Exercise physiologist Peter Janiszewski, PhD, wrote yesterday for the PLoS blog Obesity Panacea about a fantastic video that my colleague posted here last month. The video comes from the University of Toronto’s Mike Evans, MD, an associate professor of family medicine and public health at the university and a staff physician at St. Michael’s Hospital in Toronto. According to Evans’ bio:

My interests are in evaluating sustainable interventions that make for more informed health decisions. My target has traditionally been the primary care provider, but now has developed more into targeting the patient in the clinic or at “the kitchen table”. Specifically, what is the best way to bring together academic evidence-based information with the common media that people use (TV, news, print, social networks, Dr. Google, email, etc.). I also have a significant interest in shinny hockey, but am still working on a research angle.

I’d say this kitchen-table approach is working: The video has been viewed over a million times and has garnered 13,000 ‘likes’ on YouTube, and its popularity was featured on CBC last week. As for me, I just got around to watching the entire 10 minutes and am now planning to sneak out to the gym – that is, after I start following “Dr. Mike” on Twitter (@docmikeevans).

Previously: Fitness research: A year in review, What you can do in thirty minutes per day and How sedentary behavior affects your health

Tumor suppressors are potent cancer fighters. These molecules are primed to note a cell’s behavior and to stop its division, or even trigger a suicide program, if it violates certain predetermined cellular rules. Many powerful tumor suppressors were first identified because they were missing or mutated in cancerous cells, but some have continued to fly under the radar. Now Stanford researchers have identified a protein complex that appears to function as a tumor suppressor in pancreatic cancer. From our release:

A well-known protein complex responsible for controlling how DNA is expressed plays a previously unsuspected role in preventing pancreatic cancer, according to researchers at the Stanford University School of Medicine.

Technological advances in the way researchers can compare normal and tumor DNA showed that the gene for at least one subunit of the multi-subunit SWI/SNF protein complex was either deleted, mutated or rearranged in about a third of the 70 human pancreatic cancers that the Stanford team examined. Additionally, the researchers found that restoring the expression of one of the missing genes slowed the growth of pancreatic cancer cells in the laboratory and caused them to enter an arresting state called senescence. [...]

The tumor-suppressing role of the SWI/SNF complex had not been previously discovered because the disabling changes were spread among five of the complex’s protein subunits. In other words, one person’s pancreatic cancer might have a mutation or deletion in one protein subunit, while another’s could have a change in a different subunit. Considered individually, each variation occurs relatively infrequently.

The research, conducted by graduate student Hunter Shain and pathologist Jonathan Pollack path, MD, PhD, was published today in the Proceedings of the National Academy of Sciences. They are hopeful that the identification of SWI/SNF’s tumor suppressing function may contribute to new ways to fight the deadly disease.

Validation is always a good thing, whether in our personal or professional lives. It shows we’re on the right track. Even research studies need ways to compare their findings with studies that use similar methods and to confirm their conclusions. But that can be difficult to do when the technology or concepts are very new. Stanford researcher John Ioannidis, MD, DSc, chief of the Stanford Prevention Research Center talks about the problem, and offers some possible solutions, in a perspective (registration required) in today’s Science magazine:

The exponential growth of the “omics” fields (genomics, transcriptomics, proteomics, metabolomics, and others) fuels expectations for a new era of personalized medicine. However, clinically meaningful discoveries are hidden within millions of analyses. Given this immense biological complexity, separating true signals from red herrings is challenging, and validation of proposed discoveries is essential

Ioannidis co-authored the piece, which appears in a special issue of the magazine on data replication and reproducibility, with researcher Miun Khoury, MD, PhD, from the CDC’s Office of Public Health Genomics. The two researchers suggest applying a multi-step way to validate large studies, including assessing the analytic validity, repeatability, replication, external validation, clinical validity and clinical utility of the studies. The authors conclude:

One may argue that this is not easy because of technical and cost considerations. However, similar arguments were made for fields such as human genome epidemiology, which then saw the cost of DNA sequencing decrease over a billionfold over the past 20 years and the amount of information increase proportionally. Costs could decrease for other technologies as technologies attract the attention of many investigators, especially in large consortia, thereby driving data reproducibility in a field. Funding incentives, reproducibility rewards and/or nonreproducibility penalties, and targeted requirements for repeatability checks may enhance the public availability of useful data and valid analyses.

