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

Smoking or non?
Womb therapy
Mission: Vision
Stem cell growth
Bye bye bread
Esteemed teacher dead at 62

Smoking or non?

Never-smokers get lung cancer more often than thought, with women even more at risk than men, Stanford researchers have found.

Their data, published in the Feb. 10, 2007, Journal of Clinical Oncology, make plain never-smokers’ risk. “People tend to banter about this number of 10 to 15 percent of lung cancer cases in people who have never smoked,” explains lead author Heather Wakelee, MD, assistant professor of medicine. “But when you actually try to find the hard data to show that, it’s very limited.”

Jeffrey Fisher

The researchers used multiple collections of data from both the United States and Sweden that tracked the incidence of lung cancer in more than 1 million people from the ages of 40 to 79. They calculated the lung cancer incidence rates in terms of new cases per person-year, representing every year that someone was included in the study.

Among women, the lung cancer incidence rate in never-smokers ranged from 14.4 to 20.8 cases per 100,000 person-years. In men, it ranged from 4.8 to 13.7 incidents. For current smokers, the rates were about 10 to 30 times higher. If these statistics are representative of the overall U.S. population, the authors infer that around 8 percent of lung cancer cases in males and close to 20 percent of cases in females are among never-smokers.

Co-author Ellen Chang, ScD, an epidemiologist at the Northern California Cancer Center, cautions that it is difficult to study many of the factors that could affect these statistics. For example, secondhand smoke exposure could explain part of the gender difference. Because more men smoke than women, explained Chang, women may be more likely to be exposed to secondhand smoke, even when they are classified as never-smokers.

Clinical observations have suggested an upward trend in non-smoking-associated lung cancer rates, and the researchers hope their data can eventually be used to test this. They also hope that by studying lung cancer in never-smokers, they can alleviate some of the stereotypes associated with the disease. More than 180,000 Americans are diagnosed with lung cancer every year, and it kills more patients than breast, colon and prostate cancers combined.

“I have a lot of patients who have never smoked,” says Wakelee. “And because of the stigma, people are embarrassed to speak out about their disease. They feel like as soon as they say they have lung cancer, everyone judges them.”— SARAH C.P. WILLIAMS

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Womb therapy

Mice engineered to have cleft palates can be rescued in utero by injecting the mothers with a small molecule to correct the defect, say medical school scientists.

In addition to shedding light on the biology of cleft palates, the research raises hopes that it might one day be possible to prevent many types of human birth defects by using a similar vaccination-type technique in pregnant women likely to have affected fetuses.

Jeffrey Fisher

Pediatric craniofacial surgeon Michael Longaker, MD, professor of medicine, is the senior author of the study, which was published in the March 1, 2007, issue of Nature. The research is the first demonstration that a technique known as chemical genetics — in which small molecules are used to modify gene expression or protein activity — can reach a fetus when administered to a pregnant animal.

“It’s such a cool concept,” says Longaker. “We injected a small molecule into mom, and it goes into the embryo and works.” There are tremendous implications for preventing conditions in unborn patients rather than trying to treat them after birth. Cleft defects are the second-most-common birth defect worldwide, and affect about one in 2,000 births.

For this study, postdoctoral scholar Karen Liu, PhD, used a short amino-acid tag to disrupt the function of a protein called GSK-3 beta. GSK-3 beta function is important in a variety of biological processes, and mice with the tagged protein exhibited many problems in utero, including cleft palates and sternum defects. However, Liu was able to reverse the defects by injecting the pregnant mice with rapamycin — a small molecule that stabilized the tag and restored the protein’s function.

In addition to revealing for the first time that GSK-3 beta is important in palate formation, Liu discovered that the technique could identify the specific times during development that the protein’s function is required. For example, maternal rapamycin treatment between embryonic days 13.5 and 15 corrected the palate defect, but normal sternal development required functional protein between days 15.5 and 17.

This means that doctors undertaking fetal therapy wouldn’t need to treat the mother long term, just during the time that the organ or structure is forming, Longaker says.

Although promising, direct human applications of the research will require several key advances: an ability to predict which women are likely to have fetuses with birth defects before the defects occur; knowledge of an effective, small-molecule based therapy that can prevent the defect; and an accurate method of tracking fetal development to allow time-appropriate administration of thetherapy.— KRISTA CONGER

This research was funded by National Institutes of Health, the Berry Foundation and the Oak Foundation.

