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Volume 84 Issue 13 | pp. 17-18
Issue Date: March 27, 2006

Cover Stories: Small-Town Kid Makes It Big

Drug Discovery: Chemistry, Innovation & Caring

Department: ACS News

Joseph Priestley believed in timeless universal laws that govern all things and provide guidance for the improvement of society. Perhaps this perspective was a reflection of his religious background. Interestingly, it would be equally appropriate for an experimentalist broadly interested in natural philosophy, particularly chemistry.

Indeed, Priestley is best known to us for his study of chemistry and discovery of oxygen. Despite his remarkable capacity for insightful experimentation and advanced thinking, I think that he would have been amazed at the degree to which chemistry has influenced and shaped modern society.

Gains in chemical knowledge and its subsequent applications for creation of valuable new products have been nothing short of spectacular. In fact, economists tell us that science and technology have produced 75% of economic growth in the modern world. Directly or indirectly, chemistry and chemical engineering have been key to creating this growth.

Today, chemistry touches every aspect of our lives, including our most basic needs for food, clothing, shelter, transportation, and medicines. It has made food more abundant by improving agricultural production. It also gave us the frozen-food industry. This industry has grown to over $100 billion a year in sales, indicating how much frozen food and microwave ovens have become a part of our lifestyle.

Priestley Medal Address

Paul S. Anderson is scheduled to present the Priestley Medal Address on March 28 during the award ceremony at the American Chemical Society's 231st national meeting in Atlanta. Anderson, 68, retired in 2002 after serving for nearly 40 years in the pharmaceutical industry. He is recognized for "his outstanding contributions to chemistry in the service of society" and, in particular, for achievements in drug discovery that led to development of anti-AIDS therapies and other medications, including Zocor (a lipid-lowering agent), Trusopt (to treat buildup of pressure within the eye), and Aggrastat (platelet aggregation inhibition). Published here is the text of his address.

Clothes made from synthetic fibers and cotton that has been treated to make it flame-retardant and wrinkle-resistant fill our wardrobes. The advantages of water-resistant, breathable fabrics are well-known to all who enjoy outdoor activities. Latex paint was key to the creation of the "do-it-yourself" home-repair industry.

In the span of 65 years, we have progressed from a world in which physicians had little more than aspirin, sulfa drugs, morphine, and a few natural product preparations in the medicine chest to a world in which doctors have safe, effective medicines to treat high blood pressure, elevated cholesterol, peptic ulcer disease, diabetes, inflammation, allergy, osteoporosis, and glaucoma, as well as most mental diseases, some forms of cancer, and a variety of deadly infections including several viral diseases.

All of this was achieved through research and development work in industry, and much of the research involved collaborations with academic institutions and government laboratories. These achievements clearly illustrate the concept that innovative new science can give rise to new industries, which serve human needs and simultaneously stimulate economic growth.

How was so much accomplished in such a short period of time? In the U.S., much of the answer can be found in the creation of a federal science policy at the end of World War II. In 1944, President Franklin Roosevelt put a very profound question to an equally remarkable leader of the scientific community, Vannevar Bush: How can the mobilization of civilian science that supported the war effort be profitably used for the benefit of the nation in times of peace? The answer came in the form of a report named "Science—The Endless Frontier: A Report to the President on a Program for Postwar Scientific Research."

It set forth a simple concept. The health, prosperity, and security of the nation would rest on our ability to create and use new scientific information. A significant federal investment in science and technology would be required to achieve this goal. The analysis concluded that the investment would be worthwhile because the payback in improved quality of life and new business and employment opportunities would far exceed the cost.

This vision of the future was achieved. The National Science Foundation was created in 1950, and the Public Health Service expanded into the National Institutes of Health. Federal support for research in our public and private universities and the national laboratories produced the desired new scientific knowledge and a cadre of highly skilled scientists and engineers.

Industry provided opportunities for this skilled workforce to use the new knowledge to create valuable products and new businesses. Thus academe, industry, and government became partners in a powerful research enterprise that propelled the U.S. into a position of global scientific and economic leadership.

The chemical process industries, such as pharmaceuticals, grew and prospered. Industries as diverse as biotechnology and computer software were created. Our research enterprise partnership continues to keep science- and technology-dependent industries at the cutting edge. Improvements in health care that have been achieved through drug discovery in the pharmaceutical industry are an example of this partnership at work.

Historically, drug discovery was driven by a need to discover a lead molecule with measurable biological activity that was perceived to be of potential therapeutic value. Medicinal chemists then used synthetic organic chemistry to improve the druglike properties of the lead. During the 20th century, advances in medicine and the basic biological sciences that support its practice provided a deeper understanding for the biochemical basis of many diseases. Much of this latter information was generated in academic institutions and government laboratories.

Over time, the totality of this knowledge created a more rational basis for drug discovery. Today, one frequently can link an opportunity that addresses an unmet or unsatisfied clinical need to a specific biological mechanism for drug action. Thus, the biological mechanism can be used to facilitate discovery of molecules to modulate it.

