GeneWatch Vol. 22 No. 5

VOLUME 22 NUMBER 5 SEPTEMBER-OCTOBER 2009

THE MAGAZINE OF THE COUNCIL FOR RESPONSIBLE GENETICS • ADVANCING THE PUBLIC INTEREST IN BIOTECHNOLOGY SINCE 1983

IN THIS ISSUE • Cloning-based Stem Cell Research JESSE REYNOLDS 4 • ‘Donating’ Eggs for Research JUDY NORSIGIAN 6 • Stem Cell Task Force WITH STORY LANDIS 8 • Cloning for Kicks PETE SHANKS 10 • Livestock Cloning 13 • GM Beets Rejected 14 • Cloning Ancient DNA ROB DESALLE 15 • International Cloning Governance WITH ROSARIO ISASI 17 • Book Review: Genetic Rounds ANDREW THIBEDEAU 20

GENEWATCH

Editorial

Sam Anderson

SEPTEMBER-OCTOBER 2009 VOLUME 22 NUMBER 5 & DESIGNER Sam Anderson

EDITOR

EDITORIAL COMMITTEE

Ruth Hubbard

Sheldon Krimsky

GENEWATCH is published by the Council for Responsible Genetics (CRG), a national, nonprofit, tax-exempt 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 NET www.councilforresponsiblegenetics.org BOARD OF DIRECTORS SHELDON KRIMSKY, PhD, Board Chair Tufts University TANIA SIMONCELLI, Vice Chair Science Advisor,ACLU PETER SHORETT, MPP Treasurer GEORGE ANNAS, JD, MPH Boston University EVAN BALABAN, PhD McGill University PAUL BILLINGS, MD, PhD, University of California, Berkeley SUJATHA BYRAVAN, PhD ANDREW IMPARATO, JD President and CEO, American Association of People with Disabilities RAYNA RAPP, PhD New York University LOLA VOLLEN, MD, MPH University of California, Berkeley PATRICIA WILLIAMS, JD Columbia University STAFF Jeremy Gruber, President and Executive Director Sheila Sinclair, Manager of Operations Sam Anderson, Editor of GeneWatch Kathleen Sloan, Program Coordinator

COVER ART Sam Anderson Unless otherwise noted, all material in this publication is protected by copyright by the Council for Responsible Genetics. All rights reserved. GeneWatch 22, 2 0740-973

2 GENEWATCH

I would not usually suggest that we turn to Michael Crichton for insight into the ethics of genetic technologies; after all, "man clones dinosaurs, dinosaurs eat man" seems a perhaps overly blunt rebuttal of scientific accomplishment gone awry. However, one character in Jurassic Park, the preachy chaos theorist Dr. Ian Malcolm (he's the guy played by Jeff Goldblum), hits on some of the notions that make up the foundation of our most visceral reactions against the technology who's name draws up so many polarizing images: cloning.

Perhaps the most significant contributor to the widely shared discomfort at the thought of cloning anything embryos, cows, dinosaurs - is the notion that doing so is "playing God," that it's a reckless and perhaps even blasphemous endeavor. As both Pete Shanks (p. 10) and Rob DeSalle (p. 15) point out in this issue, curiosity is hardly a rationale for attempting to clone a pet or an extinct species. Malcolm objects aggressively to that kind of recklessness, snapping at Jurassic Park's jolly dinosaur-cloner: "Genetic power is the most awesome force the planet has ever witnessed, yet you wield it like a kid that's found his dad's gun."

Crichton's character actually takes a nuanced, if perhaps inconsistent, view of when cloning is and isn't OK. He accepts the morality of cloning condors to save them from extinction because of humans' hand in sending them towards the brink; whereas "dinosaurs had their shot, and nature selected them for extinction."

Some of the general public appears to share the notion that cloning technologies are morally acceptable, so long as they are done for a good reason. Gallup polls in 2001 and 2007 found essentially unchanged figures: only 11% support human reproductive cloning, but 33% accept therapeutic cloning and 63% support embryonic stem cell research. 80% disapprove of pet cloning, while 64% disapprove of cloning endangered species.

Malcolm's concerns that the dinosaur cloning experiment would end badly prove well-founded, though the ensuing chaos owes more to the requirements of the action thriller genre than to actual science. Cloning extinct species, or anything in the animal kingdom, is a highly uncertain process - and not because the clones might rise up and eat their creators.

Success rates are low; many clones have abnormalities - some fatal, some difficult to locate yet significant and hereditary; and somatic cell nuclear transfer, the technique used to create Dolly the sheep, has its own set of problems, particularly when human embryos are involved (see Jesse Reynolds, p. 3).

The ethics get messier in human cloning. Human reproductive cloning is expressly forbidden in the U.S. and generally around the world, although as Rosario Isasi discusses on page 17, there is no truly binding global measure to prevent it. The Continued on page 12

JULY - AUGUST 2009

Contents

Cloning-based stem cell research is getting hype, but not results (p. 4)

Symbol Over Substance 4 JESSE REYNOLDS Eggs for Sale 6 JUDY NORSIGIAN

New York allows researchers to pay women to ‘donate’ eggs (p. 6)

Interview: Dr. Story Landis 8 Dr. Landis heads the NIH stem cell task force

Cloning for Kicks 10 PETE SHANKS Topic: Livestock Cloning 13 GM Sugarbeets Rebuffed 14 Genetic Time Travel 15 ROB DESALLE Cloning for curiosity’s sake started with pets.

Next up: Neaderthals? (p. 10)

Interview: Rosario Isasi 17 A discussion of international stem cell research and cloning governance

Book Review: Genetic Rounds 20

BY ANDREW THIBEDEAU Endnotes

23

Cloning DNA from extinct species isn’t synonymous with resurrecting them (p. 15)

25 Years of GeneWatch GeneWatch Anniversary Archive: 1983-2008 The Council for Responsible Genetics was founded in 1983 to provide commentary and public interest perspectives on social and ecological developments of biotechnology and medical genetics. For a quarter of a century, the Council has continued to publish its magazine GeneWatch with articles by leading scientists, activists, science writers, and public health advocates. The collection of GeneWatch articles provides a unique historical lens into the modern history, contested science, ethics and politics of genetic technologies. The full archive of GeneWatch has been incorporated into this special anniversary DVD that includes an index of all the authors and titles.

Copies of the anniversary DVD are available for a $100 donation to: Anniversary CRG DVD Council for Responsible Genetics 5 Upland Rd., Suite 3 Cambridge, MA 02140 VOLUME 22 NUMBER 3-4

GENEWATCH 3

Symbol Over Substance The shortcomings of cloning-based stem cell research

BY JESSE REYNOLDS Despite over a decade of hype, cloning-based stem cell research has offered little in the way of scientific progress. It has been more symbol than substance; more moving target than realistic goal.

However, by complicating both politics and policy, is has been a monkey wrench in the gears for progressive advocates of responsible biotechnologies.

Although there had been previous technological and policy developments in reproductive cloning, the 1996 birth of Dolly the Sheep the first cloned mammal - catalyzed widespread concern and numerous laws about human reproductive cloning throughout the world. It quickly became clear that, outside of a handful of extreme techno-enthusiasts, reproductive human cloning had few defenders. Prohibitions in every nation, and even internationally, seemed to be just around the corner.

But two years after Dolly’s birth, scientists led by James Thomson at the University of Wisconsin isolated human embryonic stem cells. These cells’ power to differentiate into any tissue type – a characteristic called pluripotency – represented the foundation of a potential new type of medicine, in which cellular therapies could be used to repair the degenerative tissue at the core of many diseases.

Furthermore, because they could be cultured as cell lines, another more feasible use of embryonic stem cells would be as in vitro standards in which human biology— both normal and abnormal – could be observed and tested at cellular level.

However, many stem cell scientists focused on the limits of this source of stem cells for therapeutic 4 GENEWATCH

purposes. Because the cell lines were derived from embryos created but not used for fertility treatment, their genomes were essentially random. Any potential cellular therapies posed the risk of immune rejection by the patient.

Furthermore, researchers wanted stem cell lines that harbored all the genetic contributors to a particular disease to serve as a “disease in a petri dish.” Thus, some scientists and advocates called for the derivation of stem cell lines from human embryos created by the same cloning method used to produce Dolly.

Proposals for such cloningbased stem cell research, often called somatic cell nuclear transfer (SCNT), complicated the politics and policy of both embryonic stem cell research and reproductive cloning. Because the great majority of opposition to embryonic stem cell research was based on the moral status of embryos, it was a divisive issue which mirrored the abortion debate. In contrast, reproductive cloning was opposed nearly unanimously. Proposals to use cloning technology in stem cell research, though, linked these two issues, conflating them in the minds of some observers and policy makers.

Beliefs that assign full moral status to human embryos preclude support for any embryonic stem cell research, whether the cell lines are derived from excess IVF embryos or from (hypothetical) cloned embryos. But there are reasons unrelated to embryo destruction to be concerned about SCNT, and many who support stem cell research using IVF embryos have raised significant concerns about SCNT. Most obviously, SCNT could lay the groundwork for reproduc-

tive cloning. Technically, it would perfect cloning methods.

