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

Triangulate yourself
The Cohen age closes
Cancer stem cell emphasis grows
Worn genes
Bigger med center
The blogtor is in

Triangulate yourself

Global-positioning system aficionados know that it’s possible to define any place on Earth with just three geographic coordinates: latitude, longitude and altitude. Now scientists have discovered that specialized skin cells use a similar mapping system to identify where they belong in the body and how to act once they arrive.

Christoph Niemann

By sending location cues to their neighbors, these cells direct embryonic patterning and wound healing. Scientists might be able to use them to help grow tissue for transplants or understand metastatic cancer.

“Our skin is actively maintaining itself throughout our life, and these ‘address codes’ help the cells know how to respond appropriately,” says John Rinn, PhD, a postdoctoral scholar in the laboratory of Howard Chang, MD, PhD, assistant professor of dermatology. Their research was published in the July 28, 2006, Public Library of Science-Genetics.

Until now it’s been a mystery as to how adult skin knows to grow hair in some areas of the body but manufacture sweat glands, calluses and fingerprint whorls in others. In 1969, biologist Lewis Wolpert, PhD, authored a famous treatise that described two possible explanations: Either cells infer their location in the body and adjust their behavior based on interactions with nearby cells, or they deduce their “positional identity” through some type of coordinate system. The Stanford findings bolster the second scenario.

The scientists analyzed the gene-expression profiles of adult fibroblasts from more than 40 areas of the body. They found about 400 genes whose expression patterns varied with the cells’ original location. Those from the top half of the body shared expression patterns that were markedly different from the patterns among cells lower on the body. Similar patterns existed among cells originating close to or far from the center of the body, and those from the outer or the inner layer of the skin.

These three rough anatomical divisions help explain similarities between the skin on the palms of the hands and the relatively distant soles of the feet. Both the palms and soles are on the outer layer of the skin far from the center of the body and are more like one another than like their biological neighbors.

Rinn says the findings may make it easier to regenerate certain parts of the body. “For example, if we need to grow skin in the laboratory to graft onto someone with badly burned palms, we’ll know how to turn on the specific genes that make that type of skin,” he notes. — KRISTA CONGER
The research was funded by the National Institutes of Health, the Damon Runyon Cancer Foundation and the Howard Hughes Medical Institute.

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The Cohen age closes

After more than a decade of administrative duties, Harvey Cohen, MD, PhD, handed over the titles of chief of staff of Lucile Packard Children’s Hospital and chair of pediatrics on Nov. 15 without regret.

Leslie Williamson

“These past 14 years have been the best of my life,” says the racquetball-playing, bicycle-riding 63-year-old, “but it’s time for someone to come in and take the hospital to the next level of greatness. I’ve missed not being a doctor.” Kenneth Cox, MD, and Christy Sandborg, MD, will serve as interim chair and chief, respectively, until a permanent replacement can be found.

Although his leadership responsibilities left little time for appointments with patients, Cohen made a lasting impact on children’s health care — locally and nationally — through his dedication to mentoring, recruiting, legislative lobbying and fundraising.

“Harvey and his colleagues have transformed the department of pediatrics and children’s services at Packard Children’s,” says medical school dean Philip Pizzo, MD, who was an intern with Cohen in 1970 at Children’s Hospital Boston.

Over the course of Cohen’s tenure, hospital admissions more than doubled; outcomes for kids with transplants, cancer, heart disease and cystic fibrosis dramatically improved; outreach programs blossomed; and grant support for research in the Department of Pediatrics increased fivefold. The hospital was recently ranked as one of the top children’s hospitals in the country by U.S. News & World Report.

It wasn’t always so well known. Packard Children’s was in its infancy when Cohen arrived from the University of Rochester in 1993.

“The hospital’s youth was really exciting,” says Cohen. “It was not encumbered by views and thoughts that would prevent the development of a unique institution.” Thanks in part to Cohen, the hospital had sufficient funds to grow. In 2001 the hospital, the School of Medicine and the Lucile Packard Foundation for Children’s Health embarked on what was at the time the largest ever fundraising campaign for a pediatric hospital — and reached their five-year goal of $500 million two years early.

“We could not have accomplished this without Harvey’s help,” says LPFCH campaign director Linda Collier. “He is the heart and soul of Packard, welcoming patient families and donors alike.”

In contrast, Cohen did not enjoy managing what has become a chronic bed shortage. Despite the current construction, Cohen foresees an ongoing demand. “We want to be able to take care of any child in the community who needs us,” Cohen says.

