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Drug discovery and development: A complex team sport

This Advertising Feature has been commissioned, edited, and produced by the Science/AAAS Custom Publishing Office

Academic drug discovery is taking on a whole new character now, with technology and new partnerships between academia and industry and disease institutes and the government.

To succeed in drug discovery today, you need to be a jack of many trades and a master of (at least) one. Depth and breadth. Both are required of scientists working on making new drugs. So say managers in big pharma, biotech, and government programs in drug discovery and development.

"When you're working toward a Ph.D., you're focused like a laser on whatever your area of work is," says Joe Bolen, the chief scientific officer at Millennium Pharmaceuticals in Cambridge, Massachusetts. While such focus may suit the current educational paradigm of doing serious benchwork and publishing, Bolen says, "You can get so focused that you lose track of everything else. And that's not what we're looking for. We want experts in their field, but we want people who appreciate what's going on in the broader area."

The path to new drugs is long and costly, fraught with potholes and littered with failures. As compound libraries flood the known chemical space (and analytic capacity), new drugs on the market have slowed to a trickle. "Everything has gotten much more complex. People say the so-called easy things have been done," says Bolen, and what's left is really hard. "I think that's true to some extent."

As new models of drug discovery are developed, those working in the field say it's a time of exciting science, with nontraditional targets to be investigated, new technologies to be harnessed, and better ways to process reams of information to be created. Drug discovery and development, whether housed in private companies or supported by public funds, is goal-oriented science, where teams of people work to solve specific disease issues. This can be a good thing for those who like solving problems, who thrive on the steep part of a learning curve, and who gain satisfaction from a feel-good contribution to society.

Hiring for preclinical drug discovery remains strong in the pharmaceutical industry, says Rich Pennock of Kelly Scientific Resources, a human resources firm. "The pipeline is so important to the health of these companies." Hiring in biotechnology is more cyclical, he says, tending to follow the financial markets, as young companies are more dependent on outside capital to invest in new resources.

Interdisciplinary teamwork

Drug discovery runs the gamut of disciplines from synthetic organic chemistry to molecular and cellular biology, from in vitro to in vivo pharmacology and toxicology, from basic science to clinical testing. Expertise in engineering, computer science, and bioinformatics also is required to help integrate new advances in technologies such as high throughput screening of compounds and in silico modeling.

No one scientist is trained in all those areas; rather, project teams are standard operating procedure in the pharmaceutical industry. In addition to chemistry, biology, and associated subdisciplines, the process "requires Ph.D.-level people in math and statistics, as well as engineers, automation specialists, computer specialists, and physicists," says Bolen, all of which are represented at Millennium. "The list just goes on and on. It's an incredible group that has to come together to make new medicines."

Lois Lehman-McKeeman is a toxicologist at Bristol-Myers Squibb in Princeton, New Jersey, but she works closely with biologists and chemists in discovery. The toxicology group works to predict adverse effects and tries to assess them early in the discovery process. In addition to this proactive strategy, her group has to react when toxicities arise and investigate "whether that's related to the chemistry that we're working with, or whether that's a function of the target that we're manipulating," she says. "The fun part of the pharmaceutical industry is that all of those parts have to come together. Being able to work together is important."

The team approach to drug discovery and development differs from the stereotype of an academic scientist working independently on his or her own project. "You really do work in groups," says Lehman-McKeeman, which comes with advantages. "You learn from each other―that helps your own professional growth―and eventually you get to the end." Learning new things is a plus for many people, she continues. "The science behind discovering a drug is as intellectually challenging as any academic problem there is. We've got to have the best science underlying everything that we do. It is intellectually demanding. It requires continuous learning and continuous growth."

Bolen agrees. "What we've rediscovered is that making new medicines is the most complex team sport on the face of the earth," he says.

Project teams exist outside of industry as well. At the US NIH Chemical Genomics Center (NCGC) in Rockville, Maryland, engineers, informaticists, biologists, and chemists work together, and deputy director Jim Inglese specifically looks for people who are willing to do that. "We have people who know what their strengths and weaknesses are and are happy to work with people who complement those," he says.

Part of the NIH Roadmap's Molecular Libraries Initiative, the NCGC is one of a network of screening centers, which provide access to a large chemical library, expertise in developing assays for high throughput screening, and the subsequent synthetic chemistry to develop the active compounds.

Most of the people at the NCGC are excited by technology and process, says Inglese. "We really are committed to making the whole paradigm of early drug discovery work better. How do you do all that efficiently when the target or assay is different every time? It's always different and it's always challenging. The perk is being able to work on a different type of biologic system every couple of days or weeks."

New models

The government effort is all about integrating the biology from academic labs with the NCGC's screening and chemistry resources. Postdoctoral fellows there learn the technological aspects of scaling up an assay they've developed with an investigator on the NIH campus. They also learn the informatics aspect of identifying promising compounds and work with chemists "to do the optimization of a compound to improve its potency or solubility or selectivity," says Inglese. "That's a whole chunk of the drug discovery process."

It not only prepares postdoctoral fellows for a career in industry, but also for drug discovery efforts in government and academia. "Academic drug discovery is taking on a whole new character now, with technology and new partnerships between academia and industry and disease institutes and the government," Inglese says.

In addition to the work done at the NCGC, other elements in the Roadmap's theme of "new pathways to discovery" include biological pathways, structural biology, bioinformatics, and nanomedicine. With these initiatives, the NIH aspires to provide a toolbox for medical research to take advantage of the human genome sequence and the latest progress in molecular and cell biology for the development of new therapies.

