Ethics

A million years ago (all the way back in 2006!) I wrote an article for Stanford Medicine magazine about genetic technologies and the eugenics movement in this country during the first part of the 1900s. I still remember it as one of the most fascinating of my articles to research, demanding as it did that I speak with a variety of geneticists and ethicists about the increasing control that humans have over their genetic destiny.

When, last year, I had the privilege of writing about Stanford biophysicist Stephen Quake, PhD, and his work on whole-genome sequencing of fetuses before birth, I couldn’t help but remember that article of yore. What are we getting ourselves into?

Now MIT Technology Review has recognized whole-genome fetal sequencing as one of its “10 Breakthrough Technologies 2013.” Accompanying the designation is an in-depth review of the technology and its implications - which are far more complex than I could have imagined six years ago. The article contains comments from several experts, including Stanford law professor and bioethicist Hank Greely, JD, and Quake:

Quake says proving that a full genome readout is possible was the “logical extension” of the underlying technology. Yet what’s much less clear to Quake and others is whether a universal DNA test will ever become important or routine in medicine, as the more targeted test for Down syndrome has become. “We did it as an academic exercise, just for the hell of it,” he says. “But if you ask me, ‘Are we going to know the genomes of children at birth?’ I’d ask you, ‘Why?’ I get stuck on the why.” Quake says he’s now refining the technology so that it could be used to inexpensively pull out information on just the most medically important genes.

In my opinion, experts are right to consider the impact of this type of technology before it becomes commonplace. The ethical implications of parents learning their child’s genome sequence within a few weeks of conception - and of possibly using that information to make decisions about the pregnancy’s outcome - are substantial. Thankfully, some really smart people have been asking these questions in one form or another for years, even though the answers seem to end up more grey than black and white. From that ancient article I wrote six years ago:

For example, even though sex selection of embryos fertilized in vitro has many people up in arms, there’s no evidence that it’s on track to alter the gender balance in this country: Boys and girls are nearly equally sought after, says [medical geneticist and associate chair of pediatrics Eugene Hoyme, MD]. And although some parents will terminate a pregnancy if the fetus has a genetic or developmental problem that they feel isn’t compatible with a meaningful life, different families draw this line at dramatically different points in the sand. For some, it’s too much to consider having a child with Down syndrome. For others it’s important to sustain life as long as possible regardless of the severity of the condition. Still others might choose to have a child as similar to them as possible, down to sharing disabilities such as deafness.

“Eugenics is here now,” says Stanford bioethicist David Magnus, PhD. “So what? We allow parents to have virtually unlimited control over what school their child attends, what church they go to and how much exercise they get. All of these things have a much bigger impact on a child’s future than the limited genetic choices available to us now. As long as these are safe and effective, why not give parents this option as well?”

Previously: New techniques to diagnose disease in a fetus, Better know a bioengineer: Stephen Quake and Stanford bioethicists discuss pro, cons of biotech patents
Photo by paparutzi

Genetic and genomic testing for medical purposes is becoming increasingly common. But what should a doctor do if a patient undergoing testing for a disease-causing mutation in one gene is discovered to have another, unrelated mutation for a different, unsuspected condition? The American College of Medical Genetics and Genomics today issued recommendations regarding this very situation (called an “incidental finding”). The results may surprise some people.

ScienceInsider summarized the results nicely in a post earlier today:

Fourteen genetics experts, with the backing of the American College of Medical Genetics and Genomics (ACMG), are proposing a radical shift in how and what patients learn about what’s in their DNA. They argue that anyone whose genome is sequenced for any medical reason should automatically learn whether 57 of their genes put them at risk of certain cancers, potentially fatal heart conditions, and other serious health problems. The information would be provided whether [or not] patients want it—and often when they’re seeking care from a doctor for something else entirely—because, the experts say, knowing the makeup of this DNA could save an individual’s life. The recommendations apply to sequencing children’s DNA as well, even if there’s no preventive care available until adulthood.