As a former graduate student, I found this round-up of advice for graduate students really interesting. Says Travis Saunders, who co-hosts the smart and topical PLOS blog Obesity Panacea:

Grad school is not always an easy ride. In fact, it can sometimes be a soul-sucking experience. But it can also be an incredibly fulfilling experience that leaves you waking up excited to head to the lab every morning (seriously!)

Saunders, who is himself a graduate student, goes on to talk about his involvement in the blog roundtable organized by fellow blogger Atif Kukaswadia. Topics include how to choose an adviser, what to do if you’re falling behind or losing interest in your research project, and what it takes to be a successful graduate student. The series of posts is over, but Kukaswadia is encouraging current and former graduate students, as well as faculty members who serve as mentors to maintain the discussion in the posts’ comment threads. Says Saunders:

If you have even a passing interest in grad school, then take a few minutes and read through the posts that sound most relevant to you. The posts are broken down into easily-digestible chunks, so you can get through them all rather quickly. And if you’ve already played the grad school game or have gone on to *gasp* supervise grad students, then please add your own two cents in the comments section.

At the risk of being overly depressing, we’re all getting older. And there’s more to bemoan than just the gray hairs and wrinkles that might be popping up. Every cell in our body is aging, including the hematopoietic stem cells that generate our blood cells and immune system. According to our release:

Specifically, the researchers found that hematopoietic stem cells from healthy people over age 65 make fewer lymphocytes — cells responsible for mounting an immune response to viruses and bacteria — than stem cells from healthy people between ages 20 and 35. (The cells were isolated from bone marrow samples.) Instead, elderly hematopoietic stem cells, or HSCs, have a tendency to be biased in their production of another type of white blood cell called a myeloid cell. This bias may explain why older people are more likely than younger people to develop myeloid malignancies.

It could also be why elderly people find it hard to shake off colds, flu and other viruses, say graduate student Wendy Pang, MD and stem cell biologist Irving Weissman, MD, who co-authored the study in today’s Proceedings of the National Academy of Sciences.

“In both mice and humans, the puzzle has been how the system ages,” said Weissman, who is also the Virginia & D.K. Ludwig Professor for Clinical Investigation in Cancer Research and a member of Stanford’s Cancer Institute. “Because HSCs in old mice and humans are derived from the HSCs they had in their youth, there are two possibilities to describe how these differences occur. Either individual, young HSCs change their gene expression patterns as they age, undergoing heritable adaptations that favor the myeloid lineage, or each young HSC already has a specific lineage bias and is battling for precious niches through the natural selection of aging, which favors those biased toward myeloid cells.” Understanding which possibility is true could help clinicians of the future encourage the survival of HSCs with more-appropriate properties in patients with age-related diseases, Weissman believes.

Previously Freshen up those stem cells with young blood

Anyone interested in the trials and tribulations of bringing a new cancer therapy to market, and keeping it there, is likely already aware of the fate of Genentech’s Avastin. Last Friday, the FDA revoked its approval of the use of the drug to treat metastatic breast cancer, to the dismay of many patients and their advocates. The revocation was based on studies showing that the drug, which can have serious side effects, failed to help patients live longer.

FDA Commissioner Margaret Hamburg, MD, issued a 69-page document explaining her decision. Today David Kroll, author of the PLoS Blog Take as Directed, called my attention to the fact that the lengthy document includes a good Q&A about the issue to help patients and their physicians understand what the new ruling means to them. Topics include whether physicians can continue to prescribe the drug for metastatic breast cancer, how the FDA ensured that Avastin got a fair hearing, and whether it’s possible that Avastin could again be approved at some point in the future for use in breast cancer patients.