Logistically, it would entail creating numerous clonal embryos, requiring only implantation into a woman’s womb for potential reproductive application.

Moreover, SCNT requires human eggs, and its experimental development or application to create stem cell lines would call for large numbers of them, perhaps hundreds of thousands. Their only source is women, and egg extraction is an unpleasant, invasive procedure that poses nontrivial health risks. From whom would these eggs come? Should researchers offer cash incentives? Would it be appropriate to do so, knowing that the women who would put their health at risk for a speculative line of research would likely be disproportionately poor and simultaneously less likely to have access to any medical advances?

The political landscape shaped by these questions was a surprising hodgepodge. Of course, opponents of embryo-destructive research stood against any type of cloning, while most scientists and research advocates backed SCNT. But many progressives oriented toward social justice were concerned about the potential exploitation of poor women.

Women’s groups themselves were divided: Most backed embryonic stem cell research, but some balked at SCNT due to its need for widespread egg extraction.

Although public opinion polls on this topic are susceptible to strong wording effects, the most clearly phrased ones indicated that a slim majority of the American public was opposed to cloning for stem cell research.

In the face of these uncertainSEPTEMBER-OCTOBER 2009

ties about research cloning, federal progress toward prohibiting reproductive cloning slowed. Policy makers faced the question of whether to ban both types of cloning, or just reproductive cloning. A divided answer led to stalemates not just in the US Congress, but also at the United Nations. Today, the United States remains one of the few industrialized countries with no national law prohibiting reproductive cloning.

Despite the fact that cloning-based stem cell research appears unlikely ever to be a feasible endeavor, its supporters indulged in a great deal of hype in the VOLUME 22 NUMBER 5

early part of this decade. Although most scientists were measured in their assessments, SCNT enthusiasts portrayed it as an essential and inevitable component of cellular therapies. For example, at the 2004 Democratic National Convention, Ron Reagan, Jr. asserted that we would each soon have our own “personal biological repair kit standing by at the hospital.”

Such unrealistic proclamations helped fuel strange policy proposals and political debates. For example, in 2006 Missouri devoted a lot of political attention and campaign cash to a constitutional amendment that would have done little besides protect SCNT from potential state laws - despite the fact that no ban on SCNT was likely to ever be enacted in Missouri, and that no researchers there were conducting cloning-based stem cell research. Nevertheless, a single wealthy couple poured over $30 million into the ballot battle, in a state with slightly more than two million voters.

That made it not only the state’s most expensive contest, but more expensive than all the state legislative races combined. Although the proposal passed, SCNT research is still not taking place in Missouri.

More relevant policy debates have focused on whether to permit payments (beyond reimbursement for expenses) for providing eggs for cloningbased stem cell research. Many jurisdictions both in the U.S. and abroad prohibit such payments.

For example, California’s Proposition 71, which passed in 2004 to make that state the world’s largest funder of embryonic stem cell research, doesn’t permit financial inducements. The following year, this was reinforced nationally with the National Academies’ recommended guidelines for human embryonic stem cell research. A number of countries (including South Korea, China, Japan, Israel, Australia, and the United Kingdom) also ruled against the practice.

More recently, efforts have been made to chip away at this near-consensus. The United Kingdom now permits fertility clinics to give significant discounts if the woman agrees that some of her eggs can be diverted to research. And New York State, which like California has its own funding program, just became the first jurisdiction to explicitly endorse payments for eggs.

In 2007, the political and scientific landscapes for stem cell research were dramatically rearranged when two research teams – one again led by Thomson, the other by Japan’s Shinya Yamanaka—reprogrammed normal body cells into fully powerful stem cells. These “induced pluripotent stem cells,” or iPS cells, meant that stem cell lines could be produced without destroying embryos. But the development did more. It Continued on page 19 GENEWATCH 5

Eggs for Sale Egg donation for research and the need for greater caution

BY JUDY NORSIGIAN Despite ongoing concerns about the safety of multiple egg extraction techniques, many young women see misleading ads in college newspapers and on the Internet that portray the risks of egg “donation” as quite minor and inconsequential. Most of these ads seek women who would provide eggs for reproductive purposes and often offer a hefty payment that brings the transaction well out of the realm of egg “donation.”

Some carry rather blatant headlines (for example, “Genius Asian Egg Donor Needed - $35,000 compensation”).1 Generally, regulations governing payments to women who provide eggs for research purposes (somatic cell nuclear transfer, or SCNT) have limited the compensation substantially, but that may change in the near future, especially since New York State set a precedent this past year in allowing much larger payments (up to $10,000) to women providing eggs for research purposes.

Elsewhere, we have noted the unresolved safety issues that need greater attention.2 Dr. Jennifer Schneider, whose daughter developed colon cancer and died after several egg extraction procedures conducted during a 2-3 year period, has also written eloquently on the need for more long term safety data.3 Time Magazine noted in its March 31, 2009 issue, “As egg donations mount, so do health concerns.” Although a good deal is known about the potentially lifethreatening complication of ovarian hyperstimulation syndrome – a rare response to drugs that hyperstimulate the ovaries to produce multiple follicles – there are no 6 GENEWATCH

good long term data on the risks of ovulation suppression from drugs such as leuprolide acetate (Lupron). These drugs are typically administered first, in order to allow for more controlled hyperstimulation with the stimulatory drugs.

A recent editorial in Nature magazine unfortunately endorses the decision of New York State to pay women to undergo multiple egg extraction solely for research purposes, even after reporting in August 2006 that “Health effects of egg donation may take decades to emerge”:4 “... More states should take New York’s lead, and allow researchers to pay for egg donation. The potential for coercion, although real, is manageable. And the technique’s move to the clinic would certainly be faster, and arguably more ethical, if donors were paid.”5 The editorial glibly asserts that the potential for coercion is “manageable,” while there is little evidence to support this claim.

Moreover, it fails to mention that the lack of adequate long term safety data continues to make it impossible to secure true informed consent from women undergoing these procedures.

In addition, some ethicists now argue that payments to egg donors for SCNT should parallel payments recognized as acceptable for IVF clinics by the American Society for Reproductive Medicine. Ethicist Nancy Dubler, a member of the Empire State Stem Cell Board, explained her view of the board’s role this way: “I think that we are an ethics committee, and I actually think that, if good science

demands these oocytes, that we have the obligation to provide them, and I’d like to see language like that. … I think that this will be a larger national discussion, and this might be an important statement to get out there.”6 Prominent ethicist Art Caplan is among those criticizing the New York State’s stem cell program for departing from the international consensus against paying women to provide eggs for cloning-based stem cell research: “The image of women having their eggs harvested in a market is one that the industry is going to find difficult to destigmatize ...

That notion of being treated as an object to derive those kinds of materials is not one that will sit well.”7

“The image of women having their eggs harvested in a market is one that the industry is going to find difficult to destigmatize.”

- Art Caplan Fortunately, the National Institutes of Health has enhanced access to funding for responsible embryonic stem cell research, while at the same time excluding federal funding for stem cell lines that are created with cloning techniques. This reflects an appropriately cautious stance given what we still need to learn about the SEPTEMBER-OCTOBER 2009

potential risks of multiple egg extraction. Also, given that many aspects of this research have thus far failed to produce the hoped-for results, there is even more reason for discouraging other states and institutions from adopting the inappropriate payment incentives now being offered by New York State.

In addition, should scientists be able to demonstrate that cell reprogramming methods may be adequate for producing disease-specific stem cell lines, it may not ultimately be necessary to ask women to undergo the risks of egg extraction solely for research purposes.

Meanwhile, in the absence of well-designed, long term clinical trials, more anecdotal experiences are appearing on the Internet and serve to offset the misleading ads.

One woman’s lengthy story ends with the following: “When I decided to sell my eggs, I never thought I’d get cancer… I know that breast cancers are hormone sensitive and can be affected by hormone treatments.

During my cancer treatment, two doctors mentioned that anecdotally they see more cancer in women who have had fertility treatments.

I’ll never know for sure if the egg donation caused my breast cancer, but now I know that it is likely to be a contributing factor. I think often about how much I love my husband, and it breaks my heart that my desperation for a couple thousand bucks has caused him such pain. A bad decision made seven years ago may cost me my life.”8 A thoughtful Princeton student writing an article titled “Truth in egg-donor advertising” for the Daily Princetonian noted the following key points: “Proponents of a free-market egg-donation system may claim VOLUME 22 NUMBER 5

that cases of abuse are rare, but the simple reality is that no one knows the true scale of abuse. The Centers for Disease Control is only required to ask fertility clinics how many successful births result from donor eggs. They don’t ask important questions like the amount of times a donor has previously donated, reported side effects or long-term medical issues.

With practically no government regulation and increasingly astronomical compensation prices, the blossoming egg donation system is rife for potential abuses.

Donors have financial incentives to cover up their medical history, and growing evidence suggests that repeated egg donation may result in decreased fertility for the donor and damaged eggs for the recipient. Without a system to monitor and control egg donations, both donors and recipients could be abused.”9 In an effort to improve the quality of informed consent for potential egg donors the California legislature passed AB 1317 in 2009. This bill involves no cost to taxpayers and no new burdens on fertility clinics and brokers already operating in ethical fashion. It would improve both the public oversight of embryo acquisition for stem cell research as

well as the quality of informed consent for donors providing eggs for IVF purposes.

