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Immunology, Mental Health, Stanford News

Stanford Medicine magazine traverses the immune system

Stanford Medicine magazine traverses the immune system

cover_fall2014_2If you want to understand the human immune system, try studying humans – not mice. That’s what Mark Davis, PhD, urges in a special report on the immune system in the new issue of Stanford Medicine magazine.

For decades, most research on the immune system has used mice. Davis, director of Stanford’s Institute for Immunology, Transplantation and Infection, launched Stanford’s Human Immune Monitoring Center a few years ago to change the immunology research paradigm.

“Inbred mice have not, in most cases, been a reliable guide for developing treatments for human immunological diseases,” Davis says in the special report, titled “Balancing act: The immune system.”

As the editor of the magazine, I wanted to feature a story that showed how human-focused immunology research plays out. So I was glad to learn that the center is in the midst of its largest study so far – one to figure out the cause of chronic fatigue syndrome. A team led by Stanford professor of infectious diseases José Montoya, MD, is looking for meaningful patterns in the components of blood samples gathered from 200 patients with chronic fatigue syndrome and 400 healthy subjects.

“It’s like dumping a hundred different puzzles on the floor and trying to find two pieces that fit,” Davis says in our story. We also have a video about a patient’s seven-year battle with chronic fatigue, from despair to recovery.

Also covered in this issue:

  • “I can eat it”: on a revolutionary treatment for food allergies
  • “Brain attack”: on the struggle to help children with psychiatric illness caused by a malfunctioning immune system – a condition known as PANS or PANDAS
  • “When bones collide”: on a new view on the cause of osteoarthritis: autoinflammation
  • “My rendezvous with insanity”: a Q&A with Susannah Cahalan, author of Brain on Fire: My Month of Madness, her memoir of surviving an autoimmune attack on her brain
  • “The swashbuckler”: on look back to the early days of molecular biology when Mark Davis cracked one of the greatest mysteries of the immune system

The issue also includes an article on efforts at the VA Palo Alto Health Care System to use peer-support services to help veterans with post-traumatic stress disorder, and a story on the growing concern that biomedical research results are often erroneous and efforts being made to solve the problem.

The issue was funded in part by the Institute for Immunology, Transplantation and Infection.

Previously: Stanford Medicine magazine opens up the world of surgery, Mysteries of the heart: Stanford Medicine magazine answers cardiovascular questions and From womb to world: Stanford Medicine Magazine explores new work on having a baby.
Illustration by Jeffrey Decoster

Medicine and Literature, Stanford News, Surgery

Stanford Medicine magazine opens up the world of surgery

Stanford Medicine magazine opens up the world of surgery

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It used to be “big hole, big surgeon” — but no more, according to Stanford’s chair of surgery, Tom Krummel, MD, who’s one of the surgeons featured in Stanford Medicine magazine’s report on surgery and life in the operating room, “Inside job: Surgeons at work.”

During his career of more than 30 years, Krummel has seen a massive shift from open surgeries to minimally invasive procedures — major surgeries conducted with tools that work through small openings.

“We do the same big operation. We just don’t make a big hole,” he said in the article leading off the report.

In the same issue, CNN’s chief medical correspondent, neurosurgeon Sanjay Gupta, MD, talks about why he’s “doubling down” on his support for medical marijuana.

As the editor, I’m biased — but I think it’s worth a read, along with the rest of the issue, which includes:

The issue also includes a report on research on Alzheimer’s disease, and an excerpt from Surgeon General’s Warning, a new book by Associated Press medical reporter Mike Stobbe on the fall from power of the U.S. surgeon general. The digital edition offers audio interviews with Gupta, Stobbe, Stanford surgeon and humanitarian-aid volunteer Sherry Wren, MD, and photographer Max Aguilera-Hellweg, MD.

Previously: The vanishing U.S. surgeon general: A conversation with AP reporter Mike Stobbe, Mysteries of the heart: Stanford Medicine magazine answers cardiovascular questions, From womb to world: Stanford Medicine Magazine explores new work on having a baby and Factoring in the environment: A report from Stanford Medicine magazine
Photo by Max Aguilera-Hellweg

Obesity, Research, Stanford News

Secrets of fat cells discovered

Secrets of fat cells discovered

fat_and_skinnyWhy aren’t we all drowning in fat? Before talking with Mary Teruel, PhD, this question certainly never occurred to me. (On a personal level, though, I admit I’ve wondered about the opposite!) But after our conversation I saw why it’s such a good question — and how great it is that Teruel has come up with an answer.

