. This indicates that the fundamental concepts and incorporatedsocial values among various regulations cannot always be identical.
Dr Mathews and her coauthors have mentioned, through this paper, that our current laws,
regulatory bodies, and other governance structures—both ’hard’ (such as legally binding laws andregulations) and ‘soft’ (such as voluntary guidelines, standards, and norms)—were largely built fora research, development, and market landscape that has changed substantially over recent years.
As a result, our current approach to governance is no longer fit for purpose. I somewhat agreewith their opinions, and to address the current challenges of regulations, I am interested in thenature of regulations.
Here, I want to share a conventional characteristic of regulations for biomedical research in Japan.
In Japan, until recently, soft laws, namely non-legally binding guidelines, have been widely adopted
in Japanese medical research to ensure regulatory responsiveness and flexibility regarding
scientific advancement and societal changes. I would like to clarify this point further in terms ofJapanese soft-law culture.
This paper, published in 2004, is entitled “Administrative Legislation in Japan: Guidelines on
Scientific and Ethical Standards.” Dr. Akabayashi and his coauthors, through this article, showedthat many regulations, including legal regulations, non-legal binding regulations, and ethical15

guidelines, were set around 2000. There was a strong tendency at that time for ethical guidelines,
namely soft laws, to be proactively adopted and established by relevant ministries. In this table,
we can see various sets of ethical guidelines for genome research, research using ES cells, genetherapies, epidemiological research, and clinical research. An example of a legal regulation is the
Human Cloning Prohibition law. In the article, they argued that “a further problem is that thepresence of several guidelines...has caused difficulty and confusion for researchers.”
Another researcher, Dr Tashiro, published an article in 2010, entitled “Unintended Consequencesof Soft Regulations: The Social Control of Human Biomedical Research in Japan.” In the article, hepointed out several things. First, the Japanese framework for the regulation of biomedical researchhas generally been shaped by discussions in ad-hoc committees. Second, this inevitably leads to asituation in which there are no fundamental principles integrating a number of rules. Finally, thecase-by-case response also leads to a confusing situation for researchers. In fact, having many
guidelines without harmonization creates discrepancies among their provisions. These sentencesindicate that a case-by-case approach can be useful for a particular type of research, but there isa negative risk that fundamental rules have not been shaped and formed, causing discrepancies inthe stipulations between different regulations.
Based on the perspectives obtained from these papers, I will explain the second topic, an analysisof regulations for genome research in Japan.
We published this article in 2021. In it, we focused on two sets of regulations for genome research.
One is the Fundamental Principles of Research on the Human Genome, established in 2000 by the
Bioethics Committee of the Council for Science. The other is Ethical Guidelines for Human
Genome/Gene Analysis Research, established in 2001 by three ministries. The former, thefundamental principles, clarifies the conceptual ethical framework for the human genome and its
related research; the latter, genome guidelines, presents concrete practical procedures, including
the specific requirements for informed consent, research protocols, and ethical review. In thearticle, attention was paid to changes in the regulations over the last 20 years, their challenges,
and opportunities to improve the regulations. In particular, we identified three key challenges
regarding regulations.
The first challenge concerns the relationship between fundamental concepts and specificprocedures. While the fundamental principles remain unchanged and are referenced less in thepractice of genome research, ethical guidelines have been repeatedly and dynamically revised toaddress scientific, ethical, and social issues, becoming more detailed and procedurally concretized.
These phenomena could be partly regarded as a formalization of the principles elaborated on in
the fundamental principles and an increase in procedural formalities (not necessarily linked withthe conceptual background) of the ethical guidelines. Therefore, there is an increasing gap
between fundamental principles and ethical guidelines and an increase in the procedural
formalities of ethical guidelines.
The second challenge concerns the relationship between non legally binding regulations andlegally binding regulations. This challenge mainly comes from the specificity of the ethicalguidelines themselves. As I previously mentioned, non legally binding regulations, also called softlaws, have been widely adopted in medical research in Japan to ensure the regulatory flexibility ofscientific and societal changes. However, due to the nature of soft laws, they should complement
relevant hard laws, such as the Act on the Protection of Personal Information (APPI). The ethicalguidelines were revised twice to comply with the APPI. In such situations, there is potential
regulatory-related instability in research developments due to the amendment of both ethicalguidelines and related hard laws, namely, the APPI.
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On a related note, this slide shows the history of governmental ethical guidelines associated withthree medical research fields in Japan: genome research, epidemiological research, and clinicalresearch. Two of the three sets of guidelines were integrated in 2014, and a unified set of
guidelines, Medical and Biological Research Involving Human Subjects, was established in 2021 asa result of the integration of the three sets of guidelines. These guidelines have been strongly
influenced by the APPI. The APPI increasingly influences the nature of ethical and legal regulations.
The last challenge concerns biomedical ethics and the protection of personal information in
regulations. This challenge is primarily associated with the conceptual nature of human-derived
data. Biomedical ethics has mainly been established based on considerations of physical rather
than informational harm. Based on this perspective, specific informed consent, withdrawal ofconsent, and potential risks are stipulated in regulations. While this approach can be useful for
protecting research participants, it can raise challenges in the promotion of data sharing,biobanking, and data-driven research. On the other hand, increasing attention to the protectionof personal information is required. As a result, the concepts of (bio)medical ethics and personal
information are currently mixed in the ethical guidelines. Thus, there is an increasing need to
explore the ethical and legal norms of human-derived data in (bio)medical research.
Here are five key lessons learned from the Japanese regulatory experience of genome research forcell and gene therapy. The first concerns careful consideration of case-by-case approaches. The
second is to address optimizations for the coexistence of hard and soft laws. The third is toconstantly connect fundamental concepts with specific procedures. The fourth is preparation toaddress conceptual confusion, for example, regarding human-derived data. The last is related tothe securement of regulatory stability, with some flexibility. Potential factors that could lead toregulatory instability include research and technological developments, social changes, frequent
revisions and integrations of regulations, and international coordination of regulations. These
things are very important for adjusting and optimizing existing regulations on the one hand; onthe other hand, they could possibly destabilize the current regulatory orders. Therefore, carefulmanagement is needed for these adjustments of regulations.
Lastly, I will present the final topic, an analysis of recent regulations for regenerative medicine andgenome editing therapy.
In Japan, there are at least two key legal regulations specifically related to regenerative medicine,both of which were passed in 2013 and came into force in 2014. One is the Act on the Safety ofRegenerative Medicine, or ASRM, which regulates unproven medical technologies andinterventions using processed cells. The other is the Act on Pharmaceuticals and Medical Devices,or PMD Act, which regulates products seeking marketing approval. We first focused on the left one,
ASRM, to gain an understanding of the concepts and ideas of the law due to its uniqueness.
Regarding the PMD Act, further discussions are increasingly needed in that several key regulations,such as Good Clinical Practice and EU pharmaceutical legislation, will be revised, as I mentioned
earlier.
Regarding the ASRM and PMD Act, this perspective is very important. It is that Japanese oversightof stem cell-based interventions thus distinguishes clinical trials for pharmaceutical marketing
authorization and approval from all other clinical research (e.g., academic research) andunapproved therapies. The former is covered by the PMD Act and the latter, including SCBI
provision by healthcare professionals, hospitals, and private clinics, by the ASRM. In thispresentation, I focus more on the necessity and implications of the ASRM, but not the PMD Act.

17

Regarding regenerative medicine, we recently published an article entitled “Reflection on the
Enactment and Impact of Safety Laws for Regenerative Medicine in Japan.” In this article, we
focused on one set of regulations for regenerative medicine, the ASRM. Two specific reasons forfocusing on the ASRM are that this law includes unique regulations that broadly cover unproveninterventions and therapies in regenerative medicine—in other words, it covers both research andclinical care—and the revision of the ASRM was planned within five years after its enactment.
The article addressed the origin, process, and impact of the regulations and the challenges andpossibilities of improving them. Before the implementation of the ASRM, there were Guidelines
on Clinical Research Using Human Stem Cells for Research, established in 2006 by the MHLW and
Director Notification, set in 2010 by the MHLW for clinical care. At that time, this indicated thatstem cell-based interventions for clinical research and clinical care were separately managed
through two different regulations. In this situation, the progress of regenerative medicine andincreasing concerns about the safety of unproven therapies mainly required robust legal
regulations for both research and care, leading to the establishment of the ASRM.
However, there was significant concern about setting additional regulations. That is, that while thesafe provision of stem-cell based interventions needed to be managed by additional regulations,both academic freedom in research contexts and the broad discretion of medical professionals in
the context of clinical care had to be carefully ensured under the Japanese Constitution and otherspecific laws. I would like to clarify this point further.
The Japanese Constitution stakes out a broad commitment to individual rights and freedoms,
including access to healthcare, in Article 13, and it protects freedom of occupation (associatedwith physicians’ discretion) and academic freedom in Articles 22 and 23, respectively. Again, theJapanese Constitution covers individuals’ free access to healthcare in Article 13, physicians’
discretion through clinical care in Article 22, and academic freedom in Article 23.
In this situation, the committee, associated with the formation of the legal regulation, eventually
advocated that it is acceptable for these freedoms and discretions to be limited in the interest ofprioritizing the protection of human life and health. This helped to justify additional regulation of
medical practice, namely the ASRM. This indicates that the protection of human life and healthcan be clearly prioritized in comparison to individuals’ free access to healthcare, physicians’
discretion through clinical care, and academic freedom.
In the committee discussions, two of the main focuses were determining the ASRM’s scope andshaping terminology. We clarified the discussion in this slide. Which term is better: regenerative
medicine or cell therapy? In the case of regenerative medicine, the term is used to convey the
purpose of a given medical treatment or the outcome of that intervention. If it were defined solely
in terms of the aim of the intervention, the concept could apply to interventions with little or no
efficacy in achieving regenerative functions (namely, the regeneration of biological functions andbodily organs and tissues). In this case, there was concern that non-evidence-based interventions
could easily fall within the official definition of regenerative medicine. If the term were definedfrom the perspective of therapeutic outcomes, however, it would exclude from the act allregenerative therapies in development, including innovative clinical research and practices.
The term “cell therapy” was considered to present an understanding of a given treatment’s
methods to the public. However, it was felt that it might undervalue the concept of regeneration,
which was relatively familiar to the Japanese public, and mislead patients or the public to thinkthat it included nonregenerative cell and tissue transplants. This contradiction reflects the
emergence and development of new, unfamiliar, and unclarified medical interventions.
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Eventually, “regenerative medicine, et cetera” was adopted for consistency with other legal
instruments. This term indicates medical intervention using processed cell products for two
purposes. This definition encompasses a tripartite structure using a specific method and two aims.
“Two aims” mean reconstruction, repair, or formation of the structure or function of the human
body, or treatment or prevention of human diseases, respectively. This approach, which includes
both medical intervention using processed cell products with the aim of reconstruction of thestructure or function and the aim of treatment and prevention of diseases, plays a key role inbroadly covering unproven stem cell-based interventions in research and clinical care.
The emergence and development of genome-editing technologies occurred around the same timethat the ASRM was being considered and developed. In 2015, New Scientist reported that gene
editing saved a girl dying of leukaemia in a world first. In fact, genome editing technologies were
expected to cover many applications, such as cell therapy, organ transplants, and gene drive. There
was a partial revision of the ASRM in 2020, in which it was decided that gene-edited cells (with exvivo genome editing) would be regulated in the same manner as gene-transferred cells, namely
iPS cells, and ES cells. Therefore, the ASRM can achieve some degree of flexibility through a
tripartite structure composed of a method and two aims.
However, regarding genome editing technologies, ASRM covers ex vivo but not in vivo genome
editing. This is because in vivo, namely, the direct injection of the technologies into bodies, isdifferent from medical intervention using processed cell products and is therefore not covered by
the tripartite structure.
This is a tentative map of the regulations associated with genome editing in Japan. After the
emergence of genome editing technologies (i.e., CRISPR-Cas), many regulations were establishedor partly revised. Ten years were needed for these adjustments of regulations. Here is the pointthat I am now explaining. Regarding clinical applications for somatic genome editing, ex vivo
genome editing and in vivo genome editing are regulated differently.
This point is a key challenge of stem cell and gene therapies in clinical research and care and isrelated to regulatory consistency. Regarding stem cell therapy, including ex vivo genome editing,
the ASRM covers both clinical research and clinical care. Regarding gene therapy, including in vivo
genome editing, specific guidelines, such as soft laws and two laws, cover clinical research but notclinical care. These regulations include the Guidelines for Gene Therapy Clinical Research, theClinical Trials Act, and the Japanese Cartagena Act.
Recent discussions about ASRM revisions have noted that the ASRM will cover both gene therapy,
including in vivo gene therapy, and stem cell therapy, including ex vivo gene therapy. In addition,
under the ASRM, these two therapies will be recognized differently, so an additional regulatory
framework for gene therapy will be included in the ASRM. However, we are facing a situation
where further discussion will soon be needed to consider the relationship between the ASRM andother relevant therapies, such as mRNA vaccination and exosome therapy.
In this situation, I think that more attention must be paid to diachronic aspects that reflect theperspective (or nature) of regulations to bridge the past, present, and future. In the current
scenario, while ad hoc regulations are important short-term solutions, fundamental regulations
must be established over time. Moreover, the two types of regulation must always be compatible
with one another.
This concludes my presentation. While rapid developments in cell and gene therapies haveoccurred, model changes in conventional regulatory frameworks have been initiated. In this regard,19careful consideration of the current regulatory culture is needed, where the coexistence offundamental and contextual perspectives should be ensured. In addition, I believe that more
attention should be paid to the diachronic aspects of regulations.