You can read the full Q&A on Kroll’s blog post, or find it in the opening pages of the FDA document

The National Academy of Sciences has released a report recommending the development of a new tool linking diseases with molecular and genetic data to help clinicians and researchers. The concept has been termed “precision medicine” and it calls for a revamping of the 100-year-old diagnostic practice of simply matching up symptoms with diseases. As explained in ScienceInsider:

Precision medicine is already emerging in cancer diagnosis and treatment, the report says: some patients now receive drugs matched to a specific molecular marker in their tumor, and relatives can be tested for certain cancer risks. By contrast, a middle-aged man diagnosed with type II diabetes typically receives a 50-year-old drug that may or may not help him. And no type II diabetes risk tests are available for family members.

What’s needed, the report says, is for patient’s health records to be combined with layers of genomic and other molecular measurements, such as blood proteins and the microbes in a patient’s gut. Like the GPS data used to make Google maps, these data could be plumbed in detail by researchers and used more superficially by others, such as doctors to treat patients, the report says. Separate databases would be combined to form a single network.

The data bank would also be a boon to researchers seeking to identify shared molecular threads that link different conditions. However, the effort is likely to take decades and may require new, more permissive attitudes about patient privacy, notes Nature News today. Stanford’s Stephen Galli, MD, who chairs the department of pathology, was a member of the committee that wrote the report. Galli also co-directs the Stanford’s Center for Genomics and Personalized Medicine.

Previously: New Stanford genomics center to bring personalized medicine to patients

The beta cells of the pancreas are the only cells in your body that can produce insulin. While beta cells proliferate robustly in newborn and very young animals, they stop growing in adults. Developmental biologist Seung Kim, MD, PhD, describes why in a paper (subscription required) published today in Nature. From our release:

The researchers found that, in mice and humans, the pathway is governed by the expression of a molecule called platelet-derived growth factor receptor. PDGF-receptor expression declines over time in mice and humans in a pattern that parallels the decrease in the proliferation of pancreatic beta cells, which produce insulin to control blood sugar levels.

Figuring out a way to artificially activate the PDGF receptor pathway in adults could possibly lead to new treatments for diabetes, the researchers say:

“We’re hopeful that soon we might be able to manipulate this pathway in a therapeutic way in humans,” said professor of developmental biology Seung Kim, MD, PhD, “perhaps by rekindling its expression and then activating it through a drug we could give in an injection or through some other route. This could be a kind of one-two punch against diabetes.”

Photo by Seung Kim and Hainan Chen showing an increase in beta cell mass and number after PRGF receptor stimulation

Happy International Stem Cell Awareness Day! Researchers from the New York Stem Cell Foundation are celebrating by publishing (subscription required) the first reports of human stem cell lines created through a technique called somatic cell nuclear transfer, or SCNT. Although the technique is similar to that used to clone Dolly the sheep in 1996, the resulting human embryonic stem cell lines have three copies of each gene, rather than the normal two. As a result, they can not be used for therapies. But the research is an important proof of principle that will set the stage for future work, said study co-author Scott Noggle, PhD, in a press briefing yesterday:

The goal of this research was to create patient-specific embryonic stem cells. We have shown for the first time that the human oocyte has the capacity to reprogram somatic nuclei to a pluripotent state.

To conduct the research, Noggle and Dieter Egli, PhD, used donated human eggs. They first tried removing the eggs’ own haploid genomes (as reproductive cells, eggs and sperm each have one half the normal complement of genetic material) and replacing it with the nuclei of a somatic, or specialized adult, cell. They found that the resulting cell underwent only a few cell divisions before halting. When they simply added the somatic nuclei to the eggs, they had much better luck: the cell went on to form a multi-cellular structure called a blastocyst, from which Noggle and Egli successfully prepared human embryonic stem cell lines with three, rather than two, copies of each gene. Says Egli:

We are now trying a number of approaches to remove the egg genome. Although the long-term goal is to generate cells for use in therapies, we can use these cells now for several important studies, including comparing them to human iPS cells.

iPS cells are pluripotent cells created from somatic cells by using viruses or other genetic manipulation. While they, like cells derived from SCNT, can be generated from the patient they are meant to treat (and thus should not generate an immune response), researchers agree that they are not genetically identical to true embryonic stem cells and more research is needed to determine their therapeutic usefulness.

