Published by
Stanford Medicine

Category

Science

Neuroscience, Podcasts, Science, Stanford News

Stanford neurobiologist Bill Newsome: Seeking gains for the brain

Stanford neurobiologist Bill Newsome: Seeking gains for the brain

14601014695_30cfe1972d_zBill Newsome, PhD, knows the brain perhaps as well as the back of his hand. The Stanford neurobiologist was vice chair of the federal BRAIN Initiative launched by President Obama, and he directs the Stanford Neurosciences Institute. From that spot, he’s just funded a first round of interdisciplinary grants to Stanford faculty that he calls “risk taking.”  The need, he told me in this just-published 1:2:1 podcast, is critical:

When biomedical research money gets tight, as it now is, the funding agencies tend to get conservative. Right now we have these talented faculty at Stanford, many of them young faculty. They’re at the most creative parts of their career.  They’re at a place where they’re thinking big and dreaming big. We wanted to create this mechanism to allow them to do that.

I asked Newsome about the greatest challenges for neuroscience in the next few years. He had one word: technology. “If we were to improve the technology… If we could read out signals from the human brain and read in signals, actually do the circuit-tuning in the human brain non-invasively, at a spatial scale on the order of a millimeter or less and with fairly rapid time, it would revolutionize neuroscience,” he said.

So paint the picture, I asked, and  look ten years out. What would you like to see as far as progress? He told me:

I would like to see fundamental, substantive change on at least one devastating neurological or psychiatric disease. I don’t really care which one. Give me Alzheimer’s. Give me autism. Give me depression. Give me Parkinson’s disease. At the end of 10 years, if we can really have a breakthrough in the understanding of what causes one of those diseases mechanistically and have a therapy that dramatically improves people’s lives… I would say, ‘It’s worth it. We’ve done our job.’

Any worries or words of caution? He laments the current state of federal funding for science and worries that fiscal constraints will squeeze out young star scientists. “How do you keep convincing talented people to come into the field?” he said. “We’re deprioritizing science… How do we convince our brightest, our best, that this is a field with a really bright future?”

Previously: Deciphering “three pounds of goo” with Stanford neurobiologist Bill Newsome, Neuroscientists dream big, come up with ideas for prosthetics, mental health, stroke and more, BRAIN Initiative and the Human Brain Project: Aiming to understand how the brain works, Brain’s gain: Stanford neuroscientist discusses two major new initiatives and Co-leader of Obama’s BRAIN Initiative to direct Stanford’s interdisciplinary neuroscience institute
Photo by Allan Ajifo

History, Neuroscience, Research, Science, Stanford News

Illustration from 1881 resolves century-old brain controversy

Illustration from 1881 resolves century-old brain controversy

Figure2_WernickeThese days, a person can get through graduate school in the sciences practically without touching a physical publication. Most journals are available online going back decades. So it was a bit unusual when graduate student Jason Yeatman and postdoctoral scholar Kevin Weiner found themselves in the basement of Lane Medical Library trying to get to the bottom of a medical mystery.

It all started when Yeatman found a nerve pathway in brain images he’d taken as part of his work studying brain changes as kids learn to read.  This pathway didn’t appear anywhere in the available literature. He and Weiner became curious how this pathway – which clearly showed up in their work – could have escaped the notice of previous neuroscientists.

Their curiosity eventually led them back to an 1881 publication, still available in the basement of Lane Medical Library, where Carl Wernicke, MD, described identifying this brain pathway. Weier said, “That was a really cool experience that most people don’t have anymore, when you have to check your belongings at the door because the book you are about to look at is worth thousands of dollars per page. You are literally smelling 100 year-old ink as you find the images you have been searching for.”

Wernicke’s discovery contradicted theories by the eminent neuroanatomist at the time, Theodor Meynert, MD. I describe the controversy that led to this pathway expulsion from the literature in this Stanford News story:

Meynert strongly believed that all of the brain’s association pathways run from front to back – horizontal. This pathway, which Wernicke had called the vertical occipital fasciculus, or VOF, ran vertically. Although Yeatman and Weiner found references to the VOF under a variety of different names in texts published for about 30 years after Wernicke’s original discovery, Meynert never accepted the VOF and references to it became contentious before eventually disappearing entirely from the literature.

The group, whose work was published this week in the Proceedings of the National Academy of Sciences, says this was all more than just an exercise in curiosity. Psychologist Brian Wandell, PhD, in whose lab Yeatman was working, says it also shows the value of modern publishing methods, where making data available means scientists worldwide can try to reproduce results. He says it’s now less likely that a dispute could lead to a discovery being lost to history.

