Drug Discovery And Development

Fulfilling careers are available for chemists in the pharmaceutical industry. But to be successful, candidates must have very special skills, aptitudes, and personal qualifications.

In general, chemists are much more likely to be hired and to pursue a satisfying career if they have at least some training in biology and computational chemistry, as well as in synthetic organic chemistry and other traditional fields. Nearly all work in drug firms involves multidisciplinary groups, so chemists must enjoy functioning in a team setting.

C&EN contacted pharmaceutical industry recruiters, current and former executives of drug companies who have been deeply involved in research, and scholars who study the industry. They describe promising, unexplored areas where chemists can contribute to the discovery of new drugs. They also note problems in today's R&D environment that may short-circuit research before it has a chance to come to fruition.

Some observers also call attention to interesting new opportunities to develop drugs outside profit-making firms. Over the past few years, nonprofit drug companies and groups have started to fund research on medicines to cure the most deadly neglected diseases in developing countries.

Chemistry is central to modern drug discovery and development. For most of the 20th century, the majority of drugs were found either by identifying the active ingredient in traditional remedies or by serendipity. The newer approach devised over the past two decades is to try to understand how disease is controlled in the body at the molecular level and find specific compounds that block progress of an illness or stop it in its tracks.

"In the early phase of drug discovery, we try to identify a target where a biomolecule is causing disease, and then we try to invent an approach to prevent it from causing disease," says Magid Abou-Gharbia, senior vice president for chemical and screening sciences at Wyeth Research. "First, biochemists work hand-in-hand with biologists to identify the target," which is usually a protein, he says. Then, biochemists and biologists turn those targets into assays or screens, he explains. Chemical engineers and analytical chemists, along with biochemists, next take those lab-scale screens and convert them into automated screens for high-throughput selection of potential drug compounds, he says.

During high-throughput screening, many compounds chosen from a large collection or library of chemicals owned by the drug firm are tested for their ability to inhibit or stimulate the target, Abou-Gharbia says. Medicinal and computational chemists select the compounds from the large library, which often consists of 100,000 to 1 million chemicals, he says.

"After you have identified the molecules that work on the target, analytical chemists make sure these are the right molecules—that they have not been degraded from sitting in the library for 20 or 30 years," Abou-Gharbia says. But even if a compound has decomposed to some extent, analytical chemists may be able to determine what part of it is still active, he says.

In the second phase of discovery, medicinal chemists turn the early leads—called "hits"—identified through high-throughput screening into optimized leads, Abou-Gharbia notes. Initial screening is unlikely to identify an ideal drug candidate. Generally, it turns up several compounds that have some degree of activity against the target. So medicinal chemists use structure-activity relationships to improve the candidates by increasing their activity against the target and reducing their activity against nontargets.

The improved compounds are then tested with in vitro assays and in lab animals to determine if they are active against the disease. A compound that passes these assays then goes on to clinical testing.

During animal testing and later clinical trials in humans, analytical chemists play an important role, Abou-Gharbia says. "We try to understand the effects of the compound on the body as well as the effects of the body on the compound-the changes the chemical undergoes inside the body, which we call the pharmacokinetics." This involves measuring absorption, distribution, metabolism, and excretion of the candidate drug.

"When you want to do toxicology studies and clinical trials, process chemists are needed," he says. "They use synthetic chemistry and chemical engineering skills to produce 100-g to kilogram quantities of the candidate drug." If the compound is successful in clinical trials and is approved by the Food & Drug Administration, chemical engineers design a pilot plant for even larger production.

Abou-Gharbia has advice for chemistry students who aim for careers in the drug industry: "Choose a discipline based on your interest in analytical or synthetic organic chemistry and try to get an internship with a pharmaceutical firm to expand your horizons. Internships at pharmaceutical firms help students acquire skills during their undergraduate years. The drug discovery centers at some institutions, such as Northeastern University in Boston and Rensselaer Polytechnic Institute, can also provide valuable experience."

Wyeth's drug discovery division employs chemists at all degree levels, but it has a high concentration of Ph.D.s, says Martin C. Coyle, human resources director for the division. "We are typically looking for people whose Ph.D. research has relevance to drug discovery or development," he says. To be hired at Wyeth, Coyle says, a chemist must have a "deep passion for science and innovation" and be willing to work on teams with scientists from other disciplines. In addition, the employee must set productivity goals and strive to meet them.