The full study requires a subscription to access. But you can read a nice review of the work in today’s Nature News.

Brendan Maher has a fantastic story out this morning in Nature News about using whole genome sequencing in the clinic. The article reviews some of the technique’s successes (mostly in finding the causes of rare, inherited diseases or cancers) while pointing out hurdles that still need to be overcome:

…unlike the results of most medical tests, a genome sequence provides a vast amount of difficult-to-interpret data, not all of which will be necessary for diagnosing or treating the patient’s condition and which could provide unwanted clues to future health risks. The few success stories published so far also suggest that wringing information from the human genome and counselling patients and their families adequately may be too big a burden for medical systems that are already stretched to their limits. “You can’t immediately jump from those few profound but limited stories and think that you can reduce this to practice for clinical care,” says Eric Green, director of the National Human Genome Research Institute (NHGRI) in Bethesda, Maryland.

There are also regulatory issues that need to be ironed out:

Moving whole-genome sequencing from research to clinic is beset with challenges. Unlike in research, DNA sequencing that is intended to inform a diagnosis must be done in accredited laboratories, such as those used by Illumina. The institutional review boards that oversee research in humans have not reached a consensus on whether approval is needed for clinical genome sequencing; and the US Food and Drug Administration is yet to work out how to regulate the coming wave of clinical sequencing.

Previously: Researchers analyze family’s whole genome sequences, predict members’ inherited health risks, Economic impact of human genome sequencing, Stanford researchers work on ‘molecular autopsies’ and Whole genome sequencing data vaults into clinic

On Saturday, Stanford and Santa Clara Valley Medical Center (SCVMC) treated the fourth of ten patients in Geron’s trial of cells derived from human embryonic stem cells. The patient is the first on the West Coast to receive the treatment, which is intended to test the safety of the procedure in paralysis patients before moving into larger trials. Stanford neurosurgeon Gary Steinberg, MD, PhD, implanted the cells.

From our release:

“We are extremely excited to participate in this landmark clinical trial,” said Steinberg, who is the Bernard and Ronni Lacroute-William Randolph Hearst Professor in Neurosurgery and Neurosciences at Stanford and the principal investigator of the Stanford/SCVMC portion of the trial. “It signifies a major advance in translating an innovative research discovery into clinical therapy. I believe it is critically important to encourage and take part in stem cell trials like this, which represent a new era in the effort to restore function for patients with stroke, brain injury, Parkinson’s disease and other devastating neurologic disorders.”

Those sentiments were echoed by Stephen McKenna, MD, chief of the Rehabilitation Trauma Center at SCVMC. “It has been an extraordinarily collaborative process at every step, from developing the screening process and identifying possible patients to evaluating these patients for surgery,” McKenna said. “Although it’s been an intensive commitment of resources, we understand the importance of advancing new therapies for patients.”

The trial is being run by Geron Corp. of Menlo Park, Calif., which developed and manufactures the cells being tested. In May, Geron received a $25 million grant from the California Institute for Regenerative Medicine to continue and extend the trial to include a greater proportion of spinal cord injuries.

The patient entered an intensive inpatient rehabilitation program at SCVMC and will be monitored for any adverse events to confirm that the cells are safe for use in humans.