Image courtesy of PNAS

Genetics, NIH, Research, Science, Stanford News, Technology

Of mice and men: Stanford researchers compare mammals’ genomes to aid human clinical research

Of mice and men: Stanford researchers compare mammals' genomes to aid human clinical research

Scientists have long considered the laboratory mouse one of the best stand-ins for researching human disease because of the animals’ genetic similarity to humans. Now Stanford researchers, as part of a consortium of more than 30 institutions, have confirmed the mouse’s utility in clinical research by showing that the basic principles controlling genes are similar between the two species. However, they also found some important differences.

From our press release on the work:

“At the end of the day, a lot of the genes are identical between a mouse and a human, but we would argue how they’re regulated is quite different,” said Michael Snyder, PhD, professor and chair of genetics at Stanford. “We are interested in what makes a mouse a mouse and a human a human.”

The research effort, Mouse ENCODE, complements a project called the Encyclopedia of DNA Elements, or ENCODE, both funded by the National Human Genome Research Institute. ENCODE studied specific components in the human genome that guide genes to code for proteins that carry out a cell’s function, a process known as gene expression. Surrounding the protein-coding genes are noncoding regulatory elements, molecules that regulate gene expression by attaching proteins, called transcription factors, to specific regions of DNA.

The Mouse ENCODE consortium annotated the regulatory elements of the mouse genome to make comparisons between the two species. Because many clinical studies and drug discovery use mice as model organisms, understanding the similarities and differences in gene regulation can help researchers understand whether their mouse study applies to humans.

Continue Reading »

Big data, Cardiovascular Medicine, Chronic Disease, Research, Science, Stanford News, Videos

Big data approach identifies new stent drug that could help prevent heart attacks

Big data approach identifies new stent drug that could help prevent heart attacks

Ziad Ali, MD, PhD, was a cardiovascular fellow at Stanford with a rather unique skill when a 6-year study published today online in The Journal of Clinical Investigation first began.

The multi-talented physician-scientist – who is now associate director of translational medicine at Columbia University Medical Center – had figured out a way to put tiny little stents into mice with clogged arteries as a PhD student.

The skill would become key as he and colleagues set out to find a better pharmaceutical for the drug-eluting stents that are used in combination with angioplasty to treat coronary artery disease. In order to prevent stent disease, the often serious medical problem caused by stents themselves, chemotherapy drugs were added to bare metal stents. But these drug-eluting stents have their own problems: The drugs work like “hitting a pin with a sledgehemmer,” as Ali describes it, often damaging the lining of the arteries which can lead to heart attacks. As a result, patients are required to take blood thinners for up to a year after the procedure to prevent clots.

“A lot of our patient population is on the elderly side with bad hips or diabetes,” Ali told me. “Once you get a drug-coated stent, you can’t have surgery for a year. And if you stop the blood thinners for any reason, you’re at risk of a stent clotting off. And that actually causes a heart attack. Stent thrombosis has a high mortality rate.”

By using a “big data” computational approach, learning about the genetic pathways involved in coronary artery disease, then testing the new theories on mice models in the lab, researchers were able to pinpoint a potential new treatment for patients: Crizotinib, a pharmaceutical approved by the FDA for treatment in certain cases of lung cancer.

“This could have major clinical impact,” Euan Ashley, MD, PhD, senior author of the study, who discusses the work alongside Ali in the video above, said.

Previously: Euan Ashley discusses harnessing big data to drive innovation for a healthier world, New computing center at Stanford supports big data, Trial results promising for new anti-clotting drug and A call to use the “tsunami of biomedical data” to preserve life and enhance health
Photo in featured entry box by Mark Tuschman

Events, In the News, Research, Science, Stanford News

Breaking through scientific barriers: Stanford hosts 2015 Breakthrough Prize winners

Breaking through scientific barriers: Stanford hosts 2015 Breakthrough Prize winners

6018618935_38997291a8_zYoung scientists, I have good news: Nearly all of the 2015 winners of the Breakthrough Prize in Life Sciences pledged to devote at least some of their new-found riches to education programs that encourage budding scientists. No details yet, as the prizes were less than a day old when the researchers announced their plans at the Breakthrough Prize Life Sciences Symposium hosted by Stanford  yesterday.

