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Clinical Trials, Medicine and Society, Research, Science Policy, Stanford News, Stem Cells

Very small embryonic like stem cells may not exist, say Stanford researchers

Very small embryonic like stem cells may not exist, say Stanford researchers

There’s a shake-up happening today in the world of stem cell research. Very small embryonic-like stem cells, or VSEL cells, have been proposed by some researchers as an alternative to human embryonic stem cells. Because they’re said to exist in the bone marrow of adult humans and mice, they could obviate the ethical issues surrounding the use of human embryos.

The research has sounded promising enough that a New York-based company, NeoStem, was awarded a grant from the National Institute of Dental and Craniofacial Research to investigate the use of the cells to stimulate bone growth after tooth extraction.

But in a study published today in Stem Cell Reports, Stanford stem cell scientist Irving Weissman, MD, casts doubt on the existence of the cells. From our release:

“It has become important to know to what extent and where these VSEL cells exist to understand how they may affect the field of stem cell research,” said Weissman, who directs Stanford’s Institute for Stem Cell Biology and Regenerative Medicine and the Ludwig Center for Cancer Stem Cell Research and Medicine at Stanford. “We tried as hard as we could to replicate the original published results using the methods described and were unable to detect these cells in either the bone marrow or the blood of laboratory mice.”

Although other groups have seemingly confirmed the existence of these cells as defined by size and the expression of key cell-surface molecules, Weissman’s study is the first to evaluate the biological potency of the cells.

An article in today’s Nature magazine summarizes the controversy surrounding the cells, and calls Weissman’s study a “major blow to the field.” Alison Abbott writes:

Led by Irving Weissman, a prominent stem-cell researcher at Stanford University in California, the study is the fourth to refute the cells’ existence — and the most thorough yet.

“Weissman’s evidence is a clincher — it is the end of the road for VSELs,” believes Rüdiger Alt, head of research at Vita 34, a private bank for umbilical cord blood in Leipzig, Germany, who last year published the first failure to replicate claims for the cells2.

Robin Smith, chief executive at Neostem, disagrees. She compares the attacks on VSELs to those suffered by Charles Darwin and Nicolaus Copernicus when they proposed their world-changing scientific theories.

It will likely take some time for the controversy to end. In the meantime, Weissman and his colleagues have concluded that “the existence of adult mouse VSELs in the bone marrow remains dubious.”

Previously: Stanford’s Irving Weissman on the (lost?) promise of stem cells

In the News, NIH, Science, Science Policy

Senate proposes to increase NIH’s budget in 2014

Senate proposes to increase NIH's budget in 2014

During this time of federal budget woes, it’s refreshing to get at least a little good news on the topic. As reported by Nature’s newsblog yesterday, a U.S. Senate subcommittee has recommended that the National Institutes of Health’s budget be upped in 2014, from just over $29 billion to around $31 billion. Meredith Wadman writes:

…The increase would include $84 million new dollars for Alzheimer’s disease research at NIH’s National Institute on Aging and $40 million for the much-watched Brain Research through Advancing Innovative Neurotechnologies Initiative announced by the White House in April.

The Senate panel would also quintuple, to $50 million, funding for the Cures Acceleration Network, an effort by NIH’s new translational medicine centre to speed bench discoveries to the bedside. And the bill would extend to other agencies in the Department of Health and Human Services a requirement that is now operative only at NIH: that researchers deposit their taxpayer-funded manuscripts in a publicly accessible database.

Though, as Wadman writes, these budget plans are “far from a done deal,” the Senate’s support for the agency is encouraging:

Senator Barbara Mikulski, the Maryland Democrat who chairs the full committee, made it clear at a press event yesterday at Johns Hopkins Hospital in Baltimore, that she plans to go to the mat for NIH, which under recent sequester cuts lost $1.55 billion of its original 2013 budget of $30.8 billion.  Health and Human Services Secretary Kathleen Sebelius’s transfer of $173 million in NIH 2013 funds to other agencies in the department added to the damage.

“We want to say ‘no’ to the slash and crash of reckless cuts to American biomedical research,” she declared against a backdrop of white-coated medical researchers who had gathered to emphasize the impact of sequestration on NIH-funded scientists.

