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Progress In Medicine Unites Recipients Of 1997 Lasker Awards

The Albert and Mary Lasker Foundation honored three medical researchers at an awards luncheon on September 26 in New York. According to a foundation official, the 1997 award winners represent the distinct approaches and scientific perspectives that must combine in the fight against disease. Victor A. McKusick, a professor of genetics at Johns Hopkins University, was given the Special Achievement in Medical Science Award; Mark S. Ptashne, the Ludwig Professor of Molecular Biology at the Mem

By | October 27, 1997

Lasker Award The Albert and Mary Lasker Foundation honored three medical researchers at an awards luncheon on September 26 in New York. According to a foundation official, the 1997 award winners represent the distinct approaches and scientific perspectives that must combine in the fight against disease.

  • Victor A. McKusick, a professor of genetics at Johns Hopkins University, was given the Special Achievement in Medical Science Award;

  • Mark S. Ptashne, the Ludwig Professor of Molecular Biology at the Memorial Sloan-Kettering Cancer Center in New York, was presented with the foundation's Basic Medical Research Award; and

  • Alfred Sommer, dean of the Johns Hopkins College of Public Health and Hygiene, received the Clinical Research Award.

Each received $25,000 and a statuette of Nike of Samothrace, an international symbol of perseverance and triumph over adversity. The Lasker awards, known in some circles as the "American Nobels," are regarded as a leading predictor of the Nobel Prizes. Fifty-seven recipients of the Basic Medical Research Award have gone on to win a Nobel. Earlier this month, Stanley B. Prusiner, who received a Lasker award in 1994, was named as the 1997 winner of the Nobel in physiology or medicine.

The research of this year's recipients represents how medicine is pushed forward by studies from both microscopic and macroscopic perspectives, according to Joseph L. Goldstein, chairman of both the awards jury and the department of molecular genetics at the University of Texas Southwestern Medical Center in Dallas.

"We have chosen three scientists who represent and often bridge the prominent perspectives and approaches in science-nature/nurture and basic/global," Goldstein says. "On one side, you have the genetic discoveries of Ptashne and McKusick representing nature at the basic molecular level and at the global level through inheritance. On the other side, you have Sommer and again McKusick representing the nurturing side of medicine through their clinical work. Sommer looked at whole populations to help the individual. McKusick looked at extraordinary individuals to help us all."

"Each beautifully demonstrates how one discipline in science builds on itself and allows progress in another until the circle is completed and the process starts over again," Goldstein adds.


MAN BEHIND MIM: Victor McKusick was honored for a lifetime of achievement, including the publication of the bible of inherited diseases, Mendelian Inheritance In Man.
McKusick was cited for his lifetime achievements as the founder of medical genetics. Summarizing the many contributions of McKusick is a "humbling task," Goldstein proclaimed in introducing just the second winner of the Lasker Special Achievement Award. The inaugural award was presented in 1996 to Paul C. Zamecnik for research in protein and antisense DNA (K.Y. Kreeger, The Scientist, Oct. 28, 1996, page 1).

McKusick recalls with precision the beginning of his long stay at Johns Hopkins. "It was Washington's birthday, 1943, that I began there," he says. "I never imagined that I wouldn't leave. I probably deserve the award for staying at one place for so long."

In the years to come, he would rely on a "mixture of opportunism, chauvinism, and dilettantism" in building a canon of research crossing four vocations as cardiologist, medical geneticist, clinician, and editor. "I say opportunism because a lot of opportunity came to me by chance," McKusick explains. "I say dilettantism because I've studied so many things. I say chauvinism because I've never needed or wanted to leave Hopkins. It's a crossroads where I could pitch my tent, never having to leave to get the latest in medical research."

The first phase of McKusick's career began as a cardiologist soon after he completed his M.D. at Johns Hopkins in 1946. The budding medical geneticist began to explore patterns of inheritance among his heart patients with connective tissue disorders. In 1950, McKusick became interested in Marfan syndrome, a connective tissue disorder associated extreme height, elongated bones in the extremities, and weakness of the aorta. President Abraham Lincoln is thought to have suffered from Marfan syndrome. After collecting patient and family data, McKusick concluded that the syndrome was an inherited disorder expressed in connective tissue wherever it was found in the body. Based on these studies, McKusick published Heritable Disorders of Connective Tissue (St. Louis, C.V. Mosby, 1956), which appeared in its fifth edition in 1993. Many years later Marfan syndrome was mapped to chromosome 15.

In 1957, the chairman of the school of medicine at Hopkins charged McKusick with the creation of a medical genetics clinic. The old syphilis clinic soon was converted in the Division of Medical Genetics.

With his rise to prominence at Johns Hopkins, McKusick was appointed to its University Press committee. John A. Hostetler's soon-to-be classic cultural study Amish Society (Johns Hopkins University Press, 1963) was passed on to him to review. McKusick's interest in the Amish was sparked as he learned of a variety of rare diseases common among Old Order congregations.

In 1963, McKusick began studies of the Old Order Amish, who reportedly had high rates of rare and recessive forms of dwarfism such as Ellis-van Creveld syndrome, or "six-fingered dwarfism." He went on to discover two types of heritable dwarfism and a rare liver disorder through his study of the Amish.

In the 1960s, McKusick's reputation was established in medical genetics as students came to Hopkins to study under him. With his wife, Anne McKusick, also a physician at Hopkins, he began a study group where students were directed to comb medical literature for information relating genes and phenotypes for certain diseases.

From this effort, the Mendelian Inheritance in Man (MIM) index was born. First published in 1966, MIM provided a listing of more than 1,500 human phenotypes of diseases known to be inherited. MIM has grown to more than three volumes and lists more than 9,000 phenotypes, most of which are linked to certain genes. The 11th edition of MIM is now available online (http://www3.ncbi.nlm.nih.gov/omim), receiving more than 31,000 "hits" per day.


PIONEER IN REGULATION: Mark Ptashne was cited for his trailblazing studies in gene regulation.
Ptashne was cited by the foundation for elucidating the molecular basis of gene regulation and isolating the "lambda repressor," which functions as an on/off switch in gene expression. Ptashne's work in molecular genetics represents the power and necessity of basic science in attacking diseases, according to Goldstein. By understanding the fundamental process of gene regulation, medicine is in a position to attack a variety of gene-linked diseases like cancer and pituitary hormone deficiency, Goldstein says.

Success seems to be a constant companion to Ptashne. He began a 30-year tenure as a professor of biology at Harvard University just three years after completing his Ph.D. there in 1968. Now a professor at the Memorial Sloan-Kettering Cancer Center, Ptashne received numerous awards and honors while at Harvard, including the Gairdner Foundation International Award in 1985.

That Ptashne's research on the lambda repressor and other transcription factors, groups of proteins that bind DNA and initiate transcription at specific DNA sites, has become "textbook knowledge" in molecular genetics is evidence of his "giant status" in medicine, according to Goldstein. Ptashne's work inspired a virtual industry in gene regulation research with more than 11,000 articles published in the field last year, Goldstein notes.

Ptashne hung out a shingle in the fledgling field of molecular genetics in 1965 as a junior fellow at the Harvard Society of Fellows. Two years later, he made a mark in science by isolating a regulatory protein, the lambda repressor, in bacteriophage (M.S. Ptashne, Proceedings of the National Academy of Sciences, 57:306-17, 1967). The lambda repressor controls the genes of a virus that reproduces by invading the bacterium cell. With the lambda repressor isolated and identified, Ptashne was able to discover other related regulatory molecules that combined to form elaborate switches, allowing the virus to lie dormant in the bacterium until signaled by various environmental factors.