L a rg e r Q u e s t i o ns The growing number of reproductive technologies offered by an expanding “fertility industry” has posed other challenges dealing with commercial, economic, and ethical aspects of these technologies. For example, abuses related to reproductive “tourism” are appearing more frequently in the news. In 2009, two Israeli doctors were arrested in Romania following allegations that their Sabyc fertility clinic in Bucharest made payments to human egg donors, a practice which is illegal there. [10] Internationally, Sama Resource Group for Women and Health (India) is organizing a major consultation in January of 2010 to address these challenges and to explore strategies for responding to the growing phenomenon of poorer women being sought as ‘suppliers’ of cheap labor (as “gestational” mothers “renting” their wombs) or as providers of eggs used in IVF procedures. India, in particular, has become a “surrogacy” outsourcing capital because of the lower costs involved, the lack of regulation in provision of ARTs, and the highly regulated situation in many European countries. Some GENEWATCH 7

estimate that the surrogacy business alone is worth $445 million in India.11 Sama is also involved in action research focusing on social, medical, economic and ethical implications of the ARTs. They are exploring such issues as poverty, religion, caste, gender and state apathy. They note that medical care providers in India often develop their own eligibility criteria for the couples according to which, quite often, single or homosexual women/men fall outside the purview of these services. Their analysis of advertisements seeking surrogates and egg donors identifies stereotypes that reveal an obsession with particular kinds of physical features and an emphasis on eugenics. Because infertility has never been addressed as a public health issue in India, there has been little attention given to the underlying, sometimes preventable, causes of infertility.

Finally, it is also important to remember that SCNT lays the technical groundwork for human reproductive cloning. Until the United States joins the dozens of other countries that have already prohibited reproductive cloning, it is even more critical that we restrict SCNT research in this country.

Judy Norsigian is Executive Director and a founder of Our Bodies Ourselves, also known as the Boston Women’s Health Book Collective.

Interview: Dr. Story Landis A conversation with the head of the NIH Stem Cell Task Force

Story Landis, Ph.D., is head of the Stem Cell Task Force at the U.S. National Institutes of Health (NIH) and director of the National Institute of Neurological Disorders and Stroke (NINDS).

The stated purpose of the stem cell task force is to (advance stem cell research). Am I right to assume, based on their affiliations, that the members of the task force all have an interest in advancing the same aim?

Yes, we do. The task force was set up after President Bush, in his address in 2001, announced that NIH could conduct and fund research using embryonic stem cells, and he asked NIH to put together a task force that would accomplish those aims. So the task force has been in place since 2001; and interestingly enough, given the Obama executive order, which has completely changed the landscape for NIH funding and stem cell research. Given the advances in stem cell research and the new opportunities provided by the Executive Order, we rethink what the task force is doing and make sure that the membership reflects the new goals.

How has the task force’s member ship changes since 2001?

These are basically the members who were in place eight years ago.

There may have been some turnover, but the same institutes are represented – those that support human embryonic stem cell research. One change that we should make would be include program staff with expertise in induced pluripotent stem cell biology.

8 GENEWATCH

With the last administration there were some fairly clear ethical boundaries on the use of human embryonic stem cells, and of course there’s also an ethical issue in terms of the benefits that could be derived from research using stem cells. Do you find yourself or the Stem Cell Task Force dealing much with that push and pull?

The Stem Cell Task Force has focused its attention on identifying and supporting the best science. We have also been engaged in providing resources for human embryonic stem cell research including funding a stem cell bank to provide stem cells lines and training courses to teach scientists how to work with stem cells. Between 2001 and 2009, the National Academy of Sciences/Institute of Medicine and the International Society for Stem Cell Research played a key role in developing guidelines for the derivation of human embryonic stem cells and their uses. The discussions during the Bush administraSEPTEMBER-OCTOBER 2009

tion about concerns about responsible derivation and responsible use either happened in the President's Council on Bioethics or, to a very large extent, were happening in the National Academy of Sciences or in the ISSER or in states like California or Connecticut or Maryland. NIH had marching orders from the President regarding what kind of stem cell research we would fund and how we would fund it.

So what are your marching orders now?

The recent executive order asked NIH to come up with guidelines that would enable us to support responsible and scientifically worthy research. Now the focus is on actually implementing those guidelines as expeditiously as we can.

Once Obama issued the executive order, a small working group of policy experts from the NIH Office of the Director and scientists with stem cell expertise from the institutes developed draft guidelines.

NIH then sought public comments on the draft guidelines. We received more that 49,000 comments and based on that input modified the guidelines to address all the very useful input that we got. The preamble to the final guidelines which were published in August summarizes the comments and the changes that were made in response to them. One of the important changes was to create a mechanism for central NIH review of eligibility of stem cell lines and a registry that would list them. We have now created a website so that individuals or institutions can submit information so that lines can be considered for eligibility. Within a day or two of opening up the website, complete information on 12 lines had been submitted and partial information on another 50.

Each week additional requests for consideration are added. The website allows scientists and the public to check progress.

And the guidelines include limits VOLUME 22 NUMBER 5

on how embryos can be obtained and what kind of research can be funded?

The guidelines propose certain criteria – for instance, that the embryos donated for derivation of lines should be from in vitro fertilization for reproductive purposes and no longer needed for that pur-

“While there’s a public focus on transplantation, many of us think that drug screening and pathogenesis are even more important.’” pose – and that the donation should be made with informed consent.

While detailing the requirements for donation, the guidelines provide for the different review processes for donations before the final guidelines were released as compared to after. I think those guidelines establish clear limits on what NIH will fund and the conditions under which embryos should be donated. And there are two very specific pieces at the end of the NIH guidelines that restrict uses of embryonic stem cells in NIH funded research.

What sense do you have of the direction of stem cell research?

I think most people have focused on using human embryonic stem cells to generate tissues for transplantation. As you probably know, the FDA approved the first clinical trial using embryonic stem cells in humans, the Geron trial for spinal injury, in January of 2009.

While the public believes that cell replacement will be the first and probably most important use, many in the scientific community, including at NIH, believe that as important, and maybe even more important, is the use of human embryon-

ic stem cells to understand human pathogenesis and also to test potential therapeutic strategies.

Human embryonic stem cell lines have been generated from embryos identified through preimplantation genetic diagnosis to carry serious disease mutations, such as Huntington's disease or cystic fibrosis. Cells from those lines can be turned into different classes of cells – for example, secretory cells for cystic fibrosis or neurons for Huntington's disease, that will allow us to understand disease pathogenesis and to develop assays to screening for treatments. So while there's a public focus on transplantation, many of us think that elucidating pathogenesis and drug screening are even more important.

For instance, we don't really know why the mutant Huntington's gene kills cells. Studies have been done in mouse models but to date the mice don't get Huntington’s disease in a way that neurologists and neuropathologists would recognize.

In contrast, research on the human embryonic stem cell lines that carry the mutation can give us important clues about what kills cells in Huntington’s. And you can imagine there are other diseases where preimplantation genetic diagnosis can identify embryos carrying the disease such as lysosomal storage diseases.

Diseases where the genetic component is clear.

Yes, where the mutations in the gene are absolutely defined as causing devastating diseases, and people who choose to do in vitro fertilization so that they can be confident that the blastocysts that are implanted don't carry the disease can donate the ones that carry the disease for research. I got a call once from a woman who knew that both she and her husband carried mutations in the cystic fibrosis gene. She wanted to know how to donate blastocysts that would be Continued on page 14

GENEWATCH 9

Cloning for Kicks Dogs, goats, mammoths, and Neanderthals: an overview.

BY PETE SHANKS

Pet cloning is a terrible idea and, we now know, an extremely unpopular one. Cloning endangered species is equally foolish. Recreating extinct species is an absurd concept, whose worst extreme is the proposal to re-make a Neanderthal. Taken together, they represent a triumph of reckless technological tinkering, and of adolescent curiosity over meaningful ethics.

The idea of cloning pets immediately followed the 1997 announcement of the first mammal cloned from a somatic cell. John Sperling, a multi-billionaire, was reading about Dolly the sheep when he whimsically wondered if it would be possible to clone his girlfriend’s dog, Missy. He delegated the project to his girlfriend’s son, Lou Hawthorne, who ran with it for the next decade.

A dozen laboratories are said to have been interested, but the initial contract went to Texas A&M. They estimated that the project might cost a million a year and take five years. Sperling could afford it — and the A&M team got an entree to the intriguing world of mammalian cloning.

That was a hot new field in the late 1990s, and a lot of scientists wanted to dive in. By July 2002, 50 papers had been published in peerreviewed scientific journals, describing 68 experiments involving about 45,000 eggs, 552 “live births” that did not live long and 386 surviving clones, of 7 different species. Cattle accounted for almost half of the survivors, and mice for most of the rest, followed by goats, pigs, sheep, a few rabbits and one cat (a side experiment by the A&M team).