“The Breakthrough Prize winners have done such amazing things,” said Lloyd Minor, MD, dean of the School of Medicine. Minor lauded the  founders of the award, Silicon Valley luminaries Sergey Brin and Anne Wojcicki, Jack Ma and Cathy Zhang, Yuri and Julia Milner, and Mark Zuckerberg and Priscilla Chan. “They have put together this wonderful way of rewarding and awarding scientists for the work they are doing. It’s a real privilege for us at Stanford to host the symposium.”

The six scientists, who each won a $3 million award, fielded questions and let the audience in on a secret: the path toward scientific success wasn’t always easy.

“I would have never, ever in a million years have predicted I would have been sitting up here,” said C. David Allis, PhD, a professor at The Rockefeller University who was honored for his discoveries in chromatin biology, or the study of the proteins associated with DNA. Chromatin was once thought to be useless and Allis said he received plenty of criticism about his research focus.

Jennifer Doudna, PhD, a professor of molecular and cell biology and chemistry at UC Berkeley, said she didn’t know any scientists growing up in Hawaii. It wasn’t until a cancer researcher visited her high school, giving Doudna her first glimpse at her future career. Doudna, who is also affiliated with the Howard Hughes Medical Institute and the Lawrence Berkeley National Lab, won along with microbiologist Emmanuelle Charpentier, PhD, for their work on genome editing. Charpentier leads the department of regulation in infection biology at the Helmholtz Centre for Infection Research in Germany.

Gary Ruvkun, PhD, said that although he’s a professor of genetics at Harvard Medical School and the Massachusetts General Hospital, he still hasn’t mastered the art of mentoring. “I’ve had people in my lab refer to me as the least grown up,” he said.  Ruvkun was recognized — along with molecular biologist Victor Ambros, PhD, of the University of Massachusetts Medical School — for their work on microRNAs, small pieces of RNA that regulate gene expression.

All of the winners thanked their family, mentors, colleagues, but Alim Louis Benabid, MD, PhD, thanked his patients as well. Benabid, board chairman of the Clinatec Institute in France, said many patients are embarrassed when their doctor asks them to take off their clothes. His patients let him stick his fingers in their brains, he joked. Benabid was honored for demonstrating that deep brain stimulation can alleviate some symptoms of Parkinson’s disease.

In the full-day symposium, several former Breakthrough Prize winners spoke, and Bay Area graduate students and postdocs hosted a poster session.

Previously: Are big-money science prizes a good thing?, Funding basic science leads to clinical discoveries, eventually and Why basic research is the venture capital of the biomedical world
Photo by Petras Gagilas

Aging, NIH, Public Health, Research, Science, Stanford News

Tick tock goes the clock – is aging the biggest illness of all?

Tick tock goes the clock - is aging the biggest illness of all?

3821120232_d1452b4109_zIt’s an uncomfortable truth that aging is the single biggest risk factor for many chronic diseases. It’s also completely out of our control. (The alternative is, well, not so fun to contemplate.) But although we all think we’d like to live longer, longevity in and of itself is not necessarily a good thing. Living longer rapidly loses its appeal if you’re too sick or feeble to really enjoy your extra “golden” years.

But researchers from many scientific disciplines are now working to understand how and why our bodies tend to break down as time passes. The Trans-NIH Geroscience Interest Group (a group of researchers from numerous NIH institutes) interested in aging held a summit in 2013 to explore mechanisms of aging and identify common themes that could serve as research targets. The thought is that understanding, and slowing, aging may be an efficient way to tackle many chronic diseases simultaneously.

Now the group, which includes Stanford geneticist Anne Brunet, PhD; neurologist Tony Wyss-Coray, PhD; and Thomas Rando, MD, PhD, has released the conclusions of the summit and outlined a plan for the work that lies ahead. (Rando is the director of the Glenn Center for the Biology of Aging at Stanford.) Many of the findings focus  on a concept called “healthspan,” which designates the portion of a person’s lifespan in which he or she is relatively healthy and fully functional. From the Cell article:

While life expectancy continues to rise, healthspan is not keeping pace because current disease treatment often decreases mortality without preventing or reversing the decline in overall health.  Elders are sick longer, often coping with multiple chronic diseases simultaneously.  Thus, there is an urgent need to extend healthspan.

The researchers identified seven intertwined “pillars of aging” for targeted research, including adaptation to stress, stem cells and regeneration, metabolism, macromolecular damage, inflammation, epigenetics and a concept called proteostasis, which describes the intricate dance in which proteins are made, transported and degraded within a cell. They suggest the creation of an Aging Research Initiative that works to merge the emerging field of geroscience with research on chronic disease and to search for therapeutic interventions that could extend both lifespan and healthspan.

