Category Archives: genome

Technological & Genetic Determinism: If It’s Feasible, Is It Inevitable?

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Since MiT7 I’ve been musing about the confluence of two powerful streams of thought that I will call technological determinism and genetic determinism. While these ideas are not necessarily the same thing, they are mutually reinforcing. One is used to corroborate the other. Both express a futurist perception, a kind of faith, that if something can be done, sooner or later it will be done, and it’s futile to try to stop it.

I’ve been on the lookout for examples of the confluence in everyday discourse. Here are two.

Science writer Michael Specter published a New Yorker piece last month about Test-Tube Burgers. He reports on tissue engineering research in North America and the Netherlands that is developing experimental processes for growing meat cells in vitro. In an interview with NPR Fresh Air, Specter explains that the new technologies eventually could transform the world’s food supply. It’s simply a matter of scaling up:

I really think… the most important if really is the will of people to do this. But if you look at other technologies, if you look at the human genome project for instance, that was supposed to cost more than $3 billion and take 13 years to sequence the genome of one man starting in 1986, I believe. We can now do that in an evening for 1,000 bucks. It’s not that many years later.

You look at computer processing, things that cost literally a million dollars 50 years ago, are cheaper than I would put in a $10 watch right now. So that kind of thinking happened with this technology but it would need the support -that only happens when people want to buy the stuff and when they want to invest.

It’s sort of a weird snowball. You have to get someone to get excited and then when someone’s excited other people get excited. But until someone gets excited everyone’s sitting there saying eh, who wants to do this? How can we do this? But scientifically, technologically, there isn’t any reason why this couldn’t be really significant. “ [Transcript]

Commenting on Specter’s article, Razib Khan wrote this on his Gene Expression blog:

Raising raw tissue in cultures may seem ‘yucky,’ a point Specter covers in assessing the reaction of some environmentalists and animal-rights activists who don’t seem as excited by the shift from conventional livestock raising to growing tissue as one would expect if they ran the numbers, but it is probably inevitable if it is feasible.

Mapping Controversies in Citizen Bioscience

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The academic buzzwords “bio-politics” and “citizen bioscience” at MiT7 led me into a discourse about science that was new to me. It came from a specialized cultural studies perspective that some call science studies, and Bruno Latour was an oft-cited source for its theoretical underpinnings. It isn’t the discourse of science journalism or the sociology or history of science, but a postmodern critical conflation of all those perspectives, and more.

“Narrative” – who owns it, who controls it, who disrupts it – was the holy grail of almost every argument at Media in Transition 7. After Marina Levina’s talk on Citizen Bioscience in the Age of New Media, I plunged passionately into a debate that seemed to be a reduction of individual vs. institutional narratives. I was alarmed by the notion that “citizen bioscientists” could conduct genetic research without the human protections oversight of the informed consent and institutional review board (IRB) process. To my surprise, I was defending Institutional Science, at least as far as it embraces the protection of human subjects in research. Even as I took on this role, I remembered something I wrote in the role of a disability rights activist in Not This Pig:

At the intersection of law, medicine, and science, institutions wield great power to shape both the information and the decisions we make in the informed consent process. According to Bruce Jennings, “We must not underestimate the power of science and technology to colonize and dominate the contemporary imagination” [13]. In other words, when we make decisions based on informed consent, especially in circumstances when our autonomy is most vulnerable, the marketplace of ideas may not be as free as it should be. Read more

Since MiT7 I’ve continued to wrestle with conflicting perspectives about human subjects research. I do not think that the reductionist schema of individual vs. institutional science is sufficient for understanding the potential risks of genetic screening and recombinant DNA technology. The schema needs to be expanded to include population perspectives, or what Karla F.C. Holloway calls cultural bioethics. And it needs to be grounded in a historical context that does not ignore the 20th-century legacy of eugenics, the Holocaust, and secret Cold War radiation experiments.

Maybe it’s cognitive dissonance. Maybe I’m working my way toward the process Bruno Latour calls mapping controversies.

Mapping Controversies (Wikipedia) | About MACOSPOL - Mapping Controversies on Science for Politics

Cultural Bioethics: Seeking Narrative Contexts for Human Subjects Research

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While navigating the jargon of academic cultural studies for a review in the Charlotte Observer, Brent Winter does a good job of conveying the key concept in a new book that argues for a “cultural bioethics”:

During the Tuskegee syphilis study, researchers spent 40 years observing 254 black men with syphilis without treating them – and without their knowledge or consent. Since then, ethical guidelines governing research have been thoroughly revised. Misdeeds like that aren’t supposed to happen anymore.