There is an active postdoc program across the whole discovery organization, Coyle says. "At any one time, about 40 postdocs, including about a dozen chemists, are employed there." Each year, Wyeth's drug discovery division hosts about 12 interns who assist with chemical research.

At AstraZeneca, Boston, chemists work primarily in three different areas, says Jeffrey H. Hanke, vice president of cancer research. One is medicinal chemistry. "Chemists who have specialized in organic synthetic chemistry or have industry experience in synthetic medicinal chemistry may work on one or two specific drug discovery projects at any one time," he says. Over the course of a few years, they tend to work on many different projects involving a variety of chemical series. Chemists "have the job basically of taking early drug leads from high-throughput screening or deduced from other information and optimizing these early leads against quite a broad range of parameters, including drug metabolism," he explains.

"We also hire computational chemists," who focus on computational modeling of structures, Hanke says. Using computer modeling, they dock some of the drug leads onto the protein structure of a target and help the synthetic medicinal chemists optimize the early drug leads, he explains.

Hanke describes one example of optimization. "If we are working on epidermal growth-factor receptor, the computational chemist has an X-ray crystal structure of that protein in the computer," he says. Within that structure, which looks like a moonscape, are pockets or holes or clefts. A small-molecule drug candidate is bound to this receptor and crystallized. In the crystal structure visualized on the computer, the computational chemist may then see a pocket right next to where the small molecule is bound. He or she can then advise the medicinal chemist on a way to add something to that small molecule that will get into the pocket and increase its activity. "Computational chemists tend to be Ph.D.-trained chemists who also have a background in computational structure," he says.

"Analytical chemists are a third specialty we hire," Hanke says. They help determine the structures and properties of compounds and assist with their purification. AstraZeneca employs analytical chemists with bachelor's, master's, and Ph.D. degrees. One of the most important qualifications for researchers at the company is the ability to work on teams, he says.

Roche Palo Alto is trying to develop drugs, particularly biologics, for a large variety of health problems, says Hans Maag, vice president of chemistry at the firm. These include viral diseases, such as HIV and hepatitis C; inflammatory and immune system diseases, such as rheumatoid arthritis; and neurological problems, such as depression and peripheral nervous system diseases. "At the start of their careers, chemists should recognize that they will encounter many types of diseases and molecular agents over time," Maag says. In the future, drug targets are likely to become more complex, he explains.

Most of the small molecules that have already been investigated in pharmaceutical research either stimulate or inhibit the targets they interact with, Maag explains. But in coming years, he says, chemists will be studying more challenging target classes, such as receptors that are modulated by small-molecule drugs, rather than being directly stimulated or inhibited. To succeed in this research, organic chemists will need to interact closely with computational chemists and protein crystallographers, he says. "To be best prepared for research at Roche Palo Alto, a strong foundation in synthetic organic chemistry is essential," Maag says.

According to Steve Bertram, director of human resources for Amgen's research division, R&D there focuses on serious illness. Rather than limiting itself to only one type of therapeutic agent, such as small or large molecules, it develops agents that best fit the target. After testing a potential drug for efficacy in lab animals and healthy human volunteers, Amgen also conducts clinical trials in patients.

"Amgen believes it has to have the full armamentarium of therapeutic choices to interact with biological systems," Bertram says. "If it limited itself to one modality—whether that be small or large molecules—it would limit its potential to cure disease. Amgen scientists choose the best therapeutic agent to block a specific disease process. It is studying the use of proteins, monoclonal antibodies, and small molecules."

Currently, Amgen's chemistry organization employs about 600 people, including medicinal, process, and analytical chemists, as well as chemical engineers, Bertram says. To be hired there, candidates must be outstanding in several respects, he observes. "In addition to core chemistry and science curriculum courses, we look for a blend of studies in strategic and project planning, general courses in biotechnology, management and leadership courses, and courses requiring team projects," he explains. Also, "the quality of the candidate's research and postdoc experience is very important to our selection process."

Today, chemists will probably find more employment opportunities in the biotech sector than in traditional large pharmaceutical companies, says Paul S. Anderson, a former ACS president who held executive research positions at drug firms for four decades. "My sense is that hiring at big pharma is relatively flat. When people retire, they are replaced, but the industry is not in an expansion mode," he notes. "Although there is a little more activity in the biotech sector, it is not hiring as aggressively as it was a few years ago. Because chemists must compete very hard for a limited number of positions in the drug industry, how well they perform in their graduate work and what their references say are very important."