Continue Reading »

Genetics, History, Immunology, Research, Science, Stanford News

Knight in lab: In days of yore, postdoc armed with quaint research tools found immunology’s Holy Grail

Knight in lab: In days of yore, postdoc armed with quaint research tools found immunology's Holy Grail

charging knightA human has only about 25,000 genes. So, it’s tough to imagine just how our immune systems can manage to recognize potentially billions of differently shaped microbial or tumor-cell body parts. But that’s precisely what our immune systems have to do, and with exquisite precision, in order to stomp invading pathogens and wanna-be cancer cells and leave the rest of our bodies the heck alone.

How do they do it?

Stanford immunologist Mark Davis, PhD, tore the cover off of immunology in the early 1980s by solving that riddle. As I wrote in  “The Swashbuckler,” an article in the latest issue of Stanford Medicine, T cells are one of two closely related, closely coordinated workhorse-warrior cell types that deserve much of the credit for the vertebrate immune system’s knack of carefully picking bad guys of various stripes out of the lineup and attacking them:

[Q]uite similar in many respects, B cells and T cells are more like fraternal than identical twins. B cells are specialized to find strange cells and strange substances circulating in the blood and lymph. T cells are geared toward inspecting our own cells for signs of harboring a virus or becoming cancerous. So it’s not surprising that the two cell types differ fundamentally in the ways they recognize their respective targets. B cells’ antibodies recognize the three-dimensional surfaces of molecules. T cells recognize one-dimensional sequences of protein snippets, called peptides, on cell surfaces. All proteins in use in a cell eventually get broken down into peptides, which are transported to the cell surface and displayed in molecular jewel cases that evolution has optimized for efficient inspection by patrolling T cells. Somehow, our inventory of B cells generates antibodies capable of recognizing and binding to a seemingly infinite number of differently shaped biological objects. Likewise, our bodies’ T-cell populations can recognize and respond to a vast range of different peptide sequences.

In the late 1970s, scientists (including then-graduate student Davis, who is now director of Stanford’s Institute for Immunity, Transplantation and Infection) unraveled the genetic quirks behind B cells’ ability to recognize a mind-blowingly diverse  set of different pathogens’ and tumor-cells’ characteristic molecular shapes. As a follow-on, Davis and a handful of colleagues – working with what would today be considered the most primitive of molecular-biology tools – isolated the gene underlying the T-cell receptor: an idiosyncratic and very important surface protein that is overwhelmingly responsible for T cells’ recognition of myriad pathogen- and cancer-cell-specific peptide sequences. And they figured out how it works.

The result? (Again from my article:)

With the T-cell receptor gene in hand, scientists can now routinely sort, scrutinize, categorize and utilize T cells to learn about the immune system and work toward improving human health. Without it, they’d be in the position of a person trying to recognize words by the shapes of their constituent letters instead of by phonetics.

Previously: Stanford Medicine magazine traverses the immune systemBest thing since sliced bread? A (potential) new diagnostic for celiac disease, Deja vu: Adults’ immune systems “remember” microscopic monsters they’ve never seen before, Immunology escapes from the mousetrap, Immunology meets infotech and Mice to men: Immunological research vaults into the 21st century
Photo by davidmclaughlin

Aging, Men's Health, Research, Science, Stanford News, Stem Cells

Viva la hedgehog! Signaling protein also shown to be important in prostate growth

Viva la hedgehog! Signaling protein also shown to be important in prostate growth

6111053153_5b14f4570d_zOk, so it may *appear* that this post is just an excuse to post a cute hedgehog picture. After all, who could resist that little face? But this is really meant to be a quick shout-out to Stanford developmental biologist Philip Beachy, PhD, who has shown yet again that the signalling protein called hedgehog is critically important during many aspects of development.

In Beachy’s latest work, published earlier this week in Nature Cell Biology, he and his colleagues show that the precise control of when and where the hedgehog protein is made dictates the branching of tubules in the adult prostate (you may remember other recent work from Beachy’s lab about the role that hedgehog plays in bladder cancer, and what that could mean for patients). The findings of the current research suggest that aberrant hedgehog signalling could play a role in the prostatic hyperplasia, or non-cancerous enlargement of the prostate, which often happens as men age.

Previously: Drug may prevent bladder cancer progression, say Stanford researchers, Cellular culprit identified for invasive bladder cancer, according to Stanford study and Bladder infections – How does your body repair the damage?
Photo by Tiffany Bailey

In the News, Science, Videos

Using dance to explain science

Using dance to explain science

Circus enthusiast and University of Georgia PhD candidate Uma Nagendra used her aerial talent to create this year’s winning “Dance Your PhD” video. The contest is sponsored by Science AAAS and challenges scientists to use dance to translate their work. For the contest, Nagendra joined forces with her aerialist colleagues to produce the above video based on her research on how tornadoes can alter the dynamic of the ecosystem.

