A quick look at the latest developments from Stanford University Medical Center

Off to a bad start
Real genius
Mixed up on purpose
Stomach shrinking for obese teens
Stanford's great big data mountain
Flicking the 'Myc'

Off to a bad start

At the dawn of the 21st century, young adults were more likely to be smoking, eating badly and sitting on the couch than their counterparts a decade earlier.

Illustration: Greg Mably

That was one of the most surprising findings of a Stanford Prevention Research Center study looking at more than 187,000 adults. Researchers discovered that the most worrisome health habits of the past decade are occurring in people younger than 45, with those 18 to 24 faring the worst in terms of smoking, diet and exercise.

“Our findings show that young people are headed toward more illness and shorter life spans,” says associate professor of medicine Marilyn Winkleby, PhD, and lead author of the study that appeared in the September/October 2004 issue of The American Journal of Health Promotion. “I don’t think the future bodes well given what changes there are.”

Winkleby and research associate Catherine Cubbin, PhD, analyzed health
behavior responses to a telephone survey of black, Hispanic and white women and men conducted by state health departments and the Centers for Disease Control and Prevention in 1990 and 2000.

The researchers fully expected to see high rates of obesity, which increased in every group over the decade. But there were some unexpected results, such as the groups thought to have the most difficulties in remaining healthy — elderly minorities — making the greatest strides in fighting bad habits. The positive changes are great, says Winkleby, but they occurred in people over the age of 65. “What you would like is to prevent the onset of the unhealthy behaviors or to change them much earlier,” she says.

Puffing up

Most surprising was the steep increase in smokers; more than one-third of white men and women ages 18 to 24 smoked compared to one-quarter of them a decade earlier.
If these trends continue, the result of these increased risk behaviors could be higher future rates of heart disease, cancer, diabetes and lung disease.

“These are chronic diseases that have their onset early in life and that have a great deal of morbidity and cost associated with them at a time when the health-care system is in a very precarious situation,” says Winkleby. “Schools and neighborhoods and governments have a responsibility to say that this is the health of the future.”

The researchers emphasize the necessity of conveying to young people that societal forces — such as the marketing of high-fat, high-sugar foods served in super-sized portions — do not necessarily have their best interests in mind. They recommend community-wide actions such as establishing smoking cessation programs, restricting tobacco advertising and providing safe public spaces to promote physical activity. — Mitzi Baker

This research was funded by a grant from the National Institutes of Health.

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Real genius

Julie Theriot, PhD, has $500,000 over the next five years at her disposal and the distinction of being part of an elite group of people to have won a MacArthur “genius” award.

Photo:Steve Gladfelter

But the 36-year-old scientist, who shuns the limelight, says the award
has had little practical impact on her life, other than to convince her to continue studying the intersection between biology and physics.

“It gives me a lot more confidence in the research direction I’ve chosen,”
says Theriot, assistant professor of biochemistry and of microbiology and immunology. “I’m interpreting it more as a vote of confidence rather than an indication that I should be doing anything differently.”

Theriot was surprised and thrilled to be named a MacArthur Fellow in September 2004, one of 23 talented individuals nationwide to receive the prestigious award. The fellows are selected by the John D. and Catherine T. MacArthur Foundation for their “originality, creativity and the potential to do more in the future.”

Theriot has always looked for creative and different approaches to biology. Some of her work has focused on how bacteria, including the food-borne germs Shigella (which causes dysentery) and Listeria, move within and between cells to do their damage.
These nasty bugs have similar modes of action and can evade detection by the immune system by covertly slipping into cells, where they dart around like little speedboats.

Ultimately, they propel themselves through the cell membrane to infect another cell and spread disease. In recent years, Theriot has been applying the principles of math and physics to help understand the forces at work in this dynamic biological process.
Since she received the MacArthur award, she has been talking to colleagues in the field to discern where there are gaps in this interdisciplinary research that might be filled with her newfound funds.

“I want to do something I wouldn’t be able to do otherwise,” she says. “I’m particularly looking at things that involve new scientific interfaces that need more beefing up.”

Theriot came to Stanford in 1997 from the Whitehead Institute for Biomedical Research in Cambridge, Mass. She’s currently up for tenure at Stanford and hopes to take a sabbatical when she achieves tenure status. She expects to continue to teach, an activity she treasures, while carrying on her research.

“I love to teach, I love my research, I love doing seminars,” she says. “If I could double the amount of time in the day, that would be freedom for me.” — Ruthann Richter

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Mixed up on purpose

The School of Medicine is working to enhance its capabilities for interdisciplinary research through the recent creation of four institutes and the planned launch of three strategic centers.