Previously: NIH director on scaring young scientists with budget cuts: “If they go away, they won’t come back”, Sequestration hits the NIH – fewer new grants, smaller budgets,
NIH director polls Twitter for real-world responses to budget cutbacks, A federal push to further brain research and As budget sequester nears, a call for Congress to protect funding for scientific and medical research

Cancer, Genetics, In the News, Medicine and Society, Science, Science Policy

How will the Myriad decision affect patient care? Stanford experts comment

How will the Myriad decision affect patient care? Stanford experts comment

I recently had the opportunity to talk in-depth with Stanford clinicians and faculty members about how the U.S. Supreme Court decision on the Myriad gene-patenting case may affect patient care. The answer? Surprisingly little (at least in near future). That’s in part due to the large proprietary database of BRCA mutations amassed by the company. As I wrote in my article:

…Although the ruling may be an ethical and philosophical triumph for those who believe that human genetic information should not be claimed by any corporate entity for profit, it’s not likely that patient care will change immediately, according to breast cancer clinicians at the Stanford Cancer Institute. Myriad’s experience in the field of BRCA gene testing and interpretation will be difficult to surpass, at least for a while, they said. Over time, however, the ruling should result in a freer research atmosphere that will translate into improvements for patients.

The piece includes the thoughts of leaders of the Stanford Cancer Institute, the institute’s breast oncology and molecular therapeutics program, big data experts and bioethicists. I hope you enjoy reading it as much as I enjoyed writing it!

Previously: Reaction on gene-patenting ruling from around the web, A closer look at Supreme Court’s decision on gene patenting and Examining how the Supreme Court ruling on gene patenting affects medical and scientific research

Cancer, Genetics, In the News, Medicine and Society, Science, Science Policy

Takeaways from last week’s gene patenting decision

Takeaways from last week's gene patenting decision

Maybe, like me, you read everything you could get your eyes on last week about the gene patenting case, and spent several days pondering the implications of the ruling by the Supreme Court that companies like Myriad Genetics can’t patent isolated human genes. Or, maybe you’re a busy person with not much time to dive deeply into the issue. If so, you might find today’s summary by the National Geographic - 7 Takeaways from Supreme Court’s Gene Patent Decision – a useful primer.

The article quotes Jake Sherkow, JD, and Hank Greely, JD, from the Stanford Center for the Law and Biosciences, who each provided comment on the case for us and other members of the media last week. I found point 2 – “Synthetic DNA is fair game” – to be particularly interesting, since it’s one of the first discussions of what the ruling allows, rather than prohibits:

While companies can no longer patent genes with the same sequences found in cells, the decision allows edited forms of genes not found in nature—known as complementary DNA, or cDNA—to be patented.

cDNA is not useful for diagnostic tests, but it is crucial for producing protein-based drugs, explained Robert Cook-Deegan, a professor of genome ethics, law, and policy at Duke University’s Institute for Genome Sciences and Policy.

“Those are the billion-dollar molecule patents,” Cook-Deegan said. “Biotech companies care a great deal about cDNA patents, and it should be reassuring to them that those patents are still fine.”

Hank Greely, a bioethicist and law professor at Stanford University, predicts cDNA patents will become even more valuable as scientists move beyond merely exploiting naturally occurring proteins.

“In the longer run, as we move into an era of synthetic biology, where we start trying to improve upon nature, then I think [cDNA patents] will be important,” Greely said.

Previously: A closer look at Supreme Court’s decision on gene patenting, Supreme Court rules on Myriad’s “gene patenting” case and Are genes patentable? A summary of the Supreme Court case

Cancer, Genetics, Medicine and Society, Research, Science, Science Policy

Examining how the Supreme Court ruling on gene patenting affects medical and scientific research

Yesterday’s Supreme Court ruling declaring that isolated genomic DNA is not eligible for patent protection, but that cDNA – “cloned” or “complementary DNA” – can be patented ignited a frenzy of news stories and commentaries about the decision. In a segment on KQED’s Forum this morning, Mildred Cho, PhD, associate director of the Stanford Center for Biomedical Ethics and a professor of pediatrics,  joined the discussion on how the ruling will affect medical and science research. Listen to the full discussion here.