10 GENEWATCH

Endangered Species Some of these attempts involved endangered, or at least vulnerable, species. The first publicity went to Advanced Cell Technology (ACT), which took time out from cows to clone a gaur (Bos gaurus, a species of wild cattle), which unfortunately died two days after its birth. One of the sheep was of a wild, endangered variety (Ovis orientalis musimon, a European mouflon), which was cloned using a surrogate from a closely related domestic sheep, Ovis aries. In 2003, a threatened African wildcat was cloned, using a domestic cat surrogate; in the same year, a banteng (another cow) was born. More recently, there have been a couple of gray wolves, and that seems to be the sum total of ‘success’ so far.

There are a few legitimate environmentalists who think that cloning could be one of the tools used to assist endangered species.

But the problems are substantial.

Cloning does nothing to improve their environment; it adds no genetic diversity; it requires many surrogates and egg donors, who may be harmed; and it may distract from lower-tech but more practical conservation measures.

Some of the people involved in endangered species cloning may have been well-meaning, but publicity was always part of the point.

(ACT in particular was chronically short of capital, and developed a reputation for stunts.) Just look at the names given to these clones: Ditteaux for the Louisiana-based wildcat, CC for the domestic cat, Noah for the gaur, and so on. The master of this was Hawthorne, who first dubbed the dog-cloning effort

the Missyplicity Project and then set up a company called Genetic Savings and Clone (GSC), to do gene-banking for pets and eventually to sell pet clones at a profit.

Except that the technology did not work very well. The A&M team never did clone a dog, though there was one stillbirth. And the cat was, to Hawthorne, “a disaster” in terms of public relations: she did not look like the genetic donor. In retrospect, the choice of donor was a mistake, since she was calico. This multi-color pattern is caused by the random silencing, in early development, of one of the two Xchromosomes in each cell. The result is that a clone might be black and white (like CC), or orange and white, but never a combination of the three, as the donor was.

Enter Hwang Woo-Suk GSC eventually stopped funding Texas A&M’s efforts, and began their own, without much success, though they did beyond selling a couple of cats. Meanwhile a team at Seoul National University (SNU) led by the soon-to-be-notorious Hwang Woo-Suk was working intensively on the dog problem.

They had the advantage of access to animals bred for food and the preparation of a local tonic; reportedly they used 5,000 dogs in their experiments. Finally, in 2005, they succeeded in cloning an Afghan hound — after creating 1,095 embryos and transferring them, over the course of two years, into 123 surrogates, which resulted in three pregnancies, one miscarriage, one puppy that died after 22 days, and one success. (Their cute name: Snuppy, for SNU-puppy.)

This triumph of persistence SEPTEMBER-OCTOBER 2009

was rapidly overshadowed by the discovery that Hwang had faked some of his work on human embryonic stem cells, embezzled millions of dollars in government funds, and violated laws and ethical guidelines about acquiring women’s eggs. He left SNU in disgrace; at the time of writing, he is still awaiting sentencing. In the meantime, he set up his own research establishment, and Hawthorne hired him. GSC had gone bust, but Hawthorne now headed two other companies: BioArts and Encore Pet Services.

And eventually, five clones of the original Missy were born — after a decade of work, millions of dollars and who knows how many surrogates and egg donors.

The one peer-reviewed paper to emerge from all this only covers the work of Hwang’s team, and is largely devoted to comparing two different embryo activation methods. In the best case, 14 dogs were needed to produce one live clone.

That’s with essentially unlimited funds and animals, and some of the most skilled technicians aroundavailable. A 2008 survey article estimated that only 1%–5% of all cloned embryos transferred

VOLUME 22 NUMBER 5

into surrogates develop into viable offspring. A 2007 paper by mouflon-cloner Pasqualino Loi et al. described the production of living offspring as “phenomenological,” which in this context seems to be a high-falutin’grandiose way of saying that the process is “trial and mostly error.”

“Error” is in fact too bland a word. Some animals grow too large in the womb, sometimes to the point of killing their surrogate mothers. Some seem to be developing normally but then are miscarried or still-born. Some are born unable to breathe, or with skeletal malformations. Some seem healthy at first but rapidly show such signs of discomfort that they have to be killed before they die in agony.

Extinct Species Despite this, and despite the overall lack of success in cloning endangered species, there has been at least one serious attempt to recreate an extinct one. This was a Pyrenean goat called a bucardo.

The last bucardo died in 2000, but tissue samples were saved. In January, 2009, there were actually headlines claiming success, even though the kid was unable to breathe and died within minutes.

Several other species have been discussed for re-creation, including the saber-toothed tiger, the short-faced bear, the giant ground sloth, the moa, the Irish elk and the giant beaver.

The one that has attracted most attention is the wooly mammoth. Both Hwang and a Japanese team tried and completely failed, because the frozen tissues were too degraded, but now hopeful scientists are estimating that it could be done for $10 million or so.

Here’s the plan. First scientists must finish sequencing mammoth DNA, which seems to be less than 1% different from an elephant’s (about 400,000 gene variants).

Then they take an elephant cell, reprogram it to an embryonic state, and modify it to match the mammoth’s sequence. This could then be the basis of a mammoth clone in an elephant’s egg, which would be brought to term in an elephant surrogate. That is, if they can find one.

Elephants are themselves threatened, but this does not seem to stop the speculation.

Even if all this is possible, which is not certain, it is not entirely clear what the result would be. Genetically, it would be a mammoth, at least essentially. (It would presumably include a tiny bit of elephant mitochondrial DNA, and it seems inevitable that there will be gaps in the code, bridged with stretches of elephant DNA.) But it would surely be one disturbed beast, even if it were physically healthy. There would be no herd, so the social aspect would be lacking, or severely distorted; the vegetation, climate and entire ecological surroundings would be quite different from that of 5–30,000 years ago; it would be a mammoth-like simulacrum.

An even more disturbing prospect has been mooted: cloning a Neanderthal through a similar process. The obvious surrogate would be human, but that’s off the table. Instead, the idea would be to modify a chimpanzee, which is genomically very similar to both humans and Neanderthals. Then a chimpanzee surrogate would bring the near-Neanderthal to term. “The big issue,” George Church of Harvard has said, “would be whether enough people felt that a chimp-Neanderthal hybrid would be acceptable, and that would be broadly discussed before anyone started to work on it.”

GENEWATCH 11

The Dog Business The nascent dog cloning business was rocked by two announcements in the late summer of 2009.

First, a Korean company, RNL Bio announced a major investment in it, with the expressed intention of dropping the price to $30,000.

Second, Hawthorne quit. His company, BioArts, had been trying to sell the service at $138,500, and the price-cutting announcement seems to have been the last straw.

Hawthorne seems to think that RNL just wanted to drive him out of business, perhaps because they were involved in litigation over cloning patents. His envoi was a 3200-word statement that revealed, among other things, just how few people want cloned pets. BioArts ran a well-publicized essay competition in 2008 to give away a clone.

They expected hundred of thousands of applications, and received 237.

Opinion polls always suggest animal cloning was unpopular, and this confirms it. Evidently people understand the absurdity of trying to clone a once-beloved pet. Clones are not copies, and the attempt to make them causes obvious harm to animals. Hawthorne has now admitted that not only did some cloned dogs have unexpected coloration, some had skeletal malformations, and (weirdest of all) one clone of a male was actually born female, presumably because something very strange happened in early development.

Quite Exactly what RNL Bio expects from the market is not clear. Until now, they have been using the SNU team, now led by Hwang’s former colleague Lee Byeong-chun, who cloned a “drugsniffing” dog that works for Korean Customs for them; the seven puppies cost over $700,000, which may be too much for the government. (When announced, they all had the same cute name: Toppy, for Tomorrow’s Puppy.) There has

12 GENEWATCH

been discussion of cloning endangered wolves and “a new breed of dogs known for their talent at detecting cancer cells.”

None of these seem like much more than publicity stunts. RNL is an ambitious multi-national with a major focus on human stem-cell treatments. Their president has talked about making human-dog hybrids for medical research, which might give them a reason to develop cloning technologies. The pets, however, seem like a sideshow.

Conclusion In 1997, it was surprising that somatic cloning worked at all. A decade on, it seems that there has been more to learn from its failures than its successes. In any case, the basic science of developmental biology should not be driven by technological whim.

The very idea of cloning seems to fascinate some scientists, however, and to drive them to find excuses to pursue it. Consider the work on endangered species: What is the question here that researchers are trying to answer?

From the outside, it appears to be not so much “How can we help endangered species?” as “How can we use cloning?”

This enthusiasm has survived

the failure of the technique to develop as once expected.

Efficiency has improved a little, but not much. Every failure involves living, breathing and too often suffering animals. And for what? To replace a pet? To add an attraction to a zoo? Animal -welfare arguments are tricky enough in medical research, where the justification is human benefit. When the benefits are so trivial, the harm to animals clearly outweighs them.

A deeper — probably unconscious — motivation may be one of control, a desire to mold the natural world into shapes we ourselves imagined. Let’s see what a Neanderthal looks like! Wouldn’t that be neat? No, it would not. The result would either be a failure or, in the unlikely and unprovable event that it succeeded, an ethical monstrosity — a near-human created for pure curiosity.

Cloning for fun is simply a bad idea.

Pete Shanks is an author and commentator who writes on the eugenic possibilities of biotechnology for the Center for Genetics and Society. He is the author of Human Genetic Engineering: A Guide for Activists, Skeptics, and the Very Perplexed.

