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Clinical Trials, Research, Science Policy, Stanford News

At the heart of reproducibility lies the problem of transparency

At the heart of reproducibility lies the problem of transparency

spare ribsImagine recreating a recipe — say, your uncle Darryl’s BBQ sauce. Without a detailed recipe — including not only the list of ingredients but how long he cooked the sauce and when he added which ingredients — you’re not likely to be able to exactly reproduce his delicious sauce.

The same is true of research.

One of the frustrating recent discoveries about biomedical research is that, all too often, initially exciting results can’t be reproduced. And how do we know if an effect is real if we can’t make it happen again?

Researchers say that billions of dollars are wasted on research that has never been reproduced.

Lately, research funders and others have become obsessed with reproducible research. One problem is that most researchers aren’t motivated, financially or otherwise, to copy someone else’s study exactly. Better for your reputation and funding to do something original. The result is still another irreproducible study.

A second problem at the heart of irreproducible studies is transparency. Without a good understanding of a scientific paper’s methods, exact protocol and full results (which researchers rarely include in their paper), it’s very challenging for other researchers to reproduce the work.

Yesterday, Stanford’s John Ioannidis, MD, PhD, and his team at Stanford published one of two inaugural papers for the launch of PLoS Biology’s new Meta-Research Section. The paper by Ioannidis and colleagues provides a baseline that shows just how far we have to go to create a fully transparent biomedical literature.

Ioannidis, a professor of health research and policy, and colleagues took a random sample of 441 journal articles from biomedical journals from between 2000 and 2014. From that sample, they found that no team of authors made all their data available, only one team provided a full protocol, and the majority did not disclose funding or conflicts of interest.

With such low levels of transparency, it wasn’t surprising that replication studies were likewise rare. We can hope funders can find ways to motivate researchers to offer better transparency and reproducibility.

Previously: On communicating science and uncertaintyA conversation with John Ioannidis, “the superhero poised to save” medical research
Photo by jeffreyw/Flickr

Applied Biotechnology, Ethics, Medicine and Society, Public Safety, Science Policy, Stanford News

Stanford experts slam government’s myopic biosecurity oversight

Stanford experts slam government's myopic biosecurity oversight

blindfoldedJust because we can, does that mean we should?

In a hard-hitting editorial in Science, three Stanford thinkers – Stanford microbe wizard David Relman, MD; synthetic biologist Megan Palmer, PhD, of Stanford’s Center for International Security and Cooperation; and political theorist Francis Fukuyama, PhD, of the Freeman Spogli Institute for International Studies – have issued a scathing wake-up call to the scientific community and the federal government, sternly questioning the latter’s current plans for ensuring biosafety and biosecurity in the United States.

“Our strategies and institutions for managing biological risk in emerging technologies have not matured much in the last 40 years,” they write, adding:

With the advent of recombinant-DNA technology, scientific leaders resorted to halting research when confronted with uncertainty and public alarm about the risks of their work. To determine a framework for managing risk, they gathered at the now-fabled 1975 Asilomar meeting. Their conclusions led to the recombinant DNA guidelines still used today, and Asilomar is often invoked as a successful model for scientific self-governance.

But, the authors suggest, Asilomar’s legacy may not be all it’s cracked up to be:

Asilomar created risky expectations: that leading biological scientists are best suited for and wholly capable of designing their own systems of governance and that emerging issues can be treated as primarily technical matters.

“Unfortunately,” the editorial goes on to say, “today’s leadership on biological risk reflects Asilomar’s risky legacy: prioritizing scientific and technical expertise over expertise in governance, risk management, and organizational behavior.” Political leaders have largely ceded a strategic leadership role, leaving it up to the scientific community itself to judge the ethical and social implications of its own work.

“Leadership biased toward those that conduct the work in question can promote a culture dismissive of outside criticism and embolden a culture of invincibility” regarding emerging biotechnology risks,” the authors write.

The world of today is not the world of 1975. Since then, the scope and scale of biological science and technology have changed radically. To wit: The increased ease of reading and writing genetic information means that securing materials in a handful of established labs is not feasible, the editorial states. Like it or not, the tools for putting potentially dangerous knowledge into practice are increasingly portable.

For a scary scenario of what such new facility portends, please see this article I wrote a couple of years ago, which begins with the rhetorical question: “What if nuclear bombs could reproduce?”