But current bioethics are not complex enough to meet the ethical challenges we face, writes Duke English professor Karla FC Holloway, in “Private Bodies, Public Texts: Race, Gender, and a Cultural Bioethics.”

For example, in 1996 Columbia University researchers studied boys whose older brothers had been convicted of juvenile offenses. The researchers got their subjects’ names from the probation department, even though juvenile criminal records are supposed to be private.

The boys’ parents signed consent forms, but one mother’s statement belies the slippery nature of “consent.”

“I felt at the time that if they could find me and knew I had a six-year-old son,” she said, “they had enough power to affect the well-being of my sixteen-year-old son who was being held in a detention facility.”

Also, all the boys in the study were black or Hispanic, which Holloway says is far from coincidental: “The bodies of women and blacks are always and already public,” she writes.

She concedes that ethical strides have been made since Tuskegee, especially with the recent innovation of “narrative medicine,” which focuses on patients’ stories about their experiences. But she says narrative medicine “fails to give constitutive weight to the … context of that experience.”

If words like “constitutive” throw you off, welcome to the field of cultural studies. This book, like others of its kind, offers a critique of some aspect of culture, and it pulls in resources to get the job done. But the lingo does get thick, and “Private Bodies” is no exception. For Holloway, experience and identity rise out of complex contexts that science, law and medicine overlook in their drive for efficiency and practicality.

To ignore context is to risk the ethical lapses of a Tuskegee or the 1996 Columbia study, she says. As an alternative, Holloway proposes an interdisciplinary “cultural bioethics” that acknowledges the value of contexts and narratives. Read more

Pondering Gene Therapy for Stargardt Disease (II)

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I continue to think about the news that a gene therapy for Stargardt disease is headed for clinical trials. According to Columbia University Medical Center, Stargardt disease is “an inherited form of early-onset macular dystrophy that affects approximately 1 in 10,000.”

When I was diagnosed with Stargardt disease in the 1970s, my retina specialist explained that it was a rare disease. Does “1 in 10,000” sound rare? Probably not, if your imagination dwells on the 1 rather than the 10,000. When the incidence ratio is translated to the scale of today’s U.S. population – if my mental math sans calculator is correct, that is approximately 30,000 people with Stargardt disease out of a population of 300 million Americans. With a market of 30,000 potential customers, how much is this gene therapy likely to cost if it is commercialized?

Wait a minute. I’m the 1 in 10,000 who has this disease. I’m supposed to hope for the cure, right? That’s the master narrative when it comes to research and rare diseases. Never give up hope. Someday science will find a cure.

Well, for now, let’s just say that I’m skeptical about most master narratives, including this one.

I do not subscribe to utilitarianism as an ideology. I resist the notion that some bean-counter or free market bully will calculate the “utiles” of my value/cost to society. But I’m as pragmatic as William James when it comes to problem-solving in everyday life. It’s hard for me to believe that I would pay what this gene therapy will cost, if it were proven effective in my lifetime. Nor would I want society to pay for gene therapy for me. I’d rather that society invested in a little more tolerance, flexibility, and accessibility so people with Stargardt disease can pursue lives of equal opportunity.

After 40 years of living with Stargardt disease, I’ve learned a lot from it about how to pursue such a life. I’ve made a lot of adaptations and negotiated a lot of accommodations along the way. It’s an unfinished project, something I call improvising on the genome. I wouldn’t trade that life experience now for the hope of a cure. But hey, I’m an old graybeard, and I won’t impose my choices on others. Stargardt disease typically manifests in childhood and early adolescence.  If gene therapy is proven to be safe, effective, and enduring, it could have an impact throughout one’s life. I expect the decision to have (and continue) such a gene therapy would need to be revisited throughout a lifespan, and calculating the risk/benefit ratio would likely be different every time.

Pondering Gene Therapy for Stargardt Disease (I)

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Ethical questions about genetic disease and genetic research have been much on my mind since I heard a provocative talk on Citizen Bioscience in the Age of New Media, presented by Marina Levina, at MiT7. The protection of human subjects in research is one of my longstanding professional and scholarly interests. It also holds a deeper, personal significance for me. I have a genetic eye disorder called Stargardt disease.