Other institutes within the NIH have medication development programs. "We take in compounds and evaluate them in various screens," says Frank Vocci, who directs the division of pharmacotherapies at the National Institute on Drug Abuse (NIDA). Groups in chemistry, toxicology, regulatory affairs, and clinical research make up the broad spectrum of expertise within the division. It's a service to external researchers and companies―they submit compounds and receive confidential reports in return. But NIDA also hopes to stimulate progress in filling the pipeline with lead compounds, especially in a therapeutic area like drug abuse that is not well served by industry. Progressing to drug development typically involves working in joint ventures with industry and academia, says Vocci.

These innovative government programs are filling a need for rare diseases and unmet targets, but they also show that alternative models of drug discovery and development are possible. Industry is changing as well, says Jim Barrett, an industry veteran now at Drexel University College of Medicine in Philadelphia. "Industry is going through some fairly sophisticated attempts to incorporate new technologies to the drug discovery process―things like expanded chemical libraries, very high throughput screening, combinatorial chemistry, and then the whole genome initiative―the promise of genetics and genetic therapies and new targets," he says. "I think we're still sitting on the edge of real breakthrough medicines and haven't yet coupled all of those new technologies and techniques together with the emerging science."

Peter Schafer, who directs the biology group at Celgene in Summit, New Jersey, puts it another way. "I think we're entering an era when one has to think outside that box, which is very difficult, because it means that you have to have the humility to admit that you don't understand everything that's happening in a disease and a pathway."

Goal-oriented problem-solving

Keeping the long-term goals in sight is crucial to drug discovery and development, whether the setting is academic or industrial. "I think stamina is a very important aspect," says Jerry Skotnicki, who directs chemical and screening science at Wyeth in Pearl River, New York. "I don't mean the ability to trudge, but to sustain one's effort and dedication, because sometimes things don't work out as quickly or as clearly as one would like."

Staying focused is another aspect. "Scientists spend a lot of time thinking about tangential questions, that are academically interesting but not so important for getting a drug approved," says Schafer. "To accumulate the appropriate data to put into a regulatory submission, you just need to focus on the required information," he says.

Lehman-McKeeman calls it doing the last experiment first. "It's the way we have to think. What is the critical question? And how do we get that answer?"

Goal-oriented science also requires a willingness to be flexible. "Once we solve a problem, we move on―as opposed to continuing to drill deeper down into an academic question," says Lehman-McKeeman. The fact that there's a clear resolution can cut both ways, rewarding when you have a drug and frustrating when you don't.

Indeed, project team goals in industry are often of the go/no-go variety, where a weak project might get scrapped at short notice and the researchers need to be able to let go and move on. A similar dynamic is present in the fast-paced lab at the NCGC, says Inglese, where timelines are relatively short.

But with flexibility comes opportunity―the opportunity for researchers to continually learn new things and to push their knowledge base into new areas. "Even within the confines of a company, there will always be so many possibilities," says Schafer. Companies are looking for new angles of disease, new drug targets. "We're constantly challenged to look outside of what we're doing, because the best opportunity might be two steps removed from where you're currently working."

Importance of education

Most scientists in drug discovery and development today have learned what they need to know on the job. NCGC's Inglese has compound screening experience in both biotech and pharmaceutical companies. NIDA's Vocci has a regulatory background from more than a decade of work at the US Food and Drug Administration. Drexel's Barrett has a resume that includes an academic faculty position and research and senior management experience in industrial settings from big and established (Wyeth) to small and startup (Memory Pharmaceuticals).

Barrett now has returned to academia, starting an educational program in drug discovery and development at Drexel. "To my knowledge, there is no such formal program that integrates the details, complexity, and all of the nuances of drug discovery and development into the graduate education program," says Barrett, who hopes to ease the transition for students interested in an industrial career.

Making the most of the resources at Drexel and at other institutions in the greater Philadelphia area, Barrett plans to grow the program into a minor or specialization for graduate students in the biomedical sciences. Through the program and internship experience, students will be better prepared to start a career in a biotechnology or pharmaceutical setting. "They'll have had experience working in project teams, experience in how you identify a target all the way through to preclinical evaluation and toxicology, as well as marketing and postmarketing surveillance."

Hard and soft skills

While such tertiary education may tip the balance in your favor, depth of knowledge in a specific scientific area―whether it's synthetic organic chemistry or molecular pharmacology―is one of the most important things on your resume, say hiring managers.

"What I look for is someone with good bench skills, first and foremost," says Celgene's Schafer, because someone has "to generate the work product."

Beyond how you look on paper, how you present your work in person is key for Bristol-Myers Squibb's Lehman-McKeeman. "You cannot hide enthusiasm for what you do. Nor can you hide the fact that something isn't that interesting to you," she says.

"Number one, you have to be passionate about what you do," says Millennium's Bolen. If you're not, no one else will be. "Number two, you have to have perspective," he continues. "That perspective says that what you're doing is no more important than the guy or the gal in the lab next to you. Everybody's work is important."

A certain breadth of experience is vital as well, because when you're talking about industry, you're talking about teamwork. In addition to bringing your own skills and know-how to the project team table, you have to appreciate and be curious about what the other team members have to offer.

"Communication is important, because in a mid-size company like Celgene, you wind up wearing many different hats," says Schafer. Drug discovery scientists may serve as the drug discovery group representative on product development teams. When a change in clinical direction occurs, that person has to convey the change back to drug discovery to work on a new set of data.

Another hat may be to provide scientific information to a company's marketing group, "to help in the messaging and to help describe to clinicians and sometimes even to investors what the features of the product are and how it relates to efficacy and the disease," says Schafer.

Says Wyeth's Skotnicki, "The successful people are those who have collaborative skills, leadership qualities, and a respect for people, coupled with the drive to get things accomplished."

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