Timeline:
Department of Pharmacology decade by decade

Joseph Schlessinger, once a captain in the Israeli army, says that the pharmacology department “should adopt creative guerrilla tactics” as it seeks a role for drug discovery efforts within the academic setting.

Building a better drug

While new technologies and industrial-scale approaches to drug discovery are changing the field, academic pharmacology remains a mixture of art and science.

By Marc Wortman

“Serendipity” is a word pharmacologists use to describe the way they discovered many effective medications. Even with modern molecular tools, scientists still stumble upon drugs in unexpected ways. “Serendipity” is what happened one afternoon in 1983 in the Yale Co-op bookstore. Leafing through an old chemistry textbook, Krishnamurthy Shyam, Ph.D., came across a chemical reaction that he thought might be adaptable to the design of a new series of antitumor agents. He brought his idea back to the laboratory of Alan C. Sartorelli, Ph.D., the Alfred Gilman Professor of Pharmacology, where Shyam was a postdoctoral associate and is today an associate research scientist.

Sartorelli urged Shyam to follow his hunch. “If we knew what was going to happen ahead of time,” says Sartorelli, “it would be trivial. I want people to have a chance to invent.” Shyam synthesized a compound that targeted DNA and tried it on five mice transplanted with a leukemia. Two were cured, but three suffered rapid toxic—and fatal—side effects. Shyam continued synthesizing compounds in this family. Three years later Philip G. Penketh, Ph.D., now an associate research scientist, joined Sartorelli’s laboratory as a postdoc and began to study how these compounds worked. Based on Penketh’s findings, Shyam synthesized versions of the compound called “prodrugs,” which reduced host toxicity. One of these drugs was selected for clinical trials.

Today the compound, VNP40101M, is being tested in humans by Vion Pharmaceuticals, a New Haven-based biotechnology company that Sartorelli and outside investors founded in 1993. The data from the Phase I clinical trials appear promising. “If this agent works in refractory [drug-resistant] tumors,” says Shyam, “that would be a great breakthrough.” Two decades after Shyam’s hunch, it will still take a great deal of luck for the drug to gain approval from the Food and Drug Administration (FDA). Animal studies and even early human studies often raise hopes that later, larger trials dash. According to Sartorelli, “The chances of a compound succeeding are very, very slim.” Still, Shyam is pleased. “Many scientists,” he says, “spend a lifetime without getting a drug into the clinic.”

A mix of old and new
Yale pharmacologists have, over the years, achieved remarkable successes by following their hunches. In the 1940s the department produced the first anticancer drug, nitrogen mustard, to treat lymphoma. In the 1950s the first antiviral agent was developed at Yale. The work of Paul Greengard, Ph.D., on molecules that regulate metabolism led to his Nobel Prize in 2000.

Now the trend in pharmacological research is to move away from serendipity and happenstance. Science and industry are looking to evidence and statistics, rather than hunches, to lead them to successful drug discovery. Automated, industrial-scale analysis of compounds—so-called high-throughput screening—is the norm.

“It is becoming more and more difficult to develop drugs in an academic setting,” says the pharmacology department’s new chair, Joseph Schlessinger, Ph.D., also the William H. Prusoff Professor of Pharmacology. “The technology requires such a huge investment that academic labs can’t compete with the Pfizers and Mercks.”

Moreover, there are fewer and fewer of what Schlessinger calls “classical pharmacologists” such as Prusoff, who discovered the first antiviral medication, idoxuridine, and codiscovered the AIDS drug Zerit. Rare is the individual today who possesses advanced chemistry skills, knowledge of molecular biology and a “nose” for sleuthing out the recipe for a compound that can hit a disease target without harming the patient.

Recognizing this new landscape, Yale has taken several steps that embrace new approaches while coexisting with the old. This fall Yale is celebrating the completion of a four-story extension to Sterling Hall of Medicine’s B Wing, as well as two floors of renovated laboratories in the original B Wing. Most of that space is for Department of Pharmacology faculty. (A gift from Bristol-Myers Squibb included $2 million to help defray part of the construction costs.) In 2001, the department recruited Schlessinger from New York University, along with his wife, Irit Lax, Ph.D., an assistant research scientist in pharmacology. Schlessinger, an expert in cell signaling and founder of two biotech companies, was charged with reshaping the department by hiring seven new full-time faculty members to complement the department’s 14 full-time members and 16 others with secondary appointments. Discussions have also been under way for establishing a quasi-independent unit, to be known as the Center for Drug Discovery, which would seek to increase Yale’s chances of finding industrial markets for its benchside discoveries.

