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Pioneers of cell receptor research share America's top prize in medicine

ALBANY, N.Y., April 26, 2007 - Three pioneering investigators who determined how cells communicate with their environment through the use of receptors, or signaling pathways, have been named the recipients of the $500,000 Albany Medical Center Prize in Medicine and Biomedical Research, America's top prize in medicine. Their groundbreaking discoveries of how receptors transmit signals from hormones, drugs and other stimuli to trigger action within the cell helped give rise to a new and rapid phase of drug development, including many of today's most commonly used prescription drugs.

The 2007 recipients are: Dr. Robert J. Lefkowitz, James B. Duke Professor of Medicine and Howard Hughes Medical Institute Investigator at Duke University Medical Center in Durham, N.C.; Dr. Solomon H. Snyder, Distinguished Service Professor in the Department of Neuroscience at Johns Hopkins School of Medicine in Baltimore, Md.; and Ronald M. Evans, Ph.D., Howard Hughes Medical Institute Investigator at The Salk Institute for Biological Studies in La Jolla, Calif.

The researchers, working independently and simultaneously on cell receptors, will each receive one-third of the Albany Prize's $500,000 award.

"The discoveries by Drs. Lefkowitz, Snyder and Evans of how receptors function unlocked the mystery of how all types of hormones and neurotransmitters affect cellular activity. These innovations unleashed a revolution within the pharmaceutical industry that allowed researchers to develop drugs which parodied the effects of these naturally occurring substances," stated James J. Barba, president and chief executive officer of the Albany Medical Center, who chaired the National Selection Committee. "Together, their work has led to the development of countless prescription drugs used to treat a wide variety of ailments and conditions from coronary artery disease to schizophrenia and other common psychological illnesses, to breast and ovarian cancer, atherosclerosis, asthma, arthritis and diabetes," he explained.

Among the new drugs that evolved from their work are the next generation of better, safer and more effective beta blockers, cortisone, antihistamines, anti-depressants, estrogens, androgens, contraceptives, insulin sensitizers and obesity pills, Barba added.

The Albany Medical Center Prize is the largest prize in medicine in the United States and second worldwide to the Nobel Prize in Physiology and Medicine. The annual Prize - announced each spring - has been created to encourage and recognize extraordinary and sustained contributions to improving health care and promoting biomedical research with translational benefits applied to improved patient care.

The Prize was founded by Morris "Marty" Silverman, who passed away in January 2006 at the age of 93. Silverman endowed the Albany Prize in November 2000 with a $50 million gift commitment to Albany Medical Center.

Both Lefkowitz and Snyder were faced with a daunting task when they set out on their research to learn just how cells communicate with their environment. The receptors they sought occur on the outer membrane of cells, which is impenetrable to most of the body's hormones and transmitters, and which can bind many chemicals non-specifically making identification of the true receptors a major challenge.

Evans' receptors, on the other hand, were located inside the cell. The hormones he was working with were steroid based, made from fat-soluble building blocks that glide right through the cell membrane and go directly to the nucleus of the cell. Still, like Lefkowitz and Snyder, the question remained: How do these various classes of hormonal signals trigger cellular activity?

Lefkowitz and Snyder were the first to unlock the mystery behind how cell receptors functioned. Each working independently made the seminal discovery that receptors could be labeled "or tagged" by radioactively labeled forms of drugs thus facilitating their identification and analysis.

What's more, they discovered that the receptors performed like a lock for hormones which acted like a key. By allowing the hormones to enter them, much like a key might fit a lock, the receptors served as the conduit for cellular activity. As the key activated the lock, the hormone or transmitter was able to act upon the cell in its designated way.

While the notion of cell receptors dates back to the beginning of the 20th century, Snyder and Lefkowitz were among the first to confirm their actual existence.

Lefkowitz made a remarkable contribution in the mid-1980s when he and his colleagues cloned the gene first for the ?-adrenergic receptor, and then rapidly thereafter, for a total of 8 adrenergic receptors (receptors for adrenaline and noradrenaline). This led to the seminal discovery that all G protein-coupled receptors (which include the ?-adrenergic receptor) have a very similar molecular structure. The structure is defined by an amino acid sequence which weaves its way back and forth across the plasma membrane seven times. Today we know that about 1,000 receptors in the human body belong to this same family. The relevance was that the "unlocking" mechanisms held true for the entire family of receptors so that pharmaceutical researchers now understood how to effectively target the largest receptor family in the human body. Today, as many as 30 to 50 percent of all prescription drugs are designed to "fit" like keys into the similarly structured locks of Lefkowitz' receptors - everything from antihistamines to ulcer drugs to beta blockers that help relieve hypertension, angina and coronary disease.

