GeneWatch Vol. 27 No. 3

Volume 27 Number 3 | Sept-Nov 2014

ISSN 0740-9737

GeneWatch September-November 2014 Volume 27 Number 3 Editor and Designer: Samuel Anderson Editorial Committee: Jeremy Gruber, Sheldon Krimsky, Ruth Hubbard GeneWatch is published by the Council for Responsible Genetics (CRG), a national, nonprofit, taxexempt organization. Founded in 1983, CRG’s mission is to foster public debate on the social, ethical, and environmental implications of new genetic technologies.

The views expressed herein do not necessarily represent the views of the staff or the CRG Board of Directors.

Address 5 Upland Road, Suite 3 Cambridge, MA 02140 Phone 617.868.0870 Fax 617.491.5344 www.councilforresponsiblegenetics.org

board of directors

Sheldon Krimsky, PhD, Board Chair Tufts University Evan Balaban, PhD McGill University Paul Billings, MD, PhD Life Technologies Corporation Robert DeSalle, Phd American Museum of Natural History Robert Green, MD, MPH Harvard University Jeremy Gruber, JD Council for Responsible Genetics Rayna Rapp, PhD New York University Patricia Williams, JD Columbia University staff

Jeremy Gruber, President and Executive Director Sheila Sinclair, Manager of Operations Samuel Anderson, Editor of GeneWatch Andrew Thibedeau, Senior Fellow Vani Kilakkathi, Fellow Cover Photograph Angie Garrett (www.flickr.com/photos/smoorenburg) Cover Design Samuel Anderson Editorial & Creative Consultant Grace Twesigye Unless otherwise noted, all material in this publication is protected by copyright by the Council for Responsible Genetics. All rights reserved. GeneWatch 27,3 0740-973

2 GeneWatch

Editor’s Note

Samuel Anderson

Although it isn’t specifically named on the cover, this issue of GeneWatch focuses on a particular reproductive technology (or “technique,” or “procedure,” or “set of procedures,” depending on how you look at it and who you ask). Already you may have noticed me being oblique about this technique/technology/procedure – there, I did it again! – and throughout the issue you may notice that even those who are intimately familiar with it have some trouble knowing quite what to call it. As you can imagine, the popular press hasn’t agreed on a term yet, either. A few of the ones you’ll see most often: Mitochondrial transfer Mitochondrial replacement Three-parent (or three-person) babies Three-parent/three-person embryos Three-parent/three-person IVF Nuclear genome transfer Before getting any further into that mess: What is this mitochondrial nuclear three-parent whatever-you-call it? The rest of this issue contains plenty of explanation, as you might imagine, but the short version is that nuclear genome transfer (this publication’s preferred term) involves removing the nucleus from one woman’s egg and replacing it with the nucleus from another woman’s egg.

The goal is to allow a woman with mitochondrial disease to have a healthy child. That’s where terms like “mitochondrial replacement” come in: Mitochondria have their own DNA distinct from nuclear DNA, so by removing the nucleus from an egg with problematic mitochondria and swapping it into a donor egg with healthy mitochondria, you are in effect replacing the “bad” mitochondria with “good” mitochondria. (See Stuart Newman’s article in this issue for numerous reasons that terms like “mitochondrial replacement” can be misleading, at times perhaps purposely so.)

If this is the first you’ve heard of all this and you have nonetheless managed to stick with me so far, you may be wondering: What’s the big deal? Who would this really affect? And what does this have to do with human genetic engineering? For that, I’ll turn you over to the experts – read on. nnn

comments and submissions GeneWatch welcomes article submissions, comments and letters to the editor. Please email anderson@gene-watch.org if you would like to submit a letter or any other comments or queries, including proposals for article submissions. Student submissions welcome!

founding members of the council for responsible genetics Ruth Hubbard • Jonathan King • Sheldon Krimsky Philip Bereano • Stuart Newman • Claire Nader • Liebe Cavalieri Barbara Rosenberg • Anthony Mazzocchi • Susan Wright Colin Gracey • Martha Herbert • Terri Goldberg Sept-Nov 2014

GeneWatch Vol. 27 No. 3

4 DEDICATION: Liebe F. Cavalieri 5 Introduction: What Is Mitochondrial Disease?

6 Deceptive Labeling of Radical Embryo Construction Methods Besides being unscientific, the terms “mitochondrial transfer” and “mitochondrial replacement” far understate the potential hazards of these techniques. By Stuart Newman 8 Providing Choices, Carefully How would mitochondrial transfer techniques fit into the field of reproductive medicine? Interview with Paula Amato 10 The Patient Perspective In the debate over techniques for preventing mitochondrial disease, one group is often overlooked: The people who are actually living with the disease. Interview with Sharon Shaw Reeder 14 Enabling Technology A case for moving forward – carefully – with human trials for mitochondrial transfer techniques. Interview with Nita Farahany 16 Why Worry About Genetically Modified Babies? Here’s what’s at stake if the UK walks back its prohibition on human germline modification. By Jessica Cussins and Marcy Darnovsky 19 Manipulating Embryos, Manipulating Truth In considering whether to allow new embryo manipulation procedures in the UK, regulators seem more interested in shaping public opinion than listening to it. By David King 22 Is Ooplasm Transfer Safe for the Offspring? Adapted from testimony submitted to the FDA’s Cellular, Tissue, and Gene Therapies Advisory Committee. By Sheldon Krimsky 23 Endnotes

Volume 27 Number 3

Image: Kenny Louie (www.kennymatic.com)

GeneWatch 3

DEDICATION: Liebe F. Cavalieri This issue of GeneWatch is dedicated to the memory of Liebe F. Cavalieri (1919-2013).

Liebe Cavalieri was a founding member of the Council for Responsible Genetics. An early pioneer in nucleic acid research, Liebe was educated as a biochemist at the University of Pennsylvania. The focus of his many scientific publications was on DNA and DNA polymerases. His career was spent largely as a Professor at Sloan-Kettering Institute for Cancer Research in New York City, now part of Memorial-Sloan Kettering Cancer Center.

Liebe was a frequent writer, lecturer and commentator in the public media on the impacts of science on society. In the early days of genetic engineering technology, Liebe was among the first scientists to alert the general public to its potential dangers, with an article in the New York Times Magazine published Aug. 22, 1976 titled “New strains of lifeor death,” where he wrote that “recombinant DNA technology is so overpowering and far reaching in its potential for harm that decisions on how to handle it must not be left to scientists alone.” Later he offered public commentary and the seminal book The Double-Edged Helix: Genetic Engineering in the Real World (1981 & 1985). In it, Liebe noted the high social price that often has to be paid for scientific innovation: We must ask ourselves whether a

4 GeneWatch

continuing process of scientific discoveries and technological applications is what we need for the advancement of mankind. We already have an abundance of goods (whether or not they are equitably distributed), yet evidence abounds that we are experiencing a generalised malaise throughout the industrialised nations of the world, which strongly suggests that we do not need more hardware but that we should utilise more humanely what is already at hand.

He reminded us that we “shouldn’t be carried away with fantasies promised by scientists and companies engaged in biotechnology research”: Science is, however, of necessity committed to its sources of support: government (including the military) and industry. They themselves are inextricably intertwined to form what some call the corporate state, the single most important determinant of modern industrialised

society, characterised by a primary drive for self-perpetuation and expansion. The corporate state controls the economy, and in so doing it mandates, directly or indirectly, the direction and growth of science and technology. Economic necessity thus presses the public to accept indiscriminately the technological system as a whole, in spite of its antisocial tendencies.

Liebe advocated an early moratorium on recombinant DNA research until appropriate safety studies had been conducted and raised concerns that the technology might be used to “create an atmosphere in which genetic procedures in general become an accepted solution to many sorts of problems – problems which are basically social and political.

To deal with them at a genetic level enables us to accommodate the social and political trends that give rise to the problems – but not to overcome them.”

Following retirement from SloanKettering, Liebe moved to the State University of New York at Purchase and pursued his longtime interest in mathematics to analyze procedures for controlling the environmental spread of foreign genes in agriculture. nnn

Sept-Nov 2014

Introduction: What Is Mitochondrial Disease?