204) The Identity Problem, Gene Editing and the Two-Tier Deontic View
Dr Dominic Wilkinson, Professor
Director of Medical Ethics, Oxford Uehiro Centre for Practical Ethics
University of Oxford
So I should start by thanking the Uehiro foundation for supporting this conference and of course
for supporting the Uehiro centre, Julian and NUS for supporting my visit to NUS as a visiting
professor in Biomedical Ethics, it's fantastic to be here. I'm going to take this discussion in adifferent direction. We've had some very applied, very practical discussion of regulations, I'm going
to wind back to thinking about some fundamental philosophical questions.
So I want you to imagine that you're a decision maker considering ways of preventing a genetic
problem. The particular genetic problem that I have in mind is a condition called familial
adenomatous polyposis, FAP. This is an autosomal dominant genetic disorder, a nasty genetic
disease that causes a predisposition to cancer. Seventy per cent of those who are affected by thisgene will have polyps that develop into cancerous lesions in early adult life. Without intervention,
100% of them will die from cancer in early adult life. And the decision makers are contemplating
two different ways of dealing with this serious genetic disease. One is a type of intervention that
we've been talking about: gene editing, So this is Joanne. Joanne has this disorder. She's had partsof her own colon removed. And she's undergone IVF in the hope of having an embryo without FAP.
Unfortunately, she only has affected embryos, and she's unable to have further cycles of IVF
because of limited access to funding. So she wants to gene edit one of her affected embryos sothat they won't have this condition which she has suffered from. So that's option one. But here's
a different option that the policy makers consider: which to offer funded embryo selection – sothat parents who carry the gene can afford IVF and are able to choose unaffected embryos. So
which of these would be better?
Here’s a different type of choice. This is a population level choice. You're in charge of a publichealth program, and are aware that a commonly used anti-epileptic and I have in mind sodium
valproate, causes a significant rate of malformations, about four in 10. Women who become
pregnant while taking sodium valproate, their fetus could be affected some with very severe
abnormalities, but quite a lot have milder abnormalities affecting their development and learning.
And the decision-makers are considering two different options for preventing these malformations.
One is to identify women taking this drug early in pregnancy and then switch them to analternative drug, or those who are about to start on the on the medication but who are pregnant
to stop them starting on the valproate and start on a different drug instead. Or option B ispregnancy prevention, and to mandate as occurs in the UK, that women who are taking sodium
valproate take contraception. As a consequence, women who are taking Valproate will delay theirpregnancy until a point in time that they're not taking Valproate and fewer children will be bornwith these malformations. So these are the two types of problems.
If we're thinking about a single gene disorder like this cancer gene, we could try and treat it withgene editing or try to prevent it with embryo selection. If we're trying to prevent birth defects, we
could try and do so with pregnancy detection or with pregnancy prevention, which should wechoose?
And one thing that many of you will be aware is there's a crucial or arguably crucial difference
between these types of interventions. So, in terms of the first of these, if we gene edit an embryo,we change a scenario where a child, we can call him Jack, is born with a genetic disorder. If we edit21

a gene, edited Jack will be born instead who will not have this, this phenotype, not have thepredisposition to cancer. Compare this with embryo selection, where a different embryo will be
implanted instead of Jack with familial adenomatous polyposis. Joe will be born who has whodoesn't have this gene.
And the same for our public health program: if we embark on pregnancy detection in earlypregnancy, instead of developing these malformations, these children will be born without thesemalformations. But if we embark on pregnancy prevention, instead of this group of embryos, adifferent group of children will be conceived instead, who will be born without thesemalformations.
Now one attractive answer to which of these we should choose simply says whichever of these isgoing to be most effective, whichever is going to be most likely to prevent the genetic problem ormost effective at preventing the genetic problem, whichever is going to prevent the most numberof cases. However, as I've alluded to already, these are different types of choices. And philosophers
have highlighted that these are different in a potentially morally relevant way. In some of thesecases, the same individuals will exist regardless of the decision that we make. We might call these
individual affecting choices or cases or reasons. The other type are non-individual affecting cases,
where different future individuals will exist, depending on what we decide. For example embryo
selection, or pregnancy prevention. And as Derek Parfit famously described, when we makedecisions that affect who exist, if we fail to make those choices those decisions can't be criticizedon behalf of the children who are born with the malformations, or with the genetic disorders,
because if those decisions had been made, those children would not have been born, a different
children would have existed instead. This is the challenge of the non-identity problem.
Famously, there are three different ways of responding to the non identity problem. One is to thinkof these two types of choices, the individual affecting choice, the non-individual affecting choice
as being very morally different, there's a huge moral significance. Indeed, there is on someaccounts, there is no moral reason to choose between embryos, or to choose to delay a pregnancy
as there will be no children who will be benefited or harmed if we simply prevent pregnancy. So
this is what might be called the “great difference view”. And on this basis, we should morally makeindividual affecting choices. For example, thinking about embryo selection versus embryo editing,
we've got no moral reason to select between embryos, but we have a strong moral reason toembryo edit. That's going to favor genetic modification or pregnancy detection. The alternative
view which was the view that Derrick embraced, was the no difference view: claiming that there's
equal moral reason to choose greater or lower or lesser well being in non-individual affecting or
individual affecting cases. So we might toss a coin, or indeed, we might look at whichever of theseis going to be more effective, which is going to have the greatest chance of preventing the cancer.
Which of these is going to prevent the greatest number of birth defects. Well, there's a third view,and this is a view that a number of philosophers have been drawn is some sort of compromise inbetween. The third view, some difference view, also sometimes called the two tier or midway view,is an attractive sort of compromise, which says, look, there's greater moral reason to make anindividual affecting choice than a non-individual affecting choice, but it might be outweighed by
the numbers. So that's going to tend to favor gene editing or pregnancy detection. But it will
depend on the numbers, on just how different they are in terms of the numbers that will beaffected. The ‘two tier’ in the title refers to the idea that there's this higher tier or the stronger
moral reason for individual affecting and this lower tier of non-individual affecting cases. And there
22are a number of reasons for being drawn to this type of compromise view. The great difference
view seems to have some implausible implications for thinking about climate change, or major
policies that will cause much worse lives to be lived by people in the future, but will affect theconception of many individuals. And the great difference view appears to suggest that there isnothing wrong with risky forms of gene editing like that done by He Jianqui or negligently
preventing failing to prevent teratogenic malformations because different children would be born.
But the no difference view also has seems to have some challenges. It seems to suggest that it's
very wrong to fail to select an embryo with a malformation. In fact, it's equally wrong, asdeliberately causing harm. If we deliberately conceive a child with a disability or we deliberately
deafened a child, for example, in cases of hereditary deafness, it's equally wrong. So the nodifference view also seems somewhat unattractive. So we might be drawn to this compromise.
But the problem which I've come to call the two tier problem is the difficulty of deciding. If wethink there are these two classes of reasons, how much difference is there? These are reallysignificant practical questions. We're interested in practical questions, regulation, questions, policyquestions here. We need to know how different these tiers are. There's good reason to think that
pregnancy prevention is probably going to prevent more cases. But how many more cases does it
have to prevent before we choose this given that it's on the lower tier?
There are a series of problems, in fact, for the two tier view, and I'm going to run through some ofthese and suggest a way of responding to them. One of the problems, which I've already alluded
to, is to identify how many non-individual affecting cases or harms are equivalent to an individual
affecting harm? One of one of the challenges is that the nature of the harm here, and the natureof the reason seems to be different. And it seems very difficult to answer. Nobody that I know ofhas been able to come up with any plausible weighting. It just seems utterly arbitrary to say how
different these are. It's unclear, even how we would begin to generate some sort of weighting
between these two types of reasons.
Next, if we think that, that non-individual affecting reasons are less moral important than
individual affecting reasons, it potentially has some absurd implications. Here's an example tobring it to light. A pharmaceutical company becomes aware that one of its best selling medications
is associated with rare teratogenic side effects. The company decides to mitigate the problem bycombining the medicine with a harmless second agent that has the side effect of altering thetiming of ovulation. As a consequence, any children who develop malformations related to thedrug will be different from children who would have been conceived if the mothers had not taken
the medicine. Now, the idea that this is in some ways a moral improvement, or that thepharmaceutical company has done something good just seems bizarre.
For another example, we might think that more significant phenotypic changes, for example, thoseaffecting the brain might be identity altering, rather than minor changes. But if that's the case, it
seems to suggest that there's a moral reason to make lesser changes or to deal with minor
problems or non-brain problems, because individual affecting choices are more morally significant
than non-individual affecting choices. Again, that seems deeply counterintuitive.
One of the challenges is uncertainty about which cases the same individuals will exist or not.
Sometimes, this is because of challenges with understanding the timing of conception. So Derek
Parfit, made the argument that even small delays in the timing of when parents conceived us
23

would actually have resulted in a different individual existing rather than us. But at least within a
one month period, when there's a single ovum, there's going to be a degree of uncertainty. There's
a possibility, even if very small, that the same sperm and egg could have combined. How do wedeal with cases where it's possible that that the same individual would have existed? There arereal uncertainties, not only in whether the individual would have existed, but also whichcounterfactual we think is the relevant one for deciding whether this is an individual or nonindividual affecting case. And I've alluded already to the idea that, depending on the nature of thegenetic intervention, we may or may not think that that affects the identity of the individual who
exists. But it's, again, it's very difficult to, to know, in individual cases, whether that will effect thatwill mean that a different individual will exist. Presumably, very small, genetic modifications won't
lead to a different individual existing, while very large will. But in between, there's going to besignificant uncertainty. Should we treat these as on the high or the lower tier? I think there's, it's
very difficult to know.
One of the challenges that Derek Parfit identified for this view, which he explored in his final paper,
published in Philosophy and Public Affairs after he died, were some intransitivities if we think thatthat that these reasons are on different tiers, and we're considering different options. We may be
led to paradoxical sequences of choices where Option A is inferior to Option B, option B is inferior
to Option C, but option C is inferior to Option A. One of the things that, in particular, these
intransitivities seem to be a problem for is a view that we might call the Two Tier Telic view. And
that's the view according to which the outcome of individual affecting choices is of greater value
than the outcome of non-individual affecting choices with equivalent effects on wellbeing. This is
the claim that the outcome, and when you've got a child who's been gene edited, who doesn't
have the cancer gene is better than the outcome of a different child existing, who doesn't have the
Adenomatosis Polyposis gene. When you have these notions that there's different value to theseoutcomes, it leads to these particular problems of intransitive choices. But this particular way ofinterpreting Two Tier views is not the only way that we might interpret Two Tier views. In particular,
we might be led to think that the reason for responding to these different choices in a different
way, comes from a different source.
So here's an example, that is developed from an example of Derek's but is one I developed a bit
further. It's a case that I call Death at 60. Geneticists have recently identified a rare genetic disorderthat's asymptomatic until it causes sudden death at age 60. There's no cure for this genetic disorder.
But with costly medical treatment, it's possible to postpone the effect of this genetic disorder fora short period, Jack has just turned 60 and has been identified with a gene. And I'm Jack's doctor.
With treatment, I could enable him to live for a year to the age of 61. However, there's limited
funding available for treatment of this disorder. And for the same cost. population screening could
identify a couple who are carriers for this gene, enable them to undertake IVF and embryo
selection. And if this is chosen, future Jane, who will live for 80 years, rather than future Sall, who
would live for 60 years, will come into existence. Now, if we think about a case like this, should this
doctor choose to prolong Jack's life, save Jack's life, give him an extra year of life, or cause it to bethat a different individual, Jane, rather than Sally will come into existence and live for 20 years
longer. It's very clear that the outcome of the latter would be much better. But nevertheless, if
you’re Jack’s doctor, you have a very strong reason, I think, to save the person in front of you. And
the source for that comes not from the value of the outcome, it comes from a different source.

24

So this is the view that I call the Two Tier deontic view. And the idea is that the moral reason to
make an individual affecting choice is stronger than the reason to make an equivalent nonindividual affecting choice, if and to the extent that agents have special obligations to benefit orprevent harm occurring, to existing or to specific future individuals. So the idea is that the greater
reason that we have to make individual affecting choices comes from our moral obligations, rather
than from some difference in the value of the outcome itself. Here is another case which mightprovide some intuitive support for this for this view. This is what I call Future Death at 60. So,
geneticists have recently identified this rare genetic disorder that causes sudden death at age 60.
There is no current cure or treatment for the disease. Exactly as described before. there are limited
resources available to research this disorder. In one option, resources are spent developing
medical treatment, which is not yet currently available, and future Jack will be able to be treated
and live to age 61 rather than dying at age 60. Or for the same cost, population screening could
identify a couple who are carriers for this gene, enable them to undertake IVF and embryo
selection. And if this is chosen, future Jane will live for 80 years, rather than future Sally will comeinto existence. So in this scenario, we're contemplating whether we should invest in developing atreatment that will be of limited effectiveness, or in identifying couples who carry this gene,enabling them to have embryo selection. These are not individuals who currently exist, they're notindividuals to whom we at present have ethical obligations. And I think in this case, it seems much
more plausible that we should choose to devote our efforts on pre Implantation Genetic Diagnosis,
identifying the carriers and preventing the disorder through embryo selection.
Why should why should we be drawn to this two tier deontic view? Well, I think if there is a reason
between these two tiers, between individual affecting and non-individual affecting choices, it can't
be related to the outcome, because the outcome is the same, the same number of individuals, inthese cases, will exist with disabilities or with serious disorders. And if it is, if there is a difference,
it relates, obviously to the idea of causing harm or benefit to individual; it's a function of what weare doing to them. And potentially, it’s agent relative because it's a function of our relationship to
the individuals who will be thereby harmed or benefited. One advantage of this view is that it
explains the significant intuitive difference. One of the puzzles of the two tier views is that in somecases, it seems that there's a big difference between these individual affecting and non-individual
affecting cases. And in others, it seems that there isn't. So the public health program I describedat the start of this talk is based on an example that Derek Parfit gave, where it seems reallystrikingly obvious that there isn't a big difference that you should go with whichever is going to be
more effective. Whereas other cases, particularly the Death at 60 type case, but maybe some ofthese gene editing cases, we have a different intuitive response. And one of the reasons one of the
explanations, I think, is because of our relationship to the individuals who will be affected. Here's
a type of explanation that Julian might be sympathetic with, even though I'd suspect you won't
embrace the conclusions that I come to. So we can think of these reasons that apply as vectors.
There are two types of reasons that apply in these cases. One is in terms of the consequences, theother is in terms of our ethical duties to the individuals who will be affected. And when we thinkof them as vectors, we can see that sometimes these will converge, and sometimes these will
diverge. It also explains why I think people come to different answers about these cases.
Consequentialist, typically tend to focus on this particular reason (the outcome), and identify nodifference between cases. But those who identify the significance of moral duties, even at a costof consequences, have often said, that it feels different when individuals are harmed or benefited.

25

What are the practical consequences if, drawing on this model, we adopt the two tier deontic
view?
Well, I think in terms of public health policy, for programs like preventing birth defects, thosepolicymakers have duties to the population to minimize the harms of drugs that are prescribed toprospective parents. They have duties to society, but they have low or no duty to specificindividuals. And I think that they ought to, as a consequence, choose the option that will optimize
the outcome, that will prevent the most cases of valproic acid associated fetal malformations. Oneof the attractions of this type of answer is that when we're thinking at a policy level, it takes awaysome of these headaches of working out, how many of these cases are actually individual affecting
and how many are non-individual affecting? It takes away this concern that people will manipulate
the reasons because actually, they're equivalent. And the challenge of indeterminacy, either ofconflicting counterfactuals, or degrees of genetic manipulation no longer become as troubling.
What about fertility treatment and gene editing? We've had lots of talk about gene editing. Well,again, if we think about this at a policy level, I think there's a strong reason that we should think
about gene editing versus embryo selection, in a parallel way, and look at which is going to be mosteffective, and most cost effective. In terms of preventing these significant genetic disorders, weshouldn't necessarily prefer non-individual affecting forms of gene editing because there'll be lesslikely to harm individuals.
However, it may be that particularly when you're thinking about the professionals who are
involved in providing fertility treatment, and gene editing, that they may feel that they have somespecific obligations to the individuals who will be conceived as a result of their actions. So they
may be particularly concerned about the harms and benefits that will result to the individuals who
they've been instrumental in conceiving. And it's possible, that legal liability might track individual
affecting harm and benefit. Some of you may have encountered the case of Evie Tombes. This is ayoung Paralympian with spina bifida who is now 20, who sued her GP, because the GP had failed
to give advice to her mother about taking folate during pregnancy. Her mother had been to the
GP seeking conception advice, and the GP had not advised taking folate prior to conceiving her
child. Her child developed Spina Bifida, a disorder that's significantly preventable by taking folic
during pregnancy. It was absolutely clear and accepted by the court that if the GP had told themother to take folate, that she would have delayed conception, because she got pregnant actually,
very soon after seeing the GP. And so if he had given that advice, a different child would haveexisted. Evie Tombes would not have been born and nevertheless, in this case, the judge awardeda large amount of damages. Now, you can interpret this case in a number of ways, you could saythat the judge was philosophically mistaken to award liability in this case; this is a non-individual
affecting case. You could say, look, what they were identifying is that there was a significant wrong.
They needed to compensate for it. They thought it was an important, albeit non-individual
affecting wrong and that they didn't think that the fact that she wouldn't have existed changed thenature of the wrong. But in terms of the argument that I'm making, what this suggests is thatliability may apply or may not differ in these types of cases, purely on the basis of, of whether thesame individual will exist or not.
I've alluded to different decision makers. I talked about policymakers and professionals. But ofcourse, parents make these types of decisions. And parents may have a consequentialist duty,
Julian's duty of procreative beneficence to think about the well being of the different possible
26

children who they could bring into existence. But they arguably also have duties to the specificfuture children who they will conceive, and they may, on that basis, plausibly have a stronger
reason to cause an individual affecting benefit to avoid an individual affecting harm. So from thepoint of view of individual prospective parents, they may have greater reason to choose gene
editing than embryo selection, thinking about the children they may conceive.
I'm conscious of time, I'm going to run through the some of the potential counter arguments fairly
quickly. So one of the obvious arguments against the two tier deontic view is that it will predictably
lead to a worse outcome if you think that there's a, a greater reason, in at least some cases, tochoose individual affecting choices, notwithstanding that will lead to more cases of disability morecases of, of harms from taking drugs during pregnancy, for example. But as I've alluded, that's going
to be diminished, because I think these large scale choices, these policy choices, these choices
about whether we should fund gene editing, or embryo selection, we should treat thesesymmetrically. When we make decisions at scale, we ought to treat them symmetrically. So that
won't lead to, to, to worse consequences overall. And of course, it's inevitable that whenever we
deviate from the consequentialist outcome for other reasons, that will have that will have negative
consequences. And that in itself doesn't mean we're wrong to deviate from it. Again, it's a questionof weighing up these vectors.