Editorial Continued from page 2

more timely human cloning issue is its role in embryonic stem cell research, a topic which reaches beyond cloning and incites heated arguments over the ethics of how (and whether) human embryos should be obtained and used for research. In this issue, Judy Norsigian, Executive Director of Our Bodies Ourselves, takes up problems with the way researchers obtain eggs (p. 6), and Story Landis of the National Institutes of Health's Stem Cell Task Force relates her angle (p. 8).

‘Cloning’ is a broad and complex topic, and some cloning technologies could have far-reaching and disturbing repurcussions.

Some potential consequences of these technologies - eugenics, food safety failings, disturbing animal welfare problems, or the ethical bankruptcy of attempting to create Neanderthals for our own amusement - are exceedingly serious ... even if somewhat more subtle than being eaten by dinosaurs.

SEPTEMBER-OCTOBER 2009

Topic: Livestock Cloning How is livestock cloned?

Livestock cloning has been accomplished through embryo splitting - in which a multicellular embryo is split into "twins" - and through somatic cell nuclear transfer (SCNT), in which the nucleus of an adult cell is inserted into an egg which has had its own nucleus removed. A team of scientists led by Ian Wilmut used the latter method to clone Dolly, but Wilmut and others have since shifted their favor toward a newer approach which skirts concerns about obtaining eggs and destroying embryos. This method, pioneered by Kyoto

the meat of clones shows no significant nutritional difference from the meat of non-clones, and products derived from clones and the progeny of clones can be legally sold in the U.S. Furthermore, FDA Center for Veterinary Medicine director Stephen Sundlof asserts that FDA does not have the authority to require labeling of food from cloned livestock if that food is not determined to be substantially different from the product of non-clones. He suggests, however, that FDA might police "clone-free" labels if they imply that food from clones or their progeny is less safe. This recalls the disputes over bovine growth hormone (rBGH) labeling in milk: despite legal actions by Monsanto, which produces rBGH, states have generally allowed milk to carry "rBGH-free" labels so long as they include a disclaimer that milk from cows treated with bovine growth hormone is not significantly different.

B e s id e s th e 'y u ck ' fa ct or , w h at' s wrong with cloning livestock?

Despite the FDA's confidence, there are some potentially serious food safety concerns. According to Wilmut himself, along with MIT's Rudolph Jaenisch, the technology used to locate early abnormalities in clones does not reveal epigenetic reprogramming, which can lead to undetected abnormalities which do not appear until later, could cause food safety problems - and are passed on to future generations.[1] The National Academy of Sciences has echoed these concerns.[2] Jaenisch points out that in a cow,

D o e s t hi s m e a n c l o ne d m e a t i s already at the grocery store?

University's Shinya Yamanaka, reprograms adult cells to an embryonic-like state - known as induced pluripotent stem cells - creating a blank slate from which the cells can emerge as any kind of cell in the body. This approach is less difficult and expensive to carry out than SCNT, but remains inefficient and not fully understood.

Is livestock cloning legal?

Some form of animal cloning is legal all over the world; the issue arises with the prospect of cloned animal product in the food supply.

Surveys in Europe and the U.S. have shown a general public distaste for the idea of eating clones; however, in the U.S., the Food and Drug Administration has concluded that VOLUME 22 NUMBER 5

Right now that's unlikely for two reasons. Firstly, cloned livestock is still in its early stages: a 2006 industry estimate put the numbers at only 600 cloned cows and 200 cloned pigs in the U.S. Secondly, because of the expense of successfully cloning an animal, clones would be for 'breeding, not eating.'

That is, farmers would have the animals with the best genetics cloned for use as breeding stock, in order to preserve those genetics and sell them to other producers. Selling a cloned animal for meat would be quite a waste of money. It could well be, however, that the products from the progeny of clones will soon appear unannounced on grocery store shelves.

some abnormalities may not become visible until as many as 15 years of age. To put that into perspective: Dolly was cloned only 12 years ago. Some of the abnormalities associated with cloning raise animal welfare concerns, as they can be fatal to the clone or the host 'mother.'

While some farmers might find use for livestock cloning, the companies carrying out the cloning - such as Viagen and Cyagra - stand to benefit most. Efficient cloning technologies could usher in the ability for laboratories to create and sell genetically modified livestock. In other words, livestock cloning could be just the tip of the iceberg.

GENEWATCH 13

Update: GM Beets Rebuffed Court overturns USDA approval of Monsanto’s genetically modified sugar beets

In late September, the Federal District Court in San Francisco found that the U.S. Department of Agriculture fell short in assessing environmental impacts when it approved Monsanto's genetically modified sugar beets for commercialization. The Center for Food Safety and Earthjustice brought the case against USDA in January 2008, and although it was the Bush administration that deregulated the beets, the Obama administration decided in March not to change the rule.

The product in question is Monsanto's Roundup Ready sugar beets, which are genetically modified for resistance to glyphosate, the active ingredient in Monsanto's Roundup herbicide. The first crop of Roundup Ready sugar beets was harvested last fall, but may now be facing a ban.

The court ruled that USDA's

Animal and Plant Health Inspection Service failed to prepare an environmental impact statement and rebuked the agency's determination that introduction of GM beets would not affect farmers' choice not to grow GM varieties or consumers' choice not to eat genetically engineered foods. Judge Jeffrey White also found that USDA failed to assess the potential for cross-contamination. Beets are wind pollinated, and many of the Roundup Ready sugar beets were grown in a region of Oregon shared by related crops such as table beets and Swiss chard.

Although many producers adopted the GM beets when they became available, over 100 companies have signed a Non-GM Beet Sugar Registry, pledging not to use GM beet sugar in their products.

Interview: Dr. Story Landis Continued from page 9

homozygous for the disease mutation. I referred her to one of the societies that deals with in vitro fertilization.

There is a recent controversy in Britain regarding the creation of animal-human “hybrid” embryos, which were first allowed and now have been abandoned. Am I right in thinking that this type of study would not be approved for NIH funding?

NIH guidelines say NIH funding 14 GENEWATCH

can't be used for that – and NAS and ISSCR guidelines say "don't do that" – but we don't have laws that prohibit it.

I should note that the stem cell task force is primarily charged with implementing NIH guidelines, not with creating guidelines or dealing with these kinds of questions.

director, which meant that I was not involved in or responsible for trans-NIH issues. So that knowledge was way above my pay grade at that time!

Being in the position of implementing these policies, do you get a sense of when new policy is headed your way – for instance, when Bush was elected?

Remember, both McCain and Obama had as part of their campaign commitments that they would enhance NIH funding for stem cell research. So I think most of us expected that whoever won the election, there would be changes to the Bush policy.

When Clinton left office and Bush took office, I was a scientific

Did you and others at the NIH have an idea of what policy shifts were coming ahead of the 2008 election?

SEPTEMBER-OCTOBER 2009

Genetic Time Travel Cloning ancient DNA: the good, the bad, and the bizarre

BY ROB DESALLE, PHD

Our ability to go back in time, so to speak, using genetic techniques is hardly a new endeavor.

The first ancient DNA isolated and analyzed was from the Tasmanian Wolf – extinct for over 100 years – using tried and true DNA cloning methods in the early 1980’s.

When the Polymerase Chain Reaction (PCR) was invented in the mid 1980’s, the hunt was on for older and older sources of DNA. It is safe to say, though, that tissue from any long dead organism will have DNA that is badly degraded and in extremely low concentration. PCR was recognized as the best technique to overcome these technical difficulties and subsequently became the method of choice for examining long dead specimens. The same reasoning is used when forensic samples are worked with. But just as contamination is a big problem to be dealt with when working with forensics, so it is with long dead specimens.

Reports of isolation of DNA from amber-preserved plants and insects older than 100 million years began to appear. These claims were shortly rebutted based on extrapolation studies of the degradation of nucleic acids.

Specifically, researchers such as VOLUME 22 NUMBER 5

Tomas Lindahl suggested that no DNA fragments longer than 1 residue would be left after 30,000 years after death (Lindahl’s Line) of an organism. Since Lindahl’s Line was established, few studies have attempted to go much beyond that age when working with ancient specimens. Instead, there has been a steady stream of research papers on museum specimens and recently extinct organisms. In addition, some paleo-

“Just as contamination is a big problem when working with forensics, so it is with long dead specimens.” anthropological specimens and mammal and bird subfossils (the remains of organisms that have not yet been mineralized) have been used to obtain information from long dead organisms.

With the development of next generation sequencing methods such as the 454 method (the approach used to sequence James Watson’s genome) and Solexa

sequencing, it was recognized that these approaches are even better suited for ancient DNA. Why? Because the length of the sequence reads are of the order of the length of badly degraded DNA fragments found in old tissues.

Most degraded DNA will be on the order of 100 bases and the next gen sequencing approaches target fragments of about this size. One of the more interesting and more visible organisms that has been examined in this way is Homo neanderthalensis , our closest extinct relative (there are some who feel H. florisensis, the Hobbit, is our closest extinct relative, but that’s another story). Currently, according to Svante Paabo and his group at the Max Planck Institute in Germany, is about 63% complete and should be finished by the end of this year.