Normally your body replaces about 10 percent of your fat cells a year, explained Teruel, a Stanford assistant professor of chemical and systems biology. Little by little, the old ones die, and new ones develop from flat, spindly precursor cells.

Teruel knew, based on her previous experiments, that the switch that triggers the conversion of precursor cells into fat cells is an “on-off” sort, not a dimmer which can be dialed up and down.

Here’s what’s going on in a little more detail: The switch controls the amount of PPAR-gamma in a cell. PPAR-gamma is a nuclear receptor protein that is the master regulator of fat-cell development. In precursor cells, the switch is in the “off-state” and there’s no PPAR-gamma in the cell, but when the cell senses a stimulus that can cause fat cell development, the switch flips to the “on-state” and the cell rapidly makes huge amounts of PPAR-gamma which then turns on hundreds of downstream genes that create a full-fledged fat cell over a period of up to 12 days.

So here’s what was puzzling Teruel: Every human has a large number of precursor cells that all sense the same stimulus, but rather than all converting at once to fat cells (causing us to “drown in fat”) for a given strong stimulus, only a few cells develop into fat cells at any given time, allowing a healthy, constant renewal of our fat tissue. What allows this slow, controlled renewal of fat cells, as well as prevents the unhealthy situation in which all fat cells would turn back into precursors when PPAR-gamma drops below the threshold needed to flip the switch on?
If you can manipulate the rate fat cells mature, you could do a lot for obesity.
Experiments she did with postdoctoral researcher Robert Ahrends, PhD, and colleagues, explain, and provide clues about how to control the rate at which fat forms.

The answer, they discovered, has two parts. First of all, they discovered that the master fat-regulator switch has multiple layers of feedback. Teruel, who has a PhD in aeronautical engineering, explains that these multiple layers allow the body to control the rate of fat cell formation much as a pilot would control the pitch of an aircraft. Second, they found that not all precursor cells are alike — they vary in the quantity they carry of PPAR-gamma and other regulatory proteins.

This realization is a big deal. For one thing, it gives researchers new ideas for treating obesity and diabetes — so far, conditions that resist effective treatment without serious side effects.

“If you can manipulate the rate fat cells mature, you could do a lot for obesity,” she pointed out.

“This might be the heart of how you treat disease,” said Teruel. “We can’t just use one drug for treatment. Disease is more complicated than people think. It would be like trying to control an airplane and only being able to turn the rudder. This might work in a car or boat, but an airplane can move in three-dimensions, and a change in any one dimension affects the other two. Only controlling one dimension is a sure way to crash the plane.”

Teruel’s Stanford website has more info about her research as well as a striking depiction of a fat cell’s development.

They published the results of their studies on Friday in the journal Science (subscription required). They were supported by Stanford University New Faculty Startup Funds, the National Institutes of Health (grant P50GM107615), the German Research Foundation, and the American Heart Association.

Previously: Early findings show nutrigenomics could make weight loss more efficient, Study shows banning soda purchases using food stamps would reduce obesity and type-2 diabetes, Fed Up: A documentary looks for answers about childhood obesity
Photo by Jason Eppink

Imaging, Ophthalmology, Research, Stanford News, Technology

Instagram for eyes: Stanford ophthalmologists develop low-cost device to ease image sharing

Instagram for eyes: Stanford ophthalmologists develop low-cost device to ease image sharing

eye-phoneThis probably won’t grab as many headlines as the news of a smartphone that wakes you up with the sizzle and smell of bacon, but it should!

A team of Stanford scientists is using 3D printing to create inexpensive adapters that make it easy to use a smartphone and an ordinary examination lens to capture high-quality images of the front and back of the eye. And – what seems to me as just as important – providing a nearly effortless way to share those images.

“Think Instagram for the eyes,” said one of the developers, assistant professor of ophthalmology Robert Chang, MD.

This is a big deal because most primary-care doctors have no good way to see into patients’ eyes, and no easy way to share the images. The usual eye-imaging instruments are expensive and hard to use, and even ophthalmologists who have the equipment and know-how find capturing and sharing the images slow going.