275) Drugs, Genes and Screens: The Ethics of Preventing and Treating Spinal Muscular Atrophy
Dr Chris GynGell, Senior Research Fellow in Biomedical Ethics
The University of Melbourne
I want to thank the Uehiro Foundations for supporting this event. I also want to thank Julian, firstfor inviting me to talk, but also because this talk I'm giving is based on a paper which we've co
authored, together, along with a medical geneticist at the Murdoch Children's Research Institute.
I'm going to be speaking about ethical considerations for cell-based interventions for spinal
muscular atrophy. I'm hoping this talk sort of melds together some of the earlier practical andempirical talks with some of the philosophical issues raised by Dominic.
So first, a bit of background on spinal muscular atrophy. It's the most common inherited lethal
neurodegenerative disease.
Carrier rates for spinal muscular atrophy (SMA) vary by ethnicity. In Australia, about one in 40
people are carriers. This results in approximately 30 babies being born with SMA annually. In
Singapore, this number is slightly higher, with around 50 to 60 children born with the condition
each year.
SMA is caused by a deletion or mutation in the gene responsible for the production of the survival
motor neuron 1 (SMN1) protein. This protein is crucial for muscular function and facilitatescommunication between nerves and muscles. In severe cases, affected children can't produce thisprotein due to the gene's mutation. The outcome is heart-wrenching: children develop typically
until about six months of age, after which there's a noticeable decline. By then, they stop meetingdevelopmental milestones and eventually lose the ability to use their muscles. This can lead tofatalities from respiratory failure. In the most extreme cases, the maximum lifespan is roughly two
years.
This genetic condition is intricate. Besides the SMN1 gene, there's another called the survival
motor neuron 2 (SMN2) gene. Though it sometimes produces a functional protein, it does so at
about 15% of the rate of the SMN1 gene. People have varying numbers of SMN2 gene copies,
which leads to four different types of SMA, the severity of which depends on the presence andfunction of these genes.
Up until a decade ago, witnessing a child with SMA was heartbreaking as there were no available
treatments. However, in recent years, interventions have emerged, providing some hope. One
such treatment is Nusinersen, which costs approximately $750,000 initially, followed by yearly
treatments costing around $375,000. It doesn't act on the mutated SMN1 gene but targets the
SMN2 genes to increase the production of the functional SMN protein. Another significant
breakthrough is Zolgensma, a gene therapy that introduces a functional SMN protein to cells. It
was one of the most expensive treatments ever approved by the FDA. Yet, as time has progressed,
similar therapies have been approved, some reaching up to $3.1 million for a single treatment.
While these developments are groundbreaking, we must also consider preventive measures. Preimplantation genetic diagnosis (PGD) is a widely recognized method. Relevant for those with afamily history of SMA, it involves producing embryos through IVF, testing them for mutations, and28

only implanting the ones with a functional SMN1 gene. This process costs roughly $15,000.
Another approach involves prenatal testing and potentially terminating pregnancies where SMA is
detected. As technology advances, SMA could be a target for gene-editing techniques like CRISPR,
providing another preventive avenue.
However, for any treatment or prevention strategy to be effective, early diagnosis is essential.
Newborn screening programs, such as the one added to the US's recommended uniform screening
panel and some in Australia, are critical for timely intervention. Similarly, for preventive measures,
carrier screening programs, like Australia's "Mackenzie's Mission", are essential.
The availability of multiple options now raises questions for governments and individuals regarding
prioritization. In a world with limited resources, challenging decisions need to be made. While I'll
mainly focus on government policies, it's essential to recognize that individuals also face criticalchoices concerning their health and that of their offspring. In the subsequent discussion, I will
delve deeper into the ethical considerations to provide a framework for these decisions regarding
SMA interventions.
The first area of ethics I'll explore is the disability critique of disability screening. Evidently, asignificant difference between ex ante and ex post approaches is that the former involves selecting
against or preventing the birth of someone with a disability, while the latter treats the individual.
There's an extensive discourse about the disability critique of such screening.
I've identified two primary considerations. The first is the expressiveness argument, which posits
that when we select against embryos predisposed to disabilities, we may be conveying a
prejudiced view towards disabled individuals. This could mirror the everyday discrimination facedby people with disabilities. However, applying this argument to conditions like SMA, which can befatal in early childhood, is challenging. Some types of SMA might allow a person to live longer, butconditions causing death before age two express a different sentiment.
The second critique is the intolerance argument. It suggests that by screening against disabilities,
we display an intolerance for diversity, not valuing the insights and contributions disabilities mightbring. For instance, some argue that conditions like autism or dyslexia bring cognitive diversity
beneficial to society. Yet, it's challenging to extend this viewpoint to diseases like SMA that lead toearly death. While diversity is valuable, not all diversities, especially those causing early mortality,
should be preserved or regarded neutrally.
To summarize this section, while the disability critique literature offers valuable perspectives, it
doesn't decisively guide our decisions on SMA interventions.
Turning to fundamental ethical principles, autonomy stands out. This principle underscores that
individuals should have the autonomy to make decisions about their lives. In the context of SMA,
this means providing people with various options. In essence, all the interventions expand theoptions available to individuals, especially compared to a decade ago.
However, to genuinely make informed choices about all treatments, one needs to know theircarrier status for the SMA mutation. We argue that this is only feasible with carrier screening
options. Without carrier screening, options like PGD and potential future gene editing treatments
29are not genuinely accessible. Thus, if we aim to support maximum autonomy and offer individuals
a full suite of options, prioritizing carrier screening seems essential. This would allow individuals
to understand all available treatment options and make informed choices among them.
Let's consider beneficence. The central idea is that we aim to benefit people through theseinterventions. The concept of benefit can be segmented into two primary facets: the duration oflife and the quality of life.
Comparisons between ex post treatments are straightforward. For instance, consider the genetherapy which introduces a functional plasmid into your bloodstream to produce the necessary
protein, versus nusinersen which necessitates annual spinal injections. Preliminary studies suggest
the gene therapy yields more significant benefits, potentially extending life by anywhere from 19
to 74 years compared to nusinersen's 5 to 20 years. Additionally, the gene therapy is less invasive.
However, it's more challenging when comparing the beneficence of ex post and ex anteinterventions. Pre-implantation Genetic Diagnosis (PGD) results in a child with a functional SMA
gene, leading to normal life expectancy and motor function. Moreover, PGD is considerably morecost-effective than ex post treatments. Yet, the catch is that PGD alters the identity of the childthat would be born. For instance, if a couple chooses nusinersen and has a child, Julian, with SMA,
the treatment can prolong Julian's life from an expected two years to potentially seventy. However,if the couple opted for PGD, they might have a different child, Kathy, with a normal lifespan. While
Kathy benefits from a standard life expectancy, it's not because of the PGD.
Essentially, ex ante methods offer an "impersonal" benefit; they don't provide person-specificadvantages or disadvantages. How one approaches the philosophical 'non-identity problem' will
influence how one prioritizes these treatments. Some might argue PGD doesn't benefit anyone,
while others may deem its benefits equivalent or even superior to ex post methods due to its
outcomes and lesser invasiveness.
Now, shifting to justice. When contemplating health resources, an intuitive perspective is that weshould maximize the number of people who benefit. In public health systems with limited
resources, choosing an expensive therapy comes with the opportunity cost of forgoing treatment
for another condition. Therefore, justice often necessitates the selection of the most cost-effective
option, a principle rooted in distributive justice.
This necessitates an examination of the economic efficiency of possible medical treatments.
Knowing one is an SMA carrier presents a compelling case to endorse preventative measures, like
PGD and prenatal testing and termination, rather than post-diagnostic interventions such as
nusinersen. There is a need for further empirical studies to evaluate the cost-benefit analysis ofcarrier screening, particularly for SMA. However, when this screening is paired with tests for other
Mendelian disorders, it becomes increasingly apparent that advocating for such programs isjustified on ethical grounds. Moreover, there is a compelling argument rooted in distributive justiceto provide carrier testing, PGD and IVF, or prenatal testing and selective termination at no cost to
the couples affected.
In summary, A variety of new strategies are emerging that aim to alleviate the impact of SMA on
affected families. These developments bring about complex issues concerning the allocation of30

resources. The ethical principles of autonomy, beneficence, and justice favor addressing SMA
through preventative measures, such as PGD, prenatal testing, and termination.
A couple opting for PGD to have a healthy child—especially when their subsequent child is at riskof SMA—bestows significant advantages upon their future child, granting them the prospect of alife without disability and with normal longevity. This benefit is substantially more pronounced
than what is typically achieved through post-diagnosis treatments, which are not expected toentirely eradicate SMA. Prenatal testing and termination also emerge as highly advantageous
options for couples likely to conceive again. However, the ethical principle of beneficence doesn’t
uphold these measures in scenarios where termination doesn’t pave the way for the birth ofanother child.
Justice-based arguments also advocate for preventative measures. PGD and prenatal testing andtermination are considerably less expensive than post-diagnosis SMA treatments. Prioritizing costefficient solutions facilitates a fairer distribution of medical resources across the population.
The superiority of preventative measures underscores the importance of enhancing SMA carrier
screening. Prospective parents, when informed of their carrier status, are empowered to makewell-informed decisions regarding the choice of treatments. Autonomy is thus bolstered by carrier
screening initiatives. Furthermore, as these screenings bring prenatal testing and PGD to the fore
for at-risk couples, they concurrently foster beneficence and autonomy.
Thank you for your time, and I again want to express my thanks to the Uehiro Foundation forsupporting this conference.

316) Moral Obfuscation: The Sad Story of Synthetic Embryos
Dr Julian Savulescu, Chen Su Lan Centennial Professor in Medical Ethics
Director, Centre for Biomedical Ethics
National University of Singapore
Scientists this year have created embryo models. According to The Guardian newspaper(“Synthetic human embryos created in groundbreaking advance”, June 14, 2023), scientists saythese model embryos, which resemble those in the earliest stages of human development, could
provide a crucial window on the impact of genetic disorders and the biological causes of recurrent
miscarriage.
However, the work also raises serious ethical and legal issues as the lab-grown entities fall outsidecurrent legislation in the UK and most other countries. The structures do not have a beating heartor the beginnings of a brain, but include cells that would typically go on to form the placenta, yolk
sac and the embryo itself.
Prof Magdalena Żernicka-Goetz, of the University of Cambridge and the California Institute ofTechnology, described the work in a plenary address at the International Society for Stem Cell
Research’s annual meeting in Boston in 2023.
“We can create human embryo-like models by the reprogramming of [embryonic stem] cells,” shetold the meeting.
The motivation for the work is for scientists to understand the “black box” period of developmentthat is so called because scientists are only allowed to cultivate embryos in the lab up to a legal
limit of 14 days.
Robin Lovell-Badge, the head of stem cell biology and developmental genetics at the Francis Crick
Institute in London, said: “The idea is that if you really model normal human embryonicdevelopment using stem cells, you can gain an awful lot of information about how we begin
development, what can go wrong, without having to use early embryos for research.”…scientists in the UK and elsewhere are already moving to draw up voluntary guidelines to govern
work on synthetic embryos.
“If the whole intention is that these models are very much like normal embryos, then in a way theyshould be treated the same,” Lovell-Badge said. “Currently in legislation they’re not. People areworried about this.” (The Guardian)
There is also a significant unanswered question on whether these structures, in theory, have thepotential to grow into a living creature…. Scientists say it is not clear whether the barrier to moreadvanced development is merely technical or has a more fundamental biological cause.
“That’s very difficult to answer. It’s going to be hard to tell whether there’s an intrinsic problem
with them or whether it’s just technical,” Lovell-Badge said. This unknown potential made the needfor stronger legislation pressing, he said. (The Guardian)…So far, no one has made embryo models that have the capacity to develop into human beings,
but a recent study on monkey embryo models showed that such models could induce pregnancy(which terminated spontaneously soon after) if placed in the uterus.
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… Research on natural human embryos tends to observe a widely adopted guideline — enforcedby law in many countries — that human embryos should not be cultured in the laboratory beyond
14 days.
But because in most countries’ embryo models do not meet the formal definition of an embryo,they are not subject to such restrictions.
“We sought to develop a tool to ask specific questions about the second week of human embryo
development, since using actual human embryos in research is ethically and technicallychallenging,” says Zernicka-Goetz (The Guardian)David Albert-Jones, writing in Bioedge (“Why are scientists boasting of creating ‘synthetic humanembryos’?, June 20, 2023), observed,“If this really is an embryo, and it looks a bit like one, then this is a new way of generating anembryo without fertilisation. If cells from an adult could be used, then synthetic embryos would
be a new form of cloning. This would be wrong for all the same reasons that the old way of cloning
a person … was wrong.
“A synthetic embryo is not a ‘model’ of an embryo, it is an attempt to make an embryo. If thisattempt is successful, scientifically, then it will be wrong ethically, but if it is not successful
scientifically then it will not be able to tell us much about normal human development.”“So far they have not succeeded even in mice in getting ‘synthetic embryos’ to develop to birth.
So perhaps this is not an embryo but an uninteresting clump of cells. On the other hand, if we haveany doubt then the embryo-like being should be given the benefit of the doubt.”
That is an argument I have made in relation to brain organoids and chimeras.
Moral Obfuscation
One of the work-arounds scientists have employed is to develop these with genetic modification
to ensure they cannot form a placenta. Thus they do not have the potential to form a human being.
But this kind of work-around is essentially disabling something with the potential to form a humanbeing so that it no longer has the potential to form a human being. This argument would not be
persuasive if we took a normal human embryo and genetically engineer it so it could not produce
a placenta, and then saying, “It no longer has the potential to form a human being so we canexperiment on it as we would on non-embryos.” Clearly, it would involve the destruction of ahuman embryo.
This is what I call “moral obfuscation.” Obfuscation means to intentionally confuse. What scientists
want to do, quite legitimately, is to experiment on human embryos. But because of the restrictions
on research on human embryos, and the limitations of the current definitions of human embryos,
they create new life forms: embryoids, blastoids and synthetic embryos. They argue that these are
not embryos, so research is permissible.
However, in all likelihood these have, or will have in the future, the potential to create a humanbeing.
One objection is that synthetic embryos lack the potential to form human beings because of
imprinting problems. However this is likely or at least possibly only a current technical limitation.
33