However a problem arises with sequencing ancient tissue using next gen methods and it is related to the contamination of the long dead specimens with bacteria, molds and the DNA of well meaning researchers. Often times what is obtained when sequencing DNA from long dead tissue is a mix of “authentic” DNA and contaminant DNA. The first sequences from GENEWATCH 15

the Neanderthal genome using next gen sequencing approaches are a sobering example of this phenomenon where it was estimated that 70 to 80 percent of the sequences came from contamination. More recent work by the groups sequencing the Neanderthal genome have improved this contamination problem to about 3%.

Nonetheless, the potential for obtaining DNA sequences from a wide array of extinct and rare organisms is approaching reality.

How does this affect the way

“One of the reasons people would want to clone a dinosaur or a Neanderthal is just to see one with their own eyes.” geneticists do research? Some very reasonable uses for analysis of ancient DNA do exist. Analysis of extinct organisms or extirpated populations gives conservation geneticists benchmarks for how variable populations were in the past. Such information is important for a couple of reasons.

First, such measures tell us something about the natural state of things and we can guage current population genetic measures with undisturbed measures.

Such

16 GENEWATCH

benchmarks assist conservation geneticists in making recommendations about how to conserve and manage populations of endangered species. Second, any genetic information on extirpated populations tells the conservation geneticist which genotypes are the most appropriate for reintroduction. On the purely research side of things, knowing which genes are involved in the differences between extinct species and living ones gives the researcher an unprecedented window on evolution. A good example of this importance brings us back to Neanderthals. Any information on what made these extinct humans like us or different from us would be incredibly interesting, and the Neanderthal genome sequences promise to give us some of that information.

On the other hand some extremely silly things come up, such as the suggestion that a Neanderthal or a dinosaur might be resurrected using the whole genome sequences obtained from genome projects. George Church of the Harvard Medical School suggests that, once obtained, the entire Neanderthal genome could be inserted into a chimp egg and allowed to develop in a surrogate chimp mother. Why a chimp mother? To avoid ethical problems, according to Church. That seems silly, as the ethical problems don’t just start with which egg or which surrogate is used, but actually

with the reason why the experiment would be done in the first place.

Resurrecting a Neanderthal conjures up what I call the Jurassic Park Distraction, only it hits a bit closer to home. When the Jurassic Park books and movies first came out and when scientists first published claims of isolating DNA from amber preserved insects, the public response was to ask immediately: will we be able to resurrect a dinosaur? Little thought was given about why it might be useful in a scientific context or about the ethics involved. One of the reasons people would want to clone a dinosaur or a Neanderthal is just to see one with their own eyes.

Scientists have found excellent uses for using long dead tissues as sources of information, but those using the approaches should be careful about how they convey the uses to the general public. It is a disservice to the public if the ethical ramifications of the work are not made clear, and an equal disservice not to explain to the public the real scientific utility of an approach.

Rob DeSalle, Ph.D., is a curator in the American Museum of Natural History’s Division of Invertebrate Zoology and co-director of its molecular laboratories.

SEPTEMBER-OCTOBER 2009

Interview: Rosario Isasi A discussion of international cloning and stem cell policies Rosario Isasi, J.D., MPH, is an attorney specializing in human rights and genetic technologies and a Postdoctoral Fellow for the Centre de Recherche en Droit Public at the University of Montreal. She is a member of the advisory board of Global Lawyers and Physicians.

T h er e i s of ten a tr an s- A tla nt i c divide in how genetic technologies are regulated. Is this true of U.S. and European approaches to regulating stem cell research?

In a way, the U.S. position, with the disparities between states, is similar to the European situation you have legislation at each end of the policy spectrum. So in the U.S. you have some very conservative and restrictive approaches that ban all embryo research and hold that an embryo should be treated like a human being; and then you have states that are more liberal, the California approach, which allows more research using stem cells from embryonic sources as well as adult sources, and also research of what they call therapeutic cloning. Then you have all of the policy in between, allowing research on stem cell lines from embryos providing that the embryos are those no longer needed for reproductive treatments.

That same spectrum appears at the European level in terms of how they classify their policy approaches. It goes from very restrictive in Italy, where the embryo is given a full personhood moral status, to the UK, Sweden, and others that allow cloning for a variety of research initiatives, including stem cell research - but with strict government oversight.

That is the main distinction, I would say: in the U.S. there is a vacuum, which the NIH is starting to VOLUME 22 NUMBER 5

fill now, on considering stem cell research at a national level through some federal approach or regulation. However, the scope of this federated approach is limited to NIH funding. The U.S. has more of a free market approach, whereas in Europe there is more strict government oversight - not only of obtaining embryos for research purposes but of the research methods, to ensure that it is not only scientifically sound but ethically sound.

That is an important distinction.

Meanwhile, Canada adopts a moderate approach: stem cell research is allowed and is publicly funded, and research is only allowed on surplus embryos no longer needed for reproductive projects. What is interesting is that only Europe has an international and regional binding treaty on human reproductive cloning.

How has the U.N. addressed reproductive cloning?

George Annas and I wrote a series of articles calling for a legally binding document to ban human reproductive cloning, but the U.N. process ended in a declaration.

Everybody in the world so far has agreed that human reproductive cloning should be prohibited, but on research cloning there are different positions. So the U.N. adopted a nonbinding declaration. They used some of the language of the European treaty regarding preservation of human dignity, sanctity of human life, et cetera - but it doesn't have teeth, it doesn't have any force.

And in a way it's repetitive, because UNESCO in 1998 already had condemned reproductive cloning. So it was expected that when the U.N. took it up there would be a legally binding instrument, a mandate to

all countries - a ban. But it didn't happen. This is what UNESCO was subsequently trying to do, but they have also backtracked.

W h a t w a s U N E SC O d o i n g be f o r e they backtracked?

In 2007, UNESCO asked the U.N. to do a sort of exercise to see how human reproductive cloning could be addressed internationally. They found that all of the countries involved accepted that human reproductive cloning is impermissible and a violation of human rights and human dignity. It has been only one year since UNESCO put this topic into their agenda, and they have had some arguments back and forth over whether it was the right time to address it. And there has been a lot of wrestling going on in terms of setting a definition from a legal standpoint: what is an embryo, what is stem cell research, what is cloning?

And that prevented UNESCO from really taking a strong hand in this issue. So the last position by the UNESCO bioethics committee was to say, "We're not ready to move into the adoption of a legally binding instrument, but we will continue monitoring development in the area."

And they still think that it's premature for the international community to engage in this effort. It's a shame - I think that the time is right. There are researchers in enough different countries working GENEWATCH 17

on fast approaching scientific advances that will someday lead to the technology for reproductive cloning of human beings. There are not enough checks and balances, mechanisms for governance or oversight of this kind of research ‌ so we should take action now. There are reasons to be concerned. I don't want to be apocalyptic, but looking at the worst case scenario, I think it is the time now to take a brave approach - to say, "We're not against science; we're not against stem cell research, we're not against a number of interventions; but this particular one, which we all agree is unacceptable, should finally have some meaningful regulation to put on the brakes."

Do you think that a legally binding U.N. resolution is the best way to address that?

Well, what I think is that we need some authoritative international body, independent - as much as it can be - that will monitor and sanction violations, or at least that will have enough authority to compel countries to take action at an international level. I think the United Nations would be the best place to start this. So far we have nothing else suitable.

If human reproductive cloning was to ever happen - or some attempt at it - where do you think it could happen?

To be clear, I don't think that human reproductive cloning is right around the corner. But most likely, this would be in developing countries, in a context where there's not enough national oversight for this type of research. I think those countries would provide a safe haven for this kind of rogue scientist. And reproductive cloning is the best example of technologies that eventually will have eugenic purposes.

Some people find it very inflammatory and apocalyptic to talk about eugenics and cloning, but it seems to have some sense. I'm talking about, certain technologies, like 18 GENEWATCH

germline genetic engineering, used for enhancement purposes - things you do at the embryo level which have nothing to do with improving human health or medical purposes, but are done for some sort of genetic enhancement. Transhumanists will say this is creating a 'better human.'

So how do you suppose, in a regulato r y s e n se , y o u c an d is ti n g u is h between researchers' intentions?

That is something that is hard to regulate, but I think that the most important thing is to establish what type of research is allowed and to have a proper governance mechanism that regulates and monitors the research. If you have a comprehensive governance system that tracks, for example, the research, you can monitor and control what end results are permissible and which are not. And of course there will always be a slippery slope, and intentions are very hard to prove.

On an international level, where do you find this conversation is taking place?

I think that ever since the United Nations' efforts, there was kind of a vacuum of discussions. We were kind of distracted by the hype of a lot of scientific discoveries and for many of them, much praise but we forgot about seriously looking at the implications. But now the discussion is again taking place, in academic circles and at the policy level as well.

What kind of international movem e n t s e x is t r e g a rd i n g a d u l t ( i nd u c ed p lu r i p ot ent ) ste m c ell research?

The ISSCR is, I would say, so far the most legitimate organization encouraging researchers to operate within a sound ethical framework.