With so much at stake, we may not want to restrict oversight of scientific advances to those who are making the advances. There’s knowledge, and there’s wisdom.

Previously: How-to manual for making bioweapons found on captured Islamic State computer, Microbial mushroom cloud: How real is the threat of bioterrorism? (Very) and Stanford bioterrorism expert comments on new review of anthrax case
Photo by Mirko Tobias Schafer

Cancer, FDA, In the News, Science Policy, Women's Health

Gynecologists call for revision of FDA ruling on device to remove uterine fibroids

Gynecologists call for revision of FDA ruling on device to remove uterine fibroids

6095122430_9cf3ac4ec8_zA group of gynecologists is calling for the Food and Drug Administration to reverse its 2014 ruling banning the use of a device called a power morcellator to remove uterine fibroids, or non-cancerous masses also known as leiomyomas.

The ruling stemmed from several high-profile cases and a concern that morcellators could chop up and spread tissue that might contain a rare but deadly cancer known as leiomyosarcoma. The FDA overstated the risk of morcellation and failed to consider the risks involved in more invasive surgeries needed to avoid using a morcellator, said Jonathan Berek, MD, the chair of obstetrics and gynecology.

Berek is the senior author of the paper published today in Obstetrics and Gynecology and one of 48 gynecologists, oncologists and women’s health advocates who sent an open letter to the FDA yesterday calling for a revision of the ruling.

With a morcellator, surgeons can remove fibroids with very small incisions, usually with a laparoscope, reducing the complication rate and speeding the recovery time needed for fibroid removal or hysterectomy using a large incision, Berek said. But the FDA estimated that 1 in 458 women undergoing the procedure could have an undiagnosed leiomyosarcoma that could be spread by the morcellator.

The gynecologists, with lead author William Parker, MD, from the University of California-Los Angeles, say the FDA is overstating the risk, because recent data analyses put the likely risk at no higher than 1 in 1,550-1,960 cases. In fact, a recent population-based study placed the risk as low as 1 in 4,360 women having surgery for fibroids. In addition, it isn’t even certain that morcellators actually spread the cancers, Berek said.

“A leiomyosarcoma is a highly malignant, rare tumor that tends to spread readily, most often prior to surgery of any type, regardless of whether morcellation is used in the operation,” he told me.

The ruling has had the unintended consequence that many women who might have benefited from a minimally invasive surgery, with lower risks, now undergo a more risky, invasive surgery, he said. The authors list 10 procedures affected by the FDA’s ruling.

In the paper, they suggest six steps that could improve the FDA’s ruling, including advising women of the risks involved with power morcellation and conducting more research into the biology of these rare malignancies.

Previously: Stanford expert weighs in on ovarian0-cancer screening recommendation, Stanford researchers protest NIH funding restrictions and “A historic moment for women”: FDA approves the first drug to treat hypoactive sexual desire disorder
Image by Lady Ro

Science, Science Policy, Stanford News

At Stanford, Rep. Jerry McNerney discusses life in Congress, science funding and the value of squash

At Stanford, Rep. Jerry McNerney discusses life in Congress, science funding and the value of squash

McNerny on campusFor many of us who work in or around science, it can be baffling to watch some of the decisions made by politicians. Some neuroscience faculty, staff and students got a look behind the scenes of what it’s like to be a scientist in government on Friday from congressman Jerry McNerney, PhD, who represents California’s 9th district. (His degree is in math). McNerney was at Stanford touring neuroscience labs at the VA and on campus, hosted by the Stanford Neurosciences Institute, and he took a pause at lunch for a town hall to answer questions about science, policy, and life in government.

McNerney talked about the challenges of explaining science to his colleagues and advocating for science-based policy on issues relating to energy and the environment as well as funding for biomedical research. He said one of his greatest tools is athletics. If he plays squash with someone he disagrees with, it’s easier to have calm conversations about policy. “If you communicate in an aggressive way you make it worse,” he said. “But you have to work at it.”

He encouraged scientists in the audience to talk with those they disagree with because their voices need to be heard. “To be a great country and a leader we need great research,” he said. Ensuring funding for that research is going to require scientists to be actively involved in explaining the value of their work.

McNerney was particularly interested in research related to traumatic brain injury, which is a critical problem for veterans returning from duty. He visited the lab of bioengineer David Camarillo, PhD, who is developing better ways of measuring head impacts and the damage they cause.