Previously: A closer look at Supreme Court’s decision on gene patenting and Supreme Court rules on Myriad’s “gene patenting” case

Cancer, Genetics, In the News, Medicine and Society, Science, Science Policy

Reaction on gene-patenting ruling from around the web

Reaction on gene-patenting ruling from around the web

Wow, what a busy day for gene patenting discussions! This morning’s decision (.pdf) by the Supreme Court that isolated DNA is not patentable has sparked a wave of stories, press releases and announcements across the web. I thought I’d pull together some of the most useful information I’ve found today on the topic.

Twitter provided a forum for immediate responses to the ruling, my favorite of which was authored by NIH director Francis Collins, MD, PhD:

(Collins later followed-up with a much more staid official statement, but I still love the “Woo hoo.”) The Twitter feed from the National Human Genome Research Institute was only a bit more restrained:

Several Stanford experts weighed in as well, including Stanford law professor and bioethicist Hank Greely, JD, who had a slightly different reaction to the ruling:

Geneticist Carlos Bustamante, PhD, also tweeted his thoughts about the issue of consumer choice (scroll down to read tweet series).

As the day wore on, it became apparent that those on both sides of the issue were claiming a victory of sorts. Myriad issued a positively worded release highlighting the Court’s decision to uphold the company’s cDNA patents. Stock in Myriad (and other biotechnology companies) initially jumped after the announcement, but ended the day down about 5.6 percent.

Two genetic testing companies (Ambry Genetics and Gene by Gene, Ltd) that I know of (there could well be more) jumped into the fray this afternoon with announcements that they will immediately begin offering BRCA1 and BRCA2 testing to patients at prices much lower than the $3,000 to $4,000 charged by Myriad. It remains to be seen, however, how much of an advantage Myriad’s proprietary database (used to interpret the sequence results and deliver risk estimates to patients) will confer to savvy patients who may choose to pay a premium for access to this cloistered information. Personally, I’m really interested in the effect the ruling will have on an end-around effort by researchers trying to reconstitute Myriad’s database by compiling individual patient’s reports from the company.

Finally (for now), for a general overview of the history of BRCA gene patenting and the field of genetic testing, check out this excellent article from Nova Next. I have a feeling I’m going to be reading it more than once as I (along with many experts in both law and biology) puzzle through the issues for these next few days and weeks.

Previously: A closer look at Supreme Court’s decision on gene patenting, Supreme Court rules on Myriad’s “gene patenting” case and Are genes patentable? A summary of the Supreme Court case

Cancer, Genetics, Medicine and Society, Science, Science Policy

A closer look at Supreme Court’s decision on gene patenting

A closer look at Supreme Court's decision on gene patenting

As previously discussed here and elsewhere, the Supreme Court today issued its opinion in the gene patenting case Association for Molecular Pathology vs. Myriad Genetics, Inc. In a unanimous decision (.pdf) authored by Justice Thomas, the Court declared that isolated genomic DNA was not eligible for patent protection, but that cDNA – “cloned” or “complementary DNA” – could be patented. This was largely the outcome some predicted after oral argument. And while the actual business and research effects of the decision remain to be seen, this does bring to a close the longstanding practice of patenting isolated portions of the human genome in its native state.

This likely brings to a close Myriad Genetics’ saga of aggressively enforcing its patents directed to BRCA1 and BRCA2 testing

The Court’s decision was relatively simple. It began with a largely accurate, and lengthy, recitation of the molecular biology behind transcription and translation. This factored significantly into the Court’s discussion of the differences between isolated genomic DNA and cDNA, particularly the absence of introns from cDNA molecules. It then assessed the patents’ claims at issue, which were generally directed to “an isolated DNA” of varying lengths and sequences. The opinion noted that, “Myriad’s patents would, if valid, give it the exclusive right to isolate an individual’s BRCA1 and BRCA2 genes… by breaking the covalent bonds that connect the DNA to the rest of the individual’s genome.” And the Court concluded its opinion by declaring that claims directed to molecules of isolated genomic DNA, themselves, were unpatentable “products of nature” because Myriad did not “alter any of the genetic information encoded in the BRCA1 and BRCA2 genes,” nor did the isolated genomic DNA possess “markedly different characteristics from any found in nature.”