Dean Philip Pizzo, MD, says the institutes and strategic centers will unite the faculty’s strengths — in both its research enterprise and in the clinical expertise at Stanford’s two hospitals — in areas ripe for innovation in the coming years.

“Our goal must be to transform medicine and biomedical research,” he says. “We must think boldly and beyond traditional boundaries.”

Organized to interact

How will the school’s departments, institutes and strategic centers work together?
The school’s leaders have outlined the roles of each type of organization this way:

  • Departments continue to be defined along traditional clinical practice and graduate bioscience program lines and will carry out the bulk of the basic science research. They have relatively small, clearly defined faculty communities.
  • Institutes are defined by disease systems and embrace all aspects of translational research — basic science, discovery, clinical innovation and application. They include a large community of scientists and clinicians from the school, the hospitals and the university. The four institutes were created during the past two years in the areas of cancer/stem cell biology and medicine; neurosciences; cardiovascular medicine; and immunity, transplantation and infection.
  • Strategic centers are defined by methods of investigation and cover the
    spectrum of related tools that could be used to further investigation across all disciplines. Like the institutes, they will include a large faculty community.

The first of the centers, dealing with clinical informatics, is scheduled for launch this winter. A center dealing with genomics and human genetics and another involving imaging are in the planning stages. A possible fourth dealing with translational research is under discussion.

The bedrock for the interdisciplinary efforts is the school’s continued commitment to basic research, Pizzo says. “One cannot predict where the next big discovery will come from, and we want to have a fertile ground of basic discovery that helps fuel our missions in translational research.”

The dean notes that a survey conducted in late 2003 indicates that more than 95 percent of the faculty would be aligned with at least one institute or center when all of the new organizations are fully operating.

“While faculty members may have trained in developmental biology or biochemistry they can have interests in cancer, stem cell biology, neuroscience or other areas,” he says, adding that the broad range of disciplines encompassed by the new organizations “will help virtually everyone to feel part of a common mission.”— Susan Ipaktchian

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Stomach shrinking for obese teens

The idea of surgically reducing obese teenagers’ stomachs to the size of a walnut isn’t new. Doing it at a respected academic children’s hospital is.

Illustration: Greg Mably

Craig Albanese, MD, professor of surgery, says it’s time adolescent specialists step up to the plate and begin taking care of these youngsters in appropriate facilities. That’s why he is now performing bariatric surgery on morbidly obese teens at Lucile Packard Children’s Hospital.

“It’s paramount that adolescent specialists care for these children in kid-centric facilities,” says Albanese, MD, chief of pediatric surgery and surgical director for the hospital’s Center for Healthy Weight. “This is not a quick-fix operation. This is a tool that helps people achieve a more healthy lifestyle and it requires an appropriate sup-port system for the patient and the family.”

One-half to three-quarters of all obese adolescents will carry their obesity into adulthood, increasing their risks of developing serious or life-threatening conditions. The risk increases to 80 percent if one parent is also obese.

“Surgery, because of the risk, is only offered to the most severe cases,” Albanese says. Only obese adolescents who already suffer from serious obesity-related illnesses are eligible.

The children’s hospital’s first patient underwent the surgery last November. The 18-year-old, 270-pound teen had a body mass index of 44 (a BMI of 20 to 24 is considered healthy) and had struggled with her weight since kindergarten.

“I have been through every weight-loss program you can name,” she says. She suffered from headaches, blurred vision, back and knee problems and restricted breathing, all brought on by her weight. And she’s at high risk of developing Type-2 diabetes — a disease her mother has.

Model patient

Her mother wants a healthy adulthood for her child. “I’ve been obese all my life,” she says. “I have tremendous health problems. I don’t want this life for her.”

Albanese describes the patient as a “poster-child” bariatric surgery candidate. In addition to meeting the hospital’s stringent physical requirements for eligibility, “she adhered to the diet regimen we gave her, kept a nutrition record, followed an exercise program and has a supportive family,” he says.

“People are so ignorant when it comes to obesity,” adds the patient’s mother. “Telling my daughter to see a psychiatrist and go on a diet is like telling someone with cancer to put a Band-Aid on it. Obesity is a chronic disease. It’s like cancer. It just kills in a different way.” — Katharine Miller

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Stanford's great big data mountain

When famed criminal Willie Sutton was asked why he robbed banks, he answered, “Because that’s where the money is.” A similar line of reasoning could apply to scientists who want to do microarray research at Stanford: That’s where the information is.