As one of Chang’s fellow developers, Stanford ophthalmology resident Dave Myung, MD, PhD, told me when I interviewed him for an article in Inside Stanford Medicine:

“A picture is truly worth a thousand words… Imagine a car accident victim arriving in the emergency department with an eye injury resulting in a hyphema – blood inside the front of her eye. Normally the physician would have to describe this finding in her electronic record with words alone. Smartphones today not only have the camera resolution to supplement those words with a high-resolution photo, but also the data-transfer capability to upload that photo securely to the medical record in a matter of seconds.”

The scientists describe the adapters, currently dubbed the EyeGo, in two articles in the new issue (volume 3, issue 1) of Journal of Mobile Technology in Medicine. And you can read my story to learn more about the development process, including how Myung pieced together the first prototype (with plastic bits he ordered from the Internet and a few Legos), how mechanical engineering graduate student Alex Jais created the first printed model on his own 3D printer, and how residents Lisa He, MD, and Brian Toy, MD, are leading studies to test them out.

Those interested in using an EyeGo adapter for research or beta-testing can e-mail the team at eyegotech@gmail.com.

Previously: Image of the Week: Sigmoid volvulus and Treating common forms of blindness using tissue generated with ink-jet printing technology
Photograph by Dave Myung

Cardiovascular Medicine, Research, Stanford News, Technology, Transplants

Mysteries of the heart: Stanford Medicine magazine answers cardiovascular questions

Mysteries of the heart: Stanford Medicine magazine answers cardiovascular questions

spring14_magazine-coverThe heart is a paradoxical organ. It declares its presence with that distinctive thump thump, yet its moment-to-moment condition is really hard to decipher. But as I learned while editing the just-published Stanford Medicine magazine special report “Mysteries of the heart,” new technologies and research are making it easier to assess heart health and diagnose disease. With heart disease the No. 1 cause of death worldwide, that’s good news.

The issue, published during American Heart Month, was supported in part by the Stanford Cardiovascular Institute. Among its contents:

  • A change of heart“: An interview with former vice president Dick Cheney on having “virtually everything done to me that you could do to a heart patient,” culminating with a transplant.
  • Fresh starts for hearts“: A feature on using stem cells to revolutionize cardiac care, and a family for which new treatments can’t come soon enough.
  • The ultramarathoner’s heart“: Visionary computer designer Mike Nuttall’s exploits as an ultramarathoner, despite having severe heart disease (online only).
  • Hiding in plain sight“: The story of a man born with high cholesterol — a surprisingly common but hidden and deadly condition.
  • Switching course“: A piece detailing the untangling of a heart surgery that saves babies, but threatens their lives in adulthood.
  • The heart gadgeteers“: A report on the new wave of heart- and fitness-monitoring devices, and why it’s hard to integrate them into the medical system.
  • Easy does it“: An article on an alternative to open-heart surgery to replace aortic valves.
  • Dear Dr. Shumway”: Catching up with a kid who in 1968 wrote to transplant pioneer Norman Shumway, MD, for advice — on his frog heart transplant.

The issue also includes articles on the use of big data in medicine, which will be the focus of the Big Data in Biomedicine conference May 21-23 at Stanford.

Previously: From womb to world: Stanford Medicine Magazine explores new work on having a babyFactoring in the environment: A report from Stanford Medicine magazine and New issue of Stanford Medicine magazine asks, What do we know about blood?
Illustration by Jason Holley

Medicine and Literature, Stanford News

Stanford Medicine magazine's big reads of 2013

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The 10 most-read Stanford Medicine magazine stories published this year (as determined by pageviews on our website):

Almost without hope – Seeking a path to health on the Rosebud Indian Reservation: Tracie White’s report on life in one of the hardest places in America to stay healthy — the Rosebud reservation in South Dakota.

Labor day – The C-section comes under review: An article by Julie Greicius explaining the rise of C-sections and why a decrease in how often the procedure is performed should be around the corner.

Microbe computers – Built from the stuff of life: A feature by Andrew Myers on the creation of a computer made of biological molecules that can run inside our cells.

Blood, sweat and fears – A common phobia’s odd pathophysiology: John Sanford’s story about conquering blood phobia.

Against the flow – What’s behind the decline in blood transfusions?: Sara Williams explains the drop in transfusions — and why it’s good news for health.

Leo and Frida – The doctor and the artist: A feature by Catherine Reef on the friendship between artist Frida Kahlo and Stanford surgeon Leo Eloesser, MD.

Too deeply attached – The rise of placenta accreta: Erin Digitale describes the epidemic of placenta accreta and how this potentially fatal condition affected one family.

Roll up your sleeve – There’s still no substitute for blood: Jessica Shugart on why blood donation remains crucial.

In his blood – A doctor driven by hemophilia: Krista Conger profiles Holbrook Kohrt, MD, a physician who grew up with hemophilia and is dedicating his life to finding cures for life-threatening disease.

Priming the pumps – Debugging Dhaka’s water: Ruthann Richter tells how a trip to the slums of Dhaka, Bangladesh led to a radical solution for contaminated drinking water.

Previously: Stanford Medicine magazine’s big reads of 2012 and Stanford Medicine magazine’s big reads of 2011
Illustration (the cover of our special report “Blood at work”) by Renphoto

Pregnancy, Stanford News, Technology, Videos, Women's Health

Placenta: the video game

Placenta: the video game

Fetus-Placenta-copy-3

As I discovered while editing the new Stanford Medicine magazine report on childbirth, the placenta is a terribly important organ yet a big question mark for most people. To help demystify it we used a new kind of storytelling – an interactive simulation that allows you to observe and control the development of the placenta. It’s a companion to an article on the epidemic of the potentially fatal condition known as placenta accreta.

The producer, David Sarno, a former Los Angeles Times technology reporter and a 2013 John S. Knight Journalism fellow, built the simulation using the tools of video game design. It’s the first finished product of his start-up, Lighthaus, dedicated to creating interactive digital stories. If you’re curious about the placenta – or this new mixture of technology and storytelling – click on the image above to get to the video. (Note: To run the program you’ll need the Unity web player, which is free and downloads pretty quickly at the link.)

Previously: From womb to world: Stanford Medicine Magazine explores new work on having a baby, Touchable journalism technology helps to teach medicine, Species-specific differences among placentas due to long-ago viral infection, say Stanford researchers and The placenta sacrifices itself to keep baby healthy in case of starvation, research shows
Illustration by Bruce Rudolph/Lighthaus Inc.

NIH, Research, Science, Stanford News

A new era in scientific discourse? PubMed gets comments

A new era in scientific discourse? PubMed gets comments

typing - smallPubMed, the massive index of biomedical research articles, has begun an experiment: Enabling the posting of comments on the articles’ citations. This might not seem like a big deal, but in this case the comments system, PubMed Commons, is creating a buzz.

Some of the tweets following the Oct. 22 announcement: “PubMed Commons will change the way science works, but I predict a big impact on science bloggers as well” (@Neuro_Skeptic), “Science buzz and criticism gets a powerful boost” (@phylogenomics) and “Seriously get ready for a turbo-charged #PubMed (@AlbertErives).”

It was actually two Stanford professors – biostatistician Rob Tibshirani, PhD, and biochemist Pat Brown, PhD – who got the project rolling. I talked with Tibshirani for an article in Inside Stanford Medicine about the project’s beginnings and what he hopes it will accomplish. For starters, he sees it as a way for readers to note errors in the scientific literature in a place other researchers will see. But he also hopes it will generally expand scientific discourse and build community:

“Science can be lonely,” Tibshirani said. “Just having people talk about your work is nice. Sure it’s nice to have good comments. But it’s nice to have comments at all. At least someone cares enough to read your paper.”

For now, during this expanded pilot phase, only individuals who have published articles indexed in PubMed can make comments or see them. Tibshirani says he’s hopeful the leaders of the National Institutes of Health will decide to allow the general public to see the comments too. More on the how and why of the project as well as the quandary over anonymous comments (yea or nay) in the article.

For a fuller picture of the social media reaction, see this Storify created by Hilda Bastian, a blogger at Scientific American and an editor at the National Center for Biotechnology Information, the organization within the NIH that runs PubMed.
Photo by Mike Traboe

Research, Science, Stanford News, Videos

The key to speed? Inside a cell, it's trigger waves

The key to speed? Inside a cell, it's trigger waves

Think of what you see in this video as a message going viral, only it’s spreading not in cyberspace but in cytoplasm. The video shows a trigger wave, an under-appreciated chemical phenomenon that can help cells get things done fast. Stanford graduate student Jeremy Chang and professor of chemical and systems biology Jim Ferrell, MD, PhD, published a video of this scene as part of their recent paper (subscription required) in Nature. The August 29 paper describes several lines of evidence all pointing to the conclusion that in frog eggs the dramatic dance of mitosis – in other words, the process of the egg dividing and forming two new eggs – is launched by trigger waves.