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Mission: Vision

Six years ago, as a 19-year-old college sophomore, Jennifer Staple decided to battle preventable blindness. So she started the nonprofit Unite for Sight with a staff of one: herself.

What began with the recruitment of a few fellow Yale University students to help the homeless of New Haven, Conn., has since burgeoned into a cadre worldwide that has helped restore sight to thousands of impoverished blind people. In April, Staple won one of the biggest honors in the world of social change — the national BRICK award, which honors young people who have made the world better.

Leslie Williamson

Medical student Jennifer Staple runs an organization that has sponsored more than 6,000 vision-restoring surgeries for low-income patients.

She was one of 12 who received the $25,000 prize, sponsored by the nonprofit Do Something.

“I never anticipated it would actually go beyond homeless people in New Haven,” says Staple.

From her dorm room at Stanford, where she just completed her second year of medical school, Staple coordinates some 4,000 volunteers. Unite for Sight has 90 chapters in 25 countries. It provides services to 400,000 low-income patients, and has sponsored more than 6,000 sight-restoring surgeries.

“They say, ‘Life is about ordinary people doing extraordinary things,’ ” says Tamilarasan Senthil, MD, an ophthalmologist who directs Unite for Sight in India. “Jennifer is one among them.”

Staple, a quiet warrior, volunteers 40 hours a week for Unite for Sight, responding to about 100 daily e-mails in between her studies.

“I love every day of it,” she says. “I love hearing the stories from the international ophthalmologists, hearing reports from all the volunteers in the field who are so excited about their jobs.” And, most of all, hearing the stories of the people whose sight is restored.seeing the need

The idea behind the organization was originally sparked while Staple was working a summer job after her freshman year at Yale in the office of her childhood ophthalmologist. “I’d see low-income patients suffering from glaucoma who had already become blind,” Staple says. “They regretted not going to the eye doctor sooner.”

The majority of eye damage can be prevented with a little education and some fairly low-cost care, Staple says. Eighty percent of blindness is preventable or treatable, according to research sponsored by the World Health Organization.

In the early days, Staple and her volunteers went out into the community, matching up poor patients with free health-care programs. After a while, people in other parts of the world started reaching out to Unite for Sight through Internet connections asking for help.

Staple made her first visit to one of the overseas clinics last summer. She visited patients in remote villages surrounding Chennai, India, where Unite for Sight has been working for two years.

Staple, who plans to become an ophthalmologist, has no intention of slowing down as she winds her way through the rigors of medical school. “Seeing people with such joy on their faces after they have their eyesight restored, there’s nothing like it,” she says.— TRACIE WHITE

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Stem cell growth

Since the founding of Stanford’s Institute for Stem Cell Biology and Regenerative Medicine in 2002, its scientists have been frustrated by the lack of stem cell lines tailored to fight specific human diseases. Now a combination of state funding, new researchers and a substantial private donation is giving Stanford scientists the resources they need to start making these stem cell lines, using a process known as somatic cell nuclear transfer.

Nuclear transfer involves transplanting a person’s DNA into an unfertilized egg, which could then be coaxed into producing embryonic stem cells. By using DNA from people with a variety of diseases, scientists hope to create cells that will give insights into those diseases and provide a new way of finding therapies.

The process, proven in animals such as tadpoles and sheep, has yet to be carried out successfully with human cells, despite the efforts of researchers worldwide. Restrictions on federal funding for research using embryos have further stymied progress.

However, the California Institute for Regenerative Medicine has begun to make up for the lack of federal funds. The state agency handed out its initial rounds of research grants this spring, with Stanford receiving 19 grants worth nearly $26 million — more than any other single institution.

Two of those grants involve creating stem cells through nuclear transfer. Heading up these efforts will be Renee Reijo Pera, PhD, who joined Stanford this spring from the University of California-San Francisco, where she helped establish a human embryonic stem cell research center. Reijo Pera is now director of human embryonic stem cell research and education for Stanford’s stem cell institute.

Another round of state funding will be announced in June, this time to support the construction of facilities for embryonic stem cell work. Stanford is already making progress on that front with a $33 million donation from Lorry I. Lokey, the founder of the commercial news distributor Business Wire.

Lokey’s contribution to the School of Medicine — its largest single gift to date from an individual — will help launch construction of a home for Stanford’s stem cell institute.

“The important thing to me is that stem cells might not only extend life, but also improve the quality of life, as so many people suffer in their later years,” says Lokey, who turned 80 in March. “But I think stem cells will have applications across the entire life span.”