Previously: Stanford joins first human embryonic stem cell trial
Photo of Steinberg by Mark Tuschman

I’m deep in the throes of writing my article for the next issue of Stanford Medicine, and this post at Science-Based Medicine caught my attention. I’m working on a comprehensive review of the state of cancer research and therapies in the country (yeah, not intimidating at all), and one issue I’ve been pondering is the shocking problem of how many oncology medications are in scarce supply – or even unavailable – in the United States. It’s estimated that over 180 drugs are affected and the problem isn’t going away. The numbers reached a high in the first part of 2011. Some of these medications aren’t even being made available to new cancer patients at all, in order to increase the chances that current recipients will have what they need to finish their treatments.

I really had no idea.

The possible reasons for this problem are many, according to the post’s author, pharmacist Scott Gavura. And the complex regulatory system in our country means there’s no easy fix:

While there is no shortage of policy papers, summits and calls for greater (or reduced) regulation, there’s been very little concrete action taken to actually solve the problem. And that’s because no group, agency or even country has control and influence over the entire supply chain. And more importantly, no group or regulator has the responsibility for ensuring that shortages don’t occur.

Gavura’s commentary was especially interesting to me because it builds on, and somewhat refutes, a recent opinion piece in the New York Times by former White House adviser Ezekiel Emanuel. In the Aug. 6 column, Emanuel concludes that the shortage is primarily due to dysfunctional reimbursement policies proscribed by the Medicare Prescription Drug, Improvement and Modernization Act of 2003:

It required Medicare to pay the physicians who prescribed the drugs based on a drug’s actual average selling price, plus 6 percent for handling. And indirectly — because of the time it takes drug companies to compile actual sales data and the government to revise the average selling price — it restricted the price from increasing by more than 6 percent every six months.

The act had an unintended consequence. In the first two or three years after a cancer drug goes generic, its price can drop by as much as 90 percent as manufacturers compete for market share. But if a shortage develops, the drug’s price should be able to increase again to attract more manufacturers. Because the 2003 act effectively limits drug price increases, it prevents this from happening. The low profit margins mean that manufacturers face a hard choice: lose money producing a lifesaving drug or switch limited production capacity to a more lucrative drug.

Gavura argues that, because drug shortages are occurring all over the world, it’s incorrect to place all the blame on American drug reimbursement policies. He analysis is extensive, and well worth reading if you’re interested in the topic (or looking to procrastinate writing that big, intimidating article). The comment thread is also quite lively. Enjoy!

Photo by Brian J. Matis (Thanks, Brian!)

Although you may not know it, mammals (even humans!) can regrow small portions of amputated digits like fingers and toes. This remarkable ability has perplexed scientists for some time, as they pondered whether it was due to the presence of already-existing adult stem cells in each of the various tissues that make up the end of a finger (blood vessels, bone, skin and tendons, for example), or if specialized cells near the site of injury were somehow able to regress developmentally and gain the capacity to become many different tissue types. As described in our release today:

[The researchers...] have shown that damage to a digit tip is repaired by specialized adult stem cells that spend their lives quietly nestled in each tissue type. Like master craftsmen, these cells spring into action at the first sign of damage, working independently yet side-by-side to regenerate bone, skin, tendon, vessels and nerves. But just as you wouldn’t ask a mason to wire your house, or an electrician to put on a new roof, the division of labor among these stem cells is strict. Each is responsible solely for its own tissue type.

In contrast, the blastema theory invokes a new pluripotent cell type formed out of urgency from previously specialized cells. This jack-of-all-trades cell discards its former profession and instead jumps in to indiscriminately regenerate all the tissue types of the limb.

The work was performed by postdoctoral scholar Yuval Rinkevich, PhD, in the laboratory of Irving Weissman, MD. Weissman had this to say about the findings:

We’ve shown conclusively that what was thought to be a blastema is instead simply resident stem cells that are already committed to become specific tissue types. The controversy about limb regeneration in mammals should be over.

According to Weissman, the study is particularly important because, in the past, some scientists and national media reports have championed the idea that money allotted by the California Institute for Regenerative Medicine for stem cell studies would have been better funneled to blastema research.