They have adopted some guidelines (in 2006) on the ethics of conducting embryonic stem cell research, and in 2008 on the so-called stem SEPTEMBER-OCTOBER 2009

cell therapies. Now they are looking not only at embryonic stem cell research but at the big picture, of moving into other sources. So they are no longer distinguishing as much about where the stem cells come from, but rather about how you conduct the research, what constitutes sound scientific, ethical, responsible research. And they have adopted a lot of criteria and guidelines on this.

On the other hand, I think that induced pluripotent stem cells (iPS) are the new Pandora's box for us. I think the ethical and legal implications, the old rules, changed with the idea that you can take, in theory, a cell line from your body and one day maybe create gametes. So we saw that the Dolly technique was troublesome, and that's why having an international discussion on these issues and having a consensus on the technologies is important.

People sometimes say "this is pathetic, forget about it, you're mixing apples and oranges" - but it makes sense. We're talking about technologies that could have significant implications on our very

Symbol Over Substance Continued from page 5

achieved the goals of SCNT – fully pluripotent stem cells with a known genome, and the ability to produce disease-specific and patient-specific cell lines – without cloning and its need for eggs. Soon thereafter, other teams derived iPS cell lines from people with a variety of diseases, creating the cellular disease models that researchers long had wanted. As a result, scientists began to shift their efforts away from SCNT. One of the early and best known to take this step was Ian Wilmut, leader of the research team who had created Dolly.

Since then, both research on and advocacy for cloning-based stem cell research has dramatically decreased. This is not to say VOLUME 22 NUMBER 5

humanness, our human rights.

And not all of these technologies are the same. I work with stem cells - I'm a big supporter of stem cells from all sources. But I always call for careful analysis, for appropriate balancing of the pros and cons, and not forgetting the big picture.

media is reporting it - they are not telling people that this is not a proven stem cell treatment. And there are great scientific and ethical implications. We aren't telling these places, "You have to inform the patient that this is unproven intervention, that this is an experiment."

Are there any issues receiving international attention that aren't coming up in the Americas?

And it would seem that when someo ne s ay s t h ey 'r e go i ng to th e Caribbean for stem cell treatment, it would raise a red flag.

In both the U.S. and Canada, what I see is that we are overwhelmed by the hype of what stem cell research can promise, and there's a lack of information about where the technologies are now. We are only hearing "success stories" about so-called stem cell treatment, when these are really trickery or fraud. And I see that the media is not taking a responsible approach, taking a more balanced and educated approach to these issues.

Every day we see a new story about someone with a horrible condition traveling to the Caribbean, China, India or Germany for stem cell treatments. But the way that the

there has been no technical progress. In 2008, the first human clonal embryo was created, though stem cells were not derived from it, as was the first primate clonal stem cell line. But promises of “personal biological repair kits” with concomitant demands for cloning and eggs have largely subsided.

In the meantime, President Obama and the National Institutes of Health have loosened the previous administration’s unwarranted restrictions on federal funding of stem cell research using excess IVF embryos. The new rules do not permit federal funding for SCNT. In addition to drawing an appropriate line in his funding policy, the President made another important point in his March 9 remarks on stem cells and cloning, when he said that reproductive cloning is “dangerous, profoundly wrong, and

It does, but we sometimes get into the hype of the new technology and the progress. We celebrate iPS because now we won't have to use embryos - but we forget what is happening every day. Desperate people are making uninformed decisions and being exploited. We concentrate on personalized medicine, we talk about epigenetics here and there, and all these concerns are valid; but I think the way that our actions can be more meaningful and have a greater impact now is to care more about patients and informing them.

has no place in our society, or any society.”

These welcome developments direct our attention to the unfortunate fact that in the United States, human reproductive cloning remains legal at the federal level and in most states. Beyond that, those of us working to ensure that human biotechnologies are developed, used and regulated according to principles of social justice and human rights must confront proposals to tinker with, and perhaps even redesign, the human genome.

Jesse Reynolds is a policy analyst at the Center for Genetics and Society. He holds a MS in Environmental Science, Policy, and Management from University of California, Berkeley.

GENEWATCH 19

Book Review: Genetic Rounds

BY ANDREW D. THIBEDEAU

I N AR RA T I V E

“Narrative deals with experiences, not with propositions.”1 - R.W.B. Lewis In Genetic Rounds: A Doctor’s Encounters in the Field that Revolutionized Medicine , 2 Dr. Robert Marion undertakes to illuminate “the human side of the genetic revolution.” The book consists of a series of narrative essays, sporadically interposed with necessary biomedical exposition. His writing style is informal, giving his text a sense of intimacy. Looking back on thirty years in the field of clinical genetics, Dr. Marion offers a refreshingly personal account of certain patients, families, and diseases he has encountered along the way.

The first striking feature of Marion’s text is its emotional transparency. No effort is made to conceal pain or suffering, neither his patients’ nor his own.

This latter point contrasts sharply with the physician of our cultural imagination.

That image—the physician-as-scientist, detached, objective—is in truth a vestige of a now-defunct clinical methodology. Originating in the 19th century, this “traditional method” held as its chief aim “to diagnose a disease rather than to understand a patient.”

Predominant until the later 20th century, it placed no emphasis on comprehending “the meaning of the illness for the patient” or placing that illness “in the context of the patient’s biography or culture.”3 20 GENEWATCH

Unlike his iconographic forbearers, Dr. Marion’s emotions are integral to his clinical practice. More importantly, the progression of experiences and relationships he details expose the cultivation of his clinical technique. It is here that Dr. Marion’s book assumes a double aspect. In one sense, his text presents a collection of “classic” bioethical scenarios. Confronted with prenatal diagnoses of Down syndrome, women choose to keep or terminate their pregnancy. Decisions about infants with terminal defects are made. Families cohere or fragment upon the outcomes of molecular analyses.

In another, more significant sense, Dr. Marion’s essays offer a perspective from which one can encounter an evolving paradigm in clinical medicine. To understand this second, more subtle discourse, one must begin to contemplate patients’ subjective experiences of illness and its constitutive function in patients’ biographies.

II IL L NES S

“Illness is the night-side of life, a more onerous citizenship.”4 - Susan Sontag Illness, disease, and death are elemental human experiences.

But they are not experiences we share: rather, they comprise “the night-side of life,” constructed in opposition to health and wellbeing. Within the dominant Western cultural tradition, identity is conceived through a process of differentiation. We see ourselves as

distinguished from that which is different, and in so doing inscribe that difference with fear and danger—the practice of othering.5 Illness can thus be understood as a strategy of identity, a means of dividing the healthy Self from the unhealthy Other.6 Traditional clinical methodology, by emphasizing detachment and reducing patients to objects for study, reinforced this dichotomy. Though illusory, cultural stigma marked the genetically defective and biologically deformed as beyond the realm of the human.

For the ill and disabled thus banished to permanent alterity, their disease was no object for the physician-scientist’s analysis—it was the uninvited determinant of identity.

In his essay “The Skeleton in Mr. Anderson’s Closet,” Dr. Marion describes this practice of cultural banishing as experienced by Carl Anderson. The two men met when Dr. Marion was consulted regarding Mr. Anderson’s newborn daughter. Both the infant and her father suffered from Marfan syndrome, a hereditary disease that causes pronounced skeletal distortions and near-certain death at midlife.

As the infant’s physician, Dr. Marion and Mr. Anderson talked regularly. It was during one of these conversations that Carl Anderson shared his biography with Dr. Marion. Since early childhood, Carl had been marked as different by his fellow children. Taunted with names like “spider boy” and “scarecrow” on account of his elongated limbs, Carl felt “torn apart inside” and would invariably retreat to his SEPTEMBER-OCTOBER 2009

Genetic Rounds: A Doctor’s

Encounters in the Field that Revolutionized Medicine

By Dr. Robert Marion Kaplan, 2009

bedroom to cry alone. Shouts of “freak” and “ugly” followed Carl as he entered school, where verbal abuse quickly turned physical.

Neither his parents nor his teachers knew how to cope with his illness, and from his perspective they “never gave a damn.” In time, Carl attended school less and less, until he stopped going entirely.

When he met Dr. Marion, he worked as a clerk at a candy stand in New York City.

Ashamed of his appearance, he married a woman who was blind, never revealing his condition until their daughter’s birth. “The cumulative effects of having an inherited disease,” Dr. Marion laments, “touched every aspect of Carl Anderson’s life.” 7 Mr. Anderson’s biography was not his own; it was written for him by molecular happenstance and the cultural practice of othering.

What is remarkable about this story is not that Carl grew VOLUME 22 NUMBER 5

up, married, and had a child— though given his disease these were certainly momentous occasions. What is remarkable about this story is Dr. Marion’s eagerness to engage Carl intersubjectivly—not as a mere patient presenting a disease, but as a complete person. These aspects of Carl’s identity would have been immaterial to the “traditional” clinician; but to Dr. Marion they offered a window onto Carl’s subjective experience of his illness.

“The age-old, seemingly inexorable process whereby diseases acquire meanings . . . and inflict stigma is always worth challenging,” wrote Susan Sontag in AIDS and Its Metaphors, “and it does seem to have more limited credibility in the modern world, among people willing to be modern.”8 The intersubjective relationship that Dr. Marion cultivated with Carl Anderson stands as a challenge to the cultural stigma of illness and the attendant suffering of the Other. What’s more, it illuminates an emerging paradigm in the doctor-patient relationship, a paradigm rooted in narrative.