Indeed, such potentiality arguments rest on very tenuous, empirical grounds. The central claim isthat synthetic embryos, embryoids, blastoids and the like lack the potential to develop into ahuman being. (Interesting, Australia has treated blastoids as if they are embryos.) But this is likely
due to limitations in technology at this time. Whether something has a right to life, or a special
moral status, should not depend on whether technology can keep it alive. It is determined by its
intrinsic properties.
Consider an analogy. Whether a human being at the end of life is said to have a right to life, or a
special moral status, is not determined by the state of technology, whether technology at aparticular time can keep that person alive. Perhaps the person has an incurable disease – they arestill said to have a right to life in virtue of their nature as a person, even if this right cannot be
respected or fulfilled.
Another moral obfuscation is the 14 Day Rule which has dominated the regulation of embryo
research (which scientists are also trying to overturn). This was introduced by the Warnock
Committee in the 1980s to delineate a point of moral significance in embryonic development
which would determine the point until embryo research could be conducted. Indeed, as anotherexample of moral obfuscation, the embryo was redefined as a “pre-embryo” before 14 days.
But 14 days is morally irrelevant. It is similar to the Texas Heart-Beat Rule which determines whenabortion is permissible – not morally hands on when a heartbeat happens to be detected, as I haveargued elsewhere (Haining CM, Keogh LA, Savulescu J. The Unethical Texas Heartbeat Law. Prenat
Diagn. 2022 May;42(5):535-541. doi: 10.1002/pd.6136. Epub 2022 Apr 9. PMID: 35357014;
PMCID: PMC9320804)
There are two reasons that 14 days was thought to be morally significant. The first is that twinning
is no longer possible after that point. As Mary Warnock roughly put it, “Up until that point, theembryo has not decided whether it is one or two.” But imagine replication became possible andfull grown human beings could divide into identical twins, as in science fiction. It would be absurd
to suggest that a person no longer had moral status once the replicator was produced, just becauseof the possibility of division. While that individual continues to exist undivided, that individual has
moral status. Moral status is not affected by the possibility of division.
The second argument used by the Warnock Committee was that the nervous system does not
begin to exist before 14 days. Around 14 days, the neural streak forms, which is the precursor to
the nervous system. However the mere organisation of primitive neuroepithelial cells is of no
moral significance. At that point there is no brain, just a streak of cells. Most importantly there isno consciousness or any other mental phenomenon of moral significance. The embryo prior to 14
days is morally equivalent to the embryo after 14 days.
What does matter is consciousness. The reason we can treat a rock anyway we please is because
the rock is inanimate. The reason why we can pull plants up, or do what we please with them, isbecause they are not consciousness. The reason why we shouldn’t do certain things to non-humananimals, like beating or whipping them, is because they are conscious and experience pain fromthose actions. And the reason we should not kill innocent human beings is because they have highlevels of consciousness, such as self-consciousness.
But mere consciousness, the ability to perceive stimuli as painful, does not begin until much laterin fetal development, around 20 weeks. So actually research on human life should be permissible
until that point, when early termination of pregnancy (without analgesia) is permissible.
34

The 14 day rule was an example of moral obfuscation. If we rejected it, and instead allowed
creation of and research on embryos for the first trimester, there would be no need to create“embryo models.” And embryos would be more informative scientifically. Gene editing and cloning
could be used to create embryos with maximally informative profiles, such as displaying certain
diseases. Provided these embryos were not implanted, this should be ethically permissible.
Notably, the US and UK allow the creation and destruction of embryos for research. If the 14 day
rule was relaxed, there would be little impetus to create synthetic embryos.
Of course, this raises the question of the moral status of the human embryo. When does it achievemoral status?
The Puzzle of Moral Status
One way to answer to this question is to ask when does a human being’s life become devoid ofvalue, so that it is permissible to end that human being’s life. The definition of death has beenchanged from a cardiorespiratory definition to a brain death definition. If life ends, in the morally
significant sense, when our brains cease to function, then it begins in a moral significant sensewhen our brains start to function. That is considerably later than 14 days.
Indeed, life prolonging treatment is frequently withdrawn from patients who not brain dead but
are permanently unconscious. Such patients have been said to no longer have interests. If ourbiography ceases when we become permanently unconscious, it begins when we become
conscious, which is not until around 20 weeks of gestation.
Debates around moral status seem intractable. However, law and public intuition suggest a way
forward in the debate around the moral status of the embryo. Consider the case of Manishkumar
Patel.
In 2007, in the USA, Manishkumar Patel’s partner fell pregnant with their second child.
He did not want a second child because their first had medical difficulties and he was afraid thischild would too. He put abortion drug RU486 into her smoothie, but she did not drink it, instead
sending it for testing.
In the meantime, the pregnancy ended in a miscarriage.
Patel was charged with attempted first-degree intentional homicide of an unborn child. He fled for
India, forfeiting a $750k bond but in 2017, he was arrested in New York. He was sentenced to 22
years in prison for the attempted homicide. (https://www.insideedition.com/man-gets-22-yearsprison-slipping-abortion-pill-pregnant-girlfriends-drink-47528, “Man Gets 22 Years in Prison for
Slipping Abortion Pill Into Pregnant Girlfriend’s Drink” October 11, 2018)
While it was not a crime at the time to procure an abortion, it was a crime to attempt to kill awanted fetus, as Patel did. This suggests that the fetus does not have intrinsic value, but
instrumental or conditional value – conditional.
This view of the moral status of the fetus is supported by a previous case in March 2006. A 21year-old Cleveland man, Christopher Challancin, was driving home from a party with his 17-yearold girlfriend, Jessica Karos.
She was four months pregnant.
35

They began to argue about her ability to care for their child. Challancin, who had been drinking,became angry and began to weave at high speed through traffic. He lost control of the car andcrashed. Karos was left paralysed from the chest down, and the baby died. Challancin was unhurt.
Because he killed the baby, he was charged with homicide, as well as assault for “ruining her life,”
as her father put it. (http://blog.practicalethics.ox.ac.uk/2011/01/solving-the-puzzle-of-themoral-status-of-the-embryo-and-fetus/)
Again, in this case, there was a crime because the fetus was desired by the mother.
Similar judgements have been made in relation to embryos. In January 2005, Alison Miller andTodd Parrish sued their fertility clinic, the Centre for Human Reproduction in Chicago. They had
been having IVF treatment in 2002 and had stored nine embryos, one of which was “mistakenly”
discarded. The clinic apologized and offered the couple a free cycle of IVF, but they sued the clinic
for the “wrongful death” of their embryo.
However, at the other extreme, abortion is freely available in many parts of the world. For example,
every year in Australia, about 100,000 fetuses are aborted. This is not a crime because thepregnancy is not desired. Nearly all of these are normal and healthy fetuses. No one is charged
over these deaths.
It is a similar situation with embryos. Thousands of embryos are destroyed in Australia each year.
In fact, the law on IVF in Victoria, Australia requires their destruction after five years.
How can killing a fetus at once be homicide and yet no crime at all? How can the destruction ofembryos at the same time be required by law and widely practiced but also, in some places, bethe crime of wrongful death and a moral abomination? How can the one act – killing early humanlife – be both right and wrong?
We have polar opposite attitudes, moral norms, and laws relating to embryos and fetuses. How
can this conflict be reconciled? I have previously called this the Puzzle of the Moral Status of the
Embryo and Fetus (http://blog.practicalethics.ox.ac.uk/2011/01/solving-the-puzzle-of-the-moralstatus-of-the-embryo-and-fetus/)
There are two solutions to this puzzle.
First Solution: Extrinsic, Not Intrinsic Value (or Small Intrinsic Value)
The embryo or fetus has value or moral status when couples or one of the parents wants them.
We should distinguish between intrinsic value or “final” value when an entity has interests and alife of their own. The fetus
Extrinsic of instrumental value is value which resides in the capacity of an entity to produce
intrinsic value. The fetus has instrumental value in terms of its ability to produce a human person
later. It also has conditional value – conditional on the parents’ desires. It is possible to give a“relational account” of embryonic status – determined by the relations of that embryo or fetus toits future self and others.
If the embryo or fetus has instrumental, conditional or relational value, then it is not wrong tocreate embryos for research, provided it accords with the desires of those who produce them.
That is, there is consent.
36

One might argue that there is a harm to future a person if an embryo is destroyed. However, if theembryo is destroyed, there is no harm so it is not wrong on these grounds.
Consider an analogy with art. Someone creates a beautiful painting but chooses to destroy it. They
are perhaps doing the wrong thing because other people could have enjoyed it. They fail tomaximize value. But it is their prerogative. The painting only has extrinsic value.
This argument has one counterintuitive implication. It is wrong to destroy embryos if they are ofvalue to someone. Often a couple completes their family and they have spare frozen embryos.
Other couples are unable to produce their own children. It is wrong to destroy these spareembryos if others want them (Fuscaldo, G. and Savulescu, J., 2005. Spare embryos: 3000 reasons
to rethink the significance of genetic relatedness. Reproductive biomedicine online, 10(2), pp.164168). The same applies if scientists wish to use them for research. Of course, it is the prerogativeof the couple to destroy, them just as it is the painter’s prerogative to destroy his painting. But it
remains morally wrong and they should be encouraged to give them to others who want them.
Second Solution: Embryo OwnershipA second way of resolving the embryo and fetal moral status puzzle is to view the embryo andfetus as the property of the couple (or woman?) who produced it. “It is my embryo and I will dowhat I want with it.”Ownership is, of course, a human invention. We need to invent rules on who has right to control
embryos. This is an ongoing problem of embryos in clinics, when the couple has discordant wishes
for the fate of their embryos, property in tissue, etc.
One obvious route is to establish that parents own their embryo and can dispose of it however
they prefer. In cases of discordant wishes, the default could be that the party who wishes to keep
the embryo can keep the embryo.
Notably, the state has taken away that control by requiring destruction of frozen embryos. Thisshows the fluidity of ownership. The embryo might belong to an individual, a couple or acommunity, or some combination. And we might or might not allow a market in the sale ofembryos. All of these issues are to be resolved if we view embryos and fetuses as property.
Other Arguments against Embryonic Moral Status
So far, I have considered two solutions to the embryo and fetal moral status puzzle: theembryo/fetus as having extrinsic value and couples having property rights in embryos.
On both these accounts, there is nothing necessarily wrong with creating embryos for research, if
the couple consent.
There are many other arguments to supporting the view that the embryo or fetus has low moral
status.
a. Embryo rescue cases
Bernard Williams imagines a case where there is an embryo storage facility on fire and ahuman person trapped in the building. Firepersons can either rescue the human person or
many frozen embryos. Williams intuits it is obvious they should rescue the person.

37

b. The Scourge
Toby Ord points out that around 200 million embryos never develop each year because ofabnormalities. If these were persons with moral status, this would be the most catastrophic
scourge afflicting humanity. Vast amounts would be spent in preventing or curing the scourge.
Yet virtually nothing is spent preventing these embryo deaths because people do not view
them as equivalent to the death of a human being.
c. Twinning
When twinning occurs, one individual ceases to exist and is replaced by two different
individuals. No one is concerned by the ceasing to exist of the original individual. It is notviewed as the death of a person. Twinning is increased in IVF but no significant money is spentin trying to prevent it. These attitudes suggest the ceasing to exist of an embryo is not a major
moral concern.
d. Moral Theories
Many moral theories could support embryo research. Preference Utilitarianism would
straightforwardly support it. Hedonistic Utilitarianism would support it if the utility of theresearch outweighed the loss of utility in terms of happiness of a future person who could becreated from the embryo. This is doubtful when there is a person willing to gestate the embryo.
Embryo research is also supported on contractualist grounds. If we did not know whether wewould be an embryo destroyed in research, or an embryo or person who would benefit fromthat research, would we want the research to occur. It would be rational to choose embryo
research from behind a veil of ignorance if the chance of benefitting was sufficiently higher
than the chance of being destroyed and not producing a person (Savulescu, J., 2002. The
embryonic stem cell lottery and the cannibalization of human beings. Bioethics, 16(6), pp.508529). Of course the latter is also dependent on whether there are couples willing to gestatethat embryo.
e. Dog Analogy
Scientists want to create dog embryos to experiment on them to understand development anddevelop drugs. This is permissible. There is nothing wrong with creating and destroying dog
embryos. But that doesn’t mean we can do what you want to dog. We now appreciate the dog
has value because it can experience pain, etc. It has moral status because it has a life of its
own. Humans are no different – can feel pain, conceive of themselves existing across time. We
can create and destroy human embryos while also respecting human persons.
Social practice and attitudes, law and ethics all support the view that the fetus or embryo has
low or no moral status. Provided people do not wish to create children from embryos, it ismorally permissible to create and destroy them for research with the consent of those who
produced them.
Conclusion – Against Moral Obfuscation
There is nothing wrong with embryo models or synthetic embryos. They MIGHT lead to
unexpected valuable findings. It is difficult to see their advantage over embryos, including cloned
embryos, for research. Their creation represents moral obfuscation.
We should bite the moral status bullet. Embryos have extrinsic value and could be viewed as theproperty of those who create them. We should create and use embryos for sound scientificresearch. Cloning and gene editing are also acceptable, though that is the topic for another talk.
38

We need better ethics, not merely more science.
Copyright Julian Savulescu September 2023

39

7) Gene Editing, Identity and Benefit
Dr Katrien Devolder, Senior Research Fellow
Oxford Uehiro Centre for Practical Ethics
University of Oxford
I have one aim here: to challenge the claim that gene editing in human embryos is morally
preferable to genetic selection, because it benefits the child, whereas selection doesn't benefit thechild. The ideas I'm presenting are based on a paper I published with Professor Thomas Douglas
from the Oxford Uehiro Center for Practical Ethics1. They form part of an ongoing discussion andtouch upon fundamental philosophical issues about human reproduction, and benefit and harm.
To begin , I invite you to think about two hypothetical cases. The first case is that of
Edited Larry. Lesley and Lex, both carriers of cystic fibrosis (CF), have produced one viableembryo via IVF. A genetic test shows that it has two copies of the CF allele. Lesley and Lex
decide to subject the embryo to GE to replace the faulty alleles. The gene-edited embryo is
implanted, and nine months later a child, Larry, is born. Larry does not have CF, nor can hepass it on.
Lesley and Lex employed gene editing to prevent a genetic disorder in their child. We can say they‘edited out disease’. Consider now the second case, that of
Selected Barry. Bellamy and Blair, both carriers of CF, have produced two viable embryos via
IVF. A genetic test shows that one embryo has two CF alleles, while the other one has none.
Bellamy and Blair select the embryo without CF alleles for implantation, and nine months
later a child, Barry, is born. Barry does not have CF, nor can he pass it on.
Bellamy and Blair ‘selected against disease’. Many have argued that editing out disease, as in Edited
Larry, is more morally problematic than selecting against disease, as in Selected Barry since it poses
greater risks to the resulting child and their offspring (e.g., risks due to off target effects). Butothers have argued that GE also has moral advantages over genetic selection.
Chris Gyngell and Julian Savulescu wrote that:“...even when selection can be used to avoid disease, germline gene editing may provide amore desirable option. Selection prevents disease by changing who comes into existence;
whereas gene editing ensures those who come into existence have the best shot of living afull life. Using germline gene editing to avoid disease thus seems more analogous to curing
a disease than genetic selection via pre-implantation genetic diagnosis.“2The thought is this: in Edited Larry, editing out disease benefits Larry – it is better for Larry –because, had such gene editing not occurred, Larry would have been born with CF. He would havebeen, in at least one respect, worse off than he is. In that respect, gene editing is like treating a
disease.
But selecting against disease, as in Selected Barry, does not benefit the child who comes into
existence as a result – it is not better for Barry that he was selected, since it is not the case that hewould otherwise have existed with the disease. Had Bellamy and Blair made a different selection