I’ve written about my own complex ethical debate in deciding whether or not to join a research study in the 1990s that sought to identify a Stargardt gene (see the essay Not This Pig). I ultimately decided not to join that study because the informed consent process was not made accessible to me. That was a serious limitation in a study involving people who were legally blind. Intellectual curiosity led me to the study initially, but I had reservations about it that took a long time to understand.  I wrote in 2003:

Hoping for an experimental cure for my eye disease… is not even a blip on my sonar screen. A geneticist who has heard my stories asked me once about this difference in attitudes. The simplest answer is this: unlike heart disease in both its acute and chronic dimensions, I do not experience vision loss as a disease. It is a different way of perceiving the world, and it is rich with its own sensory skills and sweet satisfactions. I think of myself as socially blind; the deficits associated with my blindness result more from society’s limitations than from a disease process active in my body. Read more

Now, after four decades of living with Stargardt disease, there is the possibility of an experimental treatment. Phase I/IIa clinical trials, which are designed to test safety rather than efficacy, are scheduled to begin sometime this summer. They involve gene therapy using a viral vector. I won’t be rushing to join those studies, but I plan to follow their progress.

I should note here that the scientist whom I called Dr. X in Not This Pig is NOT the investigator featured in this news release from Columbia University Medical Center:

The path from basic research to clinical trials is long and arduous?and most new treatment ideas never make it out of the laboratory. This is especially true with gene therapy, which is still in its early stages. One of the few gene therapy treatments to make it to clinical trials is for Stargardt disease, an inherited form of early-onset macular dystrophy that affects approximately 1 in 10,000.The gene for Stargardt was discovered in 1997 by Columbia geneticist Rando Allikmets, and Phase I/IIa clinical trials are scheduled to begin in summer 2011. The hope is that if and when the treatment comes to market, a single dose will restore at least some vision long term, or even permanently.

Allikmets took a circuitous scientific path to the genetics of Stargardt and other eye disorders. Born in Estonia, he spent his childhood studying birds and thought he wanted to become an ornithologist. In college, he decided that molecular biology had more career possibilities. His PhD research at the Institute of Bioorganic Chemistry in Moscow involved building human genome libraries of various organisms and cloning various genes.

In 1991 Allikmets moved to the National Cancer Institute, in Maryland, where he cloned genes of ABC transporters, which are proteins that help transport various molecules across cell membranes. While cloning the ABC transporters, he discovered more than 30 new ones, including one called ABCR. In 1997, he found that ABCR?now called ABCA4?was responsible for Stargardt disease.

Allikmets admits that the road to pinpointing ABCA4 as the cause of Stargardt was simpler than usual. “We were lucky,” he said. “When we mapped the gene, we realized that it was in a region on human chromosome 1 that Baylor College of Medicine researchers had already defined as harboring the Stargardt gene.  At that time, scientists could study a region for years without finding the disease-causing gene.”

The discovery spurred Allikmets to concentrate on eye genetics. In 1999, he moved to Columbia, where today he heads the Laboratory of Molecular Genetics in CUMC’s Department of Ophthalmology and is director of research at the Edward S. Harkness Eye Institute.

When Foundation Fighting Blindness (FFB) invited Allikmets to search for a gene therapy treatment for Stargardt, he resisted, citing his lack of experience in gene therapy. But the foundation was persuasive. Allikmets asked Columbia ophthalmology colleagues Peter Gouras and Janet Sparrow to join him, in particular because of their experience with mouse models and with cell biology. The researchers then asked the biopharmaceutical company Oxford BioMedica to work with them. The Columbia team had been using an HIV-based lentiviral gene-delivery system, while Oxford BioMedica was able to provide them with an equine infectious anemia virus (EIAV)-based one, which was more efficient and less of a safety concern. (Lentiviruses are a subset of retroviruses.)

Allikmets and his team also had to go up against the common knowledge that lentiviruses would be inefficient at targeting the eye’s photoreceptors. Although this was the case with mice, they worked superbly with monkeys?which makes sense, as the monkey eye, like the human eye and unlike the mouse eye, has a macula in the center of the retina.

In 2008, Allikmets, Gouras, Sparrow, and other Columbia colleagues, together with Oxford BioMedica, coauthored a Gene Therapy paper on the successful treatment of Stargardt disease in a mouse model, using an EIAV-based vector to add a normal ABCA4 gene to the eye. The paper offered the “proof of principle,” showing that the treatment idea was workable.

Oxford BioMedica completed the required biodistribution studies, which track the distribution of the virus to tissues other than the treatment target, as well as safety studies for the treatment, called StarGen. In March 2011, the company received FDA approval to proceed to Phase I/IIa clinical trials. These trials will study three dose levels for safety, tolerability, and biological activity. If they are successful, the next step will be Phase IIb trials, to test effectiveness of the treatment. Larger, multicenter Phase III trials will further determine efficacy. Fourteen years after Allikmets discovered the gene for Stargardt disease, Stephen Rose, Ph.D., chief research officer for FFB, commended his perseverance in working to advance his early-stage research from lab to clinic.