Stanford genetic counselor Kelly Ormond was a member of the task force that came up with the guidelines. She elaborated the thinking of the group and the reasons behind the changes to me in a recent conversation:

We believe that there are a number of conditions that a patient would wish to know about, including BRCA1, colon cancer risk and others. This information should be given regardless of the age of the patient because it’s useful information. If the patient is a child, it’s possible that steps can be taken to reduce the risk or to incorporate screening to detect the disease as the child matures. There’s another reason, though. If a child has a mutation that clearly confers increased risk, it’s likely that he or she inherited that mutation from the parents. Informing the parents of their child’s mutation may allow them to undergo relevant screening, and hopefully keep them healthier, as well.

The college’s recommendations are just that: recommendations. Doctors can still make their own judgment calls, or even discuss with the patient or parents prior to the test the types of information they’d like to receive (in some cases, this may mean opting for a lab to process the genetic sample that doesn’t divulge any incidental findings). And the “should be informed” list is limited to those mutations that meet two criteria: They must carry a significantly increased risk of disease and there must be something that can be done clinically to mitigate this risk. Diseases (such as Huntington’s or Alzheimer’s disease, for example) for which there is a clear genetic cause, but no treatment or cure, are not included on the list.

Previously: When it comes to your genetic data, 23andMe’s Anne Wojcicki says: Just own it, Film to document Stanford student’s decision to be genetically tested for Huntington’s disease, and How genome testing can help guide preventative medicine

Say you’re a human embryonic stem cell researcher (odds are, that at least some of the readers of this blog fit this description). If so, you’re familiar with the alphabet soup of regulations that govern this type of research in California and elsewhere. In particular, depending on the specifics of your proposed experiments, you may need to seek approval from your Institutional Review Board (the IRB), your Institutional Animal Care and Use Committee (the IACUC) and an Embryonic Stem Cell Research Oversight Committee, or ESCRO. That could change, however.

Stanford bioethicist Hank Greely, JD, spoke out yesterday in an article in Nature exploring whether all these layers of approval are really still necessary. (Greely published a commentary on the topic in the January issue of the American Journal of Bioethics.) As the article explains, ESCROs were implemented when embryonic stem cell research was still in its infancy:

To encourage responsible practices, the US National Academies issued a report in 2005 calling for the establishment of stand-alone institutional oversight committees, and within two years, at least 25 so-called ‘embryonic stem cell research oversight committees’, or ESCROs, cropped up across the country. Most of these were created voluntarily, except in the few states—California and Connecticut, as well as New York if the research is performed with state funding—that made the practice mandatory. Now, however, with hESC research widely practiced and accepted, some experts are questioning whether stand-alone ESCROs are still needed.

“As that early period of figuring out ways to implement good ethical guidelines has shifted into the more normal science of applying those concerns, the need for ESCROs has gotten smaller,” says Henry Greely, a bioethicist at the Stanford Law School and chair of California’s Human Stem Cell Research Advisory Committee. “It’s not rocket science any more. A lot of [hESC research] is pretty routine, and it doesn’t necessarily need a unique institution to deal with it.”

Greely’s no newcomer to the ethical and legal issues surrounding embryonic stem cell research. He’s been a frequent commenter here on the topic. Not all experts agree with Greely in the case of the ESCROs, but it’s an interesting discussion. As he argues:

Ultimately, the decision to maintain ESCROs or not all comes down to a cost-benefit ratio, says Greely. Streamlining committee structures won’t bring “enormous benefits,” he admits, “but I don’t think they’re trivial benefits, and what are the benefits of continuing to have ESCROs after this breaking in and bureaucratization process has worked itself out? They’re not very big.”

“It’s not saying these guys have been failures and we should get rid of them,” he adds. “It’s almost saying, ‘These guys have been so successful that they worked themselves out of a job’—and that’s not a bad thing.”

Previously: Supreme Court decision on human embryonic stem cell case ends research uncertainty, and Stanford law professor on embryonic stem cell ruling
Photo by Max Braun

Yesterday, the Supreme Court declined to hear the case of Shirley vs. Seblius, which challenged the federal government’s right to fund research on human embryonic stem cells. This is good news for stem cell researchers. I asked Stanford law professor and bioethicist Hank Greely, JD, about the verdict, and he told me this morning:

At last, it’s over! To call Sherley v. Sebelius our long national nightmare is a bit of an overstatement, except as to those keenly interested in pluripotent stem cell research. This case, filed in August 2009, should have been thrown out by October 2009. (Ironically, the district court judge did try to throw it out then, but used what the appellate court considered the wrong approach.) But, at long last, after 41 months of uncertainty, leavened with occasional shock and panic, the case is dead. The Supreme Court has, not surprisingly, denied review of the decision by the Court of Appeals for the District of Columbia Circuit, which upheld the district court’s summary judgment in favor of the plaintiffs.

And so it is finally established that, no, Congress did not, in the Dickey-Wicker Amendment, as re-passed every year since 1996, try to outlaw the positions taken by the Clinton, Bush, and Obama Administration. Funding human embryonic stem cell research does not violate the NIH appropriations provisions. It does, however, still rest within the discretion of the sitting President. That seems safe for the next four years; it would be good if Congress could pass legislation expressly supporting such research for the four, and eight, and twelve, years beyond that.

Greely has been outspoken about the ongoing case on the Center for Law and the Biosciences‘ blog. You can read more about the legal background of the case here and in subsequent entries.

Previously: Judge Lamberth dismisses stem cell lawsuit, Stanford law professor on embryonic stem cell ruling and Stem cell funding injunction overturned by federal court

A U.S. appeals court has affirmed (.pdf) the ruling last year by district court judge Royce Lamberth that federal funding of human embryonic stem cell research is legal. Although the decision effectively puts to rest opponents’ arguments that such funding violates the Dickey-Wicker amendment, at least one judge asked Congress for clarification about the power of the federal government to regulate such research.

Bioethicist Christopher Scott, who directs Stanford’s Program on Stem Cells in Society, has this to say about today’s ruling:

This is a major victory for stem cell researchers. It affirms that the National Institutes of Health’s interpretation of the 1996 Dickey-Wicker amendment is reasonable. Importantly, it removes a barrier of uncertainty for stem cell scientists and the patients who stand to benefit from their discoveries. The Obama administration should be congratulated for its assiduous work to guarantee that the president’s policy makes the difference when the rubber meets the road: funding research that could lead to the next generation of treatments and cures.

Scott has previously published research showing that limiting human embryonic stem cell research is likely to also slow research on induced pluripotent stem cells-an alternate way to create stem cells that does not require the destruction of human embryos-because the two fields are so closely intertwined.

Science writer Maggie Fox, writing for NBC news, has posted a nice summary of the issues leading up to today’s decision. But I found reading the actual text (.pdf) of the ruling to be very enlightening. In particular, Judge Janice Rogers Brown (one of three judges who ruled on the case) commented about the Dickey-Wicker amendment:

The challenging—and constantly evolving—issues presented by bioethics are critical and complex. Striking the right balance is not easy and not, in the first instance, a task for judges. What must be defended is “the integrity of science, the legitimacy of government, and the continuing vitality” of concepts like human dignity. Given the weighty interests at stake in this encounter between science and ethics, relying on an increasingly Delphic, decade-old single paragraph rider on an appropriations bill hardly seems adequate.

Previously After the lawsuit, what’s next for stem cell research, Judge Lamberth dismisses stem cell lawsuit and Embryonic stem cell regulation will affect iPS cell research

Stanford bioethicist Mildred Cho, PhD, published an article yesterday in Science Translational Medicine about the pros and cons of patents in biotechnology. She and her colleagues described events surrounding the licensing of the type of non-invasive fetal genome sequencing (also known as cell-free fetal DNA) technology developed in the laboratory of Stanford bioengineer Stephen Quake, PhD. A monopoly by a single company (or even a few companies offering similar tests) could be bad for patient care by pricing tests out of reach of most women, or by discouraging other researchers from building on the technique, they feel. From the article:

A monopoly on this IP [intellectual property] could limit intended benefits of the technology and may provide yet another example of how patenting and licensing practices can frustrate the successful translation of publicly funded research. Undesired consequences may include inflated prices, decreased availability, constraints on the autonomy of patients and health care providers, and limits on further validation or development of this testing.

Cho, who is the associate director Stanford Center for Biomedical Ethics, elaborated further to me:

Patent issues are very important in the translational process but not often discussed in the scientific community. We thought that the cell-free fetal DNA technology was a good (but unfortunate) example of how intellectual property policy can impede translation, even though the policies are intended to do the opposite.

Cho points out that unlike the development of a new drug, diagnostic genetic tests are relatively easy to bring to market and don’t require large amounts of private funding. But she and her co-authors feel that patents and licenses may be more likely to slow, rather than help, the translation of these types of technologies once they’re on the market.

A fascinating report was posted earlier today about the Stanford School of Medicine’s Arts, Humanities & Medicine Program. The article, written by Corrie Goldman, provides a closer look into the initiative and how it allows students at the medical school to explore their creativity and artistic passions through the study of art, music and literature. Goldman writes:

The aim, as described on the program website is to “enhance our understanding of the contextual meanings of illness, health care, and the human condition.

The piece includes a very nice profile of Meghan Galligan, a first year Stanford medical student who uses the program to incorporate her musical passions into her work with patients:

Through the Biomedical Ethics and Medical Humanities Scholarly Concentration (BEMH), Galligan, a classically trained concert pianist and vocalist, has read King Lear and listened to Gustav Mahler compositions.

She also has read essays written by cancer survivors and heard a presentation by a man who made a documentary film about living with Huntington’s Disease in “The Human Condition,” a BEMH course taught by Dr. Larry Zaroff.

Galligan said the reflective nature of class discussions encouraged her to consider existential questions that her patients might face, such as, “How do I live my life and make a difference after I’ve been diagnosed with a serious illness?”

Stanford medical students also have the opportunity to receive a Medical Scholars Research Grant, encouraging them to broaden their perspectives toward medicine, arts, humanities and ethics.

Previously: A plan to expand educational offerings to “anyone, anywhere” and Stanford dean discusses changing expectations for medical students

Updated 06-25-12: The International Olympic Committee has adopted the gender-policing policies discussed here last week. In a statement sent to reporters yesterday, Karkazis repeated her assertion that the policies are “unfair, unscientific and possibly discriminatory against women who may not meet traditional notions of femininity.”

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06-18-12: In an article published in the New York Times today, Stanford bioethicist Katrina Karkazis, PhD, and Barnard College researcher Rebecca Jordan-Young, PhD, argue that the International Olympic Committee’s proposed new policy governing sex verification is neither fair nor rationale, and they offer recommendations for retooling the eligibility guidelines for Olympic female athletes. From the piece:

Testosterone is one of the most slippery markers that sports authorities have come up with yet. Yes, average testosterone levels are markedly different for men and women. But levels vary widely depending on time of day, time of life, social status and — crucially — one’s history of athletic training. Moreover, cellular responses range so widely that testosterone level alone is meaningless.

Testosterone is not the master molecule of athleticism. One glaring clue is that women whose tissues do not respond to testosterone at all are actually overrepresented among elite athletes.

As counterintuitive as it might seem, there is no evidence that successful athletes have higher testosterone levels than less successful ones.

…

Sex segregation is probably a good idea in some sports, at some levels and at some moments. But it is time to refocus policy discussions at every level so that sex segregation is one means to achieve fairness, not the ultimate goal. Ensuring gender equity through access to opportunity is just as important.

Unlike in doping cases, women with hyperandrogenism have not cheated. There is no reason to disqualify women whose bodies produce any of the complex ingredients that add up to athleticism, be they superb vision, big lungs, flexibility, long legs or testosterone.

Karkazis also discussed the issue of sex testing for elite female athletes in a recent 1:2:1 podcast.

Previously: Researchers challenge proposed testosterone testing in select female Olympic athletes and Gender ambiguity gets attention
Photo by Paul Foot

Over at ScienceDaily, there’s really interesting story-behind-the-story coverage of a groundbreaking but ethically complex scientific trial. Last year, the HIV Prevention Trials Network 052 trial made headlines when it showed antiretroviral therapy decreases transmission of HIV from HIV-positive individuals to their HIV-negative sexual partners. The trial is also testing whether antiretroviral drugs should be given starting soon after HIV infection is discovered, as opposed to waiting to begin therapy until HIV infection is more advanced.

Answering these questions clearly has tremendous public-health value, especially given that these findings are coming from a randomized clinical trial, the type of research that has long been considered the “gold standard” for good scientific evidence. However, the still-ongoing trial has provided scientists with several big ethical challenges, which are described in a new scientific paper published in the June 2012 issue of Clinical Trials. In particular, as the trial has progressed, researchers have had to figure out how to deal with new scientific knowledge garnered from other experiments that used different methods. The ScienceDaily story explains:

Study participants were randomly assigned to two groups - one that would receive ART earlier, and the other at a later stage of HIV progression. This became a source of ethical tensions as the trial progressed and enthusiasm for earlier ART treatment grew, whereas previously it had been considered potentially unsafe. For example, in November 2009 the World Health Organization (WHO) issued new guidelines recommending that ART treatment begin earlier.

…

The authors point to the “constant threat” from observational and ecological study data, and the official guidelines they inspire, as posing a critically important ethical lesson of HPTN 052: whether and how a randomized trial should respond in light of them. “As these necessary changes were made, they threatened the very research that might support or refute the recommendations themselves,” they write.

The fact that the scientists were testing HIV transmission rates also raised ethical concerns:

The authors also address the question of the study’s potential to encourage unsafe sex for the sake of research results into the transmissibility of HIV, a common ethical issue raised in HIV research. The authors assert that “including a ‘prevention package’ is ethically obligatory,” and should include methods known to be effective and accessible to participants.

The whole story is definitely worth reading.

Previously: WHO’s new recommendations on contraceptive use and HIV; Treat patients early to stop HIV spread, study finds; Treating breastfeeding babies to prevent HIV.

In a critique published online today in The American Journal of Bioethics, a Stanford bioethicist and colleagues warn that proposed policies by the International Olympic Committee and the International Association of Athletics Federations for testing the testosterone levels of select female athletes are unfair and may result in female athletes undergoing unnecessary, and potentially harmful, treatments to continue competing.

The testing policies adopted last year call for using testosterone levels to decide whether an athlete is “feminine” enough to compete as a woman. But as Katrina Karkazis, PhD, a medical anthropologist and senior research scholar at Stanford’s Center for Biomedical Ethics, and others explain in the paper, (subscription required) this approach could discriminate against women who may not meet traditional notions of femininity and distort the scientific evidence on the relationship between testosterone, sex and athletic performance. My colleague Tracie White reports:

Although it is widely believed that chromosomal testing or genital exams can indicate definitively a person’s sex, such methods are flawed. Contrary to the general understanding that women have two X chromosomes and men have an X and a Y, there are actually too many variations on chromosomal markers to use the test accurately in all cases. While it is uncommon for women to have a Y chromosome, it does occur in a small number of women.

What’s more, regardless of chromosomes, female anatomy and physiology vary in ways that may make it difficult to quickly classify a person as male or female. There are individuals with intersex traits who are born with reproductive or sexual anatomy that doesn’t fit the typical definitions of female or male.

….

Of particular concern with the potential policies is the possible coercion of athletes into undergoing unnecessary and potentially harmful medical treatment if they are found to have hyperandrogenism. “If the athlete does not pass, she is banned from competition until she lowers her testosterone levels,” the authors write, noting that the treatment options would entail either pharmaceutical intervention or gonadectomy, both of which carry serious potential side effects.

Rather than adopting such policies, the authors recommend against gender policing by international sporting authorities. Karkazis recently discussed the issue of sex testing for elite female athletes in a recent 1:2:1 podcast.

Previously: Gender ambiguity gets attention
Photo by Bryan Allison