III H UM A N I T Y

“One of the essential qualities of the clinician is interest in humanity, for the secret of the care of the patient is in caring for the patient.”9 - Francis W. Peabody The relationship between Carl Anderson and Dr. Marion was by no means inevitable. Disease and deformity “can evoke feelings of fear, anger, disgust, and horror not only in the non-ill, but also in physicians.” 10 What’s more, “[c]onventional medical training teaches students to view medicine as a science and the doctor as an impartial investigator.”11 Imagining an “empirical” dis-

tance between herself and her patient, the physician often initiates the doctor-patient encounter from a stance of difference. If the practitioner does not act quickly to close this distance, “a profound emotional gap can develop between healer and sufferer as a mechanism for boundary maintenance.”12 As trained scientists, practiced in assuming detached professional mannerisms, many physicians are unaware of these subtle discourses of differentiation. In this way, the physicianpatient relationship can become marked by the same process of othering that, in the extreme, led to the complete colonization of Carl Anderson’s identity. In the field of clinical genetics, where the ultimate diagnostic process is conducted at the molecular level, technology itself can widen the gap between doctor and patient. The miracle of genetic technology notwithstanding, its pervasive mechanistic idiom “runs the risk of reducing the patient to a disease, an object.”13 Dr. Marion painfully recalls one overnight shift early in his career that had left him “more frazzled and more hostile than usual.” “In retrospect,” he laments, “I’m ashamed to say that during that night I wasn’t thinking of any of my charges as human; rather, they were nothing more to me than inanimate objects.”14 The text leaves the reader to infer that this experience—and perhaps others like it—transformed Dr. Marion’s understanding of his relationship to his patients.

Discounting the impulse to objectify patients, he instead actively cultivates a heightened sensitivity to the human dimensions of his practice. Dr. Marion’s attention to the human aspects of medicine is evident in his essay “No Sweat!”

There, he recalls his encounter with six-month-old Daryn Jordan, GENEWATCH 21

who in the previous weeks had progressively lost his mobility and become “floppy as a dishrag.”

Daryn’s primary physician, Dr. Reynolds, had asked Dr. Marion to provide a genetic consultation in the case. Suspecting a potentially fatal degenerative neurological disease, Drs. Marion and Reynolds marshaled a full arsenal of biomedical machinery, aiming it at Daryn’s tiny, floppy form.

In quick succession Daryn’s body was scanned by MRI, his brainwaves recorded with an EEG, his eyes probed by ophthalmologic instruments, and his spinal column pierced by a three-inch hollow needle. All of this, and Daryn’s body yielded nothing: each test produced a perfectly normal result.

With nothing to show for their efforts, late in the afternoon on the day before the Fourth of July Weekend, Drs. Marion and Reynolds dispatched sizable samples of Daryn’s blood to specialized laboratories in all corners of the country. Unlike that afternoon’s diagnostic frenzy, the results of these analyses would take weeks or perhaps months to surrender answers. And months passed. Finally—unexpectedly— Daryn’s mother called Dr. Marion to report that Daryn was recovering well and to thank him for his medical counsel.

Perplexed, Dr. Marion inquired with Dr. Reynolds about Daryn’s condition. Dr. Reynolds had seen neither Daryn nor his mother since they had left the hospital in July. “There’s really been no need to: all the tests came back normal,” Dr. Reynolds explained to Dr. Marion, “I don’t have anything to tell her.” Dr. Marion pressed the issue: “So you don’t know how he’s doing?”

“Not at all,” Dr. Reynolds responded, “I assume by this point he’s probably close to vegetative.”15

22 GENEWATCH

Upon hearing that Daryn’s mother had reported his condition much improved, Dr. Reynolds responded: “[a]nd tomorrow, I’ll be retiring to the villa I’m planning to buy in the South of France.” He continued: “Sounds like heavy denial … [u]nfortunately, it looks like this is going to be one of those cases where the diagnosis isn’t made until we get a look at his brain on the autopsy table.”16 Although sharing some of Dr. Reynolds’s skepticism, Dr. Marion was unwilling to remain idle, awaiting a summons from the morgue.

“While specialists spent more time wielding the mighty machine, they spent less time listening to or connecting with their patients.”

Rather, he scheduled an appointment with Daryn and his mother for the following week.

Much to his welcome surprise, Daryn had indeed made substantial progress. In the ensuing conversation, Dr. Marion was able to piece together previously unknown features of Daryn’s illness. Instead of a degenerative neurological disorder, he suffered from a genetic mutation depriving him of the ability to perspire. In the summer months, his resulting inability to cool himself produced his languid demeanor. His illness now named, Daryn could proceed to develop as any other toddler, provided sufficient air conditioning. “And like a flower,” Dr. Marion proudly observed, “Daryn

Jordan blossomed.”17 Dr. Marion’s eventual diagnosis of Daryn was not the product of any transformative insight gained during his meeting with the boy and his mother. He merely observed certain previously unnoticed features of Daryn’s disease while simultaneously making the season-symptom connection in his mind. What is notable here is not his diagnostic methodology, but the fact that Dr. Marion drew closer to Daryn at a time when his primary doctor had consigned him to the hereafter.

In much of the field of medical genetics, “[w]hile specialists spent more time wielding the mighty machine, they spent less time listening to or connecting with their patients.”18 Despite Daryn’s discouraging symptoms and unhelpful laboratory results, Dr. Marion reached out to the boy and his mother at a time of potential crisis. Doing so—in the context of a profession profoundly mediated by technology—he relied on human connection rather than the mechanisms of his science. It is thus his affinity for personal closeness and pursuit of true human understanding with his patients that distinguish Dr. Marion - and his text as “the human side of the genetic revolution.”

Andrew Thibedeau, J.D., is a Fellow with the Council for Responsible Genetics.

SEPTEMBER-OCTOBER 2009

Endnotes “Eggs for Sale,” Judy Norsigian, p. 6 1. See http://www.eggdonorneeded.com.

2. See, for example: http://www.etopiamedia.net/empnn/pdfs/norsigian1.pdf.

3. http://www.ourbodiesourselves.org/book/companion.asp?id=31&compID=97&page=4).

4. www.nature.com/nature/journal/v442/n7103/full/442607a.html 5. http://www.nature.com/nature/journal/v460/n7259/full/4601057a.html 6. http://www.biopoliticaltimes.org/article.php?id=4684 7. http://www.nytimes.com/2009/06/26/nyregion/26stemcell.html 8. http://english.ohmynews.com/articleview/article_view.asp?article_class=4&no=385258&rel_no=1 9. http://www.dailyprincetonian.com/2008/11/21/22198/ 10. http://www.geneticsandsociety.org/article.php?id=4770 11. IANS, (August 25th 2008), ‘Surrogacy a $445 mn Business in India’, The Economic Times

“Topic: Livestock Cloning,” p. 13 1. Jaenisch, Rudolf and Ian Wilmut. "Don't Clone Humans!" Science 291. March 30, 2001.

2. "Cloned Food: Coming to a Supermarket Near You?" The Center for Food Safety, January 2007.

“Book Review: Genetic Rounds,” Andrew Thibedeau p. 20 1. R.W.B. LEWIS, THE AMERICAN ADAM: INNOCENCE, TRAGEDY, AND TRADITION IN THE NINETEENTH CENTURY 3 (1955).

2. ROBERT MARION, GENETIC ROUNDS: A DOCTOR’S ENCOUNTERS IN THE FIELD THAT REVOLUTIONIZED MEDICINE (2009) (Kaplan Publishing, 304pp., $24.95).

3. Ian R. McWhinney, Are We on the Brink of a Major Transformation of Clinical Medicine?, 135 CAN. MED. ASS’N J. 873, 874 (1986).

4. SUSAN SONTAG, ILLNESS AS METAPHOR 3 (Picador 1990) (1978).

5. Johanna Shapiro, Walking a Mile in Their Patients’ Shoes: Empathy and Othering in Medical Students’ Education, 3 PHIL. ETHICS & HUMAN. MED. 10 (2008).

6, Robert Crawford, Health as a Meaningful Social Practice, 10 HEALTH 401, 414 (2006).

7. Supra note 2, at 181.

8. SUSAN SONTAG, AIDS AND ITS METAPHORS 182 (Picador 1990) (1989).

9. Francis W. Peabody, The Care of the Patient, 88 J. AM. MED. ASS’N 877, 882 (1927) 10. Supra note 5.

11. Trisha Greenhalgh, Narrative Based Medicine in an Evidence Based World, 318 BRIT. MED. J. 323 (1999).

12. Johanna Shapiro, Self and Other Through the Prism of AIDS: A Literary Examination of Relationships with Patients, 4 MICROBES & INFECTION 111, 115 (2002) 13. Supra note 10.

14. Supra note 2, at 67.

15. Supra note 2, at 161.

16. Supra note 2, at 162.

17. Supra note 2, at 161-62.

18. Jack Coulehan, Viewpoint, Today’s Professionalism: Engaging the Mind but Not the Heart, 80 ACAD. MED. 982, 893 (2005).

VOLUME 22 NUMBER 5

GENEWATCH 23

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