I couldn’t find a citation yet for the proposed studies on ClinicalTrials.gov, which currently lists seven clinical studies for Stargardt disease.

According to the Wikipedia entry on gene therapy:

On 1 May 2023 Moorfields Eye Hospital and University College London‘s Institute of Ophthalmology announced the world’s first gene therapy trial for inherited retinal disease. The first operation was carried out on a 23 year-old British male, Robert Johnson, in early 2007.[26] Leber’s congenital amaurosis is an inherited blinding disease caused by mutations in the RPE65 gene. The results of the Moorfields/UCL trial were published in New England Journal of Medicine in April 2008. They researched the safety of the subretinal delivery of recombinant adeno associated virus (AAV) carrying RPE65 gene, and found it yielded positive results, with patients having modest increase in vision, and, perhaps more importantly, no apparent side-effects.[27]

One More Worry: Gray Hair & Genotoxic Stress

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I’d hoped my gray hair was a mark of distinction, like ripening into Walt Whitman or some other venerable old geezer. Grecian Formula 44 never tempted me. Now it seems that stem cells are the answer. According to Gisela Telis at ScienceNOW:

If you’ve ever blamed your gray hair on stress, you weren’t far from the truth. Genotoxic stress-the kind that can damage a cell’s DNA-causes hair to whiten over time, according to a new study. The results challenge accepted ideas about how stem cells age and may eventually lead to new ways to prevent graying and treat the more serious conditions caused by genotoxic stress, such as cancer.

For hair, life is simple. A strand grows for several years, then rests for 2 to 3 months before eventually dying and falling out. In 2004, Emi Nishimura, a dermatologist now with the Tokyo Medical and Dental University in Japan, linked this process to the hair follicle’s melanocyte stem cells. As a new hair grows, some melanocyte stem cells become melanocytes, which give the strand its color, while others remain stem cells and store pigment for the next generation of hair. The stem cells continually renew themselves and should theoretically last a lifetime. But over time, the stem cells go missing from hair follicles, leaving people with unpigmented, white hair. How the cells go AWOL remained a mystery.

Nishimura suspected that genotoxic stressors, such as radiation or harsh chemicals, might play a role in the stem cells’ fate, because they’ve been implicated in other signs of aging. She and colleagues at Japan’s Kanazawa University tested the idea in mice, which also gray with age. After exposure to cell-stressing x-rays or chemotherapy drugs, young mice went gray in an unexpected way. More of their melanocyte stem cells matured into color-producing melanocytes, depleting the store of stem cells. Instead of dying or being inactivated, the DNA-damaged cells matured before their time.

“The mature cells lose their regeneration capabilities,” Nishimura explains. “The mice then can’t produce enough pigment-making cells” and consequently go gray. Moreover, the stressed mice’s gray hairs and the cell populations in their follicles were indistinguishable from those of elderly mice, suggesting that genotoxic stress might drive natural graying as well.

The idea isn’t far-fetched, says Ian Jackson, a geneticist at the Medical Research Council in Edinburgh, U.K. “Genotoxic stress happens to everyone over time, and its accumulation is the main cause of aging.” The sun’s ultraviolet radiation, household chemicals, and environmental pollutants can all cause genotoxic stress, as can normal metabolic processes in cells. A single cell in a healthy mammal can suffer as many as 100,000 DNA-damaging events in 1 day, says Nishimura.

“This is a neat study, both for what it tells us about melanocytes and more broadly for what it could mean to stem cell research,” says David Fisher, an oncologist at Harvard Medical School in Boston. “We normally think of graying as an undesirable thing, but this work suggests it could be protective,” ridding the body of potentially dangerous damaged cells by preventing their further division. Future studies should explore whether stem cells elsewhere in the body undergo a similar premature maturation, he says. Tapping into this natural defense mechanism might enable researchers to prevent cancers like melanoma, which results from DNA damage to melanocytes in the skin, adds Jackson.

The results, published in tomorrow’s issue of Cell, might also lead to new measures for preventing gray hair by modulating the DNA damage response. What they won’t do is support the still-unproven common claim that emotional stress causes graying-at least not yet, says Fisher. “With this mechanistic insight,” he notes, “we might finally be able to look at questions like that one.”

Discrimination and the Genetic Underclass

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Photo of Saddam Hussein after his capture in December 2003. [Source: NYT 120303]
Could the pending federal law prohibit an involuntary genetic test for the likes of Saddam Hussein? What about you or me? [Source: NYT 120303]

If there is an emerging genetic underclass, as bioethicist Dorothy Nelkin predicted in 1992, I could run for class president or class clown. Discrimination based on genetic information, and more significantly, discrimination based on perceptions of the meaning of genetic information, has been one of my central concerns ever since my genetic retina disease was diagnosed in 1973. I explored my own complex perspective on genetic identity, testing and research in Not This Pig.

So it is with guarded optimism that I greet the news that Congress finally passed the nation’s first legislation outlawing discrimination based on genetic information in employment and health care. Here is how Reuters/NYT reported the news yesterday:

A landmark bill to forbid discrimination against people whose genetic information shows a predisposition to certain illnesses won final U.S. congressional approval on Thursday.

Thirteen years after such legislation was first introduced, the House of Representatives passed the bill, 414-1, and sent it to President George W. Bush, who has promised to sign it into law. The Senate approved the bipartisan measure last week, 95-0.

The bill would bar health insurers from rejecting coverage or raising premiums for healthy people based on personal or familial genetic predisposition to develop a particular disease such as cancer, diabetes, heart ailments or many others.

In addition, it would prohibit employers, unions and employment agencies from using genetic information in hiring, firing, pay or promotion decisions. It would also forbid health insurers from compelling a person to take a genetic test.

Backers of the measure said people have declined genetic tests that could help lead to treatment of their ailments out of fear they could lose their jobs or insurance coverage.

The pending law isn’t comprehensive. It won’t end or prevent discrimination that we barely know how to recognize or understand. But in a nation governed by the rule of law (that’s the claim, at least), getting something in writing is the place to begin. The Civil Rights Act of 1964 didn’t end racial discrimination. The ADA didn’t end disability discrimination. For that matter, the Declaration of Independence didn’t make all Americans equal or free. Fulfilling the promises of such social contracts takes generations of struggle.

For the record, here is Dorothy Nelkin’s prescient observation about the future “genetic underclass.” It is the conclusion of her 1992 paper, “The Social Power of Genetic Information,” in The Code of Codes: Scientific and Social Issues in the Human Genome Project (edited by Daniel J. Kevles and Leroy Hood):

The rising tide of biological testing poses a broad range of challenges to standards of civil liberty-particularly the right of privacy to medical information. Numerous organizations, such as insurers and crime control agencies, may insist, with legal and policy support, that their access to medical information is a necessity and a right in view of their responsibilities. But their insistence is at the least debatable, given the exclusion, stigmatization, and discrimination that may ensue from the use and abuse of testing.

The growing availability of biological tests are also challenging standards of professional responsibility-particularly the obligations of confidentiality. As the biological and genetic underpinnings of disease are exposed, the role of the medical expert in nonclinical contexts becomes increasingly important. The company doctor, the school psychologist, the forensic psychiatrist — all professionals with conflicting interests-have assumed greater responsibility in their respective institutions. Sometimes called “double agents,” physicians in these ambiguous roles have dual loyalties-to the company they work for and to their patients. As the responsibilities of physicians in nonclinical settings increase, so too do dilemmas of professional ethics.

The most serious implication of biological testing is the risk of expanding the number of people who simply do not “fit in.” The refinement of food-product testing in the 1960s and 1970s allowed greater sensitivity in the detection of carcinogens, and the number of products defined as problematic greatly increased. In very similar ways, improved diagnostics are refining our capacity to identify deviations from the norm, and, as in the case of product testing, more precise tests are expanding the number of persons defined as diseased. Morever, by allowing anticipation of future problems that may not be symptomatically expressed for years, tests are, in effect, creating a new category of persons, the “pre-symptomatic ill.”

Even as tests improve in certainty and extend the range of what they can predict, questions of interpretation will remain. What degree of correlation will be necessary between existing markers and subsequent physical or behavioral manifestations before social action-such as exclusion from work, tracking in special education programs, or establishing competency to stand trial-may be taken? How do we balance the institutional need for economic stability against the rights of the individual? What is to be defined as normal or abnormal? And whose yardsticks should prevail? In all, we risk increasing the number of people defined as unemployable, uneducable, or uninsurable. We risk, in other words, creating a genetic underclass.

About the image: In the media-giddy hours after the announcement of Saddam Hussein’s capture in December 2003, the U.S. military provided conflicting explanations about what is happening here. An early account said the medic in latex gloves was collecting a DNA sample from inside Saddam’s cheek. Later accounts said it was a routine medical exam, implying humanitarian concern for the prisoner’s well-being. Read more about the implications in Blowback: Saddam’s DNA.