He also won’t miss coping with the complications the rise of managed care has imposed on efforts to provide both comprehensive coverage and top-notch medical education.

After such challenges, Cohen looks forward to his upcoming sabbatical in the laboratories of Richard Zare, PhD, and Rob Tibshirani, PhD, where he’ll devise new ways to diagnose and treat pediatric diseases. They’d better prepare themselves.

“A well-known aspect of Harvey’s persona is his loving bear hugs,” says Pizzo, who recalled wondering 36 years ago whether recipients would be troubled by such ebullience from a lean, dark-haired young intern with sideburns and a moustache. Not to worry now. “Times have changed, and Harvey’s appearance is much more cuddly,” says Pizzo.

“Giving hugs is something that Harvey has grown into — and it suits him very well.”— KRISTA CONGER

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Cancer stem cell emphasis grows

When Philip Beachy, PhD, moved his lab from Johns Hopkins University to the School of Medicine in the fall, he brought an additional piece to a puzzle that lies at the heart of the school’s cancer research efforts: What is the role of cancer stem cells in the disease’s progression?

Beachy became professor of developmental biology on Sept. 1. He follows last year’s arrival from the University of Michigan of Michael Clarke, MD, who first identified solid tumor stem cells in breast cancer in 2003.

Christoph Niemann

With the addition of Beachy and Clarke, Stanford has taken another step toward cementing its position as a leader in the effort to turn the results of cancer stem cell research into new therapies.

Cancer stem cells are believed to continuously replenish cancer, like the spring at the source of a creek. The regular cancer cells, which arise each time the cancer stem cell divides, cause damage by their sheer bulk, yet they alone can’t form a new cancer.

Only the cancer stem cell can.Irving Weissman, MD, who leads both the Stanford Institute for Stem Cell Biology and Regenerative Medicine and the Stanford Comprehensive Cancer Center, has made cancer and leukemia stem cells a primary focus of the school’s expanding effort to treat cancer and develop new therapies. He and others believe many cancers return after treatment because radiation and most forms of chemotherapy leave a significant fraction of the cancer stem cells unharmed. Eliminating a cancer means eradicating its stem cells.

“The overall plan is to amalgamate the cancer stem cell work with the cancer gene discovery efforts and translate that into clinical trials at Stanford,” Weissman says.

Beachy is an expert on a protein called Hedgehog that plays a critical role in telling cells where they are in the body and what type of tissue to become. Hedgehog also appears to encourage the cancer stem cell to churn out new cancer cells. Another protein that plays a similar role in some cancer stem cells is Wnt, which is the domain of Roel Nusse, PhD, professor of developmental biology. “Hedgehog and Wnt are really sister pathways that may be fairly fundamental in many types of cancer,” says Beachy.

Weissman said that work by Beachy, Nusse and other Stanford experts in dissecting how these proteins maintain cancer and leukemia stem cells could result in drugs that interfere with those pathways, eliminating those cells.

If such drugs do come out of their research, Weissman wants to have the trials take place here to benefit Stanford patients.— AMY ADAMS

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Worn genes

“Aging isn’t like the speed of light; it’s not a constant,” says Stuart Kim, PhD, professor of developmental biology and of genetics.

Christoph Niemann

In a study published last summer, Kim and Stanford colleagues found that living cells each have the equivalent of a molecular homeowner that keeps up repairs until a predetermined time, when the owner picks up the welcome mat and moves out. Once that process kicks off, the decay happens as a matter of course.

Although Kim’s work doesn’t identify what triggers that process, it does provide a wayof detecting the point a cell has reached in its life span.

They key is his discovery of a group of genes that are less active in older animals across a variety of species. The activity of these genes proved to be a consistent indicator of how far a cell had progressed toward its eventual demise.

In a study published in the July 2006, Public Library of Science-Genetics, Kim’s team looked at which genes were actively producing protein and at what level — in flies, mice and nematode worms in a range of ages, and in tissue taken from the muscle, brain and kidney of 81 people spanning in age from 20 to 80. The group used a microarray, which can detect the activity level of all genes in a cell or tissue. Genes that are more active are thought to be making more proteins.

One group of genes consistently made less protein as cells aged in most of the organisms the group examined. These genes make up the cellular machinery called the electron transport chain, which generates energy in the cell’s mitochondria.

Kim said the gene activity is a better indicator of a cell’s relative maturity than a person’s birthday. For instance, one 41-year-old participant had gene activity similar to that of people 10 to 20 years older; the participant’s muscle tissue also appeared similar to that of older people.