The building schedule calls for groundbreaking in 2009, with completion in 2011.— SUSAN IPAKTCHIAN

Bye bye bread

The case for low-carbohy-drate diets is gaining weight. Stanford researchers completed the largest and longest-ever comparison of four popular diets, and the lowest-carbohydrate Atkins diet came out on top.

Of the 311 women in the study, those randomly assigned to follow the Atkins diet for a year not only lost more weight, but also experienced the most benefits in terms of cholesterol and blood pressure.

Jeffrey Fisher

“Many health professionals, including us, have either dismissed the value of very-low-carbohydrate diets for weight loss or been very skeptical of them,” says lead researcher Christopher Gardner, PhD, assistant professor of medicine at the Stanford Prevention Research Center. “But it seems to be a viable alternative for dieters.”

Gardner published the results in the March 7, 2007, Journal of the American Medical Association.

The pre-menopausal, overweight women in the study were randomly assigned to follow the Atkins, Zone, LEARN or Ornish diet — diets representing the full spectrum from low- to high-carbohydrate.

The diet developed by Robert Atkins, MD, represents the lowest carbohydrate diet. The Zone diet, also low-carbohydrate, focuses on a 40:30:30 ratio of carbohydrates to protein to fat, a balance said to minimize fat storage and hunger. The LEARN (Lifestyle, Exercise, Attitudes, Relationships and Nutrition) diet follows national guidelines reflected in the U.S. Department of Agriculture’s food pyramid — low in fat and high in carbohydrates. The diet developed by Dean Ornish, MD, is very high in carbohydrates and extremely low in fat.

Participants attended weekly diet classes for the study’s first eight weeks and received a book outlining their diet. For the remaining 10 months, researchers regularly checked the women’s weight and metabolism, and monitored what they ate.

Gardner says this setup mimicked real life, since women in the study had to prepare or buy all their own meals. And not everyone stuck to their diets.what they lost

At the end of a year, the 77 women assigned to the Atkins group had lost an average of 10.4 pounds. Those assigned to LEARN lost 5.7 pounds, the Ornish followers lost 4.8 pounds and women on the Zone lost 3.5 pounds, on average.

Though critics say that low-carb diets can lead to health problems, none of the factors measured in this study was worse for the Atkins group. Gardner cautions, however, that there are potential long-term health problems that could not have been identified in a 12-month study. —SARAH C.P. WILLIAMS

The research was funded by the National Institutes of Health and a grant from the Community Foundation for Southeast Michigan.

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Esteemed teacher dead at 62

Like few others at the medical school, Larry Mathers split his time between the earliest days of life and the aftereffects of death.

As associate director of the intensive care unit at Lucile Packard Children’s Hospital, Mathers helped the frailest of children struggle to survive. And as the longtime chief of the medical school’s human anatomy division, he steered thousands of Stanford’s first-year medical students through anatomy class where he taught them to honor those who had donated their bodies to medical education.

Brian Tobin

Larry Mathers at work. Read tributes to him or post your own at med.stanford.edu/news/mathers/.

Perhaps because of this focus on life’s extremes, Mathers valued the here and now. His colleagues and former students say he set an example of compassion, dignity, warmth and wisdom that they tried to emulate.

Tributes began pouring in soon after Mathers, 62, MD, PhD, professor of pediatrics and of surgery, was found dead at his home on Feb. 21, 2007; the cause of death, acute pancreatitis. A crowd of more than 500 attended a March 9 memorial service.

“Dr. Mathers was a phenomenal teacher, whose passion for teaching and care for those he taught were unsurpassed,” wrote Clark Ochikubo, MD (class of ’90), staff neonatologist at Queen of the Valley Hospital in West Covina, Calif., in an online memorial guestbook for Mathers. “He was always patient and kind.”

Others recalled Mathers’ passion for music, both singing and playing the piano. He often played the piano in the Stanford Hospital atrium, entertaining patients and staff members.

“He played everything — blues, jazz, classic, swing. You name it, he could play it,” said Lorry Frankel, MD, chief of the intensive care unit at Packard Children’s.

A native of San Francisco, Mathers spent most of his educational and professional career at Stanford. He graduated from Stanford with a bachelor’s degree in biology in 1966, and completed his doctorate in anatomy here in 1971. He graduated from Stanford’s medical school in 1982 and completed his residency and fellowship on the campus.

He was preceded in death by his wife of 30 years, Mil, who died in 2002. He is survived by his stepchildren Doug Jones, Mark Jones and Beth Jones.— TRACIE WHITE

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