Ptashne wrote another chapter in the history of molecular genetics when his laboratory shifted focus from bacteria to more complicated organisms like yeast and fruit flies. By defining transcription factors in these higher organisms, Ptashne showed that these mechanisms were essentially the same in yeast, fruit flies, plants, and people (G. Gill et al., PNAS, 87:2127-31,1990; D.M. Ruden et al., Nature, 350:250-2,1991).

While this has become accepted knowledge in molecular genetics, Ptashne hesitates to describe his studies as effortlessly progressing from one breakthrough to another and one award to another. Simplicity and elegance, which Goldstein calls the hallmarks of Ptashne's work, aroused skepticism in other scientists, Ptashne says.

"We will put forward an idea and other scientists will say, 'Yes, but it seems too simple, too obvious, not thought out,'" Ptashne explains. "But they don't realize that it is difficult to arrive at a simple picture when you've had to consider it among all possible pictures. Those who would argue against our current work are those who argued against our work on the lambda repressor. Peer recognition is meaningful because scientists are critical and you need tenacity to change minds."


GRADE 'A' WORK: Alfred Sommer was noted for linking vitamin A deficiency and increased mortality in children.
Sommer was cited for demonstrating that low-dose vitamin A supplementation in children can help to prevent death from infectious diseases as well as blindness. With the improvement of vitamin A deficiencies in children, 5 million to 10 million cases of xerophthalmia (corneal ulceration) and 500,000 cases of blindness could be prevented; in addition, more than 1 million lives could be saved by reducing mortality from diseases like measles (A. Sommer, K.P. West, Jr., Vitamin A Deficiency: Health, Survival, and Vision, New York, Oxford University Press, 1996).

But Sommer's research at one time threatened to disappear from view and never influence international health policy.

Sommer, a 1967 graduate of Harvard University, traveled to Indonesia to study xerophthalmia and vitamin A deficiency after completing a residency in ophthalmology at Johns Hopkins. One night, he pored over the data collected and noticed by chance that children with night blindness died at four times the rate of children without the disease.

"With the 1983 study, we published in Lancet [A. Sommer et al., Lancet, 2:585-8, 1983] and hoped for a big response," Sommer recalls. "But I couldn't believe it. The silence was deafening. Here, we were saying you could reduce child mortality by 3 [million] to 4 million per year for 3 to 4 cents for a vitamin A tablet. There was just one letter to the editor and it was not positive for us.

"Most people said that our discovery that [vitamin A] reduced mortality from infectious diseases was just too good to be true. We thought it was too good to not be true. Earlier studies made similar assertions, but never had an impact (J.B. Ellison, British Medical Journal, 2:708-1, 1932). So we decided to overwhelm them with evidence."

Sommer tightened the methods and widened the scope of his studies. Vitamin A trials were conducted using hundreds of villagers and tens of thousands of children. Several controlled trials were performed to duplicate and confirm early findings. Along the way, Sommer was able to prove that measles caused blindness by interfering with vitamin A metabolism.

A decade later, Sommer's discovery had a massive impact on world health programs. In 1993, the United Nations International Children's Emergency Fund (UNICEF) and the World Health Organization (WHO) officially recognized the conclusions of the original 1983 study when each named the eradication of vitamin A deficiency as one of its top 10 priorities.

But Sommer remains modest about his achievements, attributing much of his success to refusing to have his work ignored.

"Why did I win this award?" Sommer asks. "Beats me. I had the good fortune of making a chance observation during a study for an entirely different purpose. I was lucky to have found this correlation.

"But there was a similar study to ours almost exactly 50 years before. It was ignored and, philosophically speaking, it died. I dedicated myself to bringing our study to light. That's why scientists need to keep going back to their work. All scientists who want their work to make an impact must be persistent. It's not an obligation I want to hang on all researchers, but clinical researchers have this obligation if they see their studies as impacting on the health of real people. We're winning the award because we took an original chance observation and built it up to the point that it changed policy and clinical practice in health care."

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