Drug companies have mixed views about whether chemists should have formal training in medicinal chemistry before they seek employment, Anderson says. "The most common philosophy is to try to hire people who have very strong training in organic chemistry and then let them learn medicinal chemistry after they join the company," he says. But other firms prefer that chemists study medicinal chemistry as part of their formal university training, he explains.

Experts described some of the biggest challenges in pharmaceutical research today. Gaining a more complete understanding of pharmacokinetics is an important issue, says Daniel F. Veber, a drug industry consultant who directed medicinal chemistry at GlaxoSmithKline for many years. "How the body clears and handles drugs is a very complicated system that we don't understand," he says.

The greatest successes are going to be from people who learn something about how to transform a potent compound to one that has good pharmacokinetics, Veber explains. "That is a very multidisciplinary issue. We need to understand what it is in the body that causes drug clearance, what's involved in drug distribution, and the nature of the molecules that control those factors. Some researchers think that if you've got a potent compound, you've got a drug, and that's not true at all," he says. "When you tell them they have to make the drug long-lasting, they ask, 'What do I have to do, to do that?' That's where the big gap in information is."

In terms of constraining the price of therapeutic drugs, "there is a huge opportunity for chemists and medicinal chemists who can take large molecules identified through biological screening and turn them into small-molecule drugs," says Arthur Daemmrich, director of the Center for Contemporary History & Policy at the Chemical Heritage Foundation.

Complex large molecules such as interleukins and interferons that are now used as drugs are extremely expensive. Their production, shipment, and administration to patients are very complex processes. They have short storage lives and often must be given through intravenous infusion. Some biologics sell for $50,000 per month for therapies that might extend life by far less than year, Daemmrich says.

"But if chemists could find a way to engineer small-molecule chemicals that bind to the same receptors and bring about the same sequence of biological events induced by complex, large-molecule drugs, that could be a huge contribution," Daemmrich says.

New thinking and approaches are also needed on the regulatory side of drug development, Daemmrich says. He says FDA officials have told him they need chemists who have more of an interdisciplinary background than most. For example, reviewing drug-eluting stents-implants that release medicines into the body-requires expertise from broadly trained chemists. Reviewers must be able to evaluate the drugs delivered by the stents, as well as the stents' performance as materials and as devices.

Interesting new opportunities are also emerging for chemists to do research outside of profit-driven firms, yet still be involved in drug development, Daemmrich says. Some chemists are now working on research projects supported by the Institute for OneWorld Health and the Drugs for Neglected Diseases initiative (DNDi), for example.

The Institute for OneWorld Health, a nonprofit pharmaceutical company in San Francisco, is working to find potential new medicines for diseases disproportionately affecting developing countries. It has already identified a new cure for visceral leishmaniasis, the second most deadly parasitic disease in the world after malaria. The medicine has been approved by the Indian government and is being manufactured in India.

On Nov. 1, the institute was awarded a $46 million grant by the Bill & Melinda Gates Foundation to develop new treatments for pediatric diarrhea, the leading cause of death in children under the age of five worldwide.

DNDi was established in 2003 by seven organizations around the world, including a United Nations/World Bank special program on tropical diseases. So far, it has begun 20 projects aimed at inventing medicines for diseases that are common in the developing world. Ten of the medicines DNDi is working on are in the discovery phase, four are in preclinical development, and six are in the clinical phase. "For the right chemist who is really passionate about curing malaria and other neglected diseases, working for organizations like OneWorld Health could probably be exciting," Daemmrich says.

But Veber warns that these nonprofit initiatives are placing too much emphasis on the cost of potential drugs and on "trying to apply known drugs to Third World diseases." A more productive tactic would be to think about the best way to approach a disease and later worry about cost, he says. "The problem is even people who are very altruistic aren't very excited about going back to the basics to try to figure out how to cure diseases that are common in the developing world. They want to achieve a quick outcome," Veber says.

What led to good drugs in the past, Veber explains, was researchers "beating away over a long period of time and finally coming to understand what it would take to contribute to a disease." Although HIV protease inhibitors were developed over a relatively short period, he explains, they in fact resulted from "an incredible effort within the pharmaceutical industry to reach a conclusion." What is generally needed to invent truly innovative drugs is patience and intense efforts over many years, he says.