Lefkowitz' work enabled researchers Richard Axel and Linda Buck to capture the Nobel Prize in 2004 for their discovery of how the olfactory system is organized. They discovered that about half of all G protein-coupled receptors were olfactory receptors which govern the sense of smell. Axel and Buck knew that olfactory receptors were members of this extended receptor family, but had no idea just how pervasive they were. Axel and Buck used cloning techniques to match up their smell receptors with Lefkowitz' G protein family and over the next few years, it became clear that as many as 500 of the 1,000 genes in the human genome for G protein-controlled receptors were associated with smell.

Further north, Snyder was unraveling the mystery behind receptors that controlled pain and pleasure in the brain. Snyder was the first to identify receptors in the brain that are the targets of opiates, drugs like morphine, codeine and other severe pain relievers, as well as heroin and other drugs of abuse.

Before Snyder's groundbreaking research, scientists and clinicians knew what opiates did, but no one knew how they the achieved their effect. Snyder was the first to understand and identify the molecular binding actions of these drugs to specific opiate receptors in the brain. He, for example, was able to localize these receptors to discrete brain sites in order to explain the major actions of the drugs. Snyder went on to identify receptors for virtually all of the major neurotransmitters that have led to new classes of anti-psychotic drugs as well as new and more effective pain-relieving drugs designed to treat migraine headaches. His most recent research holds promise for advances in the treatment of Parkinson's disease.

Snyder's findings also led to the development of drugs to treat schizophrenia, which work by blocking the neurotransmitter receptor for dopamine. Drugs perform as either agonists or antagonists. Agonists unlock cell receptors to stimulate cell activity. Antagonists jam up the receptor lock to prevent agonists from getting in, thereby reducing or proscribing cell activity.

A short time later, out west, Evans was investigating the workings of a more secretive receptor, one that was hidden inside the cell itself, typically deep within the nucleus. His receptor would come to be known as the nuclear hormone receptor.

For Evans, whose stealthy hormones had little difficulty penetrating the cell membrane, his challenge was to figure out how they triggered cell activity once they reached the interior. Evans demonstrated that the invading hormones after finding their intracellular receptors in the nucleus latched onto the chromosomes to switch on precise genetic networks. In effect they act like molecular "software" to control the "hardware" of the genome.

Evans' seminal discovery occurred in 1985 when he successfully cloned the first nuclear hormone receptor, the human glucocorticoid receptor. This action would soon lead to the finding of a superfamily of nuclear hormone receptors, all with similar molecular and genetic structures. Just as Lefkowitz had uncovered a family of more than one-thousand closely aligned and structured receptors, ALBANY, N.Y., April 26, 2007 - Three pioneering investigators who determined how cells communicate with their environment through the use of receptors, or signaling pathways, have been named the recipients of the $500,000 Albany Medical Center Prize in Medicine and Biomedical Research, America's top prize in medicine. Their groundbreaking discoveries of how receptors transmit signals from hormones, drugs and other stimuli to trigger action within the cell helped give rise to a new and rapid phase of drug development, including many of today's most commonly used prescription drugs.

Evans had made a remarkably similar discovery. Interestingly, his superfamily of nearly 50 nuclear receptors can function like a car with forward, neutral and even reverse activities--allowing the development of unique classes of drugs. The impact on pharmaceutical research would be every bit as dramatic as that of his colleagues as the industry could now target a whole new generation of therapies.

Today, Evans' nuclear hormone receptors are among the most widely investigated group of pharmaceutical targets in the world. Among the drugs that are designed to work in tandem with them are glucocorticoids - cortisone, cortisol and other variations - found in inhalers to treat asthma and also used in the treatment of arthritis, rheumatism, and in the suppression of other inflammatory and allergic disorders; contraceptives; estrogens for hormone replacement therapy; antiestrogens to treat breast and ovarian cancer; androgens, anabolic steroids and antiandrogens for prostate cancer.

More recently, Evans has identified receptors that are targeted by drugs to treat type 2 diabetes and that play a pivotal role in helping to lower sugar levels and remove cholesterol from the body. Earlier this decade, Evans identified the receptor to create the first genetically engineered mice with increased endurance for long-distance running. These marathon mice hold out promise for treating children with degenerative muscle disease as well as helping the growing numbers of overweight people burn more calories faster.

Additional information can be found at http://www.amc.edu/Academic/AlbanyPrize/index.html.

 
*Questions & Comments:

Greg McGarry
Extension: (518) 262 - 3421
  mcgarrg@mail.amc.edu



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