The Court rejected Myriad’s claim that it created a new chemical entity because, in isolating the genes from their surrounding chromosomes, Myriad necessarily cleaved the chemical bonds of the chromosomes’ phosphate backbones. This was irrelevant because “Myriad’s claims are simply not expressed in terms of chemical composition, nor do they rely in any way on the chemical changes that result from the isolation of a particular section of DNA.”

As for Myriad’s cDNA claims, however, the Court – in a single, short paragraph – declared them eligible for patent protection because the “non-coding regions have been removed,” thus creating a new molecule not found in nature. Interestingly, the Court recognized the possibility of retrovirii potentially creating identical DNA transcripts to the cDNAs at issue, but dismissed this concern in a footnote: “The possibility that an unusual and rare phenomenon might randomly create a molecule similar to one created synthetically through human ingenuity does not render a composition of matter nonpatentable.”

Bizarrely, Justice Scalia joined the Court’s opinion in its entirety except for its preliminary scientific discussion. In a separate concurrence, Justice Scalia wrote: “I am unable to affirm those details on my own knowledge or even my own belief.” Typically, Justice Scalia does not qualify the factual portions of opinions he joins, even where they involve science. And notably, in the Court’s recent decision in Maryland v. King involving the constitutionality of warrantless DNA tests for arrestees, Justice Scalia’s dissent is replete with the factual differences between DNA and fingerprint testing.

This likely brings to a close Myriad Genetics’ saga of aggressively enforcing its patents directed to BRCA1 and BRCA2 testing. Myriad will continue to offer its BRACAnalysis product, which, because of its trade secret mutational database, is likely still the most robust BRCA test on the market. And competitors will be able to enter the BRCA testing market and make use of Myriad’s methods, although they will have to do so without the benefit of certain cDNA molecules or Myriad’s clinical data.

But the decision leaves a number of legal questions unanswered: What about other patents directed to “isolated and purified” natural products? Are cDNAs nonetheless obvious, and therefore unpatentable for that reason? And, considering the Court’s mention of retrovirii, how “unusual and rare” must a “natural phenomena” be to still be patent eligible if synthetically created? These are issues that the lower courts are likely to struggle with going forward, and issues that may, one day, be back in the hands of the Supreme Court.

Jake Sherkow, JD, is a fellow at Stanford Law School’s Center for Law and the Biosciences. His current research focuses on the intersection of patent law, biotechnology, and agency regulation.

Previously: Supreme Court rules on Myriad’s “gene patenting” case and Are genes patentable? A summary of the Supreme Court case

Cancer, Genetics, In the News, Medicine and Society, Science, Science Policy

Supreme Court rules on Myriad’s “gene patenting” case

Supreme Court rules on Myriad's "gene patenting" case

This morning, the U.S. Supreme Court issued their anxiously awaited decision in the case of the Association for Molecular Pathology vs. Myriad Genetics, Inc. Often called the gene patenting case, the case raises the issue of whether companies like Salt Lake City-based Myriad Genetics, Inc. can patent genes, in this case, the BRCA1 and BRCA2 genes. Mutations in these genes confer a substantially higher risk of breast or ovarian cancer.

The Court ruled that naturally isolated DNA is not patentable, but that synthetic DNA (such as the cDNA for the BRCA1 and 2 genes) is patentable. The decision was unanimous. From the decision:

A naturally occurring DNA segment is a product of nature and not patent eligible merely becauseit has been isolated, but cDNA is patent eligible because it is not naturally occurring.

cDNA is not a “product of nature,” so it is patent eligible under §101. cDNA does not present the same obstacles to patentability as naturally occurring, isolated DNA segments. Its creation results in an exons-only molecule, which is not naturally occurring. Its order of the exons may be dictated by nature, but the lab technician unquestionably creates something new when introns are removed from a DNA sequence to make cDNA.