The mitochondria are semiautonomous organelles with their own genomes and transcriptional machinery residing in the cytoplasm of eukaryotic cells. Mitochondrial cells contain 37 genes that encode 13 proteins, 22 transfer RNAs and 2 ribosomal RNAs. In contrast, the nuclear genome consists of about 20,000 genes. Mitochondria are the powerhouses of cells – they store and transmit chemical energy. They multiply when the energy needs of the cell increases. The primary function of the mitochondria is the generation of the molecule ATP (adenosine triphosphate) from food sources. ATP is often referred to as the energy currency of life.

Mitochondrial diseases are a group of disorders that can cause debilitating, chronic illness. They are the result of either inherited or spontaneous mutations in mitochondrial DNA (mtDNA) or nuclear DNA (nDNA), which lead to altered functions of the proteins or RNA molecules that normally reside in the mitochondrial cells. These mutations can be present at birth or develop later in life and cause mild to severe physical, developmental, and mental disabilities.

When mitochondria aren’t working properly, they can disrupt function in almost any of the body’s organs. Depending on which cells are affected, symptoms may include loss of motor

control, muscle weakness and pain, gastro-intestinal disorders and swallowing difficulties, poor growth, cardiac disease, liver disease, diabetes, respiratory complications, seizures, visual/hearing problems, lactic acidosis, developmental delays and susceptibility to infection.

Mitochondrial diseases can be difficult to diagnose. At least one in 8,500 of the population carries a pathogenic mtDNA mutation, while it is estimated that up to 4,000 children per year in the US are born with a type of mitochondrial disease.

They are progressive and incurable, though some treatments are available depending on the case. nnn

Nuclear Genome Transfer - The (Simplified) Process Nucleus removed, inserted into donor egg

Egg from woman with mutated/faulty mitochondria

Egg from donor with healthy mitochondria

Donor nucleus removed Volume 27 Number 3

GeneWatch 5

Deceptive Labeling of Radical Embryo Construction Methods Besides being unscientific, the terms “mitochondrial transfer” and “mitochondrial replacement” far understate the potential hazards of these techniques.

By Stuart Newman

Techniques now exist for generating infants which, if implemented, would constitute the first cases of large-scale human genetic engineering. These techniques are widely referred to – by their scientist-creators and other proponents, by journalists, by bioethicists, by members of regulatory panels, by legislators, and even by some critics of the procedure – as “mitochondrial transfer” or “mitochondrial replacement.” These descriptions are not only scientifically inaccurate, they are also easing the way to public acceptance of these manipulations.

What exactly are these techniques? An isolated nucleus from the egg of one woman is inserted into an enucleated (nucleus-lacking) egg of another woman. Done before fertilization, it is called “maternal spindle transfer” (MST). Done after, it is called “pronuclear transfer” (PNT).

In fact, no transfer of mitochondria (the organelles that extract energy from fuel molecules and make it available for the cell’s functions) is involved in these “three-parent” procedures. So why are they referred to as mitochondrial “transfer” or “replacement”?

The techniques are being promoted as a way of circumventing mitochondrial mutations, which can lead to severe disease. It is understandable that an affected woman who intends to become pregnant would seek to avoid passing down this genetic predisposition to her offspring.

Methods such as MST and PNT represent radical interventions in the reproductive process that, if accurately portrayed, would stir fears in prospective parents and rightly attract the attention of legislators and regulators. The laboratory scientists and doctors for whom these women are clients (not patients – their own conditions are not being treated), thus have an interest in minimizing the perceived scale of what they are proposing to do.

Since it is true that nuclear genes of an affected woman or couple will eventually find themselves in the presence of mitochondria from a second woman, from the viewpoint of the first woman the mitochondria of her egg are “replaced.” But this is only mitochondrial replacement in the sense that someone who moves into a new home may experience “refrigerator replacement,” i.e., only

by employing a highly idiosyncratic (and misleading) use of the term.

Focusing only on mitochondria ignores the other significant features of the second woman’s egg such as its cytoplasmic and membrane composition and structure. Shifting attention in this fashion must raise questions about disingenuousness of the methods’ proponents. In fact, the manipulation of the second woman’s egg (i.e., the egg that will actually be implanted) constitutes a “genome transfer” or “genome replacement.”

Choosing a conceptual frame based solely on who is soliciting or paying for the procedure (i.e., the woman seeking to avoid passing on a genetic predisposition for mitochondrial disease) is not motivated by scientific or medical concerns.

In biological terms, both MST and PNT are very much like cloning by nuclear transfer, the methodology that produced Dolly the sheep.

Like cloning, the techniques involve replacement of an egg’s nucleus by a nucleus from another cell. When cloning, the transferred nucleus is from a differentiated cell of a fully developed animal (or potentially, a person), making the resulting organism

This is only mitochondrial replacement in the sense that someone who moves into a new home may experience “refrigerator replacement.”

6 GeneWatch

Sept-Nov 2014

a genetic “copy” of the nucleus donor. When undertaking MST and PNT, the transferred nucleus is from an egg or a fertilized egg, so that the resulting organism will have a novel genome. Otherwise, however, the hazards of cloning also pertain to MST and PNT, since the manipulations are the same. Clones tend to die prematurely, as happened with Dolly, or exhibit enlarged organs and metabolic abnormalities. Some human embryos constructed by MST unexpectedly had unbalanced chromosomal duplications (aneuploidy).

This is the case because unlike the sorts of cellular aberrations repeatedly encountered over the course of evolution – breaks in DNA, the unfolding of protein molecules – the experimental combination of fragments of two broken cells generated by cloning or the two proposed techniques have no inbuilt mechanisms to correct the range of functional and developmental defects inevitably associated with their construction.

It is unfortunate that few science journalists have the training or inclination to assume a critical stance toward the assertions of the scientists they interview. It is therefore common to see these procedures described in the popular and scientific press as the mere replacement of the 37 mitochondrial genes (compared to the 20-25,000 of the nucleus). The scientists who promulgate the transfer/replacement imagery and those bioethicists who do the same know better. Indeed, bioethicists should be scrutinizing the scientists’ practice and language as opposed to promoting their fantasies and business models. Their collusion in these deceptions is inexcusable.

Moreover, anyone familiar with the relevant science would have been aware, over the period during which the techniques were being Volume 27 Number 3

evaluated by the British Human Fertilisation & Embryology Authority (HFEA) and the U.S. Food and Drug Administration (FDA), of evidence that mitochondria are not (as the impact-minimizing refrain has it) mere energy-providing organelles.

The very existence of mitochondrial DNA mutations affecting hearing, vision, pancreatic function and neuromuscular activity (the justifications of the entire enterprise), would be enough to tell us this. Indeed, in the past two years the evidence for the non-passivity of the mitochondria has become inescapable. Since mitochondria are active participants in cell function and organismal development, integration among coevolved nuclear and mitochondrial systems would contraindicate arbitrary mixing and matching. (The engines of a Jaguar and a Rolls-Royce do essentially the same thing, but they are not interchangeable.) This adds an array of hazards to MST and PNT that go well beyond those they share with cloning.

A prospective child made by MST or PNT would be the result of an evolutionarily unprecedented experiment with known, or easily anticipated, hazards. Juxtapose this against the fact that the biological identity and long-term health of the three biological parents undertaking

MST or PNT are not directly at risk in the procedures. It is, therefore, entirely unwarranted to make their perspective (or more specifically that of the nuclear gene donor) the one from which the procedure is judged, thereby allowing the techniques to be characterized as being of minimal impact. Rather, the perspective of the individual brought into being by the procedures should be paramount. Combining fragments of two damaged eggs to produce a human embryo is, despite the rhetoric of mitochondrial “transfer” or “replacement,” large-scale manipulation of nuclear genes. Its backdoor admittance to the repertoire of assisted reproduction techniques in the guise of being a trivial tweak bodes ill for future attempts to regulate gene transfer methods for any other purpose.

A kind of omertà among scientists and bioethicists has prevented a significant number of them from representing to the HFEA and FDA, and the press, the gravity of these alterations. But the health implications and the eugenic outcomes these procedures would enable are too great to ignore.

nnn Stuart A. Newman, Ph.D., is Professor of Cell Biology and Anatomy at New York Medical College.

GeneWatch 7

Providing Choices, Carefully How would mitochondrial transfer techniques fit into the field of reproductive medicine?

Interview

with

Paula Amato

Paula Amato, MD, is a board-certified Reproductive Endocrinologist and an Associate Professor in the Department of Obstetrics & Gynecology at Oregon Health & Science University.