1

Douglas, T and Devolder, K (2022). Gene Editing, Identity and Benefit. Philosophical Quarterly 72 (2):305-325.
Gyngell C and Savulescu J (2017). The Simple Case for Germline Gene Editing, in Genes for Life, 28–44.
Melbourne: Future Leaders.
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decision, presumably Barry would not have existed. So, there would be no benefit – at least not
the sort of benefit that people have in mind when they think about these issues.
It is often assumed that, other things being equal, we have stronger moral reasons to benefit
particular people than we do to bring about impersonal improvements We do not commit
ourselves to this view, but let us assume, for the sake of argument, that it is correct. One could
then argue as follows:
The benefit argument(1) Editing out disease benefits the future child(2) Selecting against disease does not benefit the future child, though it may produce animpersonal improvement (i.e. it will bring about a better state of affairs)(3) Other things being equal, we have stronger moral reasons to benefit particular people thanto produce impersonal improvements
Therefore(4) Other things being equal, we have stronger moral reasons to edit out disease than to selectagainst disease.
In this paper I want to challenge the ‘benefit argument’. I argue that premise (1) fails to hold in
relation to many likely future instances of editing out disease, and that restricting the scope ofpremise (1) to avoid this problem deprives the argument of much of its practical significance.
Qualifications
Before I proceed to this critique of the benefit argument, I want to make two qualifications. A firstone concerns premise (1). There will be cases in which editing out disease does not confer a benefit
on the gene-edited child because either (i) the gene-edited embryo never gives rise to a child (e.g.
a miscarriage occurs), (ii) the editing procedure alters the numerical identity of the child, (iii)
unusually, the genetic disorder would have increased rather than diminished the wellbeing of thechild, (iv) the editing procedure has unintended effects that result in lower wellbeing for the childthan she would have had without the procedure.
So, (1) will need to be restricted to cases in which none of these circumstances obtain. We capture
this restriction by revising (1) to(1′). If all goes according to plan, editing out disease benefits the future child.
This change presents the benefit argument in the most charitable light.
Consider next premise (2), according to which selecting against disease does not benefit the childcreated as a result. There are certain kinds of benefit that selecting against disease arguably canconfer. The selected child may for example enjoy non-comparative benefits. These are benefits
that consist in being in a state that is in one respect good for you, not compared to somealternative scenario in which you might have been or were in, but in an absolute sense. In Selected
Barry, selection may provide a non-comparative benefit to Barry because it allows him to live agood life, or a life containing good elements. Selection can be good for Barry. But it can’t be better
for Barry, because there’s no alternative state of existence for Barry. Had the parents taken adifferent selection decision, he wouldn’t have existed. With this distinction, it may seem that we
can rescue premise (2) by adjusting it. Selecting against disease does not confer a comparative
benefit on the future child, though it may produce an impersonal improvement or confer a noncomparative benefit.
41

Combining the adjustments to both (1) and (2) leaves us with the following formulation of thebenefit argument:(1∗) If all goes according to plan, editing out disease confers a comparative benefit on the
future child(2∗) Selecting against disease does not confer a comparative benefit on the future child,though it may produce an impersonal improvement or confer a non-comparative benefit(3∗) Other things being equal, we have stronger reasons to confer comparative benefits on
people than to produce impersonal improvements or confer non-comparative benefits on
people.
Therefore (4∗) Other things being equal, and if all will go according to plan, we have stronger
moral reasons to edit out disease than to select against disease.
In the remainder of this paper, I will used the unqualified term ‘benefit’ to refer to comparative
benefits.
The Problem
Let us return to Edited Larry: the case in which Lesley and Lex edited out CF alleles. The proponentof the benefit argument (who believes that editing out disease benefits Larry) seems to have one
particular counterfactual scenario in mind. They envision that, had the parents not edited out
disease, Larry would have had CF. He would thus have been worse off than he is now. But why
think that this is what would have happened had the parents not edited out disease? Consider thisalternative counterfactual scenario in which the parents change their mind about GE: Suppose
Lesley and Lex planned to use GE to ensure their child would not develop CF, but at the last
moment they became worried about the risks of GE and cancelled the procedure. Would they thenhave decided to have the CF-affected embryo implanted into Lesley’s uterus? We think that’s not
all that likely. After all, it is natural to assume that Lesley and Lex (a) want to become parents, and(b) want their child to be free of cystic fibrosis. If they decide to not edit out disease, then they canstill opt for other means for realising both these goals (e.g. IVF + genetic selection, donor
gamete/embryo, adoption). It is plausible to assume that, if Lesley and Lex had not edited out
disease, they would have opted for one of these alternatives, none of which would have resulted
in Larry coming into existence. If this is right, then their actual action of editing out disease did notbenefit Larry since, had this not occurred, Larry would never have existed. There is no comparative
benefit.
Let’s return to Premise 1 of the Benefit Argument. This is most naturally read as a general claim—'editing out disease invariably confers a benefit to the future child’—but as we have just seen, thisgeneral claim does not hold. Editing out disease doesn’t confer a benefit where the edited childwould otherwise never have existed. And, as Edited Larry suggests, there may be cases where thealternative to GE would have been discarding the embryo.
To rescue the benefit argument, we could restrict the scope of this premise. We could adjust it to(1#) Editing out disease benefits the future child, provided that the parent(s) would in any casehave brought the embryo to term(2) Selecting against disease does not benefit the future child, though it may produce animpersonal improvement(3) Other things being equal, we have stronger moral reasons to benefit particular people thanto produce impersonal improvements
Therefore(4#) Other things being equal, and if everything goes according to plan, we have stronger moral
reasons to edit out disease than to select against disease, provided that the parent(s) who editout disease would in any case have brought the embryo to term.
42But this change substantially limits the practical significance of the benefit argument. That’s
because many situations in which parents would consider editing out disease are ones in which, if
the editing does not take place, the embryo will be discarded, and parents will opt for alternative
ways to have a child free of the disease they’re trying to avoid. In all of these cases, the restrictedversion of the benefit argument will not apply.
And there’s something else: restricting the scope of the benefit argument also has a surprising
implication - one that limits the practical significance of the argument even further. Whichcounterfactual scenario would have obtained in a given case largely depends on the importancethe prospective parents accord to the genetic trait the GE is intended to avoid. There is reason tobelieve that the more serious the disorder, the more plausible it is that the parents would havediscarded the afflicted embryo had they not employed GE and would instead have pursued
alternative means of having a child. Because presumably, prospective parents are generally more
motivated to avoid severe genetic disorders in their child than less severe disorders, or, e.g, carrier
status.
Consider a modified version of Edited Larry: In the modified case, the embryo from which Larry
developed had two alleles not for cystic fibrosis, but for Gilbert’s syndrome, a common, mild andusually asymptomatic genetic disorder of the liver. As in the original version of the case, Lesley andLex choose to subject the embryo to GE and as a result Larry neither develops Gilbert’s syndrome,nor is a carrier of the condition.
In this scenario, it seems plausible that the relevant baseline counterfactual scenario for
determining whether there’s a benefit, is one in which Larry is born with Gilbert’s syndrome. Thisis because, had Lesley and Lex not edited out the disease for some reason, it is plausible to assume
that they would have decided to carry the (non-gene-edited) embryo to term anyway.
Gilbert’s Syndrome would not be considered a serious enough disorder to outweigh the burden,
risks, and possible moral costs associated with discarding the embryo and choosing an alternative
way to have a child (e.g. by undergoing another round of IVF treatment and selecting against
Gilbert’s syndrome).
This has a surprising result: the more serious the disorder the prospective parents wish to avoid
in their child, the less likely it is that editing out disease benefits the future child, and thus, the lesslikely it is that the benefit argument establishes a moral advantage for editing out disease overselecting against disease.
In other words: the putative moral advantage for editing out disease is more likely to obtain in
relation to less serious disorders than in relation to more serious ones. This further diminishes thepractical significance of the benefit argument. Why? It applies most likely in cases in which thedisorder is not serious—the case for using GE may not be very strong – the benefit argument may
be a easily outweighed by other considerations, such as considerations about the risk of GE.
The main concern that has been raised about editing out disease adverts to its risks, either for theedited individual or her descendants. These risk-based concerns are most likely to be decisive
when there is in any case a weak argument for editing out disease, since the disorder in question
is not serious or even is trivial.

43

Conclusion
The benefit argument fails because, in some cases, editing out disease does not benefit the edited
child (since that child would not otherwise have existed). Restricting the argument to avoid thisproblem deprives it of much of its practical significance:
In many circumstances where gene editing is likely to be employed, the child would not otherwise
have existed, so the restricted argument does not apply.
The cases in which the argument is most likely to apply are those in which gene editing is used toprevent a mild disorder, and these are precisely the cases in which the standard, risk-based
objections to editing out disease are most likely to outweigh the moral advantages posited by thebenefit argument.
An objection
Julian Savulescu and Jeff McMahan think Thomas Douglas and I are using the wrong sort ofcounterfactual in our analysis3. According to them, what matters is not what the parents would
have done had they not done GE but what they could have done.
Suppose parents used IVF, did PGD, discovered deafness, but implanted the embryo without
editing, thereby having a child with deafness, when gene editing was possible. (They use thisexample.) Suppose that had they not implanted the unedited embryo, they would have discarded
the embryo and either not had a child or tried embryo selection.
According to McMahan and Savulescu, the deaf child has a complaint: what the parents did wasworse for the child because they could have caused the same child to exist without deafness. If
the parents implant the defective embryo without gene editing when gene editing was possible,
the normatively salient alternative is implantation following gene editing to enable the subsequent
child to hear.
Thus, McMahan and Savulescu conclude that if the implantation of the embryo without GE wasworse for the child, even if the parents would otherwise have discarded it, then it seems to follow
that, if they had implanted the same embryo with GE, that would have been better for the child,even if the parents would otherwise have discarded the embryo.
I disagree, however, with this conclusion. I agree that if parents implant the embryo without GE,
thereby creating a deaf child, the normatively salient thing to do was to implant the same embryowith gene editing.
But in the cases Douglas and I are interested in, parents want to have a healthy child. Suppose theyuse IVF and PGD. They have two embryos. One that will result in Deaf Dylan [E(d)], and one thatwill result in Hearing Henrietta [E(h)]. Suppose their options are:(1) Do gene editing on E(d) to enable Dylan to hear and discard E(h).
(2) Discard E(d) and implant E(h).
(3) Implant E(d) without gene editing and discard E(h).
(4) Discard both.
In this scenario, the normatively salient thing to do is (2): discard the embryo that will result in
Deaf Dylan and implant the other embryo. But if that’s correct, the gene editing didn’t benefit thechild. In the relevant counterfactual scenario, Deaf Dylan wouldn’t otherwise have existed.
3

McMahan J. and Savulescu J., Unpublished draft. McMahan J., unpublished notes.

448) Lost in Translation: The Ethical Complexities of Going from Bench to Bedside Using Novel Geneand Stem Cell Therapeutics
Dr Insoo Hyun
Director, Centre for Life Sciences and Public Learning, Museum of Science, Boston
Harvard Medical School, Harvard University
I've been really enjoying this conference. Thank you so much to the organizers for having me herewith you today. This discussion so far has been so fascinating. It has been very philosophical. I feela little bit like coming back home, how am I hearing my native language again. I've been away fromphilosophy for a while.
I'd like to give you an idea of my approach to doing bioethics. If scientists are farmers working in
the field, and philosophers are up on Mount Olympus, I am sort of that little bird flying up anddown between the two. You'll get a sense of that, today. I'm going to give you a bird's eye view of
three big areas in biotechnology that are very exciting and also converging in really interesting anddynamic ways. It will draw on the work I've been doing for a long time, with researchers in thefield and doing that collaboration, you know, kind of with the farmer.
The three big areas that I want to focus on are stem cells, cell and tissue engineering, and gene
editing, in the hopes that these will lead to new therapies for patients with very intractableconditions that are not easily treated with current methodologies. These typically are the hardest
cases where it's like everything that's left, that medicine cannot currently address. So, the newmodalities are going after that.
I will unpack what I think are some really interesting ethical issues. The other thing I want to convey
is that when I started doing a lot of work with scientists, typically they would have an attitude like,“Well, Dr. Hyun, you'll do the ethics and we'll do the science. And I found it really hard to keep that
separate. I think good science is ethical science - and that raises some really interesting ethicalquestions. It's very hard for me to tease apart when someone is doing ethics and when someone
is doing science, and you'll, I think, get a flavor of that as I go through the three main areas.
So, we'll start with stem cells. Of course, the dream is to have more stem cell therapies in the clinic.
Currently, the standard of care (the only thing that's really prevalent) is stem cell transplantation
for blood disorders. Now, the typical view is to in order to get to a new therapy, you have to go
through the clinical trials process. Now, what's interesting to me about this is the clinical trials
approach had been developed historically for the development of new drugs. And so the questionis whether this pathway an appropriate one for cell based biologics, which are not like drugs. The
first way in which there's a really sharp difference for me, is that in phase one (this is where you
do your toxicity study, your dose toleration studies) for drugs, you often use healthy volunteers
who are compensated for their time and inconvenience, who will take drugs to know what is thetolerance level. If you're using a stem cell based biologic, this should ideally graft onto the patient
for their lifetime, to replace cells that have been lost in a heart attack, or even for people who havediabetes. You really can't use healthy patients; you can't use healthy volunteers. One of the things
we know about stem cell biology is that the niche environment matters for how the transplanted
cells behave. It's very important and it forms this dynamic, interactive relationship. If it's not an
injured site, the biologic is probably not going to behave the way you're intending it to in a patient.
For example, if there's no spinal cord injury, why would you put lab grown neural cells in the spinal
cord? Ideally, the product's going to last for the lifetime of the patient, so you can't withdraw a45

healthy volunteer from that study like you'd normally would. So, there are technical challenges ordifferences. But what's really interesting is that gives rise to some deeply ethical questions. And
it's hard to kind of tease apart the ethics from this scientific problem.
Thus, if you have to use patients, if you have to use persons who have the disorder, in yourtolerance stage, just to see after one or two years, whether this is a success and nobody develops
a tumor, or nothing bad happens, then you don't want to use a super high dose of cells for that.
You want to use the minimum amount to get your data that this is tolerated in the body. So, it's
going to be a patient that has some sort of disorder, that's going to get a clinically irrelevant doseof cells. It's not going to do anything. If it does, that's a happy accident. But that's not how it's
designed. How do you convey to the patient, you're going to get this stem cell therapy, but you're
really a testbed, a human testbed, to see how the product behaves in the body? Researchers, they
don't intend to kind of dehumanize people this way. But when they present their data, let's saythey show the initial platform when they went to the animal model -- that the product does this.
Now they’re going to go to human; they're really looking at the patient just like a human biologicaltestbed. So how do you convey that? Which stage of the degenerative disease do you put the
product in? You probably want to use relatively healthy people, because they have all kinds ofother issues if they're deep into the decline. So the question is at what stage you do this? Now, asa doctor, I would not want my patient to enroll in something like that, if they have lots of othergood options. A phase one trial might interfere with their standard of care down the road. I'm
thinking of Parkinson's disease, for example. But for the investigator, that's not the person you
want to test. You don't want all these other confounding adverse events and other things tohappen that are may be associated with the disease, but you're not exactly sure. You really want
to use the people who have early signs. So it's sort of like a mismatch, right? From the patient
welfare interest point of view, you want to wait until much later; for an investigator’s point of view
you want to push earlier. Where's that sweet spot? See how this is an ethical question? And atechnical one; it's both. You can't tear away the ethics and the science.
Another issue is that, as you're going through the different phases, you have to scale up yourproduct by a lot and maintain quality of that product. That's a big challenge. And it's very expensive
to do that. You have to get investment from industry to get to phase two, phase three. And that
can also raise some really interesting challenges for conflict of interest and hype and all that. I
wanted to also briefly touch on that last box, you need three clinical standards to get to the phaseone. And the pre clinical standards are not well articulated for these kinds of very complex
biologics as they are for drugs. Let me give you an example of how the FDA is building the ship
while it's sailing at the same time. This is the last box now moved up to the top. You have to havethese types of standards. And it's not always clear what the standards might mean. For drugs, youhave to know what's the purity of the drug, right? And potency of the drug. But purity and potency
for cell based products is hard to determine. What do you mean by purity? Sometimes you don't
want all the same cell type. In the bone marrow transplants that are now standard of care, it's a
mixture of cell types of works best, and it's not pure. Thus the better term is perhaps“contaminated or not contaminated.” One may need to redefine some of these categories,
because biologics are dynamic, and they work together. What does potency actually mean? You
can measure that in a drug but these cell products are supposed to interact. These arephilosophical, metaphysical questions, but also deeply scientific.

46

Once you get to the middle box, you have to scale up. And unlike pills, which you can just scale up
in massive amounts, and you can just leave on the shelf without causing any change, cells are
genetically dynamic things that could accrue mutations over time. How do you maintain quality?
How do you know that when it leaves your processing center and goes to the clinic, it hasn'tchanged in that process? When I give versions of this talk, especially in front of patients, they getkind of depressed because they realize how far away this dream is. Because somebody needs tobe working on the distribution plan. Nobody's worked that out. It’s basically like Amazon, where
you have to have these fulfillment centers all across the US where they're prepared there and sent
to the clinic. Or maybe it’s like those meal preparation kits, where you prepare the last bit at thebedside. How are you going to distribute this product and maintain quality? What's the shipping
container like?
So even if you have this clinical breakthrough, how are you going to get cell based products out topatients? How are you going to produce enough? When I point that out, people say, okay, yeah,
you're right, it's kind of far away. And then there’s proof of concept. You have to use animals for anumber of reasons before you can go to humans, and this raises all sorts of questions aboutchimeras, creating them in the lab, especially for neurological disorders – a lot of controversy
about putting human cells in an animal. That's a necessary step for development for FDA, so it's
really hard to avoid that. Chimeras also raise some conceptual problems. Therefore it's always hard
to know, what am I supposed to be working on and what are the scientists supposed to be working
on? How do I divide up this labor? I think we just have to have the conversation constantly together
about this.
Now, we're going to hear a little bit later about this other pathway – medical innovation – because
it's essentially a myth that everything has to go through clinical trials. Actually, medical innovation
outside of a clinical trials system historically has been an extremely important avenue for getting
things in the clinic. But with stem cells, this presents a very difficult problem, because the stem
cell clinics that you've been hearing about – those commercial, fraudulent clinics, -- are presenting
themselves as medical innovators that are going outside the FDA.
On the other hand, you have to have some room for responsible medical innovation, because
historically that’s how so many things have made it to the clinic. In the US, there's a lot of off labelprescribing of drugs. Off label prescribing means you're using a drug in populations that the FDA
did not approve the drug for. It is up to the physician’s judgment to use it in a new way. If you didn't
allow for off label prescribing, we would not have psychiatry, pediatrics, and a lot of treatments
for cancer. Also, without medical innovation, you wouldn’t have surgical innovations. You wouldn't
have had laparoscopic surgery, whole organ transplant, deep brain stimulation. None of thesehappened through clinical trials.
I'm not going to say much more about this except to say that it is quite challenging to tease apartwhat is responsible and irresponsible medical innovation. What's the difference between stem cell
tourism and somebody at the Cleveland Clinic offering cell therapy? I tried to map out thedifferences there in a Science article quite a while ago. But one thing that I did find completely
fascinating from this work is that we have been, I think, and this is where philosophy comes in, I
think we've been misdiagnosing the problem of stem cell tourism for a very long time. If you wantto have a good prescription or a solution to a problem, you have to have the right diagnosis. Whatis the problem for which we have to come up with a solution? When I was working with47

International Society for Stem Cell Research (ISSCR) on these guidelines, we had all been thinking
that stem cell tourism was a marketplace type problem. So at first, it was seen as a kind of fraud
problem in the marketplace. To fight this, you need better consumer information: patients need
to be armed with information. ISSCR tried to deal with the demand side of this a bit. And then
ISSCR also thought we have to have higher regulation or tighter regulation to control the supply
side. People were making wild claims, and people were being fooled, and the product wasn't good.
We all looked at it that way. And we tried to confront the argument that adults should be able tospend their money how they want and also make their own decisions about their own bodies.
But that marketplace analogy started to fall apart for a number of reasons. One of them was that
we're finding that many of the people taking patients to these clinics in Mexico, in Russia, forexample, and all these places, many of them are children who don't fit that nice, buyer bewareand personal autonomy model that the marketplace model is assuming. Stem cell tourism wasactually getting worse, it wasn't getting better. We were providing a lot more information, creating
patient handbooks and the ISSCR distributed information and asked local regulators to be moreconsistent. But we realized maybe we were misdiagnosing the problem. I got thinking about thisbecause I started getting emails at this time from patients like some scientists constantly were
getting emails from desperate patients. “Where should I go for this? What should I do for that?”
One of these emails was so memorable for me. I got an email from somebody in Italy. He said, Dr.
Hyun, I'm thinking of taking my son, my little boy to Russia to a clinic for this degenerative brain
disorder he has. What do you think about that plan? I began answering his email the way I normallyanswered such emails. I said, here's the patient handbook about stem cell therapies, the facts, alltranslated into Italian. And I said, right now, there's no other standard of care outside of maybe
some skin grafting and maybe, hematopoietic stem cell transplantation. I wrote him all thisinformation, information, information, information, I put it all there. And then I decided to try one
thing different on this email. I decided to add a sentence at the end of my usual answer. I said, if
you are asking me what I would do if I was you, I wouldn't take my son to Russia. I would spend
the rest of my time with him doing what he wants to do. And then I hit send, and he was the only
one that ever responded to me. So next morning, he emailed me back and said, Dr. Hyun, I was
afraid you were going to say that, but I think you're right.
The next day, I went to an institutional review board meeting, and the chaplain of the hospital
who's also on the committee was walking with me. He asked me how things were going. I told him
about this whole email exchange. He said, Oh, yeah, well, that's a family under spiritual distress. I
asked him what that was. He said that as a chaplain he had to deal with this all the time. It’s notthat patients have religious questions. They usually have needs because they're under a state ofspiritual distress. I asked where can I learn more about this? He said people have written a lot
about this in oncology, and in nursing. There's a lot of literature on this. I ended up reading a loton this.
That’s when I thought, well, this might be the misdiagnosis. It’s not that patients need more
information, they need support. They need support because they're in crisis. A lot of their own
family is in crisis. The antidote to spiritual distress is therapeutic hope – in order to pull yourself
out of this feeling of distress, the feeling that I am not looking forward to the things that normallygive me meaning in my life. In order to pull yourself out of that you have to fixate on hope.
Therapeutic hope has a three part structure: (1) I have a goal, (2) I can identify a pathway to that
goal, and (3) it's up to me to pursue that pathway. Those three things are called the architecture48

of therapeutic hope. In bringing these ideas forward, I was I wasn't doing anything extremely
creative. I was just bringing these ideas into stem cell tourism. If you tell a patient, don't go to
Mexico, don't do this, don’t do that, as their doctor, you close a pathway that they were fixated
upon. But then you better give them another goal, another pathway, and empower them to try to
pursue that. Otherwise, they're going to either just ignore you and just go to a stem cell clinic
anyway, and it could possibly be much more harmful for them to do that, or they're going to slip
further into spiritual distress. It’s a really interesting dynamic, and I think more attention needs tobe paid to it, so I wrote that up in a paper, and I submitted it to Cell Stem Cell.
It's funny, because this is a high level science journal. The term “spiritual distress” was in the titleof my manuscript, and the editor asked Do you mean religion? I said, No, no, just read it. It's not
religious spirituality. It's about what gives your life meaning. It could be religion, it could be yourrelationships, it could be the arts, it could be lots of things. When you feel disconnected from whatgives your life meaning, that's when you fall into an existential crisis. Sot that's what I really wanted
to say about the tourism part of stem cell therapies.
The other big area now that's really interesting, besides trying to go to the clinic through medical
innovation, or trying to go to the clinic through clinical trials, is the amazing ability to use stem
cells and their derivatives to do all kinds of great things in the lab. This other type of work isn't
necessarily to create biologics to go into patients, but it's for scientific study, or to get new tools
for discovery. A really interesting thing that we can now do with IPS cells has to do with diseasemodeling in a dish. Through this you can compare healthy controls and how those cells develop
and compare them to the disease specific cells and see where things start to go wrong. You can dothat in 2D in a dish. Of course, you can do that with screen new drugs, because you can have anendless supply of disease specific cell types. You can add different chemicals to these cell types
and do the readouts on the cells. Sometimes you may start to see some combinations that seem
to work well in altering or stopping progression. Very fascinating. I remember in the earlier daysof human embryonic stem cell research at the ISSCR, there was very little industry interest in our
meetings because the work was too controversial. It was all embryonic. When iPS cells came on
the scene, in the front rows were now Pfizer all these companies because they were reallyinterested in this technology for drug screening.
That said, I think the benefits of stem cell research are not going to be direct, as people imagine,in the form of cell-based therapies and transplants. Rather, it’s disease modeling and drug
screening that will enable the more traditional routes to the clinic with drugs to go faster. Whenpeople say they haven't seen the benefits of stem cells, they don't know about this.
Okay, but tissue and cell cultures in two dimensions are not very realistic. Organs and tissues arecomplex, they're three dimensional and involve many cell types. This motivates the move tocomplex self-organizing human systems that we didn't have before. As you know, animal models
are not perfect because they're not humans. And two dimensional cell systems are human, but
they're not realistic. Therefore the move now it to create 3D structures that mimic basic organfunctions.
But the more realistic you make these models, the more concerning they may be to people andwhat you do with the models, especially tissue systems that are associated with moral status –gonads and brains. Hank Greely, who you saw yesterday, loves to say that brains and gonads are49all that people care about. I think he's right. Brain organoids are where I started focusing on with
NIH support, working with the researchers who are doing this research. Now researchers can makeorganoids that recapitulate a particular region of the brain. No one organoid can recapitulate
everything, so you must put them together like Lego blocks. You can build more complex systems
called assembloids. Sergiu Pasca, one of my colleagues at Stanford, is famous for this. Now think
about organoid systems in the dish, human organiod systems. In addition their being linked
together, after a while you start asking, What is that in the dish? What if researchers made a brainorganoid and connected it to a heart organoid? There can be a lot of really interesting philosophicalquestions about what is in the dish. What is the moral status of that?
Our institutional research review committees are set up to oversee research with common natural
kinds. Take human subjects research, for example. We know what a human being is. And animal
research. We know what animals are. But these new organoid combinations are not natural kinds.
Many of these new things don't exist in nature. They are biological artifacts. Who reviews thiswork? These are quite unnatural.
Many people are also really hopeful about iPS cells offering more personalized diagnostics andpersonalized therapies. The big problem here however is how are you going to move these throughto the FDA? Right now the FDA cannot approve, quickly, each individual iPS cell derived
personalized intervention, because by definition each of these cell-based interventions havedifferent DNA, making them each different products. It takes years and years for approval for
products. Thus, the FDA would have to approve a process. Here’s the dream, right? If someone has
a disease, you can make an organoid, or you can make some representation of the body in a dish.
It would be like their personalized system, you can then screen drugs on that, and you might evenbe able to create tissue from them that are transplanted back. That would be a super personalized
way of providing care. If you have a process approved, how specific would this process have to be?
If it’s for blood disorders, then can it be for any blood disorder? Or would there be a difference
between leukemia and sickle cell? It is quite unclear what's going to happen. It is all very
complicated when you wake up to all the reality checks.
My last area is gene editing. As you know, there's a distinction between editing of somatic cells
and germ cells. With the latter there's another interesting distinction that carries some uniqueissues. Let’s begin with germline editing.
So the current consensus seems to be that one type of germline editing is now acceptable. You
heard Hank say yesterday that the promise back in Asilomar Conference, was that researchers
would never cross into the germ line. But now the view is that germline editing is ok as long as you
keep it in the dish. The new line in the sand seems to be the uterus; you can study the embryos orsperm or eggs in a dish and try to edit out genetic defects. No transplant into the uterus forreproductive use.
I want to pause here to point out that I think there are some big potential problems with somatic
cell gene editing. We all know about the Jessie Gelsinger case. That was a gene therapy trial andsomebody died. Somatic cell editing is not ethics free.
Back to germline editing in a dish. This too is controversial. In the US context, in Canada, and inAustralia as well, you can't make embryos for research. It's illegal now in the US. It is illegal to pay
50this research with federal funds. But whether you have federal funds for this or not in Canada andAustralia, it's illegal to make an embryo solely for research purposes. You have to use extra
embryos from fertility clinics. Well, how are you going to do this research in the germline if you
can't use frozen embryos from a clinic and edit those because they are too far along (as I explained
yesterday)?. Scientists don't want to use those, the ones that are frozen in a clinic or too far along.
So, you got to make your own. That’s an ethical issue.
Another related issue is that you got to use human eggs. How are you we're going to get the eggs?
We saw in the stem cell experience that this is very controversial. If you don't pay research egg
donors the way you normally paid women for fertility services, then nobody will volunteer. I
actually think it would be unethical to ask a woman to donate eggs for research without financial
compensation because the physical and emotional burden is so high. Every other healthy
volunteer who donates biomaterials for basic science – bone marrow, bronchoscopy, all these likereally painful things – get compensated for their time, effort, and inconvenience.
In closing, the US response for human genome editing resulted in this report. I just want to pointout what I find fascinating about this, because they offer this whole traffic light system. I call it thetraffic light system: somatic cell green light; germline editing in a dish gets a green light. But insteadof giving reproductive germline editing a red light, they gave it a flashing yellow light. It’s a flashingyellow light because right now you can't do that. It’s not permissible for now, but it might bepossible in the future.

519) The Ethics of Human Epigenome Editing
Dr Tsutomu Sawai, Associate Professor
Graduate School of Humanities and Social Sciences
Hiroshima University
Hi everyone. Good morning to all of you. I am very honoured to have this opportunity to present
at the Uehiro-Carnegie-Oxford Ethics Conference. I would like to thank the Uehiro Foundation for
their generous support and I also thank Julian for inviting me. It's been a long time since I've been
to a face-to-face international conference, and I've enjoyed it immensely so far thanks to thewonderful host and presentations.
Today I am going to talk about the ethics of human epigenome editing.
This presentation is an ongoing collaboration with a genome editing researcher who is also a
muscular dystrophy patient, so it is a good opportunity for me to share what my collaborator andI are thinking. I hope that my work stimulates thoughtful discussion and invites your valuable
feedback.
Let me begin by confirming a premise I have made when discussing the ethics of human genome
editing. The most controversial aspect of human genome editing is germline genome editing. The
reason that germline genome editing is the most controversial issue is that it may have long-term
effects on future generations and also some would say it is morally wrong to edit human germline,
especially embryos, in the first place.
The former issue, that is long-term effects on future generations may be good or bad, and germline
genome editing is often called as heritable genome editing because the effects of the intervention
are unexpectedly passed on to the next generation. Needless to say, the ethical pros and cons ofheritable genome editing are still being actively debated.
On the other hand, it is often said that somatic genome editing avoids the heritability issues thathave plagued germline genome editing by not targeting germline cells. Therefore, it is generally
assumed that somatic genome editing does not pose any additional ethical challenges to thosealready raised by conventional somatic gene therapy.
In this talk, however, I would like to emphasize that even when germline cells are not targeted bysomatic genome editing, the possibility of indirect germline effects should not be overlooked. The
risk of somatic genome editing indirectly affecting germ cells is currently considered quite low, but
the concerns have not been fully addressed.
Today's main topic is epigenome editing. Epigenome editing is as you may know "a technology that
regulates gene function by artificially controlling epigenetic states at specific locations on the
genome.”I will talk about the details later, but the overall functional regulatory information of the genome(not involving genetic changes) is known as the epigenome. Epigenetics, the regulatory mechanismof the epigenome, is responsible for the quantitative control of gene expression.
This presentation aims to raise questions for academic discourse concerning the ethics of humane-GE, rather than to derive a normative conclusion regarding human e-GE.
S Fragile X syndrome is a good example of epigenome editing in a pathological context and its
52

potential clinical application. Fragile X syndrome is a genetic disorder that causes a range ofdevelopmental problems, including learning disabilities and cognitive impairment. The diseaseaffects approximately 1 in 4,000 males and 1 in 8,000 females.
In the FMR1 gene locus of healthy individuals, DNA methylation is low and this gene is expressed.
However, in the FMR1 gene locus of Fragile X syndrome patients, DNA methylation is high and thisgene is silenced. Currently, there are some established pharmacological therapies, but thetherapies don't cover all the clinical features of Fragile X syndrome.
In 2018, researchers used dead Cas9-system for editing DNA methylation, and they succeeded in
rescuing the pathological gene suppression of FMR1 without direct gene editing.
This is the differences between CRISPR-Cas9 and dCas9. As you know, Cas9 has two basic function;
first is binding to a targeted region on the genome, and second is cutting the DNA strand. dCas9
itself maintain an ability to bind to a targeted region on the genome but has no ability to cut the
DNA strand. If the effecter domain was fused with dCas9 system, dCas9 bind to a targeted regions
on the genome and regulate epigenetics and gene expression.
e-GE does not manipulate the genome sequence so the results of epigenome editing interventions
are temporary. Four epigenome editing listed here are examples of what I call transientinterventions. This type of epigenome editing intervention and oral medicine are thought to sharethe similar level of reversibility in effects. Within the e-GE, functions and applications are varied.
First, dCas9-Tet1 reactivates silenced genes and improves neural function in models of diseases
such as Fragile X syndrome which I mentioned earlier. Second, dCpf1-CTCF alters local chromatin
structure and helps reactivate genes in diseases such as Rett syndrome, a neurodevelopmental
disorder. Third, CRISPRa activates disease-causing genes and disease-modifying genes, leading to
improved disease phenotypes, as demonstrated in a mouse model of muscular dystrophy. Forth,
CRISPRi is a transcriptional silencing system that has been successfully used to silence diseasecausing genes associated with muscular dystrophy and cancer. A clinical trial based on thisprinciple is currently being planned.
Hit-and-run silencing/CRISPRoff is an example of a different type of e-GE. CRISPRoff introduces
local heterochromatin signatures and maintains gene silencing even after the editing tool isremoved. So it offers the potential for long-lasting effects without continuous intervention. Thisdiffers from the previously introduced e-GE in the sense that the main feature is that the effectsof the intervention are long-lasting. For this reason, I call this e-GE as a persistent intervention.
These are some diseases associated with epigenome abnormality, so the listed diseases can bepotentially treated by e-GE.
So far, we have pointed out that there are two main types of e-GE. One is the "transient" type of
e-GE and the other is the "persistent" type of e-GE. Both have their advantages and disadvantages,
and their use can create dilemmas. This type of epigenome editing intervention and oral medicine
are thought to share the similar level of reversibility in effects. So the dilemma here is whichintervention to take between the advantages and disadvantages. Transient type of e-GEintervention and oral medicine are thought to share the similar level of reversibility in effects.
But if you want to maintain the effect, you should go for persistent type of e-GE intervention.

53

Here I would like to point out two issues that have been overlooked in SGE/SGT. One is that, as
mentioned in the background, SGE and SGT have traditionally been discussed under theassumption that the effects of the intervention are not inherited because they do not target germ
cells. In particular, for adult somatic genome editing, it is currently considered unlikely that
epigenome editing tools could inadvertently enter germ cells via systemic intervention. Indeed,
the fact that it is unlikely does not mean that there is no risk.
On the other hand, genome editing and gene therapy of prenatal fetuses and postnatal infants
may indirectly affect germ cells as a result of the intervention, although empirical data are
currently lacking. Particularly when it comes to genetic interventions in prenatal fetuses, someconcerns have been raised about the side effects of such interventions.
For example, in the paper titled “prenatal gene therapy for the early treatment of genetic
disorders”, one of the risks of prenatal gene therapy is the "theoretical risk of germ-line
transmission" and the related ethical concern is that "germ-line transmission may induce
transgenerational mutations or secondary infertility.” Although these points are made in otherpapers, they are limited at this time and seem to be points that should be carefully considered as
we move from research to clinical practice in the future.
The paper on the left is the result of a study reported this year showing transgenerational
epigenetic inheritance in mammals. This suggests that if e-GE directly or indirectly affects the germ
cells, the editing effects can be passed on from generation to generation.
S One of the concerns in CRISPR-cas9 is whether genetic change in germline inherit
trangenerationally or not. In case of e-GE, it makes no genetic change and some epigenetic
changes, so it used to be unknown whether those epigenetic changes can be “transgenerationallyinherited” through germline development or not, but now it can be.
So, given the traditional concerns about heritability, the potential for inheritance of effects from
SGE/SGT or “persistent” somatic e-GE (Se-GE) respectively would be a key concern for scientists
and others. That is, when such genetic interventions are used on fetuses, infants, and even adults,
the consequences of the interventions may be inadvertently inherited.
Again, while the risk of germline effects of genetic interventions in adults is thought to be quite
low, the risks of interventions in fetuses and infants have not been adequately studied empirically.
It may also be desirable to intervene in the germline to make the effects of e-GE more permanent.
In such cases, the heritability issue would be an important concern, as it is with conventional
genome editing. So, as the field of GE/GT moves from research to clinical application, there is anurgent need for accurate safety evaluation of SGE, including Se-GE.
As far as I know, two papers have been published on the ethics of e-GE. Both of papers are dealing
with the ethical issues raised by human somatic e-GE and partly human germline e-GE. And there
are like right one is done by who are in there and colleagues. Actually I am not sure I pronounce
my name correctly. But both of the papers are doing with the ethical issues raised by humansomatic cell genome editing and pottery are human germline genome editing.
In light of the ethics literature of e-GE, I roughly identified ethical issues, although this is by nomeans exhaustive. The first is a safety issue. As long as the Cas9 system is used, off-target problems
cannot be avoided. It is also not entirely clear what can be achieved with e-GE, and there are still
uncertainties in the technology. The second is the problem of unexpected side effects in future
generations as a result of targeting or consequently affecting germline cells. The third is the issue54

of interventions for non-medical purposes (e.g., enhancement or sex selection). The fourth is theissue of informed consent when genetic interventions are performed on children. Fifth is the
problem of genetic deterministic reduction, that presenting epigenetics as if it were the underlying"cause" of health conditions and presenting as if epigenetics were the (often sole) cause of disease.
Sixth is the problem of social inequality caused by the high cost of genetic interventions. As
literature shows, these are not necessarily specific to e-GE, but are issues common to SGE/SGT,
GGE, and even stem cell therapy.
If we divide the future use of e-GE into three types, that is, transient Se-GE with no inheritance,
Persistent Se-GE with inheritance, and Persistent Ge-GE, the safety and ethical issues seem to fall
into one of these categories. Transient Se-GE without Inheritance should be treated basically thesame as SGE/SGT. On the other hand, Persistent Ge-GE should be treated basically like GGE.
Persistent Se-GE with inheritance is more difficult to handle. As for this, the safety and ethicalissues depend on the uncertainty factor of the presence or absence of germline integration/editing.
I think it is reasonable to take precautionary measures, as with GGE, when there are uncertainties,
until they are demonstrated by scientific research.
Finally what I want to consider is the problem of genetic inheritance itself. As we have already seen,
persistent types of Se-GE and Ge-GE could have heritability problems. As mentioned earlier, if
persistent type of Se-GE could be inherited, it would seem that, as with existing GGEs, it would be
best to consider the safety risk to the maximum extent possible until the safety risk has beenscientifically verified to some degree. However, the question here is to what extent we should takethe heritability issue seriously. In considering the heritability issue, I would like to open thediscussion by briefly touching on three cases. The first is GGE. The second is SGE/SGT. The third isa nuclear disaster. These situations, including nuclear terrorism, seems to be possible in the future.
I tentatively classified the three cases on a pilot basis using four criteria. For GGE, the nature of
the intervention is intentional, the germline changes are intentional and direct, it is heritable, andunanticipated adverse effects are possible. In contrast, for SGE, we share all the criteria with ND
case except for the nature of the intervention. If we look at the heritability issue based on whether
the nature of the intervention is intentional or not, then we can distinguish between GGE or
SGE/SGT and ND. In other words, even if there is a germline change in ND case, it would bepermissible for that change to be transmitted to future generations. Also, if we look at the issue
based on whether the germline change is intentional or not, we can distinguish between GGE and
SGE/SGT or ND. In other words, GGE may not be acceptable, but SGE/SGT would be. If heritability
per se is not morally important, then it may be appropriate to discuss the ethical pros and cons ofgenetic interventions, taking into account other ethical issues. Of course, safety issues should be
addressed in the most scientific way possible.
Safety evaluation is essential for the clinical application of SGE, including persistent Se-GE. Given
the challenges and prospects of e-GE, even persistent Ge-GE may also be necessary, although it
has not yet been well-investigated. We should seriously consider whether the inheritance ofgenetic interventions to future generations is morally important. In contrast to the conventional
arguments, the heritability concerns may not be morally significant in and of themselves if otherheritability case considered. Nonetheless, we should consider safety and other ethical issues
raised by SGE and GGE in general.
Given the nature of evolving (epi)genome editing and the content of this presentation, an updated
ethical discussion of human e-GE in the broader context of genetic intervention seems to beimportant.
Thank you.
5510) A Framework for Encouraging Responsible Innovation with Autologous Stem Cells
Dr Tamra Lysaght, Assistant Professor
Centre for Biomedical Ethics
National University of Singapore
Introduction
Regulators internationally are faced with challenges in providing timely access to innovative
therapies with stem cells while delivering safe and effecting stem cell-based products. In theabsence of clear pathways for innovation, an industry has flourished globally marketing ‘stem cells’
direct to the consumer (DTC) for products and services that have not been approved for marketingor demonstrated as safe and effective in formal clinical trials. This industry has raised many
concerns around patient safety and exploitation, conflicts of interest, trust in science andmedicine, professionalism and institutional practices that legitimates the market. Even so,
regulators remain under pressure to accelerate the approval process with the introduction ofprograms that allow early market entry for products demonstrated as having likely, but still
uncertain, benefits and safety.
In this paper, I draw on over 10 years of research conducted in Australia, Japan and Singapore to
identify some of the ethical challenges in regulating innovation with autologous stem cell therapies.
The research included comparative reviews of regulatory frameworks and international trends,
content analyses of websites marketing stem cells DTC, stakeholder workshops, interviews withpatients and medical professionals and roundtable discussions with experts in bioethics, healthlaw, product regulation, stem cell science and regenerative medicine. I describe the challenges
regulating innovative uses of autologous stem cells in clinical practice and propose solutions withina co-operative regulatory framework. I conclude with a discussion of the opportunities and
impediments for applying this framework at the national level and across transnational contexts.
Methods
1. Scoping reviews of ethical and regulatory challenges of the direct to consumer (DTC)
marketing of stem cells 1,2
2. Documentary analysis of regulations applicable to the use of stem cell-based products in
the Australia, Japan, Singapore, United Kingdom, and United States of America 3-5
3. Content analysis of websites offering autologous stem cell-based products in Australia,
Japan, and Singapore 6
4. In depth interviews with patients seeking autologous stem cell-based products in Australia
7,8

5. Roundtable discussions with stakeholders and regulatory authorities from Australia,
European Union, Japan, and Singapore 9
6. Normative analyses of regulatory frameworks for the use of stem cell-based products inclinical innovation 10,11
Key Findings
Our analyses have articulated the many ethical and regulatory challenges of the global industry
selling “stem cells” through DTC marketing in major health economies. While initially framed as aform of medical tourism 12,13, where patients typically travel from higher to lower income countries
to access more affordable heathcare, evidence demonstrates that the DTC stem cell industry has
penetrated the domestics markets of major health economies and is most prevalent in the USA 1416
, Australia 17,18, and East Asia 19-22. Our analyses of websites marketing autologous stem cells DTC
in Australia and Japan were consistent with international studies that have identified an
implausibly wide range of diseases and conditions they claim to treat with little to no scientificevidence of safety and efficacy 6. We also showed that the majority of “stem cells” being marketed56

were sourced from the patient’s adipose (fat) tissues from lipoaspirate and infused back using
some form of ‘injection’, which included both intravenous and intrathecal. The safety of theseadministration routes is not supported with scientific evidence.
What is the harm of this industry? Besides the documented experiences of patients who haveexpended significant amounts of financial and emotional resources on accessing unproventherapies and have not benefited 7,8, we described the case of Sheila Drysdale who died after being
administered an autologous adipose-derived procedure at an Australian clinic 23. This patient was
75 years old and suffering with advanced dementia when her husband approached the owner ofthe clinic, cosmetic surgeon Ralph Bright, after hearing about the procedure on the radio. Mr
Drysdale had the procedure for his arthritis and felt he had benefited from it. He had seen theprocedure being marketed on the Internet overseas for other neurodegenerative disorders andasked Bright if it would help his wife. Bright agreed to provide Mrs Drysdale with the procedure,
who was taken to the clinic out in Sydney and sent back to her nursing home but then died withinsort of 10 hours from blood loss. Her death resulted from Bright’s failure to ensure his patient hadceased taking blood thinning medications for hypertension and not keeping her in observation
long enough after the lipo-aspiration to monitor for such an adverse event.
While this case could be viewed merely as a medical error that any conscientious doctor could
overlook, the Deputy Coroner and medical registration tribunals did not. Bright was found to havedisplayed reckless disregard for patient safety by administering an experimental intervention that
had no clinical support or scientific justification. He also was not specialist in neurologicalconditions and failed to disclose the experimental nature of the procedure. Put simply, he had nobusiness offering the procedure to this patient, who would not have bled to death in her nursing
home follow an intervention that had no benefit, had Bright not been marketing so called ‘stem
cells’ on the Internet and radio. The NSW Medical Council found Bright guilty of negligence in his
duty of care and would have cancelled his registration, but Bright relinquished his medical license
before the proceedings ended. His Sydney clinic continues to operate although its website nolonger markets ‘stem cells’.
Our comparative analyses identified weaknesses and siloes in how therapeutic products are
regulated in clinical trials or research and their uses in clinical practice as partly enabling the DTC
stem cell industry to flourish in countries that are ordinarily seen as well-regulated 3-5. One
exception we found was Singapore, where the industry has never established itself 9. Upon closer
examination of the regulatory context in Singapore, we found the centralisation of therapeutic
product regulation and professional governance of medical practitioners under a single
government authority (Ministry of Health) to be important in enforcing laws and disciplining
unethical behaviour of doctors marketing unproven medical interventions with stem cells. We
describe this approach as cooperation between regulators with authority over the marketing ofstem cells and their use in clinical practice.
Conclusions
Based on these findings, we have constructed a cooperative regulatory model for encouraging
responsible innovation with stem cell-based products without promoting an industry marketing
unproven interventions DTC 10,11. This model comprises of three overlapping spheres of prohibitive,
permissive and positive regulation under an umbrella framework. Prohibitive regulation comprisesof traditional laws (e.g. consumer protections) and are punitive in action when enforced andpermissive regulation are the legitimate pathways that allow for product marketing andmanufacturing. Positive regulation is the area of professional governance that we argue needs thegreatest attention with guidance that rewards practitioners for ethical conduct.
57

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with autologous stem cells in Australia, Japan and Singapore. Cytotherapy 20, 11031109. https://doi.org/10.1016/j.jcyt.2018.06.004.
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Ghinea, N., Eckstein, L., Neilsen, J., et al. (2020 ). Unconventional Practice, “Innovative”
Interventions and the National Law. J. Law Med. 28, in print.
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Lee, T.-L., Lysaght, T., Lipworth, W., Hendl, T., Kerridge, I., Munsie, M., and Stewart, C.
(2017). Regulating the stem cell industry: needs and responsibilities. Bull. World HealthOrgan. 95, 663-664. 10.2471/BLT.16.189977.
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Regenberg, A.C., Hutchinson, L.A., Schanker, B., and Mathews, D.J.H. (2009). Medicineon the Fringe: Stem Cell-Based Interventions in Advance of Evidence. Stem Cells 27,
2312-2319. 10.1002/stem.132.
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Clinics Online: The Direct-to-Consumer Portrayal of Stem Cell Medicine. Cell stem cell 3,591-594.
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Berger, I., Ahmad, A., Bansal, A., Kapoor, T., Sipp, D., and Rasko, J. (2016). Global
Distribution of Businesses Marketing Stem Cell-Based Interventions. Cell stem cell 19,
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Turner, L. (2015). US stem cell clinics, patient safety, and the FDA. Trends Mol. Med. 21,
271-273. http://dx.doi.org/10.1016/j.molmed.2015.02.008.
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Turner, L. (2018). The U.S. Direct-to-Consumer Marketplace for Autologous Stem Cell
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Med. Ethics 43, 744-746. 10.1136/medethics-2016-104046.

5911) A Demoralizing Approach to the Ethics of Cell and Gene Therapy
Dr Roger Crisp, Professor of Moral Philosophy
Director, Oxford Uehiro Centre for Practical Ethics
University of Oxford
1. Welfarism and Demoralization
Imagine a causally isolated world, inhabited by a single, intelligent, mentally and physically healthy,
rational human being. The world contains resources for survival. If this individual does not act,
they will die. So what should they do? In the short term, of course, they must provide themselveswith sustenance and shelter. But why should do that? To advance their own well-being. So one
relevant consideration is what well-being consists in. If hedonism is correct, then the rational way
for this individual to act will be to maximize the balance of pleasure over pain, across the rest of
their life as a whole. But if well-being is constituted by more than pleasure, and, say,accomplishment or achievement also matters, then they may, given that they have the talent todo so, be better off producing some impressive work of art, even if that is overall hedonically costly.
Well-being, however, is not the only relevant consideration here. From the prudential point of view
(and the example is of course intended to rest on some conception of that point of view), personal
identity is also relevant. Now consider two variations on the example. In the first (World 1), theexperiences of the individual over time will be continuous and very tightly connnected over thewhole of their biological existence. They remember everything, their beliefs and desires do notchange, their actions all emerge from previous intentions, and so on. On anything like a standard
Humean or reductionist position on personal identity, the rational strategy for this individual at
any time is to act so as to maximize their well-being across the rest of their mental and biologicallife. Animalists will agree, as will those who accept anything like a ‘Cartesian’ view, according towhich personal identity depends on the continuing existence of the soul. Now consider a very
different case (World 2). At the end of each 24 hours, the maximal number of the individual’s
individuating beliefs, desires, intentions, and so on, that can rationally change do so. On one day,they continue to believe that the sky is blue, for example, can remember how to think, andnaturally feel thirst and hunger. But they remember nothing of the previous day, have quite
different dispositions (are, say, cheerful rather than phlegmatic), form entirely new projects, andso on. If we also assume some lack of continuity of experience during sleep between one day andanother, many reductionists will claim that the person on the previous day has been replaced by a
new person, or at least that the radical lack of connectedness has implications for the degree ofconcern the first-day-person should have for the second-day-person (especially if we assume thatthe first-day-person is aware of the relevant metaphysical facts in their world). The animalist andthe Cartesian, however, may be more inclined to think that the first- and second-day person are
identical.
In World 1, where nothing changes, all that matters is which theory of well-being is correct, on theplausible assumption that the individual has a reason – indeed overall reason – to promote theirown well-being. In the second world, more is required: the truth about identity over time, and thetruth about whether rational egoism is correct or whether there are reasons to promote the wellbeing of other persons that may on occasion override egoist reasons. If the individual in World 2
has knowledge of the metaphysics, they might have an opportunity towards the end of a day totake steps to make the existence of the next day’s individual more comfortable, steps which would
be overall costly to today’s individual to take.
I have described one world, World 1, in which most would agree that what matters is only, or
primarily, the correct theory of well-being. That world is far from our own, in which individuals are60

in a constant state of flux. In World 2, two more things matter: the correct theory of personal
identity, and whether there are non-egoistic reasons of sufficient strength on occasion to override
egoistic reasons.
It may be tempting to think that, on, for example, a reductionist view of personal identity, World
2 requires us to ask ‘moral’ questions. Given the mental switches, for example, would it be wrongof the earlier individual not to take steps to help the later? Is it required by morality that they do
so? Would it be generous, or kind? Do they have a duty, and, if so, are they blameworthy if they
do not help?
I now want to suggest there are strong reasons to resist this temptation. The practical questions
raised for the agents in these worlds can be answered without using moral terminology, and I
believe that they should be so answered. On the face of it, it is hard to see what more these agentsneed. The answers to their questions about what to do are fully answered by a position which
provides complete accounts of well-being, personal identity, and reasons for action. The view thatthese are always sufficient to answer any practical question might be described as welfarism: allthat matters is well-being, who gets it, and how much. Practical or ethical decisions, then, are best
seen as ultimately distributive, where the only distribuendum is well-being.
The world we inhabit is of course highly complex, and we need many concepts to explain anddescribe it. But it is dangerous to think that because some concept is widely accepted and natural
to us, we need it to answer particular questions. At one point, many people thought there were
witches, and acted in accordance with that belief. Until we are offered a plausible case for using
moral terminology, we should treat it as potentially equivalent to witch-talk. It may be merely
unnecessary; but it could also be misleading, causing us to think and act in ways we have reason
not to think or act. Imagine some group of rational beings living lives very similar to us, except thatthey think about how to act using only non-moralized concepts concerning well-being, identity,
and reasons for action. Insisting to them that they are missing something of huge importance –morality – may be analogous to someone’s claiming in the C14 that the concept of ‘witch’ isrequired to understand the origin of the Black Death.
Of course, by using the word ‘morality’, I am myself using the concept. But that is true of what I
said about witches. The concept of ‘witch’ is now very rarely heard; am I recommending that wetreat the concept of ‘morality’ in the same way? I am, but primarily (though not only) within
philosophy. What we might call ‘the morality system’ – extending Bernard Williams’s notion tocover all moral terminology – has been and is hugely important in human life. It may be that, in
time, we, or our successors on the planet, might move beyond it, but for the moment I see little
advantage, and indeed some danger, in encouraging people in general to stop using moral
terminology. And because of its historical and cultural significance, philosophers should continue
to reflect upon it, as they might do on religion (even if they are inclined towards atheism). We canthink of morality as some so-called ‘positivists’ think of the phenomenon we call ‘law’. There is no‘ideal’, ‘natural’ (or ‘super-natural’) law, existing independently of human practices, against which
we might assess those practices. There are just the practices themselves, and, we might consider
legal practices without strictly using legal terminology – we might, ask for example, whether trialby jury in some species of case is overall beneficial or harmful, elucidating ‘trial by jury’ as ‘what
is called “trial by jury”’, or more directly in non-legal terminology, though that approach would
certainly complicate matters usually for no good reason. ‘Morality’, then, can be seen as a set ofpractices which have emerged over time, through cultural evolution, and which may plausibly bethought highly beneficial – at least in certain respects (like law, morality is without doubt also
seriously harmful, and continues to be put to bad uses). Most modern moral philosophers think ofmorality in the same way that natural lawyers think of positive law. Natural lawyers are now in a61small minority in the philosophy of law, and it is time that moral philosophy followed the lead ofjurisprudence. In other words, just as we can ask practical questions about legal practices without
using legal terminology at all, or at least without committing ourselves to the existence of legal
entities existing metaphysically independently of human practices as in principle to be understood
without use of legal terminology, so we can ask practical questions of the morality system.
Moral terminology may, then, be unnecessary in discussing practical or ethical issues. Whether itis helpful will depend on the case, though as yet I have not found any issue where it seems likely
to be so, and hence recommend a strategy of demoralization. It is worth noting also at this pointa fact about morality which does not apply to other non-referring concepts, such as ‘witch’. Thereis a huge amount of disagreement about morality which does not boil down to disagreement about
the genuine underlying issues on which it supervenes. Take just one notion: rights. Are there
rights? Do animals or embryos have rights? How do rights relate to duties? What are human rights,
non-legally construed? Are some rights inalienable? And so on. Some discussion is fairly
immediately translatable into the language of what matters. For example, two people arguing
about whether utilitarianism is true can be understood as arguing about whether the only ultimate
reason we have is to promote overall well-being. But much discussion is not translatable, or atleast not easily translatable, and therefore it is worth avoiding the concepts involved entirely.
A final reason for demoralizing is that the morality system has at its heart a number of emotions,in particular, forms of anger directed at perceived wrongdoers (blame, resentment, indignation)and of fear, disgust, and self-hatred, serving as sanctions and deterrents to immoral action (guilt,
shame, remorse). These are negative emotions, often extremely distressing, and are likely to
distract impartial and rational attention to the plausibility of premises or arguments. A good dealof philosophical ethics employs moral language, often of a rather portentous kind, for rhetorical
purposes, either to attract agreement from others, or to encourage disagreement with opponents.
Rhetoric is out of place in philosophy. (I have been focusing especially on philosophy, but I do
believe there are occasions beyond philosophy when demoralizing is justified, e.g. when
considering how to allocate some scarce health resource, and I shall say more about this withreference to cell and gene therapy below.)
2. Some principles
According to the view sketched above, what we need in our toolbox before considering the ethicsof cell and gene therapy are accounts of identity, well-being, and the reasons governing the
distribution of well-being.
The issue of identity is metaphysical, of course, but it is also ethical. The question is essentially oneof ethical or practical status (the demoralized notion of ‘moral status’). Who or what matters? The
most common view is that what matter are diachronic individual sentient beings, where sentienceis usually taken to involve phenomenal consciousness. But we might also wish to consider
Buddhist-influenced views according to which selves are not diachronic, but are constituted
merely as subjects of experience at a time, as well as views according to which zombies might havea well-being, even though they entirely lack phenomenal consciousness or awareness. But for ourpresent purposes, we might most productively work with the idea that what matter in the cases
under discussion are primarily the individual recipients of cell and gene therapy, and those affectedby particular distributions of such therapy.
What about distributive principles themselves? In World 1 above, perhaps the most plausible viewis that the agent has overall reason to maximize their well-being across the whole of their life,
since there seems no plausible justification for discounting the future at the theoretical level,62

though of course a maximizing strategy might well involve actual discounting in practice. Are there
principles other than egoism? This seems hard to deny. Consider a case in which I can prevent
billions suffering the most exquisite suffering for decades, at no cost, or perhaps some minor cost
(an annoying itch for a few seconds), to myself. So I have a reason to maximize my own happiness,but also that of others. That reason is not itself overriding, however. Consider a case in which I can
prevent many others – all of whose lives will go hugely better overall than mine – experiencing
some fairly brief period of exquisite suffering (say, 10 seconds) at the cost of experiencing that
suffering myself for five decades. There is here a dualism of the practical reason, which requires
judgement in particular cases. When it comes to the suffering of others, should I maximize
impartially? I think not: there is often a strong case for diverting well-being to those who are worse
off, if they are below some threshold at which maximization seems more reasonable than diversion.
So we now have in place a theory which may provide answers to questions about cell and genetherapy, according to which any agent has reasons to: 1) maximize their own well-being; 2)maximize the well-being of others; 3) give priority to those below a certain threshold. Note one
further upshot of demoralized welfarism (DW) as defended above. Many accept the so-called ‘actsand omissions’ doctrine, according to which, say, killing some innocent person is morally worse
than allowing some innocent person to die. Now we understand practical reasons properly, we cansee this doctrine as itself an unjustifiable aspect of the morality system. What matter are wellbeing, and who gets it. How they get it is entirely irrelevant, and so the causal history of any stateof affairs under evaluation is itself irrelevant. All of us do tend to put special weight on our own
agency, but that is merely a product of biological and cultural evolution which we might well want
to resist in practice, at least on occasion. Certainly the acts and omissions doctrine should be
excised from philosophical discussion.
3. Cell and Gene Therapy
We are now at the point at which we can examine the implications of DW for moral or ethicalissues in cell and gene therapy. One immediate result is that there are no moral issues! But, ofcourse, this conclusion is not as dramatic as sounds on first hearing, because there may well be
issues often described in moral terminology which, once restated within DW, are significant. These
we might call ethical rather than moral issues, using ‘ethics’ to cover practical reason in general,and to be distinct from the morality system.
Consider, then, the position that, since all innocent persons have a right not to be killed or left todie, and human embryos are persons (albeit embryonic persons), experimentation on humanembryos in stem-cell research is wrong. Within DW, that position might be restated as follows:
there is a reason not to kill and a reason to save those with ethical status, embryos have ethicalstatus, and hence there is a reason not to use human embryos in stem-cell research. It is quite
often said that early embryos have no well-being, and hence no ethical status. This may be true,
but whether it is so depends on which conception of ethical identity we should employ. On a
plausible version of the animalist view, a sentient adult is identical with the embryo from which
they came (if it did not split). But on the standard psychologically reductive view of persons, theirethical status began at the very earliest when sentience developed. On the animalist view, then, if
one believes that, other things being equal, there is a reason not to kill or to fail to save a sentient
adult, on the ground that this will deprive them of future well-being, there is also a reason – indeed
a stronger reason – not to kill or to fail to serve an embryo, since it will be deprived of an evengreater amount of well-being, other things equal. This might be thought to put pressure on the
animalist view itself, but that is not the case. What appears doubtful is the great significanceattached to killing or failing to save those with ethical status. Any reasons we have not to kill or to
fail to save post-birth individuals, then, cannot plausibly be ultimate; they are grounded in63

impartial reasons to promote well-being overall. (In that respect, then, the most plausible DW
position on killing will be broadly analogous to act utilitarianism, though of course that position isusually stated in moral terminology and DW will also include a distributive principle favouring theworse off.)
DW also enables us to distance ourselves from ethically irrelevant debates, such as that concerning
the treatment/enhancement distinction. Imagine that you are in a position to benefit me, as anindividual with a well-being and hence ethical status, to degree d either by treating me for someillness or by enhancing me in some respect (such as improving my memory, which will enable me
to gain more enjoyment from, say, bird-watching). As far as I am concerned, other things equal, it
is irrelevant which you decide to do. There may of course be reasons for a state to focus its healthbudget on what is usually described as treatment rather than as enhancement, but these reasons
will again not be ultimate. The actual distinction we draw between treatment and enhancement
is highly contingent on what we take to a norm for our species, such as cognitive capacity, height,
or life span. But it is at least plausible to claim that well-being in some existing society is likely to
be greater overall (and appropriately targeted at the worse off) if some basic health minimum is a
defeasible legal right. But it has to be admitted that such calculations will be extremely difficult,and perhaps even quite out of place if one thinks that those with little capacity for well-being –such as maggots, to use Ingmar Persson’s example – should be given very high priority over thosewith much greater well-being.
Other issues can be addressed – or rather side-stepped – in the same way. Consider for example
the claim that there is something inherently objectionable in creating human chimeras. It is truethat we would have some ethical responsibility towards them, if they have a capacity for wellbeing, but the distinction between a human being and a chimera is merely one of biology, and in
itself irrelevant to ethics. The ethical weight current human beings tend to place on thehuman/non-human distinction is clearly too great – consider, say, our tolerance of the factoryfarming of billions of chickens. But that distinction also may have some value, in the sense that it
inhibits our tendencies to harm or kill other humans. Any changes we seek to bring about in our
attitudes here will have to be carefully thought through, but in the case of factory-farming I would
imagine that the compassion we might show in abolishing it would be likely to benefit our fellow
humans rather than put them at greater risk. It has been claimed that beings such as chimeras, or
certain forms of genetically engineered humans, would be deeply alienated from others. This iscertainly relevant from the DW point of view, but what matters is the effect of that alienation onthem, and their place in the eudaimonic economy of the world as a whole. It may be, that is to say,that benefiting the better off at some cost to the worst off is justified overall, if the benefit to thebetter off is sufficiently great.
The somatic-germline distinction is in the same category as that between human and humanchimera. What matters are the effects of any action on the well-being of those with ethical status,
whether they exist now or in future. There clearly are risks here, and – unsurprisingly – the DW
view is that these have to be weighed against one another, and against the opportunity costs of
the actions in question. Should cell and gene therapy and research continue? I believe it should
not at present, but only because the resources it uses could be put to better use. If the question istaken to be – as it usually is, if only implicitly – whether it would be better to use those resources
for such therapy and research or to destroy the resources in question, I have no doubt that bothshould continue, though of course not without careful oversight and monitoring.
Roger Crisp
July 2023
64