Science recently reported:

Tornadoes are destructive events, ripping up the surface of Earth, crushing buildings, and tossing automobiles in their paths. And based on some models of climate change, they are likely to become more frequent and damaging. But according to a study of forest soil ecology, tornadoes also do some good—for trees, that is. It turns out that tree seedlings get a respite from certain parasitic fungi in a tornado’s aftermath, allowing them to flourish.

For winning the BIOLOGY category and the overall prize, Nagendra receives $1000 and a free trip to Stanford University in May 2015, where her video will be screened.

Previously: “Dance Your PhD” finalists announced

Research, Science, Stanford News

Putting biomedical research under the microscope

Putting biomedical research under the microscope

microscopeAs an immunology PhD student in the late 1990s, I spent countless hours hunched over cages on the lab bench analyzing the immune cells of mice. I was determined to find something wrong with them. If these gene knockout mice had any discernible abnormality – be it hyperactive T cells or fewer B cells or a bit too much of this molecule or that one – I could submit the data to a scientific journal. And if the paper got published, the world would be enlightened to learn that among the many thousands of proteins out there, this particular one – that one my knockout mouse lacked – was important for doing such-and-such things in such-and-such situations

Alas, there wasn’t a darn thing wrong with those mice. At least nothing I could find.

And so that data remains hidden – tucked within lab binders that got boxed up and hauled across the country days after defending my doctoral thesis. The data resurfaced 11 years later, but only for a few minutes, when it was time to move again and we had to remind ourselves what all lurked within those dusty boxes in the garage.

While preparing for that cross-town move a few months ago, I was working on a story on the inefficiency of biomedical research for the fall issue of Stanford Medicine magazine. I interviewed a handful of scientists who work in this emerging area called meta-research, among them Steven Goodman, MD, PhD, and John Ioannidis, MD, DSc, co-directors of Stanford’s new Meta-Research Innovation Center (METRICS).

In a phone chat with Goodman, I was floored to learn that nearly one-third of clinical trials funded by the NIH Heart, Lung and Blood Institute don’t get published. Much like my ill-fated mouse experiments, that trial data gets stuffed into file cabinets or abandoned on hard drives, never seeing the light of day. And yet these are incredibly costly studies involving hundreds, perhaps thousands, of people, conducted and analyzed with utmost rigor and ethics – and with much more at stake than a few years’ delay on a grad student thesis.

Researchers have studied the impact of this “file drawer problem” – that is, the failure to publish studies that don’t show hoped-for effects. In some cases, it wouldn’t take many “filed” analyses to make a published result statistically non-significant. And media coverage can make matters worse, as the hottest science and medicine stories aren’t generally the ones with the most solid evidence.

Ioannidis has mulled over this, too. In own research, he saw firsthand how often and easily things go wrong, even with the best of intentions. A college math whiz, Ioannidis applied his analytical skills in the realm of biomedicine. Using statistical models, he analyzed how various factors – such as sample size and conflicts of interest – influence the likelihood that a research study will yield a true result. The answer appears in the title of his 2005 PLoS Medicine essay: “Why Most Published Research Findings are False.”

It’s a hard-hitting message. I was curious how people react to Ioannidis’ findings. (He gets more than a thousand lecture invitations per year to proclaim, essentially, that much of the biomedical literature is misleading or wrong.) Are they receptive? Not too surprised? Relieved that researchers are giving serious attention to a problem that’s been around for years? Depressed?

Toward the end of our hour-long conversation, I asked Ioannidis how folks have responded to his lectures. His tongue-in-cheek reply: “The sample of scientists I communicate with is a biased sample. They’re very interested in what I have to say.”

If you’re not yet among the “biased,” check out this video of Ioannidis’ recent talk at Google in Mountain View. Or read my story.

Esther Landhuis, PhD, is a freelance writer.

Previously: Stanford Medicine magazine traverses the immune system, Re-analyses of clinical trial results rare, but necessary, say Stanford researchers, John Ioannidis discusses the popularity of his paper examining the reliability of scientific research, New Stanford center aims to promote research excellence and “U.S. effect” leads to publication of biased research, says Stanford’s John Ioannidis
Illustration by Kotryna Zukauskaite

Stanford Medicine Resources: