Lasker Foundation Honors Seven, Presents New Award For First Time

SIDEBAR: For Further Reading 1996 LASKER LAUREATES: Seated, from left, are John Robbins and Rachel Schneerson; standing from left, are Ferid Murad, David Smith, Robert Furchgott, Paul Zamecnik, and Porter Anderson. The Albert and Mary Lasker Foundation entered its second half-century earlier this month by presenting a new prize along with its coveted medical research awards. For the first time in its 51-year history, the New York-based philanthropy bestowed the Albert Lasker Award for Special

Oct 28, 1996
Karen Young Kreeger

SIDEBAR: For Further Reading

1996 LASKER LAUREATES: Seated, from left, are John Robbins and Rachel Schneerson; standing from left, are Ferid Murad, David Smith, Robert Furchgott, Paul Zamecnik, and Porter Anderson.
The Albert and Mary Lasker Foundation entered its second half-century earlier this month by presenting a new prize along with its coveted medical research awards. For the first time in its 51-year history, the New York-based philanthropy bestowed the Albert Lasker Award for Special Achievement in Medical Sciences. This award for contributions "of unique magnitude and immeasurable influence on the course of science" went to Paul C. Zamecnik, 84, principal scientist at the Worcester Foundation for Biomedical Research in Shrewsbury, Mass. He was recognized for his fundamental research in two areas, protein synthesis and antisense DNA, snippets of the genetic code used in disease-fighting therapies.

The 1996 Albert Lasker Basic Medical Research Award was shared by Ferid Murad, 60, the former president and CEO of Molecular Geriatrics Corp. in Lake Bluff, Ill., and Robert F. Furchgott, 80, Distinguished Professor, Emeritus, at the State University of New York Health Science Center at Brooklyn. They were honored for their fundamental research on nitric oxide, now recognized as an important biochemical messenger.

Two teams shared the 1996 Albert Lasker Clinical Medical Research Award for their research in developing a vaccine against the bacterium Haemophilis influenzae type b (Hib). John B. Robbins, 64, chief of the laboratory of developmental and molecular immunity at the National Institute of Child Health and Human Development (NICHD) and Rachel Schneerson, 64, head of the section on bacterial disease in the NICHD laboratory of developmental and molecular immunity, were jointly honored with David H. Smith, 65, the president of the New York-based David H. Smith Foundation, and Porter Warren Anderson, Jr., 59, a professor, emeritus, of pediatrics at the University of Rochester.

Commenting on Zamecnik's special achievement award, Jordan U. Gutterman, director of the Lasker Medical Research Awards Program and a professor of medicine at the University of Texas M.D. Anderson Cancer Center, notes that "there are many people in science-although recognized by their peers-who have not necessarily been recognized by some of the major prizes. So this was an incredible opportunity to really honor somebody that was long overdue."

STAR-STUDDED SHOULDERS: Special award recipient Paul Zamechnik is highly regarded as a pioneer in molecular and cellular biology.
In accepting the award, Zamecnik eloquently expressed gratitude to the foundation for acknowledging his work. "Let me thank the Lasker Foundation for a rescue from the dustbin of time and for sprinkling a little stardust on these shoulders," said Zamecnik in his speech at the awards luncheon on October 4. After his address, he was given a standing ovation, a rare event for a Lasker ceremony, according to program director Gutterman.

Each award was accompanied by a cash prize. Zamecnik received $25,000; Furchgott and Murad shared $25,000; and Robbins, Schneerson, Anderson, and Smith each received $10,000. All honorees were presented with a statuette of the Winged Victory of Samothrace, the symbol of the Lasker Foundation.

Zamecnik's scientific achievements paved the way for many modern molecular genetic discoveries. His studies in the early 1950s at the Massachusetts General Hospital revealed key aspects of protein synthesis, providing the scientific community with a completely new view of the process. "Before World War II, very little was known about how proteins were made from amino acids," he recalls. "The prevalent feeling was that protein synthesis was controlled by the same enzymes that broke them down."

But Zamecnik and colleagues surmised there was a different set of enzymes for each purpose. They worked on developing an experimental system for making proteins free of intact cells in order to study the individual components of protein synthesis. These cell-free systems were the first in which net peptide bond formation-using 14C-label amino acids-was carried out. "I think that really opened the door because we could then individually examine various molecular components we suspected to play a role in synthesis, and in time we found we could make protein in the cell-free system," notes Zamecnik.

These painstaking experiments not only revolutionized how scientists viewed protein synthesis, but also provided the first evidence for transfer RNA (tRNA), nucleotides that control how DNA is translated into proteins. Understanding the role of tRNA in the intricate process of protein synthesis allowed others to study how DNA bases are converted into the specific order of amino acids that govern protein identity and shape. This understanding, in turn, provided one of the first tools for revealing the secrets of the genetic code.

The second contribution to medical science for which Zamecnik is honored is his conceptualization of what has now become a hot area of research-antisense DNA. These short pieces of DNA are chemically synthesized to match selected RNA strands in order to inactivate specific genes.

"DNA is like Velcro, with plus and minus strands," explains Zamecnik. "We define the plus strand as the one that gives the message for the gene. The other-the negative, or antisense, strand-doesn't provide a message, but it does act like a negative on a photographic plate and is needed to make another positive strand. The idea was that if we could slip in a piece of synthetic DNA that is the same sense as the negative strand, then we could stop the whole procedure of DNA or RNA replication from continuing. And, if we could do that for viruses that are currently without good treatment, or for a bacterium for which drug resistance is growing, then we could provide a new kind of therapy."

Zamecnik's vision of new antisense drugs is in the making: Clinical trials of drugs for AIDS, cancer, and infectious diseases based on antisense DNA technology are currently being conducted in hospitals throughout the world. In addition to his position at the Worcester Foundation, he is chairman of the scientific advisory committee of Hybridon Inc. in Worcester, Mass. "It's devoted entirely to exploring the principle that antisense may work to block noxious genes from viruses such as HIV and drug-resistant parasites such as malaria," he remarks.

The American Society for Biochemistry and Molecular Biology is also recognizing Zamecnik for his contributions to the study of protein synthesis and antisense DNA. Earlier this month the organization announced that he would be the 1997 recipient of its Merck Award. He will receive $5,000 from the society.

INTERNATIONAL IMPLICATIONS: Knowledge gained in the development of the Hib vaccine is now being applied to other vaccines all over the world, says Rachel Schneerson.
In the 1960s, in independent collaborations, Robbins and Schneerson as well as Anderson and Smith began their work on a vaccine for Haemophilis influenzae type b (Hib), prompted, in part, by the limitations of antibiotics. Hib is a bacterium that primarily infects infants and young children. Prior to antibiotics, Hib-caused meningitis was almost always fatal. Still, after the advent of Hib antibiotics, about 5 percent of Hib-infected children died and another 30 percent sustained permanent damage to their central nervous systems, including mental retardation.

PUBLIC HEALTH IMPACT: Because of Hib vaccines, Hib meningitis has significantly declined in many countries, remarks John Robbins.
Robbins and Schneerson drew on past work by Rockefeller University scientists Karl Landsteiner, Oswald Avery, and Walter Goebel that showed that covalent binding to proteins converted nonimmunogenic bacterial polysaccharides called haptens to immunogens. But the synthetic methods and immunization routes of Landsteiner, Avery, and Goebel did not function well in a clinical setting. Using the hapten approach, Robbins and Schneerson-and then Anderson and Smith-developed Hib conjugates that elicited booster responses in infants. Clinical trials confirmed that these conjugates prevented Hib meningitis and other infections in infants. The Food and Drug Administration eventually licensed these new types of vaccines.

Hib conjugate vaccines have had an important impact on public health, note Robbins and Schneerson. "Soon after their addition to routine vaccination of infants, the incidence of Hib meningitis in vaccinated as well as unvaccinated children began to decline," explains Robbins. These vaccines are now routinely administered to infants in the United States and about 30 countries and are recommended by the World Health Organization in its Extended Program on Immunization.

As Hib-related diseases decline, Hib bacteria are no longer detected in pharyngeal cultures. "Since Hib is an inhabitant of and a pathogen in humans only, worldwide use of Hib conjugates has the potential for eliminating this pathogen," remarks Schneerson.

Robbins and Schneerson also point out that the principles established by the study of Hib conjugates and the vaccines for pneumococcus and meningococcus should accelerate worldwide acceptance of polysaccharide-based vaccines without extensive clinical trials.

HERETICAL IDEAS: Developing a vaccine for a bacterial disease like meningitis was once considered scientific heresay, remarks David Smith.
Smith and Anderson's Hib vaccine collaboration began at the Children's Hospital Medical Center in Boston and continued at the University of Rochester. "I came on the project in 1968 as a bacteriologist with some chemistry background and some experience in purifying biological macromolecules," notes Anderson.

"The idea of making a vaccine for a bacterial disease was a kind of heresy," remembers Smith. "From the 1950s into the 1970s you treated bacterial diseases with antibiotics, and viral diseases with vaccines." But Smith and Anderson were vociferous proponents of the development of a safe and effective Hib vaccine, and eventually saw it through licensing and commercial production.

LONG-TERM PROJECT: Porter Anderson entered the effort to develop a Hib vaccine as a bacteriologist almost 30 years ago.
"Schneerson and Robbins started out totally independent of us," says Smith. "We didn't know they were working on this at all, and I don't think they knew we were. I think our first publications were stunning to the other side, because we both came out with our early publications on the subject within a few months of each other."

Around 1979, the Smith group began to look at Hib surface proteins as a possible alternative vaccine, notes Anderson. "After a few years we decided that the surface protein approach wasn't viable and decided that the conjugate approach was indicated. We then started to look at a somewhat different approach from Robbins and Schneerson," notes Anderson.

Eventually in 1983, Smith founded Praxis Biologics (which merged with Lederle Laboratories of Wayne, N.J., in 1990) to bring a Hib vaccine to market. In the next seven years FDA approved three Praxis Hib conjugate vaccines for children two months to two years of age. Anderson also played a role in the founding of Praxis.

Smith is heartened by the fact that this year's Lasker Award for clinical research is related to disease prevention and diseases of children. "These are not usually areas at the top of the lists of these foundations that give prizes," he maintains.

The path blazed by Furchgott and Murad leading to what scientists now know about nitric oxide, one of the most important chemical messengers so far discovered, is a tortuous one. Since the early 1950s, while working at Washington University, Furchgott has been interested in how hormones, neurotransmitters, and drugs interact with receptors in blood vessels. As part of these early studies, he also described the phenomenon of photo-relaxation, a relaxation of vascular smooth muscles when exposed to ultraviolet light.

CONVERGING PATHS: Evidence from many approaches, disciplines, and laboratories came together in explaining nitric oxide's physiological role, notes Robert Furchgott.
In 1978, while working with a different type of vascular preparation, Furchgott inadvertently came upon an anomalous result that led to the discovery of a substance in the endothelium that causes smooth muscle cells to relax. He found that certain vasodilators act by releasing this substance. He and colleagues dubbed the mysterious molecule EDRF, or endothelium-derived relaxing factor.

DEBUNKING DOGMA; Discovering nitric oxide's roe as a ubiquitous molecular messenger shook up the scientific establishment, recalls Ferid Murad.
In coming up with possible explanations for the biochemical nature of EDRF, Furchgott recalls, "we thought in terms of some sort of free radical." Meanwhile, Murad, who was also intrigued with how hormones and drugs relate to cell-surface receptors, had set out to investigate how hormones and related molecules regulate cyclic GMP synthesis. Cyclic GMP is a molecular messenger involved in the control of many cellular processes.

"By combining classical biochemistry with pharmacology and physiology, in 1973 we found that the enzyme that forms cyclic GMP was activated by a few nitrogen-containing compounds," Murad says. "Hormones, unfortunately, would not activate the enzyme once you homogenized the tissue and disrupted the cells. What this told us is that the hormone coupling to its receptor to regulate cyclic GMP was involved in a very complicated pathway. But now we had some molecules that might help us work out the pathway."

Murad and colleagues found that these nitrogen-containing compounds and others were all converted to nitric oxide. "This was the first example ever of a free radical-nitric oxide-that would activate an enzyme," he points out. "The dogma for decades was that free radicals were always bad guys. This was heresy. [The scientific establishment] thought it was crazy."

The October 9 issue of JAMA-Journal of the American Medical Association contains three special articles commemorating this year's basic and clinical awards from the Lasker Foundation:

J.B. Robbins, R. Schneerson, P. Anderson, D.H. Smith, "Prevention of systemic infections, especially meningitis, caused by Haemophilis influenzae Type b: Impact on public health and implications for other polysaccharide-based vaccines," JAMA, 276:1181-5, 1996.

R.F. Furchgott, "The discovery of endothelium-derived relaxing factor and its importance in the identification of nitric oxide," JAMA, 276:1186-8, 1996.

F. Murad, "Signal transduction using nitric oxide and cyclic guanosine monophosphate," JAMA, 276:1189-92, 1996.

Protein Synthesis
M.B. Hoagland et al., Journal of Biological Chemistry, 231:241-57, 1968 (In 1985 this paper was identified by the Institute for Scientific Information as a Citation Classic.)

Antisense DNA
P.C. Zamecnik, "History of anti-sense oligonucleotides," Methods in Molecular Medicine: Anti-sense Therapeutics, 1-11, Totowa, N.J., Humana Press Inc., 1996.

P.C. Zamecnik, "Introduction: Oligonucleotide base hybridization as a modulator of genetic message readout," Prospects for Anti-sense Nucleic Acid Therapy of Cancer and AIDS, 1-6, New York, Wiley-Liss Inc., 1991.

Hib Vaccines
P.W. Anderson, R.B. Johnston, D.H. Smith, Journal of Clinical Investigation, 51:39-45, 1972; R. Schneerson et al., Journal of Immunology, 107:1081-9, 1971.

Nitric Oxide
F. Murad, Advances in Pharmacology, 26:1-335, 1994; R.F. Furchgott, Annual Review of Pharmacological Toxicology, 35:1-27, 1995.

When the Murad team exposed smooth muscle tissue to the nitrogen-containing compounds, cyclic GMP levels rose. As a result, the muscle relaxed. "From this and other experiments, we deduced that nitric oxide was the intermediate vasodilator. And we coined the term 'nitro-vasodilators' for this class of nitrogen-containing compounds," says Murad.

The biochemical properties of Furchgott's EDRF studies were similar to the effects that Murad had been reporting with the nitro-vasodilators. "We recognized that our work was related to each other's and showed that EDRF also works through cyclic GMP," recalls Murad.

"We also showed that vascular relaxation by EDRF was closely associated with an increase in cyclic GMP," remembers Furchgott. "From there we went back to the photo-relaxation work and showed that that, too, was accompanied by a marked increase in cyclic GMP."

These interconnected studies brought the two research areas together. "In 1986, after demonstrating many similarities in properties of EDRF and nitric oxide as relaxing agents, we proposed at an international symposium [at the Mayo Clinic] that EDRF is nitric oxide," remarks Furchgott. He adds that Lewis Ignarro from the University of California, Los Angeles, independently proposed that EDRF is nitric oxide at the same 1986 symposium.

Furchgott and Murad also cite important contributions to the complex nitric oxide story throughout the 1980s by research teams at such institutions as the Mayo Clinic, the University of Utah, the University of Pittsburgh, the Neuroscience Institute in Tokyo, and the Wellcome Research Laboratories in Beckenham, United Kingdom.

"By 1987, several groups of scientists-notably Salvadore Moncada [then of the Wellcome Labs] and Lewis Ignarro-confirmed that EDRF and nitric oxide are one and the same, and this triggered an explosion in the nitric oxide field, opening the floodgates of discovery," said Joseph L. Goldstein, chairman of the Lasker jury and of the department of molecular genetics at the University of Texas Southwestern Medical Center, at the Lasker awards luncheon.

Today, nitric oxide is recognized as somewhat of a super-molecule, with contradictory characteristics. On one hand, it is implicated in free-radical tissue damage, while on the other it is now known as a universal regulator of an array of vascular, neurological, and immunological processes. "When we got started, the field was rather dismal," observes Murad. "We're continuing to see a logarithmic growth of exciting publications in this area."