Working in the field of drug discovery requires a broad mix of interests and skills
LOUISA WRAY DALTON, C&EN WASHINGTON
Jim Burnett exited from his small liberal arts college, Randolph-Macon, Ashland, Va., with a biology degree and a chemistry minor. "After I graduated, I still didn't really know what I wanted to do," he says. "I knew that drugs were kind of cool, though--the legal kind--the ones that effect change in a biological system. I liked the idea of manipulating a living system with a small molecule." So Burnett entered a Ph.D. program in medicinal chemistry at Virginia Commonwealth University.
Burnett is one of a growing number of young chemists entering the field of medicinal chemistry. According to an annual survey conducted by the American Chemical Society, as of March 1, 2003, 14.8% of ACS members under age 40 specialize in medicinal or pharmaceutical chemistry, compared with 9.8% in the membership overall. The younger the ACS members are, the more likely they are to be somehow affiliated with making drugs.
And medicinal chemistry is ultimately just that: using all the tools of chemistry and biology possible to create a molecule that treats human disease.
For his dissertation thesis, Burnett decided to focus on the molecular modeling aspect of drug design. He combined modeling and synthetic chemistry to study the allosteric modification of hemoglobin. More and more, he says, drug discovery depends on the technology of molecular modeling to narrow down the options.
"MED CHEM is becoming more information driven," Burnett says. "Less and less do we see people standing in a lab synthesizing sets of compounds based on very classical structure-activity relationships, i.e., take a methyl group and replace it with a chlorine and see what happens. We're relying on the technology of molecular modeling and being able to look at protein structure--or the structure of whatever system we are interested in--and using that to narrow down the kinds of compounds we want to test in a biological assay."
Burnett graduated in December 2000 and took a job at SAIC, a company with branches all over the U.S. that, among other services, contracts for the National Cancer Institute. He now works on finding inhibitors of bacterial toxins and viral matrix proteins.
Whereas Burnett uses molecular modeling to develop therapeutics for countering bioterrorism agents, Leah Frye works at a company that creates such software. She is a senior medicinal chemist at Schrödinger, a firm of about 60 employees, with offices in Portland, San Diego, New York City, and Germany, that creates software and provides services to aid the drug discovery process.
Schrödinger hired her partly because of her broad experience in the field. She was a chemistry major at the University of Idaho and earned her Ph.D. in organic synthesis at Johns Hopkins University in 1984. She did a postdoc in pharmacology at Johns Hopkins School of Medicine, where her interest in applying organic chemistry to biological problems started. She then entered academics, first as a research assistant professor of chemistry at University of Virginia and then as a professor of chemistry at Rensselaer Polytechnic Institute. After eight years at Rensselaer, she left university life to join Boehringer Ingelheim. There, she was involved for five years in combinatorial and medicinal chemistry and got "a global picture of how the discovery and early development phases in the pharmaceutical industry work," she says.
||TAKE A LOOK Frye uses Schrödinger software to view raloxifene docked to the ligand-binding domain of the estrogen receptor.
At Schrödinger, Frye is currently testing one of their drug discovery platforms by screening for ligands to the estrogen receptor. From a virtual database of 1 million commercially available compounds, she and her group first filtered out the compounds predicted to have poor ADME (absorption, distribution, metabolism, and excretion) properties and then docked the remaining compounds to an X-ray crystal structure of the estrogen receptor. By evaluating the 2,000 highest ranked molecules, she and her group narrowed their options to 36. So far, they have purchased 18, and seven are active.
Medicinal chemists like Frye and Burnett are mainly employed by industry--84%, according to the ACS salary and employment survey. Yet government, universities, and nonprofit research foundations also hire medicinal chemists. Daniel Lindner is an associate staff member at the Cleveland Clinic Foundation in the Center for Cancer Drug Discovery & Development at the Taussig Cancer Center.
Lindner started out as a physician. After undergraduate work in biology at Massachusetts Institute of Technology, he obtained his M.D. from Georgetown University and did a residency in surgery. But at that point, he realized he "enjoyed basic science more than clinical science," and went back for a Ph.D. in microbiology at the Medical College of Wisconsin, Milwaukee. Lindner came to Cleveland Clinic after a series of postdoctoral fellowships.
Cleveland Clinic is a nonprofit institution with more than 100 principal investigators. All investigators secure their own funding--from the National Institutes of Health or other funding agencies--and maintain high-quality research laboratories. Lindner says that the environment is quite competitive, and the caliber of research benefits from it.
His laboratory has helped develop a new chemotherapeutic agent: a modified vitamin B-12 that delivers nitric oxide to cancer cells. Lindner's group tested the cancer drug at Cleveland Clinic itself, which has a nude mouse facility for researchers to use in determining a drug's preclinical antitumor activity.
Lindner says the most attractive aspect of his work is coming up with a new drug that has "little effect on normal cells, yet induces death in tumor cells," and that may eventually boost cancer survival rates. To reach this goal, Lindner must pay close attention to biological and clinical data.