In addition, Yale is seeking partnerships with industry over and above the traditional licensing of patents and formation of biotech firms. The international drug company Pfizer is building a $35 million center for clinical trials near the medical school. Although the unit will focus on testing Pfizer compounds in humans and will draw heavily on Yale’s strengths in magnetic resonance and other imaging techniques, including pet scanning, in research, Yale faculty also will have opportunities to study Pfizer’s library of compounds.

Within the Yale campus, pharmacologists can also turn to colleagues in the Department of Chemistry on Science Hill for assistance. The former chair of that department, Andrew D. Hamilton, Ph.D., now Yale’s deputy provost for science and technology, served on the committee that recruited Schlessinger to Yale. He notes that several laboratories, including his own, collaborate with pharmacologists at the medical school. “Chemistry teaches us about biology,” he says, “and biology in turn teaches us about chemistry. We can use this increased knowledge to find novel strategies for disrupting biological targets.”

Adopting “guerrilla tactics”
Schlessinger, once a captain in the Israeli army, says that the pharmacology department “should adopt creative guerrilla tactics” as it seeks a role for drug discovery efforts within the academic setting. Rather than having laboratories focus on the costly search for promising compounds, he favors “target discovery,” studies of the intracellular pathways, genes and proteins that influence disease states and lend themselves to modulation by drugs. Those high-value findings can then be licensed to outside entities, when possible, for their use in high-throughput screening of compounds.

Drug discovery at that point becomes what Schlessinger terms “a scientifically trivial step” more appropriately undertaken in an industrial setting. The medical school should instead, he contends, “explore the mysteries of nature, digging and exploring where you know nothing, where you’re in complete darkness.” Unlike pharmaceutical companies, which must be concerned with the size of the market, says Sartorelli, “We don’t care what the size of the market is for our discoveries.”

Industry already values Yale’s strengths in pharmacology and other drug-discovery-related fields. “The department’s knowledge base—especially strong in the areas of neuropharmacology and chemotherapy—and Yale’s reputation as a world leader in imaging technologies played a major part in Pfizer’s decision to locate the clinical research unit in New Haven,” says Diane K. Jorkasky, M.D., vice president of clinical sciences at Pfizer.

Partnerships between Yale and pharmaceutical companies could help diminish the huge risks of taking on new discoveries for development. Bringing new treatments to patients has proven increasingly difficult in recent years, despite the wealth of recent discoveries about genetics and gene targets. Industry figures show that only one in 5,000 compounds registered with the FDA for testing is ever approved. The costs—of manufacturing the drug, establishing study centers, recruiting patients and collecting data—for compounds that fail are astronomical. At its earliest stages, a clinical trial with fewer than 50 patients can cost between $2 million and $4 million. Later-stage trials with large numbers of patients can cost many times that. When the price of those failures is figured into the cost of a single success, by some estimates the average drug now costs more than $900 million to reach patients.

Despite the averages, Yale enjoys an enviable record of success. Several breakthrough compounds have been discovered at Yale, and Yale and its pharmaceutical partners have one compound on the market and 10 in clinical trials. Few of the largest pharmaceutical companies can boast a comparable “pipeline” of drugs in development. For instance, Bristol-Meyers Squibb, the firm that markets Zerit and one of the world’s largest pharmaceutical corporations, lists 10 compounds in clinical development.

While making money may not be the goal of Yale scientists, few areas of investigation in the medical school have as much value for outside business entities or as much potential to bring additional revenue to the school. Returns from drug sale royalties have proven a great help to Yale. For several years, Yale received around $40 million annually in royalties from sales of Zerit. That money helped fund research and facility expansion. Outright sale of all rights to the drug in 1999 to a trust created by Royalty Pharma AG helped to finance construction of the new Anlyan Center for Medical Research and Education at 300 Cedar Street.

Finding targets
In his efforts to reshape the Department of Pharmacology, Schlessinger has begun hiring faculty who will focus less on classical pharmacology and more on molecular biology, he says, “defining targets and analyzing processes which occur in cells.”

Ya Ha, Ph.D., an assistant professor who joined the faculty in 2002, typifies the new generation of academic pharmacologists. A crystallographer, he spends much of his time modeling three-dimensional molecular structures. He seeks targets for chemical intervention in the processes that form the plaque in the brains of Alzheimer’s patients that gums up and eventually kills their neurons, causing memory loss and dementia. To model those structures he crystallizes key proteins linked to plaque formation in the brain tissue of Alzheimer’s patients. He then brings these protein crystals to a synchrotron in Brookhaven, N.Y., where he shoots them with intense X-rays. The scattered X-rays are recorded, and computer workstations combine the data into a three-dimensional molecular model of the protein he is studying. He posts the images to the scientific community as part of the Protein Data Bank (www.rcsb.org/pdb), an international repository for protein-structure data.

Ha uses the data to identify molecular sites to which small compounds could bind tightly. From there, he will try to design a compound that will inhibit the processes that lead to Alzheimer’s disease. “The three-dimensional molecular model will help design a molecule that could serve as a possible drug,” he says. “That doesn’t mean it is a good drug. That has to be tested in a classical pharmacological context.” He turns to colleagues for that help in testing the compound on cells and then in animals. “The integrated approach,” he says, “is the strength of this department.”

One of the people Ha turns to is Yung-Chi Cheng, Ph.D., the Henry Bronson Professor of Pharmacology, who collaborates with a broad range of colleagues and has had a hand in a wide range of discoveries. Before coming to Yale from the University of North Carolina in 1989 he identified two compounds now in clinical use, one used for treating cytomegalovirus and another for treating hepatitis B virus. His laboratory has six other compounds in clinical trials, and clinical testing should begin on two others this year.

Despite his extraordinary success rate, Cheng has adapted to the changing nature of pharmacology studies. He now uses data derived from structural biology, proteomics and genomics to help him tease apart biological processes and find the optimal chemical to alter them therapeutically. “For many years we were hypothesis-driven,” he says. “Now we are also taking an information-driven approach. You ask your computer to help you out. That’s critical for the future of drug discovery.”

Cheng has long drawn on input from other scientists and clinicians in the Developmental Therapeutics Program, which he co-directs. Operated by the Yale Cancer Center, this consortium of 30 faculty members in multiple disciplines focuses on the discovery of new compounds for treating cancer and viruses that have strong associations with the development of cancer. While Cheng’s own research leads to the discovery of compounds, turning them into drugs requires testing in patients. “The Developmental Therapeutics Program is really translational between the clinical sciences and basic sciences. It works both ways,” he says, providing him with insights from the clinical use of drugs into ways to discover better compounds. Program co-director Edward Chu, M.D., professor of medicine (oncology) and pharmacology, directs the Cancer Center at the VA Connecticut Healthcare System in West Haven. “We can develop biomarkers to see if a molecule is hitting the target you intended,” he says. “The only way to do that is by scientists working hand-in-hand with clinicians.”

Although Yale can provide evidence of a drug’s potential effectiveness, internal efforts at Yale by themselves will never bring a drug into widespread clinical use. “You need a partner,” says Chu. He and others in the Developmental Therapeutics Program work closely with private industry to test Yale-discovered and other compounds which have been licensed to pharmaceutical companies.

Even industrial entities must attempt to reduce the risks they face in developing compounds, often choosing not to study compounds that appear to have little promise for success in humans. That is one of the major reasons few compounds ever advance to that stage of development. Discussions have been under way at Yale for several years to help improve the likelihood that university-discovered compounds will reach patients and that molecular targets for drug discovery will prove of value to industry. After arriving at Yale in 1997 from the FDA, where he had been the commissioner, former Dean David A. Kessler, M.D., encouraged the formation of a committee to consider the creation of a Center for Drug Discovery. The center would, according to Carolyn W. Slayman, Ph.D., Sterling Professor of Genetics and deputy dean for academic and scientific affairs, “sit at the boundary between the academic and commercial worlds.” Such a center would take Yale discoveries and develop them further to create increased value for partners. “If you want to do more than convince industry to make a major investment,” she says, “the more information you have that a drug will work, the more likely faculty research will progress right through to the clinic.”

Besides increasing the likelihood of discoveries reaching patients, it could provide Yale with a means of tackling discovery projects that the pharmaceutical industry might avoid for business reasons. For instance, drugs for diseases that industry deems unlikely to generate enough revenues or that might compete with their existing drugs could be developed. Cheng says, “There is a big difference between Yale and the pharmaceutical industry. We are not driven by product but for the common good without profit in mind.” Faculty and administrators continue to discuss the creation of the Center for Drug Discovery while Schlessinger and colleagues reshape the department. “We need instrumentation and a facility staffed by chemists and biologists who will carry Yale discoveries to the next step,” says Slayman. “Pharmacology is not an inward-bounded world. Our faculty members need to be catalysts whose work pushes the frontiers of science and helps translate science into treatments.”

Yale’s move away from pure serendipity in the pursuit of therapies should increase the chances of success and help improve patients’ lives. It should also push science in ways that industry cannot or will not. “Studies may not help pharmaceutical companies to market their products and may even damage their products’ profit,” says Cheng. “It would be a mistake to leave industry solely responsible for pharmaceutical science.” Pharmacology department Chair Schlessinger agrees: “We have the capacity to take on more risky projects at the forefront of science, to define molecular paradigms and involve technologies that need to be developed. If we find drugs,” concludes Schlessinger with a shrug, “that would be fine.” YM

Marc Wortman is a contributing editor of Yale Medicine.