As you know, this issue of GeneWatch focuses on “nuclear genome transfer,” or “mitochondrial transfer,” or “mitochondrial replacement,” or whatever you prefer to call it. Some of the other contributors object to the approval of this technology on ethical or medical grounds. So: What are they missing?

What’s the best argument for going forward with these procedures?

Right now there’s no cure for mitochondrial disease, but this could

8 GeneWatch

theoretically be an avenue for prevention. These children, as you know, have very devastating diseases, and they usually die at a young age. The other methods we have to try and prevent it – like preimplantation genetic diagnosis – don’t work very well for mitochondrial disease because of the way mitochondrial DNA is inherited. So this would potentially offer a way of preventing the disease in children. It has been shown to be effective in monkeys – and I would agree that monkeys aren’t people, so it certainly doesn’t guarantee that it would be safe in humans. I think it’s reasonable to do as many studies as we can using human tissues in vitro before we try it in vivo. But ultimately, the reality is that we probably won’t know until we actually do it in

humans, transfer an embryo and create a baby. And that’s true for a lot of the technologies in reproductive medicine. We’ve always tried to do it first in animals and then in vitro in humans, but ultimately until we do it in humans we’re never quite sure that it’s going to be safe.

Would you say this is something fundamentally different compared to other assisted reproductive procedures used today?

A lot of the process is quite similar.

The whole ovarian stimulation and the embryo transfer part would be similar. The difference is the technical aspect of taking the nuclear DNA out of one egg and transferring it into a donor egg that has had the nucleus

Sept-Nov 2014

removed. That part is novel; it has not been done in humans before. I mean, we’ve done it in human eggs and made embryos in the lab, but we have not created a baby. In some sense, it’s kind of similar to a donor egg, where you replace the entire genome, nuclear and mitochondrial DNA. It’s similar to that, except that this requires more manipulation of the egg.

Do you have concerns about the safety of these procedures, either for parent or child?

I do, more so for the children. I think the process that the parent undergoes – the in vitro stimulation, retrieval, and transfer – we’ve been doing that for more than 35 years. There

per se, it’s really about prevention of disease. I think that risk always exists, but I don’t think it’s sufficient reason not to pursue this technology.

Technology can always be misused, whether it’s medical technology or military technology or computer technology, but I don’t think that’s a reason not to use it for positive purposes.

You practice as a reproductive endocrinologist, right? So if a woman came into your practice and said, “I have mitochondrial disease and I want to have a baby using one of these procedures,” how might you respond? Obviously that’s making some assumptions since it’s not legal at this point …

“I don’t think in general that people ought to be making reproductive decisions for other people.” are some risks with that, but they are relatively safe procedures. I think the big unknown is the result for the child. And of course I do have questions, and I worry about whether it’s going to be safe, but I think there is a strong enough reason to try it and to find out, after appropriate numbers of studies have been done.

It’s pretty hard to argue that these procedures qualify as “eugenics,” but do you have concerns about this technology leading to something like that in the future – to use the media’s favorite term, “designer babies”?

I think that’s always a concern, but I don’t think this technology is unique in that regard. It is not enhancement Volume 27 Number 3

Right – that would be a barrier! I’d explain that currently, in the United States anyway, we can’t really do that procedure because it’s not approved by the FDA. We’d like to do a clinical trial, but we’re waiting to hear from the FDA on that.

But assuming that at some point it was approved, it would be similar to other medical or reproductive procedures: We would speak with the patient and make sure she has given informed consent about all the potential risks to her or her baby; we would offer her counseling; and we would certainly do it, at least initially, under the auspices of the IRB as part of a research protocol, since we would want to gather as much data as possible to make sure that it’s safe.

Do you have a sense of who would be using this?

I think initially it would be women who are carriers of the mutation.

Most people don’t know they are carriers until they have a child who is diagnosed with a mitochondrial disease. The mothers of those children are the ones we would be offering this technology to. It’s not a very common disease, so I don’t expect the uptake to be great, just because the numbers of eligible patients probably wouldn’t be great. And there’s always the cost issue; IVF in general is kind of an expensive procedure, so there probably will be issues of access, just as there are for anyone using IVF. There are other potential applications for this technology. Aging eggs are thought to have acquired mitochondrial mutations, so in the future, if this is shown to be safe in women who are carriers of mitochondrial gene mutations, this might potentially be a therapy for age-related infertility.

Given the cost issue, and the possible safety issues, some people might ask: Why not just adopt?

That’s an easy thing for people to say, and infertility patients hear it all the time. I really think it’s unfair. It’s fine for people to make their own reproductive choices, and I think adoption is a great thing, but I don’t think it’s unusual or selfish in any way to want to have a genetically related child. I think it’s a basic human instinct, and I don’t think in general that people ought to be making reproductive decisions for other people. nnn

GeneWatch 9

The Patient Perspective In the debate over techniques for preventing mitochondrial disease, one group is often overlooked: The people who are actually living with the disease.

Interview

with

Sharon Shaw Reeder

Sharon Shaw Reeder was diagnosed with mitochondrial disease in 1999. She has been a member of the United Mitochondrial Disease Foundation Board of Trustees for over a decade and was appointed to the FDA’s first Mitochondrial Patient Advisory Committee.

I noticed something while reading up a bit on this issue, and I wonder if you’ve noticed it too: In the popular press and in ethical debates about these procedures – so-called “mitochondrial replacement” or “three-parent babies” – the people who actually have mitochondrial disease are often overlooked.

Yes, and I appreciate your understanding of that. Living with mitochondrial disease is like trying to find corners in a round room. It is the most complicated disease out there.

Mitochondria are responsible for 90% of the energy produced in each cell in our body. This translates into everything we do – how we walk, how we talk, how we chew, how we digest, how our brains function – everything in our body requires energy, and when there is a defect in the

10 GeneWatch

mitochondria, all kinds of stuff happens. So for people living with mitochondrial disease, it can look like five to ten different illnesses. You can’t just go to one doctor; I have a team of 14 different doctors. The best analogy I have heard is trying to run your house on two batteries. You just don’t have enough energy to run your body properly.

When I was diagnosed, I got the message that I should get my affairs in order because I might not be here in a couple of years. That was 13 years ago, and obviously I’m still here. There is no treatment, and there is no cure, but there are therapies which help to manage the symptoms.

So what I did was get busy. That was my therapy, to become a part of the solution instead of just wallowing in the devastation of being diagnosed with a chronic and progressive disease. I mean, none of us are getting out of here alive, right? We all get something.

My passion comes from this point: Mitochondrial diseases are not rare. But it feels sometimes sort of like Horton Hears a Who: “We’re here! We’re here!” One in three or four thousand have mitochondrial

disease, and one in two hundred carry the possibility of passing on defective mitochondria, but there is very little money going into primary mitochondrial research.

We’re early on in the timeline of understanding this disease. First they identify the problems, then they can understand the symptomology of it, then they can develop testing for it, and then the hard part: Getting everybody to know what it is, and creating treatments and cures.

And it probably doesn’t help that it’s such a complicated disease.

You know, if you have cancer, we understand that and we say “what kind is it?” We know there are over 200 different types of cancer, and there’s pretty much a test for every kind of cancer out there. Well, with mitochondrial disease, if you ask “which kind?” … there are literally tens of thousands of different kinds, because mitochondria have their own set of DNA. So when I say this is a complicated disease, it’s times ten.

I have adult onset mitochondrial disease, which means it didn’t hit me until I was 19. All of my muscles are

Sept-Nov 2014

affected, my eyes, brain, digestion but for me, it’s been a long, slow progression. But nevertheless it is progressing. I am no longer able to do any type of activity which requires too much endurance or strength, so daily activity is now challenging. For the kids that are born and you can tell something is wrong very early, it’s faster, and the mortality rate is 50%. At this point, we are probably of more use to researchers than they are to us. It’s not their fault, it’s just where we are at this point.

You’ve been working on this for 13 years. Is there anything in that work that makes you feel especially hopeful?

The United Mitochondrial Disease Foundation is one of the very rare nonprofits out there ... we do everything all under one roof: awareness, raising money for research, lobbying on the Hill and giving support and education to our families and community. It’s exciting to see where we are today compared to 13 years ago, and I am thrilled to know that we’re pushing the needle, we’re making progress, and more people know what mitochondrial disease is.