Medicinal chemists must always come back to the biological relevance of what they create. The necessities of the work breed chemists who are not only good at communication, but are themselves extremely interdisciplinary. They must learn to interpret biological data, design organic syntheses, recognize genomic insights, predict biochemical reactions, and master computational chemistry software. As Frye puts it: "You have to know organic chemistry because you have to be able to make the molecule. You have to know enough biochemistry to be able to understand why your molecule works and how to improve it. And you need enough computational skills to effectively use the computational analysis and prediction tools."
Because of these interdisciplinary requirements, it might seem that a company hiring a medicinal chemist would look less at organic synthetic chemists and more at those with biological or computational specialties. Not so. At least in large pharmaceutical firms, organic chemistry is still the backbone of drug discovery.
"The way a medicinal chemist has to think is multidimensional," says Hans Maag, vice president and deputy head of chemistry at Roche Palo Alto, but entry-level chemists don't need to know everything. "We look for candidates with a strong synthetic background. We look for critical thinking skills. We do not expect that they have a good understanding of metabolism and pharmacokinetics. We feel that if somebody has a strong synthetic background, they can develop the additional skills, and that is something we are very committed to providing."
Martin Jefson, executive director of central nervous system discovery and general pharmacology at Pfizer, echoes Maag's advice. "We fundamentally look for very high quality and accomplished synthetic organic chemists--primarily ones who have demonstrated an ability to complete a complex project. But we don't expect a tremendous amount of expertise in either the biology that they may ultimately need to learn to be successful or in the properties that make a molecule a good drug," he says. "If you can make compounds, we can help you learn what compounds to make."
Over the past few years, as in most industries, pharmaceutical firms have slowed hiring. But drug discovery is what this industry lives on, and it depends on good medicinal chemists.
"The pent-up demand is there," Lindner says. "Companies are hesitant right now to embark on what they see as a risky project. But on the other hand, if you don't take some risk for growth, your company's going to fold."
Schrödinger's Frye believes that the field is "changing quickly, partly because of the desire to get drugs into the clinic as soon as possible. Everyone's trying to speed up the pipeline. There's a lot of interest in incorporating new tools, and you should be willing to go down that avenue of learning new things and trying out new methods."
At least in large pharmaceutical firms, organic chemistry is still the backbone of drug discovery.
ONE OF THE PRIMARY sources of new technology is small start-up firms, says Donald Abraham, a professor of medicinal chemistry and director of the Institute for Structural Biology & Drug Discovery at Virginia Commonwealth University. The general trend is that successful small companies are acquired by or make partnerships with large ones. "The large fish waits and lets the small fish take the chances," he says.
||HANDWORK Medicinal chemists still spend a good portion of the day doing synthesis and laboratory work.
"I think that the process of small companies generating lots of technology for large pharmaceutical firms to pick and choose from and incorporate into their processes has actually been very successful," says Nick Hodge, himself a founder and vice president of chemistry and technology of a small chemical genomics firm, Amphora Discovery, with offices in Durham, N.C., and Los Altos, Calif.
Amphora currently employs three medicinal chemists, and Hodge hopes to add at least two more by the end of the year. His company is typical of small firms in that it wants from its medicinal chemists not only strong fundamentals and strong synthetic skills, but also experience at a large pharmaceutical firm.
"We look for a minimum of five years' experience at a major pharmaceutical company," Hodge says. "We find, maybe partly because of our background, that that's where you learn the realities of drug discovery best--not necessarily the right way to do everything, but you learn about the different groups you have to interact with and the different disciplines that are needed to make projects successful." Hodge himself spent 12 years at DuPont Merck. The advantage of the small firm, however, is the much faster pace, he says.
Sean O'Malley directs chemistry at Hawaii Biotech, a growing biopharmaceutical company on Oahu. Hawaii Biotech attempts projects ranging from cardiovascular therapy to counterbioterrorism and is planning to add three chemists to the six it already has. O'Malley looks for a new hire who has spent "at least a year or so in the trenches of a company doing some serious medicinal chemistry."
Yet O'Malley is looking for something even more than experience and education. What makes a good medicinal chemist is "keeping your eye on the goal," he says, "continuing to move things forward in terms of its application to the drug and not getting sidetracked into either being focused on the chemical synthesis or being focused on something because the synthetic access to a class of compounds is easy or intuitive. The medicinal chemistry may not lead you to a place that is easy to do in terms of chemistry."
Finding a drug to treat a complex system is itself complex, the medicinal chemists seem to chant. It requires using all tools of chemistry and biology available, including biological assays, NMR, X-ray crystallography, molecular modeling, combinatorial chemistry, and increasingly, genomics and proteomics. But the reward, they say, is worth it.
"I once read that the best way to describe a medicinal chemist is a compulsive gambler," Hodge says. "Every medicinal chemist thinks that the next compound is going to be the one that hits the jackpot. Really, it's an intensely exciting puzzle, where the pieces are the information--the tests that you do--and they are all imperfect. They are all of varying degrees of accuracy. The process of gathering it as fast as possible and putting it together into a picture that makes sense for making the next set of decisions is extremely exciting."