Photo by Yuval Rinkevich

You’ve probably already heard about the big news in the cancer world: Researchers at the University of Pennsylvania used gene therapy to successfully treat three patients with chronic lymphoblastic leukemia. As described by Robert Bazell at MSNBC.com:

In the Penn experiment, the researchers removed certain types of white blood cells that the body uses to fight disease from the patients. Using a modified, harmless version of HIV, the virus that causes AIDS, they inserted a series of genes into the white blood cells. These were designed to make to cells target and kill the cancer cells. After growing a large batch of the genetically engineered white blood cells, the doctors injected them back into the patients.

Two of the three patients are cancer-free one year after their treatment; the amount of cancer cells in the third patient diminished significantly. Bazell quotes Stanford immunologist Edgar Engleman, MD, as saying the results were “remarkable.”

Stanford oncologist and cancer vaccine specialist Ronald Levy, MD, agrees that the research showcases an exciting way to harness the power of the immune cells to fight cancers. In fact, many groups around the world are working on variations of the technique, he told me. In particular, Stanford is currently conducting a clinical trial in patients with lymphoma that may be even more amenable for wide-spread use:

Rather than using gene therapy – which requires the efficient expression of a foreign gene designed in the laboratory – to get the T cell to attack and kill tumor cells, we vaccinate the patient with proteins expressed on the surface of their lymphoma cells. We then remove and isolate the resulting T cells, which have been naturally primed to attack the tumor. These cells are then returned to the patient after radiation treatment, where they proliferate and kill tumor cells. This may be a much more practical way to generate cancer-specific T cells.

I’ve written before about Levy’s work to recruit the immune system to fight lymphoma. It’s exciting to realize that these methods are one step closer to helping patients with cancer.

I wrote yesterday about the dismissal of the lawsuit against federal funding for human embryonic stem cell research. Now Stanford law professor and bioethicist Hank Greely, JD, has an in-depth look at the case and what could come next:

I thought this was a graceful, gracious, and fully professional opinion by Judge Lamberth.  The poor man had been been reserved twice by the DC Circuit, in different directions.  He did not attempt to play games with the latest Circuit decision and follow its letter while avoiding its intent.  While making it clear that he thought he had been right, he did what a judge is a supposed to do in applying the law in light of his position in the judiciary hierarchy.

As a former scientist and science writer, it’s really fascinating to view the legal side of how court cases like these work. I’m learning a lot about the judicial process. And it appears my education isn’t over yet, according to Greely, who asks:

So now what?

The plaintiffs could do four things:

1.   Ask Judge Lamberth to reconsider his decision:   Good luck with that.

2.  Appeal to the DC Circuit:  I think this is likely.

3.  Ask the US Supreme Court to take the case directly:  Good luck with that, too – the Court does that very rarely and only in real emergencies.

4  Quit:  I doubt it.

It looks like an appeal could drag out this process even longer–as detailed in Greely’s post. But I can’t leave you this time without also calling attention to a related post today on Science Progress by Jonathan Moreno:

Stepping back from this legal meandering, the larger importance of this incident lies in the fact that only research on biology has been subject to such a challenge. Even at the fever pitch of our culture wars, no advocates have thought to bring suit against the federal government for funding, say, geological studies that confirmed that the earth is more than 6,000 years old. Indeed, from the infamous Scopes “monkey” trial to present-day creationism lawsuits, biology (in particular, the teaching of evolution) has been the wedge into literal readings of the Biblical period of creation. The fact is that modern biology is threatening in ways that the physical sciences are not, a challenge for a country that is both founded on the promise of science and needs science to sustain its leadership role in the 21st century.

As a church-going, science-loving believer of evolution and biology (hey, we do exist!), I say Amen to that. But it’s a challenge that can be overcome. Right?

Previously: Judge Lamberth dismisses stem cell lawsuit, Stem cell funding injunction overturned by federal court and NIH intramural human embryonic stem cell research halted