The really important thing right now is that if we put more research into primary mitochondrial medicine, we could actually help not just those with mitochondrial disease, but many other diseases as well. There are links to Parkinson’s, Alzheimer’s, childhood cancers, diabetes, lupus, autism spectrum disorders … there’s an element of mitochondrial dysfunction in all of these other diseases. We have been trying to put a consortium together at NIH to bring together different types of research, to say to everyone already looking into the importance of mitochondrial function – cancer researchers, Volume 27 Number 3

Parkinson’s researchers, Alzheimer’s researchers: Instead of all working in our own little cubicles, how about we all get together and collaborate on our research on mitochondria? Forget about two birds with one stone, you’re talking about at least eight major disease populations being helped.

We are stronger if we pull together.

What do you think about so-called “mitochondrial replacement” or “three-parent babies” – procedures that aim to prevent mitochondrial disease by modifying the oocyte?

actual “designer babies”? Of course I wouldn’t want that.

But that’s not my issue with it. My issue is this: Can’t we please take the research, the effort, the brilliance, the money that’s being spent making sure that future generations won’t have mitochondrial disease, and help those of us that are suffering right now?

You’re putting all of that money into this procedure, and we can’t even get the folks that are suffering now a proper diagnosis, let alone treatment. There are a lot of patients that are suffering right now. For me,

“This kind of research we’re talking about, on these procedures to help future generations sometime down the road, will cost millions and millions of dollars. Meanwhile, there are so many families who need help right now and aren’t getting it. It’s maddening to me.”

I think that the science that is in place to primarily affect the transfer so that a mitochondrial mother – a potential mother who is a mitochondrial patient, who doesn’t want to pass on the disease to her unborn child – I think the science is brilliant.

I think this is the kind of science and research that helps future generations. I’ve heard all of the hoopla and the opinions about the moral and ethical issues, I’ve heard it called “designer babies,” I’ve heard the fear and concern about it, that because we’re manipulating the genetics to make sure the baby won’t be born with mitochondrial disease, how can we know that’s not going to lead to

it is so out of balance. We’re not helping the population that’s living with it now. We’re not helping the children that are dying from it now.

I know I’m not being very diplomatic here, but it just seems a little backwards to me.

Where does that leave women with mitochondrial disease who want to have a baby?

I was pregnant and had mitochondrial disease and didn’t know it at the time, since I was not diagnosed until one year after giving birth to my son.

Being pregnant made my disease progress and I got weaker because of GeneWatch 11

the strain on my body. It put me in a wheelchair at the time. So if I was to sit with a woman with mitochondrial disease who was thinking about getting pregnant, I would counsel her to really give that a long thought. I understand that we all have the right to procreate, but I might suggest she look into adoption or fostering. As a woman who has been through this, I know the risk she might be putting herself into.

Put it this way. U.S. News and World Report did a story when my son was about a year old, and they asked me the question: Had I known I had mitochondrial disease, would I have gotten pregnant and had a baby?

And I could easily say no. Am I glad that he’s here now? Absolutely. But no, I would not have done that. The other point is passing it on to him. As a parent, I don’t feel like we have that right to be selfish in that way: That my need to procreate and pass on my genes is stronger than the risk that I might pass it on to my child. That’s a very personal feeling, but I would find another way to love something, rather than to possibly pass on a lifethreatening chronic illness.

Say a nuclear genome transfer procedure was available, so that through a surrogate you could have a child with some of your DNA but much less chance of inheriting mitochondrial disease. In retrospect, would you have considered going that route?

The answer then would have been maybe, but my answer now is no, not after living day in and day out with my symptoms. The possibility does not personally outweigh the risks.

The procedure does not ensure that there isn’t still a risk to the child. I couldn’t be that selfish. It’s not that important to me to procreate at the 12 GeneWatch

risk of passing on known suffering.

Also there are not enough doctors right now to help our population let alone a population of new mitochondrial children; whether they are symptomatic or not they will still need to be followed.

Let me put it to you like this: What you’re asking is, “Sharon, if there’s a great chance that the baby would be OK, would you do this?” Because I’ve lived with this thing – because my whole life changed after my diagnosis and all of my plans changed, and forget Plan B, now I’m on Plan W – I cannot justify putting money into developing procedures that are only going to help someone down the road.

People right now can’t get treatment, they can’t even get proper diagnosis.

It’s like spending fifty grand on furniture and rugs when not only have I not built the house yet, I don’t even know where I’ll live. I just think that we’re way ahead of ourselves and forgetting about a population that’s here right now, and in need.

Here’s an analogy. What if someone was to say, “We’re going to put all our money into genetically engineering rice so that 10 or 20 years down the road we can feed all the hungry people in the world.” I would say: How about we put that money to use helping people who are starving today?

This kind of research we’re talking about, on these procedures to help future generations sometime down the road, will cost billions of dollars.

Meanwhile, there are so many families who need help right now and aren’t getting it. It’s maddening to me.

You were part of the FDA hearings in February that discussed these technologies, as a patient representative. Was there anything that surprised you during this process?

Was there anything you found particularly disturbing or compelling?

I think one thing that surprised me was that some of the comments around the table were similar to what I just said, along the lines of “Given where we are on the spectrum of understanding this disease, it’s so premature to be doing this. How about we just offer other solutions to a mother who wants to have a baby?”

I was pleased that the people around the table learned more about the complexity of mitochondrial disease, and that while the procedures sounded simpler, the disease itself isn’t. And even with what we already know, there’s still so much to learn. I was pleased to know that these experts sitting around the table were still learning about the disease.

I think that the way the media spun these procedures was wrong – it’s not “designer babies.”

And I think there was a compassion around the table, a desire to help people.

Did you get that from everyone, regardless of their position on the procedures being debated?

I did. There was really a compassion to help disease populations. And I appreciated that. There was really a genuineness there to think through the issue and be careful and ask questions, and I appreciated the process the FDA put together to ensure that happened.

The other thing I got at the FDA hearings was that the passion and enthusiasm from these geneticists that figured out the procedure was unbelievable, and it was genuine. I just wish more of them would have that enthusiasm for patients that have mitochondrial disease right now.

nnn Sept-Nov 2014

From the Council for Responsible Genetics

The GMO DecepTiOn What You Need to Know about the Food, Corporations, and Government Agencies Putting Our Families and Our Environment at Risk

edited by Sheldon Krimsky and Jeremy Gruber Foreword by Ralph nader

“If you do not understand why there is so much opposition to GMOs, nationally and internationally, this book is the place to start.”

—Marion Nestle, professor of nutrition, food studies, and public health at New York University and author of Eat Drink Vote: An Illustrated Guide to Food Politics “This eye-opening collection of essays by numerous experts lays bare what global corporations like Monsanto are attempting to foist upon us, as well as how activists around the world are fighting back to preserve our children’s future.”

—Dick Russell, environmental author “The GMO Deception is the most comprehensive resource covering all areas of this complex topic.”

—Ken Roseboro, editor and publisher, The Organic & Non-GMO Report

ON SALE NOW Volume 27 Number 3

GeneWatch 13

Enabling Technology A case for moving forward – carefully – with human trials for mitochondrial transfer techniques.

Interview

with

Nita Farahany

Nita A. Farahany, PhD, JD, is the Director of Science and Society and Professor of Law and Philosophy at Duke University.

She was appointed in 2010 to the Presidential Commission for the Study of Bioethical Issues and continues to serve as a member.

The technology we’re discussing – “nuclear genome transfer,” or “mitochondrial transfer,” or “mitochondrial replacement,” or “threeparent babies,” whatever you prefer to call it … actually, first off, what do you prefer to call it?

That would depend on which technique we’re talking about. I don’t ever use “three-parent babies,” because that’s just wrong. It takes far more to be a “parent” than mere contribution of mitochondrial DNA. “Mitochondrial transfer” is a more general term, which captures some of the different techniques.

You’ve talked about the need for adequate regulation of these technologies, but it seems safe to say you’re also an advocate of moving forward with it. What sort of ethical or regulatory framework do you think is needed before the technology can be adopted?

I wouldn’t say I’m an “advocate” for anything. I think that the process that the HFEA (the UK’s Human Fertilisation and Embryology Authority) used to study the safety and efficacy of mitochondrial transfer was 14 GeneWatch

a pretty comprehensive approach to understanding the scientific issues.

And safety and efficacy are ethical issues and independent criteria to consider. From a safety perspective, I think the data justifies moving to very small-scale clinical trials. But I’d want very careful oversight and follow-up of those trials.

I’d want to make sure that we carefully think about research participant selection, agreements about longerterm follow-ups so that we can be able to see what happens later on.

And we would have to think about some of the possibilities that have been raised – for example, if all of this is done using an IVF procedure, whether or not selecting for male embryos in the first generation makes sense, because then you don’t have the same concerns about the implications for future generations as far as passing on mitochondrial DNA. So I think we’d want to think very carefully about how we structure those studies, but we’re at a stage where the data is strong enough to move toward determining how to best structure small-scale clinical trials.

Since there haven’t been human clinical trials yet, so far the safety studies have been on rhesus monkeys – is that right?

Yes, and also mice.

And you don’t think more is needed before moving to human clinical trials?

Sept-Nov 2014

With any reproductive technology, for some people there will never enough data to justify a move to human clinical trials. And yet, we have as much if not more data than we did when we moved to human clinical trials for IVF. I think we’re ready, particularly given the gravity of the consequences from not moving forward, to move to small-scale clinical trials.

Different regulatory bodies around the world have chosen different places to draw the line on what should and shouldn’t be allowed as far as technologies that could result in human germline modification.

Where would you draw the line?

I’m comfortable with mitochondrial transfer at this stage, but I would draw the line and say that we shouldn’t be doing nuclear modification. Some of the data shows that with mitochondrial replacement, some of the mitochondrial abnormalities are actually coded within the nucleus, so the procedure might be more successful if it included nuclear changes. Nevertheless, I would limit it, at least right now, to only making mitochondrial transfer and not actually making nuclear changes.

You say you’d limit it “right now” – is there something that might change that?

I could imagine at some point in the distant future we might consider nuclear modifications as well, it’s just not something that’s anywhere close to being on the table.

So your concerns about modifying nuclear DNA are more about the science than about ethics?

I don’t think it makes sense to draw Volume 27 Number 3

bright lines between the science and the ethics. Good science is responsible science, so they go hand in hand.

Scientifically, we’re nowhere close to being able to reliably make nuclear modifications. I think for that reason, and for additional ethical concerns, staying out of nuclear modifications for now is the right approach. Could I imagine a future in which there were some nuclear modifications that we permitted? I could imagine such a future, but a lot of things would have to change between now and then.

In the meantime, with “mitochondrial transfer” – these technologies that could help prevent mitochondrial disease – am I right in understanding that this could greatly reduce the chances of passing on mitochondrial disease, but would not be able to altogether eliminate mitochondrial disease without also modifying the nuclear DNA? So, two things. One is: Some people don’t have such a high degree of abnormality that it would require them to have mitochondrial transfer. Low levels of abnormality could still be carried on generation to generation, and that could end up with one generation being disproportionately affected – through no intervention on our part, right, just because a fact of nature is that some people have a mitochondrial abnormality, and it may get passed on in higher concentrations to some offspring rather than other offspring. So you’re still going to have some mitochondrial abnormalities in the population.

As for the people who have some of the mitochondrial abnormality that arises from problems within the nuclear DNA, you’re right: These techniques wouldn’t eliminate that.

They do bring it down sufficiently to a level where you don’t see the kind

of health consequences you would otherwise.

Some are uneasy with these technologies because of the possibility that it enables “designer babies” or a sort of eugenics. But as I understand it, you look at a technology like this as more a matter of individual choice.

I think one of the things people worry about with eugenics is statesponsored eugenic action. That is very different from private individuals making private choices, which will vary from person to person.

You know, not everyone chooses a child with blond hair and blue eyes, one reason being that many people want children who look like them.

Of course, this is in the world of nuclear DNA modifications, which I think is far off. But imagining that future, if it’s private individuals making private choices, it’s going to lead to a much greater diversity of choices than we’d expect in a state-sponsored eugenic society. So I have less concern than some people do about dystopian eugenic futures, because I think that presupposes a very different approach to decisions about reproduction.

So in other words, the problem would be not the technology, but how it’s used and how it’s regulated?

I think technology is neither good nor evil; it’s how we use it that determines its normative value. The same technology can be put to good or evil purposes. What I would feel comfortable with is enabling technology to proceed, but ensuring that we have a prudent approach to overseeing that technology to safeguard against misuse.

nnn

GeneWatch 15

Why Worry About Genetically Modified Babies?

Here’s what’s at stake if the UK walks back its prohibition on human germline modification.

By Jessica Cussins

and

Marcy Darnovsky

The terms “genetically modified babies” and “designer babies” are attention-getters. But beyond the catchy sound bites, what do they really mean – and are they something we need to worry about?

Unfortunately, with the technical capacity to engineer inheritable traits growing quickly, and with the United Kingdom possibly on the verge of loosening its law in order to allow a limited form of inheritable genetic (germline) modification, there is ample reason for concern.

The proposed policy change in the UK would permit licensed fertility clinics to use a biologically radical technique referred to by terms including “mitochondrial replacement,” “nuclear genome transfer,” and “three-person IVF.” This procedure would produce modifications in every cell of any resulting children, and in subsequent generations as well.

In this article, we will use the term “nuclear genome transfer,” as it is the most technically accurate of the various terms.

The technique is proposed as a way for women affected by a particular subset of severe mitochondrial disorders to have children who are not affected and who are mostly genetically related to them. The researchers promoting it, and some people with mitochondrial disease, have pointed out that they would not be using the technique to produce “designer babies.” Understandably, some are 16 GeneWatch

perplexed or offended by those who object to the procedure on that basis.

But these advocates of nuclear genome transfer have missed a key element of the case against it. Those of us who oppose it on social and policy (as well as safety) grounds aren’t arguing that it would in itself create enhanced humans with specified traits. Our concerns fall into two categories. The first is that an exception to the widespread prohibitions against human germline engineering will open the door to other efforts to modify inheritable traits – that nuclear genome transfer is the thin end of a wedge that would lead to a world of genetically altered human beings.

The second set of concerns focuses on safety. This technique, like other forms of human germline modification, is in fact both medically unnecessary and profoundly risky to the children it would produce. Let’s look briefly at each of these sets of concerns, starting with the social and policy issues.

If the UK permits nuclear genome transfer to move ahead, it would break a widely observed prohibition that has been respected by scientists globally, and codified as law in more than 40 countries and several international treaties. No other country in the world has ever explicitly sanctioned human germline modification. Just as with human reproductive cloning, it is explicitly prohibited in the Council of Europe’s Convention

on Human Rights and Biomedicine, and considered to be “contrary to human dignity” in UNESCO’s Universal Declaration on the Human Genome and Human Rights.

Because human germline modification is illegal in the UK, proponents of nuclear genome transfer have elected to work toward carving out a narrow exception that would allow their particular manipulation methods to be implemented. A change in UK law to allow “mitochondrial replacement” in fertility clinics, without any required follow up of the resulting children, would inescapably set both a global policy precedent and a biotechnological precedent for the scientific community. If the UK, a country with one of the world’s most highly developed biomedical sectors, believes this is the way forward, it would shift the scales and threaten the current international near consensus on the responsible use of genetic technologies. The UK would become an outlier, and would have to carry the burden as well as the benefit that comes with that position. And as David King explains in this issue, the way this policy process has unfolded – with numerous irregularities, misrepresentations, and cherry picking of scientific evidence – deepens our concerns that approval would be used as a wedge issue.

In the United States, a committee of the Food and Drug Administration held a day-long hearing in February Sept-Nov 2014

2014 to discuss human germline modification for the prevention of the transmission of mitochondrial diseases or for the treatment of infertility. Most of the experts on the committee came away deeply skeptical about the issues they were mandated to consider: the techniques’ safety, efficacy, and necessity.

The United States is one of the few countries with an advanced biomedical sector that does not have any law against human germline modification. This means that if nuclear genome transfer were allowed, it could be used for any purpose. Unfortunately, there are concrete reasons to worry about this sort of “mission creep.” One is that Shoukhrat Mitalipov, the U.S. researcher most notably involved with advocating for nuclear genome transfer, has made it very clear that he’d like to see the technique used in efforts to treat agerelated infertility (in spite of the fact that, as several experts on the FDA committee noted, there is no clear evidence of any relationship between mitochondrial insufficiency and infertility). Mitalipov has been quoted in several articles looking forward to nuclear genome transfer being quickly adopted in fertility clinics around the country and the world.

He has applied for a patent on his version of nuclear genome transfer, and has established a company presumably to commercialize its use as a fertility treatment.