Department of Pharmacology decade by decade

1940s
• Department of Pharmacology founded with William Salter as the first chair.

• Discovery of first anticancer agent, nitrogen mustard, for treatment of lymphoma; demonstration of its effectiveness and the development of drug resistance by Alfred Gilman, Louis Goodman and Gustaf Lindskog.

1950s
• Discovery of first antiviral agent, IUdR, for the treatment of ocular herpes, a major cause of blindness, by William Prusoff.

• Arnold Welch becomes chair and develops first biochemically oriented pharmacology department in the country, steering the field away from a physiological approach.

1960s
• Work by Joseph Bertino on mechanism of action of antifolate chemotherapeutic agents which contributed to use of methotrexate, an anticancer agent still in wide use.

• Floyd Bloom and George Aghajanian pioneer electron-microscopic studies of the monoamine neurons in the central nervous system which underlie anxiety, depression and other psychiatric disorders.

• Nicholas Giarman and Daniel Freedman show that LSD alters the function of serotonin neurons, providing a connection between this neurotransmitter and psychosis.

• Robert Roth and Giarman discover that the central nervous system depressant gamma hydroxybutyrate is a naturally occurring endogenous brain metabolite that influences the function of dopamine neurons.

• Murdoch Ritchie recruited as chair, bringing with him two full professors, Paul Greengard and William Douglas.


1970s
• Alan Sartorelli elucidates the concept of bioreductive activation of prodrugs by oxygen-deficient (hypoxic) tumor cells.

• Sartorelli and Sara Rockwell demonstrate preferential kill of hypoxic tumor cells by mitomycin C, leading to clinical use of drug with ionizing irradiation in treatment of cancers of the head and neck.

• Ritchie provides seminal contributions to the understanding of the mechanism of action of local anesthetics.

• Greengard describes the function of the cyclic nucleotides, molecules regulating metabolism, which ultimately leads to his being awarded a Nobel Prize in Physiology or Medicine.

• Discovery and characterization of dopamine autoreceptors by Aghajanian, Benjamin Bunney and Roth lead to the development of dopamine autoreceptor-selective drugs for the treatment of psychiatric disorders.

• Douglas conducts pioneering work on the essential role of calcium in “stimulus-secretion coupling” in the release of hormones and neuromodulators.

1980s
• Discovery of Zerit (d4T) for the treatment of AIDS by Prusoff and Tai-Shun Lin.

• Aghajanian, Herbert Kleber and Eugene Redmond show clonidine, an antihypertensive drug, is useful in treating opiate withdrawal.

• Discovery of cyclophilin, the receptor for the important immunosuppressive agent cyclosporine, by Robert Handschumacher.

• Studies by Redmond and Roth on MPTP in monkeys lead to a primate model of Parkinson’s disease and the development of neural grafts, gene therapy and stem cells for treatment of this disease.

1990s
• Sartorelli’s laboratory discovers two anticancer compounds, Triapine and VNP40101M, currently in clinical trials.
Yung-Chi Cheng discovers one anticancer and five antiviral agents, currently in clinical trials.

• Robert Innis develops transmitter-specific SPECT and PET imaging probes to study integrity of brain dopamine systems in the central nervous systems of humans and monkeys.
Leonard Kaczmarek’s pioneering work on potassium channels reveals how a certain type of potassium channel underlies the fidelity of firing of auditory neurons.

• Bunney shows that dopamine cell depolarization blockade is a useful model for predicting the therapeutic efficacy of antipsychotic drugs.

• Eric Nestler conducts studies of molecular mechanism of drug addiction and dependence, identifying delta FosB as a molecular switch for addiction.

• Ronald Duman’s studies on synaptic plasticity and mood disorders provide insight for development of novel therapeutics.
Roth develops primate model of cortical dopamine deficiency and enduring cognitive dysfunction useful in study of drugs for cognitive disorders.

• James Howe describes fundamental properties of single glutamate-gated ion channels (which underlie most excitatory transmission in the brain).

2000s
• Joseph Schlessinger becomes department chair and oversees significant expansion.

• Tamas Horvath, Redmond and Roth demonstrate that coenzyme Q is neuroprotective in the monkey MPTP model of Parkinson’s disease.

• Marina Picciotto’s work using genetically altered mice helps in understanding the basis of nicotine addiction.

Sources: Robert Roth, Alan Sartorelli and William Sessa