These results confirm Kim’s assumption that the rate of aging is at least in part genetically determined. Those study participants whose tissues appeared younger than their true age had something — dearly sought by researchers of aging — that made their cells keep activating genes in a more youthful pattern.

Kim suggests that aging doesn’t have to happen if cells aren’t programmed to fail. With a marker for aging in hand, he thinks future research will reveal what drives the process.— AMY ADAMS
The research was funded by the National Science Foundation, the Department of Veterans Affairs, the National Institutes of Health and the Ellison Medical Foundation.

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Bigger med center

The medical center is proposing a major building project intended to meet state seismic standards, community needs and advances in medicine and education. The plan calls for replacing teaching facilities, expanding the children’s hospital and demolishing much of Stanford Hospital and erecting a larger facility on an adjacent site. In sum, the plan would add 1.3 million square feet to the 2.3 million square feet now occupied by medical center facilities.

The medical center’s campus consists of Stanford Hospital, built in 1959, with extensions built in 1973 and 1989; the medical school’s teaching and research facilities, some of which date back to 1959; Lucile Packard Children’s Hospital, built in 1991; and several buildings housing administrative offices and clinics, including the Comprehensive Cancer Center, completed in 2004.

The plan was prompted,in part, by the requirement for Stanford Hospital, which houses the Peninsula’s only level-1 trauma center, to comply with state-mandated seismic safety laws. The proposed changes also arise from the need to create a center for medical education, research and patient care that will keep up with the advances in medicine and increased community demand.

The plan for Stanford Hospital & Clinics calls for new construction, demolition of the 1959 and 1973 buildings and reuse of existing buildings. The construction would consist of a new core hospital, clinics and offices of 1.4 million square feet. Seven hundred thousand square feet of old space would be demolished, resulting in a net addition of about 730,000 square feet. The current hospital would continue operating until the new facility opens.

For the children’s hospital, the plan proposes 425,000 square feet of new facilities to be built on a site now occupied by a medical office building.

As for the medical school, the plan proposes that its Alway, Edwards, Grant and Lane buildings, which were built in 1959, be torn down and replaced with updated facilities of the same total size.

Medical center leaders presented the preliminary plan to the Palo Alto City Council Nov. 20. Because the project is on Palo Alto land, the school needs the city’s approval to move forward. The study session started a public review process that is likely to take several years. Construction of the facilities would extend into the next decade.

As building plans have not been drawn up, the project’s cost is not known. But based on typical hospital construction costs, the total would be more than $1 billion.— ROSANNE SPECTOR

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The blogtor is in

After an anatomy class, Graham Walker, now in his fourth year of medical school,discovered he no longer had a shoulder.

The class taught him to see beyond the body’s simple function and look at its tendons, bones and complex musculature. But in doing so, he lost sight of the whole. Walker documented his experience on his blog, Over My Med Body!.

“I used to always think of my shoulder as, well, a shoulder. Y’know—the rounded-off area between your neck and your arm? It always had a definite shape (‘shoulder-shaped’), it was fairly solid and, although it never had any specific boundaries, I kind of had an idea of where my shoulder started and ended,” he wrote in an October 2003 entry. “Turns out, I was completely wrong.”

For Walker, keeping a blog is more than a documentary of life as a medical student. Rather, it’s become a way for him to keep his humanity as he undergoes his transformation into a doctor.

Walker is part of the growing legions taking part in the online phenomenon of blogging. Estimates of the number of blogs are now pushing 41 million. Pretty much any topic is fair game. In fact, if there’s a subject you can think of, chances are someone will have blogged about it.

Additionally, the medical school’s Web site now features a section where MD and PhD students can blog about their experiences at Stanford and abroad.

Originally from Chicago, Walker has been keeping a blog in some form or another since 2002. Before that, he wrote in a journal.

His father was a doctor, and though Walker started out as a humanities major at Northwestern University, he decided he would enjoy the challenge of the medical profession more. His early posts on his medical school applications proved popular, and he decided to devote an entire site to the subject.

On his blog, Walker is an unabashed supporter of a single-payer health-care system and frequently posts commentaries supporting legislation to establish such a program. His site receives up to 1,700 hits a day, with 250 signed up to get it delivered automatically to their Web browser. He’s been interviewed about his blog by U.S. News & World Report.

Walker hopes his blog helps demystify what happens at medical school for readers outside of the field. “Unless you know a medical student, you don’t really know what it’s like to be in anatomy class, to see a patient by yourself for the first time,” he says. “It’s important for people to understand that doctors are human, that we are not miracle workers, that we do our best, but we make mistakes.”— ANNE PINCKARD

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