“We want to do the best we can to help these folks,” McNerney said.

Image of Rep. McNerney learning about concussion prevention by Tanya Raschke

Ethics, FDA, Genetics, In the News, Science Policy

CRISPR critters and CRISPR conundrums

CRISPR critters and CRISPR conundrums

OLYMPUS DIGITAL CAMERA

There’s much ado about the gene-editing technique CRISPR/Cas9 this week, with a multinational summit in Washington, D.C. on human gene editing, plus the clock ticking down on congressional appropriations bills, one of which would prohibit the Food and Drug Administration from spending money to evaluate research on or conduct clinical trials of gene editing in human embryos. The American Journal of Bioethics, edited by David Magnus, PhD, director of the Stanford Center for Biomedical Ethics, wades into the fray with a special issue on the ethics of CRISPR.

CRISPR is an unusually precise, fast and cheap way of snipping out and replacing genes. It has implications for preventing and treating genetic diseases, engineering new versions of the plants and animals we eat, and knocking out genes in insects so they can’t carry viruses that could kill us. The most controversial possibility is altering human sperm, eggs or embryos, because such germline changes would be heritable in future generations of offspring.

“The overriding question is when, if ever, we will want to use gene editing to change human inheritance,” said chair David Baltimore, PhD, of Caltech in kicking off this week’s summit. Ultimately, summit participants released a statement that left the door open for human germline editing, and advocated for ongoing international discussion.

Indeed, because of the low cost of CRISPR and the variability of research ethics across the globe, an international ban or moratorium would be difficult to enforce, said then-undergraduates Niklaus Evitt and Shamik Mascharak in a paper they wrote for a Stanford class co-taught by professor Russ Altman, MD, PhD. They and Altman turned it into an article for the special issue of the bioethics journal.

They propose a model regulatory framework for CRISPR human germline editing that includes vetting research for necessity and reversibility, establishing the safety and efficacy of the treatment in multigenerational animal models and conducting clinical trials over a 15-year period. “We seek concrete policies that responsibly phase in therapeutic uses of CRISPR-Cas genome editing at a pace amenable to ethical inquiry,” they write.

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Ethics, In the News, NIH, Research, Science, Science Policy, Stanford News, Stem Cells

Stanford researchers protest NIH funding restrictions

penSeven Stanford researchers, including Irving Weissman, MD, who directs Stanford’s Institute for Stem Cell Biology and Regenerative Medicine, and David Magnus, PhD, director of Stanford’s Center for Biomedical Ethics, have joined with four other prominent scientists to urge the lifting of a recent and unexpected ban on funding by the National Institutes of Health for research that involves placing human stem cells into early-stage, non-human embryos. Their comments will be published tomorrow in a letter to Science.

As I describe in our release:

At issue is the growing field of research that seeks to understand how human pluripotent stem cells, which can become any cell type, may integrate and contribute to the development of a nonhuman animal, such as a laboratory mouse. Pluripotent stem cells can be isolated from human embryos or created in a lab from adult human cells, in which case they’re known as induced pluripotent stem cells. Once obtained, these versatile cells can be injected into an early-stage animal embryo and studied as the embryo develops into an adult animal.

Tracking where these cells go and how they function in the growing embryo and the adult animal can help researchers understand early stages of human development that can’t be studied any other way. (Although researchers can and do study the development of fertilized human eggs, the study period is restricted to only a few days after fertilization for ethical reasons.)

In addition to investigating human development, the research is expected to lead to significant advances in disease modeling, drug testing and even transplantation. As cardiologist and one of the co-senior authors of the letter, Sean Wu, MD, PhD, explains:

By eliminating federal funding for all aspects of this research, the NIH casts a shadow of negativity toward all experiments involving chimera studies regardless of whether human cells are involved. The current NIH restriction serves as a significant impediment to major scientific progress in the fields of stem cell and developmental biology and regenerative medicine and should be lifted as soon as possible.

Science recently published a great background article describing the ban, and its effect on researchers like Sean Wu and geneticist and stem cell researcher Hiromitsu Nakauchi, MD, PhD, who also signed the letter. Other signees include Joseph Wu, MD, PhD, professor of medicine and director of Stanford Cardiovascular Institute; Christopher Scott, PhD, director of Stanford’s Program on Stem Cells and Society; and Vittorio Sebastiano, PhD, assistant professor of obstetrics and gynecology and director of Stanford’s Human Pluripotent Stem Cells Core Facility.

Previously: NIH intramural human embryonic stem cell research haltedSupreme Court decision on human embryonic stem cell case ends research uncertaintyUsing organic chemistry to decipher embryogenesis and The best toxicology lab: a mouse with a human liver
Photo by Fimb

Health Policy, NIH, Research, Science Policy, Stanford News

NIH tries to reduce the gray in the grant pool

NIH tries to reduce the gray in the grant pool

This 45-second animation vividly illustrates the funding crisis that young scientists face as they work to launch their research careers: For the last three decades, large NIH grants have increasingly been awarded to older investigators.

“The average age of first-time, R01-funded investigators who have PhDs remains 42, even after seven years of policies at NIH to increase the numbers of new and early-stage investigators,” said Robin Barr, director of the NIH’s Division of Extramural Activities, in a recent editorial on the NIH website.

But there is hope on the horizon, as the NIH rolls out a series of funding mechanisms that aim to give new investigators a leg up. I recently wrote about one such program, the KL2 mentored career development award, and an inspirational Stanford physician-researcher, Rita Hamad, MD, MPH, who is taking full advantage of it.

Hamad is interested in studying the cause-and-effect relationships between poverty and health. The KL2 program helps Hamad’s research through salary support, mentoring, pilot grants and tuition subsidies. In just two years, she has produced actionable data that can be used by policymakers and by health-care providers to improve the overall health of populations, including a study exploring the impact of the earned-income tax credit on child health in the United States. It will be published this fall in the American Journal of Epidemiology.

Previously:NIH funding mechanism “totally broken,” says Stanford researcher, NIH director on scaring young scientists with budget cuts: “If they go away, they won’t come back” and Sequestration hits the NIH – fewer new grants, smaller budgets
Animation by the NIH

FDA, Media, Research, Science Policy, Sexual Health, Women's Health

“A historic moment for women”: FDA approves the first drug to treat hypoactive sexual desire disorder

"A historic moment for women": FDA approves the first drug to treat hypoactive sexual desire disorder

20705116491_5351758c67_zRoughly 16 million women over the age of 50 suffer from low sex drive. Yet, until recently, there were no FDA-approved medications to treat the lack of sexual thoughts and desire experienced by women with hypoactive sexual desire disorder (HSDD).

That’s why the U.S. Food and Drug Administration’s recent approval of the drug flibanserin (sold under the brand name Addyi™) to treat women with HSDD, is such big news.

“It’s a historic moment for women,” said Leah Millheiser, MD, director of Stanford’s Female Sexual Medicine Program, in a story published today in the San Francisco Chronicle. HSDD, Millheiser explains, is more than the occasional loss of sexual desire that can result from changes in hormones, stress and discontent in a relationship. “These are women who want to have sex with their partner, they’re attracted to their partner and used to love having sex,” Millheiser said. “It’s as if someone turned off the lightbulb.”

It’s tempting to equate flibanserin to Viagra (the drug approved to treat erectile disfunction in men), but this is clinically inaccurate. As explained in the article, Viagra treats erectile dysfunction by increasing blood flow to the penis, while flibanserin works on the brain.

From the story:

The drug [flibanserin] was first developed as an antidepressant. Like other antidepressants, it works on the brain’s serotonin levels, but researchers say it works on different serotonin receptors than other similar antidepressants.

It didn’t work to relieve depression, as it turned out, but patients reported increased sexual desire.

In clinical trials, researchers said 53 percent of women who took the drug reported an increased desire for sex and 29 percent said the drug decreased their level of distress over their condition. In the trials, the number of “satisfying sexual events” reported by participants essentially doubled from an average of 2.5 per month before they received flibanserin to five while taking it.

Millheiser credits Viagra for helping to pave the way for this new approved treatment for HSDD.  “As a result of Viagra, there was an explosion in research and understanding into what sexual dysfunction is and how we treat it,” she said. “It took 17 years to … get to this day,” she said.

Previously: When hormonal issues interfere with mental healthFemale sexual health expert responds to delay in approval for “Viagra for women and Speaking up about female sexual dysfunction
Photo by Day Donaldson

Ethics, In the News, Medicine and Society, Science, Science Policy, Sports, Stanford News

Stanford expert celebrates decision stopping testosterone testing in women’s sports

Stanford expert celebrates decision stopping testosterone testing in women's sports

Female track and field athletes no longer need to have their natural testosterone levels below a certain threshold to compete in international events, the so-called “Supreme Court of sports”, the Court of Arbitration for Sport, ruled Monday.

Katrina Karkazis, PhD, a Stanford senior research scholar who was closely involved with the case, got the news on Friday, while she was in a San Francisco dog park. “What a day!” she said. “I was madly refreshing my email — I thought we were going to lose… I just started screaming and crying.”

Karkazis, who is an expert on ethics in sports and also gender, said she spent a year of her life working on the case.

She served as an advisor to 19-year-old sprinter Dutee Chand, who challenged the regulation that female athletes must have certain testosterone levels or undergo medical interventions to lower their testosterone to be allowed to compete against women in events governed by the International Association of Athletics Federations (IAAF), the international regulatory body of track and field.

The ruling suspends the IAAF’s testing regimen for two years, but Karkazis expects the decision will lead to permanent changes in women’s sports, including a reevalution by the International Olympic Committee.

“I’m thrilled,” Karkazis said. She said she was also surprised. “I didn’t think it was our time. I thought there were still too many entrenched ideas about testosterone being a ‘male hormone’ and it not belonging in women.”

Karkazis gained international attention after penning an op-ed in The New York Times in 2012 when the IAAF and the International Olympic Committee crafted a new policy banning women with naturally high levels of testosterone from competing.

“You can’t test for sex,” Karkazis said. “It’s impossible. There’s no one trait you can look at to classify people. There are many traits and there are always exceptions.”

She said that now women who have lived and competed their entire lives as women will be eligible to compete, a default policy she believes is sufficient to ensure a level playing field.

Previously: “Drastic, unnecessary and irreversible medical interventions” imposed upon some female athletes, Arguing against sex testing in athletes and Is the International Olympic Committee’s policy governing sex verification fair?
Photo by William Warby

Big data, Ethics, Genetics, Science Policy, Stanford News

Stanford panel: Big issues will loom when everyone has their genomic sequence on a thumb drive

Stanford panel: Big issues will loom when everyone has their genomic sequence on a thumb drive

When I was a biology grad student in the early 1980s, we used to joke about people who were getting their PhDs by spending six long years sequencing a single gene. They worked around the clock seven days a week – and seven nights, too, sleeping on their lab benches when they slept at all.

A few years later the Human Genome Project came along and sped things up quite a bit. But it still took 13 years and a billion dollars to fully sequence a single human genome.

It’s a different story now. With a one-day, $1,000 genome sequence in sight, a 20-minute, $100 sequence can’t be far off. It appears that within 15 years or so, the average individual’s genomic sequence will be just another lengthy, standard supplemental addition to that person’s electronic medical record.

That raises a lot of questions. Last Saturday, I had the great privilege of asking a few of them to a panel of three tier-one Stanford experts: Mildred Cho, PhD, associate director of the Stanford Center for Biomedical Ethics; Hank Greely, JD, director of the Center for Law and the Biosciences, and Mike Snyder, MD, PhD, chair of Stanford’s genetics department and director of the Center for Genomics and Personalized Medicine. (I was the moderator.)

The panel, titled “Genetic Privacy: The Right (Not) to Know,” was a lively one, part of a day-long Alumni Day event sponsored by the Stanford Medical Center Alumni Association. (Here’s a link to the video above). Cho, Greely and Snyder have their own well-developed perspectives and policy preferences on the utility of mass genomic-sequence availability, and they articulated those views with passion and aplomb.

The 300 people in the audience, most of them doctors, had plenty of questions of their own. Several were ones I’d hoped to ask but hadn’t had time.

By the time I walked away from this consciousness-raising clash of perspectives, newly aware of just how fast the future is coming at us, I had another question: Once everyone has the equivalent of a thumb drive with their complete genome on it, can you imagine a kind of online matchmaking service in which you upload your genome to a server, which then picks out a date or a mate for you? The selection is guided by what you say you’re looking for: short-term mutual attraction, an enduring monogamous relationship, robust offspring … Is that now thinkable?

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