At the end of this post I’ll explain in more detail what’s happening in the video. But first I’ll answer the question: Why study how frog eggs divide? It’s not as odd as it sounds.

The eggs of these frogs (African clawed frogs or Xenopus laevis) are popular cells to study because, as cells go, they’re huge – about 1 millimeter in diameter – which makes them relatively easy to manipulate and observe. But of particular relevance for this study is a mystery Ferrell and Chang wanted to solve concerning mitosis. Mitosis in a frog egg happens way too fast than would be possible if it were orchestrated merely by proteins randomly diffusing hither and thither – which is how most people assume things work most of the time in cells. If only random diffusion were in play, mitosis in a big cell like this would take several hours, Ferrell said. But in reality it takes just 10 minutes. So something more is going on and that something, as Ferrell and Chang have shown, is the cell’s equivalent of going viral: trigger waves.

“It’s a physical process that takes place in lots of settings,” Ferrell told me. “The spread of a fire in a forest is an example of a trigger wave. The spread of an action potential from the body of a nerve to its axon is an example. Or a joke spreading through YouTube. The main ingredient you need for a trigger wave is positive feedback. It’s an autocatalytic process.”

To learn more about mitosis in the frog egg, Chang and Ferrell looked at the master regulator of mitosis, a protein called cyclin-dependent kinase 1, or CDK1. Activated molecules of CDK1 not only start mitosis, they turn inactive CDK1 molecules into active ones. In other words, there’s positive feedback, and the result is a trigger wave spreading CDK1 activity across the cell.

To scale up the trigger wave to make it easier to see, Chang whipped up an extract from the guts of many frog eggs mixed together. He also figured out how to get the nuclei in the extract to undergo mitosis over and over again – in this video, seven rounds, and sometimes up to 15. (Ferrell said Chang is legendary in Xenopus research circles for engineering such a massive multiplicity of mitoses. Chang said it was sheer luck: Switching from a glass tube to Teflon to hold the extract did the trick.)

The flashing green spots in the video are the nuclei undergoing mitosis: They disappear when the cell pulls itself apart and reappear when the division is complete. You can see trigger waves traveling from both the top and the bottom of the tube. Take a look at the topmost nucleus and you’ll see it blink off, shortly followed by its neighbor and so on down the line. The same happens if you follow the nuclei from the bottom up. The first cycle is a little messy but later rounds are clearer.

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Research, Stanford News

Clues about kidney disease from an unexpected direction

Clues about kidney disease from an unexpected direction

Karlene Cimprich, PhD, is a Stanford professor who normally studies how cells keep their strands of DNA in proper working order. Her newly published research (subscription required) provides insights into the DNA repair process, but as a very interesting bonus it also turns up a new avenue for drugs to treat kidney disease. The unifying factor for these disparate discoveries is the mysterious antenna-like cellular structure called the primary cilium.

Most people don’t realize that nearly every cell in the human body has an antenna. Well it does, even though the rod-like projection was overlooked for decades after its discovery more than 100 years ago. An article I wrote in Stanford Medicine magazine explains:

The primary cilium is not a recent discovery. Swiss anatomist K.W. Zimmermann described the structure and suggested a sensory role in 1898, but other scientists largely ignored it. In later years it was written off as a quirk of evolution. The outburst of research over the past decade has revealed that the tiny projection is acting as the receiving station for cells’ signaling chains, the communication networks that govern and coordinate cell actions.

In the past two decades scientists have started paying attention to the primary cilium, and they’ve discovered not only its receiving-station role, but its importance for health.

Cimprich’s research started out having nothing to do with the primary cilium. About five years ago, Renee Paulsen, then a graduate student in her lab, launched a search for proteins needed to repair damage to a cell’s DNA. Another graduate student, Claudia Choi, assessed some of those proteins that were especially needed to repair DNA when the cells were stressed.

One of the big hits was a protein called NEK8.

A literature search revealed intriguing info about NEK8: It’s also faulty in certain kidney diseases — which are known to result in part from defective primary cilia.

This led Cimprich and her team to the work reported today in Molecular Cell: details of the molecular mechanism NEK8 uses to prevent DNA damage and clues to how NEK8’s malfunction relates to the primary cilium and kidney disease.

Continue Reading »

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