Would there also be pressure to permit human germline modification techniques that would alter nuclear genes, in an effort to specify physical, behavioral, or cognitive traits? There is reason to believe there would be – in fact, a small but disturbing number of prominent scientists and futurists have advocated precisely for this vision. For example, a report produced on the basis of the Volume 27 Number 3

1998 UCLA conference “Engineering the Human Germline” argued for the “open exploration” of “human germline engineering.” Currently, new precision gene editing techniques such as CRISPR have some scientists excited about the possibilities for the genetic modification of human embryos or adults. Will these new techniques, which will open the door to much more precise changes, be considered less drastic if nuclear genome transfer has already been approved?

Human germline modification would be of profound consequence whether it were to “succeed” or “fail.”

If efforts to engineer the traits we pass on to future generations succeed, they could exacerbate existing inequalities – or even introduce new forms of inequality – based on the real or perceived superiority of those whose genes had been tweaked. And we could find ourselves trapped in a kind of genetic arms race, which could lead to social disruption on a possibly massive scale.

What if such efforts fail? Germline modification in animals typically involves dozens or hundreds of nonviable offspring. If human germline modification efforts yield similar results, what would become of the people created? Who would be accountable for bouts of unnecessary human

experimentation gone wrong?

With nuclear genome transfer, the policy, social and safety issues are inextricably entangled. Some proponents both insist that it would not create genetically engineered babies, and are actively trying to redefine genetic modification completely so as to exclude this particular technique.

The U.K. Department of Health wants to make a distinction between changes to mitochondrial DNA (mtDNA) and nuclear DNA (nDNA), arguing that only the latter really constitutes genetic modification. While there are obvious differences between the two, this redefinition has no basis in scientific reality. mtDNA and nDNA are in continuous interaction with each other and changes to mtDNA would cause inheritable changes to every cell of a resulting person.

The notion that nuclear genome transfer is as non-consequential as “changing a battery” is entirely misleading. Scientists have known for some time that mtDNA have pervasive effects. A recent article in New Scientist reviews the accumulating evidence. The overall picture is now so clear that the magazine’s editors have just reversed their earlier support for “three-parent IVF,” and acknowledged that they “may have seriously underestimated the influence GeneWatch 17

that mitochondria have” and that in fact, “children conceived in this way will inherit vital traits from three parents.”

Which brings us to the second category of concerns about nuclear genome transfer. Like reproductive cloning and germline modification, it is scientifically interesting, but applying any of these techniques to human beings will never be medically necessary, and would pose serious safety risks both known and unknown.

Nuclear genome transfer involves the removal and reinsertion of a nucleus from its own egg cytoplasm to that of another woman’s. The procedure changes the environment for the nucleus, and introduces it to 37 new genes with which it will need to work in order to carry out every activity moving forward. The impacts of combining genetic material from three different people are entirely unknown, but it is certain that it will have an impact.

Safety concerns for women would include all the short- and long-term risks of egg extraction and IVF. And as members of the FDA committee pointed out, pregnancy and childbirth are often in and of themselves risky for women with serious mitochondrial disorders.

Safety concerns for resulting children would include epigenetic harm from the invasive procedure of removing and reinserting the nucleus, and “mismatch” between the nuclear and new mitochondrial DNA, which could disrupt critical biological functions. Additionally, even tiny amounts of carryover of mutated mitochondria from the first egg could lead to the occurrence of mitochondrial disease through preferential replication.

Questions of efficacy are paramount as well, given that the vast majority of mitochondrial diseases 18 GeneWatch

actually originate with mutations in nuclear DNA, and could not be helped by these techniques. Further, the few women who would be candidates for nuclear genome transfer – estimates are on the order of a dozen or so a year in the UK – have much safer options for having healthy and genetically related children.

Some proponents of nuclear genome transfer try to hitch it onto the coattails of the reproductive rights and justice movements, and to justify risky experiments as allowing women to make informed, personal choices about reproductive technologies.

But first and foremost, these are biologically extreme technologies that would use women’s and children’s bodies as ground zero for their experiments. It is women and children who will be encouraged by soothing words and images, and then be asked to bear the risks while a fertility clinic collects an estimated 80,000 pounds for each attempted treatment.

Even with conventional treatments that are far less biologically extreme, the fertility industry does not have a good track record of putting evidence-based information before its customers. And the lack of required follow-up that has already

been built into the UK’s proposed law does not bode well for women’s ability to make informed decisions about the safety or efficacy of this option, or to compare it realistically with its safer alternatives, which include preimplantation genetic diagnosis, egg donation, and adoption.

So, what is really at stake if the UK changes their law to allow a form of human germline modification into fertility clinics? Primarily, the health of women and children, and the integrity of the widespread international agreement against the most dangerous human biotechnologies.

And also, perhaps, the shape of the human future. nnn Jessica Cussins is a project associate at the Center for Genetics and Society, and a regular blogger at Biopolitical Times, Psychology Today, and Huffington Post.

Marcy Darnovsky is executive director at the Center for Genetics and Society, and writes widely on the politics of human biotechnologies.

Sept-Nov 2014

Manipulating Embryos, Manipulating Truth In considering whether to allow new embryo manipulation procedures in the UK, regulators seem more interested in shaping public opinion than listening to it.

By David King

The UK experience of the process of legalization of “mitochondrial replacement techniques” has been an object lesson in how a welloiled technocratic machine can manipulate public opinion in order to achieve the desired result or simply ignore negative public responses.

In the UK, reproductive technologies are regulated by the Human Fertilisation and Embryology Act, which was last updated in 2008. The Act prohibits the implantation in a woman of embryos produced by any means other than fertilization of an egg by a sperm. However, because the possibility of ‘mitochondrial replacement’ was envisaged at that time, there is a provision which allows the Secretary of State to make regulations permitting the use of such embryos, on a case-by-case basis. We are now at this stage, and it is expected that the government will publish the regulations this autumn. It is important to understand that there will be no significant parliamentary debate on the regulations or any possibility of amending them: the procedure simply involves a one hour discussion by a committee which can only approve or reject regulations. In essence, this is a rubber-stamping procedure.

Unlike nearly every other European country, the UK has not signed the Council of Europe Convention on biomedicine and human rights, which prohibits any intentional changes to the human germ line.

Volume 27 Number 3

How to get the answer that you want The process of legalization of ‘mitochondrial replacement techniques’ began in the spring of 2012 with a report by the Nuffield Council on Bioethics, an independent academic body funded by the Nuffield Foundation.

As expected, the Council approved the use of these techniques. Its main innovation was to decide that the techniques constituted a form of manipulation of the human germ line, something that elite opinion had previously denied. In recognizing that this crucial ethical line was being crossed, the Council insisted that any attempt to manipulate nuclear DNA through genetic modification would require further ethical consideration.

Following the Nuffield Council report, the HFEA announced its main public consultation on the ethical aspects in mid-2012. U.S. readers will probably look upon the UK regulatory system, and the existence of the HFEA, as a good thing, at least in comparison to the lack of statutory regulation in the U.S. The existence of the HFEA plays a crucial role in reassuring the public that these difficult ethical issues are being responsibly considered by the powers that be.

But in reality, although the HFEA is obliged to maintain some degree of separation between itself and the IVF industry and entrepreneurial scientists that it regulates, in terms of its ideological position, the HFEA is in

complete concord with those industries. In fact, its current head of policy was formerly director of the Progress Educational Trust, a body set up in the 1980s that has always argued for liberalization and acceptance of every new technology.

The HFEA has become practiced in using public ‘consultation’ to advance the use of such technologies and to weaken ethical restraints upon them.

In general, the HFEA is well ahead of public opinion, but only on one occasion has it failed to carry the public with it. That was in 2003, when it issued a consultation arguing for the legalization of sex selection for social reasons. An extremely strong negative public response forced HFEA to abandon that position.

HFEA’s consultation documents are written with a technocratic bias that makes little effort towards evenhandedness. In recent years it has become increasingly overconfident.

For example, in 2009 the new chair of the HFEA, Lisa Jardine, announced in a newspaper interview that she was in favor of paying egg donors for their services in advance of the HFEA’s consultation. In this case it has simply ignored the results of the consultation.

The HFEA’s manipulation of the consultation process had two main elements: (i) misleading scientific information, and (ii) biased ethical discussion.

Bad science GeneWatch 19

The key piece of scientific misinformation that was crucial to the ethical misunderstanding of these techniques was the statement, endorsed by major scientific institutions, that mitochondria act as mere “batteries” for cells, and that mutations in mitochondrial genes have no effect on an individual’s identity. The statement made an analogy with a laptop computer; its batteries do not affect the programs or data on the laptop. The purpose of this endlessly-repeated statement was to minimize the ethical significance of the changes to the germ line involved. (In these discussions, ‘identity’ was never clearly defined, but the general impression given was that it referred to visible physical differences, and perhaps personality.)

This piece of scientific nonsense is a classic example of the reductionist models of biology which dominate public debate and are clearly used by advocates of new technologies to manipulate the debate. Living organisms are simply not like computers: they are complex, whereas computers are merely complicated. Even were it true that the functions of mitochondria are restricted to generating ATP, the idea that energy metabolism can somehow be isolated from the rest of the physiology of the organism is biologically laughable. This is the same mentality that leads synthetic biologists to claim that they can separate and redesign different ‘modules’ of cellular function. One might imagine that such ambitious scientific claims would be backed up by detailed scientific evidence, but insofar as it is possible to determine the origin of what has now become an urban myth, the claim is entirely unsupported. The main quoted ‘scientific’ reference for the claim is a submission by those two august medical authorities, the UK Medical Research Council and 20 GeneWatch

the Wellcome Trust, to the Nuffield Council enquiry, which contains no scientific references whatever for this claim.

In reality, energy metabolism is entangled with many other aspects of cellular function, and mitochondria have a number of other roles. Mitochondria are emerging as a central element in the overall regulation of cell function; for example, it is becoming clear that there is constant epigenetic modification of nuclear DNA according to mitochondrial states, including the level of production of oxygen free radicals. Thus, it is not surprising that they are implicated in a variety of disease states. The New

Scientist magazine recently summarized a number of examples of mitochondrial function affecting things other than ATP levels.1 Thus, the idea that mitochondria do not affect aspects of a person’s physiology that contribute to their identity is bound to be wrong, although our knowledge of these complexities is still rudimentary. A similar claim might be made about the majority of genes in the nuclear genome that have ‘housekeeping’ functions. But the attempt to suggest that mitochondrial function is cleanly separable from other aspects of cell function in the same way that mitochondrial DNA is in a different compartment from nuclear

DNA shows how DNA-centered reductionist biology serves the effort to convince the public that they did not need to worry about this form of genetic manipulation.

In examining the way in which scientifically misleading information by key scientific authorities has been used to manipulate the public debate, one is irresistibly reminded of the example of human-animal hybrid embryos. In 2007 and 2008, while the HFEA Act was being updated, the UK witnessed a massive campaign by scientists (including several UK Nobel Prize winners) to legalize the creation of human-animal hybrid embryos which, we were told, were vital to medical research. Despite warnings by the author that such embryos were worthless for scientific research, the UK Parliament duly legalized their use. But in the following year, the Medical Research Council was forced to reject funding applications from the same research center that is spearheading the push for mitochondrial replacement because they lacked scientific merit.

In addition to misleading scientific statements for general public consumption, the HFEA has also conducted scientific reviews of the safety of mitochondrial replacement.

There are many problems with the review panel’s treatment of these issues, all of which tend in the same direction, towards permitting clinical trials as soon as possible. The panel has consistently adopted a standard of proof that is neither precautionary nor ‘evidence-based,’ but in fact anti-precautionary: ‘There is no evidence to suggest that the techniques are unsafe.’ There are certainly plenty of reasons for thinking that the techniques might be unsafe and one would have thought that under legislation that makes the welfare of the child the paramount consideration, Sept-Nov 2014

a precautionary approach would be used.

The most obvious safety concern about these techniques is the possibility that the extremely invasive manipulation of embryos may damage the embryos, for example by creating epigenetic problems which may affect the child’s health. It is well known that assisted reproductive technologies can create epigenetic errors, even when the manipulations are relatively minor, as in basic IVF. In general, the more invasive the manipulation, the greater risk of epigenetic problems; the techniques under consideration would involve the most invasive manipulations in clinical use to date. The few published papers on the mitochondrial replacement techniques clearly show that the manipulations damage the embryos, so that a relatively low percentage survive to the blastocyst stage. Given this, it is reasonable to expect that the surviving embryos will have more subtle damage, and it is imperative that comprehensive safety studies focusing on possible epigenetic issues in these embryos are concluded before clinical trials are permitted. However, the HFEA panel merely recommends such studies rather than requiring them. The downplaying of these issues is consistent with the DNA-centered reductionist biology which has already been noted: The regulators, like the lay public, are assuming that creating a healthy embryo is simply a matter of making sure it has the right DNA. Bad ethics The HFEA’s misrepresentation of ethical issues are too numerous to detail here; Human Genetics Alert has prepared an in-depth analysis of these which is available on request.

In all its materials, where HFEA Volume 27 Number 3

presented critiques, it either underor over-states the argument, and in every instance the discussion is presented in the form: “critics claim that … but others argue that... .” Its treatment of the crucial issue of germ line manipulation (see article in this issue

by Darnovsky and Cussins) is entirely inadequate. And it entirely fails to present a conventional risk/benefit analysis and repeatedly suggests that the techniques are the only way in which mothers who carry these conditions can have healthy children. Although the existence of conventional egg donation as an alternative is very briefly mentioned, it nowhere acknowledges that this means that the sole benefit of the new techniques is that the mother can be the nuclear genetic parent of her child, and that this is not a medical benefit to either mother or child, but merely a social benefit. In our view, given the safety risks of the techniques, this social benefit cannot justify exposing a child to the potentially harmful health consequences of the techniques. In my view, it is difficult to understand the devotion of millions of pounds of research funding to the development of techniques which will deliver such a benefit to a very small group of people. To cross the crucial ethical line of non-manipulation of the human genome for such a benefit is simply absurd.

Despite the HFEA’s bias in favor of legalization of the techniques, a strong majority of responses to the online consultation opposed legalization. However, the HFEA preferred to take notice of the results of its focus groups and opinion poll, both of which involved uninformed participants whose opinions are easier to manipulate. Recent opinion polls have contradicted the HFEA’s opinion poll results and suggested that less than 20% of the population

actually supports the techniques. Its press statements glossed over the negative response to the online consultation and simply declared ‘broad public support’ for the techniques.

The UK Department of Health has done the same thing in its consultation on proposed regulations.

Conclusion The experience of this public consultation process has been depressing for those who would support democratic control of reproductive technologies. The supporters of the techniques created an extremely well coordinated campaign, exploiting the public’s natural sympathy for families with sick children. The ‘watchdog’ body acted more like a cheerleader for the campaign, consistently manipulating both scientific fact and ethical issues in order to achieve the desired results, and when the public response was negative, simply ignoring that fact. A compliant media failed to raise the critical issues. It can hardly be claimed that Britain has undergone the public debate necessary to take a decision of this historical magnitude.

It is difficult to say whether an unregulated ‘Wild West’ or a technocratic regulator willing to manipulate facts to achieve its preferred result is the least desirable environment for responsible use of reproductive technologies. A better third alternative must await the advent of a genuine citizens’ movement on these issues.

nnn David King, PhD, is a former molecular biologist and is Director of Human Genetics Alert (www.hgalert.org).

GeneWatch 21

Is Ooplasm Transfer Safe for the Offspring?

Adapted from testimony submitted to the FDA’s Cellular, Tissue, and Gene Therapies Advisory Committee.

By Sheldon Krimsky

From comments submitted to the FDA’s Cellular, Tissue, and Gene Therapies Advisory Committee, February 25-26, 2014.

The first reported human pregnancy following cytoplasm transfer from donor oocytes into a woman’s egg took place in 1997.1 Like many advances in assisted reproduction, ooplasm transfer is designed to help women who seek a healthy pregnancy – a noble endeavor. However, I offer three questions that should be answered before the procedure moves forward to gain FDA approval and possibly becomes institutionalized: 1. Is ooplasmic transfer safe and effective for the offspring?

2. If the procedure is found to be generally safe but with some risks, do prospective parents have the authority to undertake the procedure, balancing risks and benefits, without additional oversight?

3. Are the potential benefits of ooplasm transfer for improving fertility or preventing the transfer of mitochondrial disease unique and sufficient to open the door to germ line genetic modification?

Question 1 is largely scientific; questions 2 and 3 are largely ethical.

My remarks today address question 1.

Most scientists who specialize in the biology of reproduction and 22 GeneWatch

who have written about cytoplasmic transfer have a clear message.

• Cytoplasmic transfer appears to be consistently associated with mitochondrial heteroplasmy.2 • Heteroplasmy, or babies born with two distinct female mitochondrial genomes, is a risk which must be understood before cytoplasmic transfer aka ooplasm transfer is considered for clinical practice.3 • While an estimated 30 babies have been born using the technique, there have been no systematic follow-up studies that examine the rate and degree of heteroplasmy in the newborn and in cases where it exists on its effect on the developmental health of the child.

A recent review in Pub Med for the terms heteroplasmy and mitochondrial disease had 501 citations, while ooplasm transfer in human cells had 58 citations. There is remarkably sparse empirical knowledge in animal studies and almost no human clinical studies on the safety and efficacy of ooplasmic transfer.

There are no follow-up studies on the 30 children born through ooplasmic transfer. As one researcher wrote: “Transfer of oooplasm was thus applied with astonishing speed in humans in the absence of extensive research to evaluate the efficacy and the possible risks of the method.”

That was written in 2004, and things haven’t changed.4

The few published animal studies report a clear and present danger: • Heteroplasmy created by the mixture of cytoplasm from different strains of mice resulted in physiological impairment, including disproportionate weight gain and cardiovascular system changes.5 • Cytoplasmic transfer used in cattle produces heteroplasmic offspring.6 • Some children born through cytoplasmic transfer have been identified as heteroplasmic.7 • There is cross talk between mitochondrial DNA and nuclear DNA; it is not known but suspected that nuclear DNA cross talk between two mitochondrial genomes will affect the development of the offspring.8 • The paternal genome may be especially susceptible to epigenetic alternations by foreign ooplasm.9 • Mixing of two different mouse mitochondrial DNA within the same female germline can lead to offspring with neuro-psychiatric Sept-Nov 2014

defects.10 • While offering the prospect of treatment to some infertile couples, cytoplasmic transfer is “capable of generating unexpected abnormalities.”11 The authors of the most current and comprehensive review article of mitochondrial DNA and heteroplasmy, referring to ooplasmic transfer and other ART procedures, wrote that “all appropriate preclinical tests must be performed in an effort to reduce the risk for adverse outcomes.”12 Many questions need to be answered before ooplasmic transfer could be considered safe and effective to the offspring. Until these questions are answered first by systematic animal studies,13 I can find no consensus within the scientific community to proceed.

Other methods for addressing the transfer of mitochondrial disease to offspring, such as Pronuclear Transfer or Maternal Spindle Transfer, introduce similar problems of heteroplasmy which have not been resolved. As noted by Spikings et al.

(2006): “Other techniques, such as germinal vesicle transfer and pronuclear transfer, have been proposed as methods of preventing transmission of mitochondrial diseases to future generations. However, resulting embryos and offspring may contain mtDNA heteroplasmy, which itself could result in mitochondrial disease. It is therefore essential that uniparental transmission of mtDNA is ensured before these techniques are used therapeutically.”14 There are ethical questions concerning germ line gene modification

for ooplasm transfer, Pronuclear Transfer and Maternal Spindle Transfer, which hold equal if not greater weight than the scientific questions.

These issues should be addressed by a national ethics commission, which should assess whether the “threeparent genome” is a stepping stone to a new eugenics.15 nnn

5. Sharpley, M.S., Marciniak, C., EckelMahan, K. et al. Heteroplasmy of mouse mtDNA is genetically unstable and results in altered behavior and cognition. Cell 151:333343 (October 12, 2012).

6. Ferreira, C.R., Bergstaller, J.B., Percin, F. et al. Pronounced segregation of donor mitochondria introduced by bovine ooplasm transfer to the female germ-line. Biology of Reproduction 82:563-571 (2010).

7. Levy et. al (2004).

8. Ibid.

9. Liang, C-G, Han, Z, Cheng, Y. et al.

Effects of ooplasm transfer on paternal genome function in mice. Human Reproduction 24:2718-2728 (2009).

10.

Sharpley et. al (2012).

11.

St. John, J.C. Ooplasm donation in humans. Human Reproduction 17(8):1954-1958 (2002).

12.

Wallace, D.C. and Chalkia, D. Mitochondrial DNA genetics and the heteroplasmy conundrum

in evolution and disease. Cold Spring Harbor Perspectives in Biology. New York: Cold Spring Harbor Laboratory Press, 2013.

13.

Acton, B.M., Lai, I., Shang, X. et al. Neutral mitochondrial heteroplasmy alters physiological function in mice. Biology of Reproduction 77:569-576 (2007).

14.

Spikings, E.C., Alderson, J. and St. John, J.C. Transmission of mitochondrial DNA following assisted reproduction and nuclear transfer. Human Reproduction Update 12(4):401-415 (2006).

15.

Rubenstein, D.S., Thomasma, D.C, Schon, E.A., and Zinaman, M.J. Germ-line therapy to cure mitochondrial disease: Protocol and ethics of in vitro ovum nuclear transplantation. Cambridge Quarterly of Health Care Ethics 4:316-339 (1995).

Sheldon Krimsky, PhD, is Chair of the Board of Directors of the Council for Responsible Genetics, and the Lenore Stern Professor of Humanities and Social Sciences in the Department of Urban and Environmental Policy and Planning and adjunct professor in the Department of Public Health and Community Medicine at Tufts University

Endnotes David King, p. 19 1. Possessed! The powerful aliens that lurk within you, G. Hamilton.

New Scientist 22/9/2014.

Sheldon Krimsky, p. 22 1. Cohen, J. Scott, R., Schimmel, T. et al. Birth of an infant after transfer of a nucleate donor oocyte cytoplasm into recipient eggs. The Lancet 350:186-189 (July 19, 1997).

2. Scott, R. and Alkani, M. Ooplasmic transfer in making human oocytes.

Mol. Hum. Reprod. 4:269-280 (1998).

3. Lane, Nick. The problem with mixing mitochondria. Cell 151:246248 (October 12, 2012).

4. Levy, Rachel, Elder, Kay, and Ménézo, Yves. Cytoplasmic transfer in oocytes: biochemical aspects. Human Reproduction 10(3):241-250 (2004).

Volume 27 Number 3

GeneWatch 23

Council for Responsible Genetics 5 Upland Road, Suite 3 Cambridge, MA 02140

GENEWATCH IS FREE

ON THE WEB - BUT YOU CAN STILL SUBSCRIBE TO RECEIVE PRINT ISSUES. ANNUAL PRINT SUBSCRIPTION RATES INDIVIDUAL: $35 NON - PROFIT: $50 LIBRARY: $70 CORPORATION: $100

(PROOF OF NON-PROFIT STATUS MAY BE REQUIRED)

All figures in US dollars.

PAYMENT INFORMATION Please send a subscription request with your full name, address and email address, along with a check or credit card (MasterCard or Visa) information, to: Council for Responsible Genetics 5 Upland Road, Suite 3 Cambridge, MA 02140

Orders are also accepted online (www.councilforresponsiblegenetics.org) and by phone (617.868.0870). Additional donations are welcome. Thank you!

IMPORTANT TAX INFORMATION: THE FAIR MARKET VALUE OF A ONEYEAR SUBSCRIPTION TO GENEWATCH IS $35.00

Support from people like you makes CRG’s work possible.

Much of our income comes from individuals.

Your support helps keep our programs free of the restrictions that come with funding from pharmaceutical and health care companies or government sources. We are the watchdogs for accurate and unbiased information about biotechnology, even when the truth doesn’t suit current political or commercial agendas.

And we depend on you to be able to do what we do.

There are many ways you can help CRG. You can become a donor: an annual gift in quarterly installments of $25, $50 or $100 gives us a wonderful and predictable support with a minimal shock to your budget. You may also be able to designate CRG through your workplace giving program, including the Combined Federal Campaign. Many companies will actually match or even double-match your donation. Check with your employer about its matching gift program. You might also consider making an investment in a future where biotechnology is properly used by remembering CRG in your will with a bequest or charitable trust gift.

To learn more about helping CRG, please call us at 617.868.0870. You may also write the Council for Responsible Genetics at 5 Upland Road, Suite 3, Cambridge MA 02140, or visit www.councilforresponsiblegenetics.org.

ISSN 0740-9737