Photo: Steve Gladfelter

Last October, the Stanford Microarray Database recorded its 50,000th experiment, marking its place at the forefront of an information processing revolution that has yielded groundbreaking insights into the relationships between genes and illness, as well as fundamental biological discoveries.

Microarrays — developed in the lab of biochemistry professor Patrick Brown, MD, PhD, in the early 1990s — are small slides spotted with fixed samples of DNA, each for a different gene. When a labeled cell extract is incubated with the slide, messengers in the sample stick to the fixed DNA, showing which genes in the sample are active.

Detecting change

Microarrays are especially useful for comparisons between normal and cancerous tissues or between different stages of development. Researchers use them to nose out the genes associated with such changes.

“Microarrays allow researchers to do in six months what previously would have taken six years of concerted effort,” says Gavin Sherlock, PhD, assistant professor (research) of genetics, who has been involved in the Stanford database from the beginning.

However, experiments with microarrays yield vast amounts of data. Brown and David Botstein, PhD, former chair of the genetics department, began assembling a database for their own microarray results in the late 1990s and soon found they needed something more sophisticated to easily retrieve data and compare it with other experiments.

A grant from the National Cancer Institute enabled Botstein and Brown to revamp the database, and by April 2000 all 5,000 experiments from the old system had been transferred to the new system.

Since then, researchers have used the database to illuminate everything from cell division in yeast to cancer-causing genes to what happens to bacteria when they’re deprived of iron. Microarray data have also allowed scientists to understand how various drugs affect the malaria bug, to find out what the immune system attacks in patients with autoimmune diseases and to pinpoint genes involved in multiple sclerosis.

Sherlock estimates the database now supports 400 campus researchers doing work on 30 different organisms, and he believes it to be the world’s largest academic microarray database.

About one-quarter to one-third of all publicly available microarray data in the world is in the Stanford system, Sherlock says. It is growing at a rapid pace, with nearly 1,000 experiments being added every month.

The breadth and depth of Stanford’s experience with microarrays make it a natural leader in the field. “It’s much less scary to be doing microarrays at Stanford than anywhere else,” says Catherine Ball, PhD, director of the Stanford Microarray Database. “In fact, if you’re not, you have to explain why.” — Shawna Williams

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Flicking the 'Myc'

With the flick of a genetic switch, Dean Felsher, MD, PhD, has shed light on how and when tumors develop. His work helps explain why children get more aggressive tumors than adults and could lead to novel treatments that reform wayward cancer cells.

Felsher, assistant professor of medicine (oncology) and of pathology, studied mice whose liver cells were genetically engineer-ed with an oncogene called Myc (pronounced “mick”) that he could easily switch on and off. In the November 2004 issue of Public Library of Science, Felsher reported that when he turned that gene on in newborn mice they quickly developed extremely aggressive liver tumors.

Doing this experiment in adult mice, the tumors developed only after a long delay and were never as aggressive as in the newborn mice.

Working with these same mice, Felsher found that turning Myc off in their liver tumors turned those cells back into normal liver structures such as bile ducts, he reported in the Oct. 6, 2004, issue of Nature. “The exciting thing is that you can turn cancer cells into something that appears to be normal,” he says.

Felsher says these two experiments show that cancer is a developmental disease. Younger animals have more immature cells that become cancerous when Myc is turned on.

Older animals have fewer immature cells that are able to respond to Myc’s cancer-causing signal and therefore develop cancer much more slowly. “Turning off Myc un-covers the ability of these cancer cells to differentiate into normal cells,” he says.

Young and old

These findings may explain why children and adults get different types of cancers. Children are prone to cancers of the brain, bone and liver — tissues that still have immature cell populations during childhood. Adults are less likely to get cancer in these slowly dividing tissues, but are prone to tumors of the lung, colon, breast and prostate, all of which still have immature cells that may be more susceptible to mutations.

This work also explains why adults may be more prone to tumors in tissues that are dividing rapidly to repair damage, such as when a wound heals or a liver regenerates after surgery.

Those quickly dividing cells revert to a less mature state in which they are more susceptible to cancer-causing mutations.

Felsher hopes his work could result in drugs that specifically hamstring individual oncogenes such as Myc, returning cancer cells to a normal state.

He says the fact that his work is in liver cancer means it could be widely applicable in cancers of the breast, colon or prostate, which all form in a type of cell called epithelial cells. — Amy Adams

Both research projects were funded by the National Cancer Institute, the American Society of Clinical Oncology, the UCSF Liver Center and the Stanford Digestive Disease Consortium, among others.

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