We’ll have a longer comment about the decision later today or tomorrow from Jacob Sherkow, JD, a fellow at Stanford Law School’s Center for Law and the Biosciences. Sherkow recently wrote a wonderful blog post for us summarizing the oral arguments in the case, which took place in April. And the SCOTUS blog carried a great, ‘made simple’ synopsis of the issue earlier this year for readers who want to quickly get up to speed.

The decision is likely to have far-reaching implications for the many other gene patents granted by the U.S. Patent and Trademark Office since the first gene (chorionic somatomammotropin) was patented by the University of California, Berkeley, in the early 1980s. The National Society of Genetic Counselors now estimate that around 20 percent of all human genes are patented.

Previously: Are genes patentable? A summary of the Supreme Court case, At Stanford event, cancer advocate Susan Love talks about “A future with no breast cancer” and BRCA patients use Stanford-developed online tool to better understand treatment options
Photo by Mark Fischer

Ethics, NIH, Patient Care, Pediatrics, Research, Science Policy

Bioethicists say criticisms of preemie oxygen study could have “chilling effect” on clinical research

Bioethicists say criticisms of preemie oxygen study could have “chilling effect” on clinical research

Thanks to a public outcry that included objections from bioethics experts from across the country, the federal Office for Human Research Protections (OHRP) has decided to suspend sanctions it imposed earlier this year on a study of blood oxygen levels used to treat premature infants. The OHRP’s sanctions, issued in March, sharply criticized the study’s leaders for not providing the infants’ parents with adequate information about the risks of the trial. But many bioethics experts disagreed with the OHRP’s assessment of the situation.

Last week, a group of more than 40 of the country’s top bioethicists, including two at Stanford, sent a letter to OHRP stating that the sanctions could have a chilling effect on much-needed clinical research. In a highly unusual action, Francis Collins, MD, PhD, the director of the National Institutes of Health, worked with two colleagues to write a similarly critical letter that said, in part:

This controversy has alarmed some of the parents of infants who were in the study, confused the biomedical research community, and befuddled IRBs. Several other studies seeking new insights to improve care for these vulnerable infants have been put on hold as the field tries to understand the OHRP findings.

The two letters appear online today in the New England Journal of Medicine (NEJM), and constitute a remarkably intense criticism of the OHRP, the agency within the U.S. Department of Health and Human Services responsible for overseeing the safety and well-being of human research subjects.

I’ve been following the developing story with the help of Stanford bioethicist David Magnus, PhD, who was one of the writers of the bioethicists’ letter. Last week, before the agency revised its stance, Magnus summarized what the bioethics community found objectionable about the OHRP’s sanctions: “They believe in an absolute interpretation of risk,” he said. The agency’s risk assessment was based “not [on] what kids who are actually sick would be exposed to, but what a healthy child would be exposed to.” Healthy babies born at term face much lower risks of severe eye disease, neurological damage and death than the babies in the study – but the tiny preemies in the study weren’t healthy term infants, and were not placed at additional risk, the bioethicists assert, because of their participation in the study.

The tussle has a complex back story that involves 1,300 fragile premature infants, their parents, 23 academic medical centers and an important piece of paperwork.

Continue Reading »

NIH, Research, Science, Science Policy

Shortfall of physician-scientists: “A national concern”

Shortfall of physician-scientists: "A national concern"

The importance of the physician-scientist is the focus of a new Perspective piece in the New England Journal of Medicine. Writing that an increasing number of MDs have moved away from the laboratory and into clinical practice, and calling the shortfall of new physician-researchers a “national, if not global, concern,” Michael M. Gottesman, MD, outlines how the National Institutes of Health is working to reverse the trend. And he notes that the awarding of the 2012 Nobel Prize in Chemistry (which went to Robert Lefkowitz, MD, and Stanford’s Brian Kobilka, MD, both trained in cardiology) “should remind us of the critical role that clinician-scientists have played in formulating the seminal concepts that govern modern biomedical science.”

Previously: Funding basic science leads to clinical discoveries, eventually, Why basic research is the venture capital of the biomedical world, At press conference, Nobel Laureate Brian Kobilka discusses his research and “irrational optimism” and Stanford’s Brian Kobilka wins 2012 Nobel Prize in Chemistry

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