Some insight into how mechanism-of-action drug discovery works can be found in the work that led to new medicines to treat HIV infection and prevent its progression to AIDS. Scientists in academic institutions and government laboratories isolated the virus and determined its genomic sequence, thus enabling identification of the molecular events critical for viral replication. This in turn revealed a set of viral enzymes as possible targets for chemotherapy. Virology, biochemistry, and molecular biology set the stage for medicinal chemists to design medicines that would inhibit the viral enzymes.

The efforts of medicinal chemists were aided by molecular modeling and X-ray crystal structures of inhibited enzymes, as well as feedback about the metabolic and pharmacokinetic properties of newly synthesized compounds provided by analytical chemists trained in drug metabolism, who used mass spectrometry to measure blood levels of drugs and characterize metabolites.

The drug design task was particularly challenging because the virus replicates rapidly and mutates quickly. Despite these difficulties, several drugs were discovered and developed. Their use in combination has proven to be lifesaving for many patients.

This discovery story reveals the interdisciplinary nature of modern drug discovery and the impact of advanced technology. It also reminds us that the concepts set forth 60 years ago in Vannevar Bush's report, "Science—The Endless Frontier," still are valid and operational today.

The discovery of medicines to treat HIV infection presents the pharmaceutical industry at its best. The needs of patients and their physicians were foremost in the discovery and development effort. Companies made large commitments of resources and capital in the face of uncertain profit. Those of us at Merck who worked on HIV projects saw our work in the light of one of George W. Merck's fundamental teachings. In a speech at Virginia Commonwealth University in 1950, he said: "We try to remember that medicine is for the patient. It is not for the profits. The profits follow, and if we have remembered that, they have never failed to appear."

This enlightened philosophy for drug discovery stands in sharp contrast to the view in today's market-driven business environment that the main responsibility of a chief executive officer in the pharmaceutical industry is to increase shareholder value. I doubt that George Merck would have been comfortable with the current practice of advertising medicines to the public, because this is a strategy driven by marketing considerations. It does not put the interest of the patient first.

Drug discovery and development is a high-cost, risky business because only a fraction of the therapeutic targets selected for study will actually yield products that achieve regulatory approval by the Food & Drug Administration. It is anticipated that new technologies like proteomics, genomics, and bioinformatics will enhance our understanding of disease processes. These and other tools should reveal new possibilities for drug discovery. However, none of the possibilities will become new medicines unless the underlying concepts prove to be clinically useful, so the risks involved in exploring them will still be high.

Nonetheless, these tools are tools for innovation, and innovation is central to the future of this industry. The impressive successes of the past clearly show that an innovative idea invariably is the critical factor in success. Certainly, there is no shortage of opportunities for innovation because better drugs are needed to treat cancer, dementia, inflammation, diabetes, obesity, and infectious diseases such as malaria and tuberculosis.

This, however, will have to be accomplished in an industry where pressure on pricing and the demands of product-cycle management have led to consolidation through mergers, acquisitions, and downsizing. While these actions can reduce costs, they are unlikely to facilitate discovery and development of innovative new medicines. Mergers and acquisitions also do not encourage the major commitment that is needed to improve treatment of malaria, tuberculosis, and HIV in underdeveloped parts of the world.

Discovery of safe, effective new medicines always has been the goal of the pharmaceutical industry. To do this, it has attracted creative people who have discovered medicines for unmet or unsatisfied clinical needs that have obvious value for both patients and physicians. As mentioned earlier, there have been many successes. Successes have created very large companies with very large products in terms of sales.

The industry now is faced with the challenge of what to do when a significant medicine becomes a generic drug, leading to a rapid drop in brand-name sales. One obvious answer is to have the R&D organization discover a new medicine that will benefit many patients. Unfortunately, innovation is hard to schedule, and prediction of sales potential for a new product is an uncertain art. Yet it is clear that some research organizations have produced several cycles of product innovation, so this is not an impossible task.

Since innovation is the key to sustainable success, it would seem that the concepts for encouraging it are: Select the right targets based on clinical need, hire the right people to drive innovation, prioritize and focus resources adequate to succeed in a competitive world, and be persistent. There is also a need to create a workplace where superior performance is expected, lifelong learning is encouraged, and the role of teamwork is understood.

Drug discovery is a team effort in which an interdisciplinary team brings a diverse array of necessary knowledge and skills to the discovery mission. The team works with an enormous amount of interdisciplinary information. When the team begins to share and discuss this information freely and openly to identify what is of value to the mission, it is engaging in a process that can lead to innovation.

Innovation is a product of both individual contributions and how the team shares and uses information. While you might not be able to manage your way to innovation, you certainly can create an environment that encourages it. Among companies that depend on sustainable innovation for survival, the successful ones, I believe, will be the ones that understand this. They will not promise job security, but they will offer opportunities to engage in lifelong learning and use new scientific information to create products that will improve quality of life.

We should not forget that the pharmaceutical industry is a global enterprise. Pharmaceutical companies operate in many countries. They can invest capital wherever they please, and they usually do so wherever market conditions are favorable and the return on investment is best. For many years, the U.S. was the best place to invest. This may not be true in the future. Desire to reduce costs has led companies to outsource some R&D activities to Eastern Europe, China, and India, where savings can be found. The outsourcing trend is likely to accelerate. Pricing pressure and the difficulties associated with managing product life cycles that require periodic replacement of products having large sales with innovative new ones will demand cost control.

In innovation-dependent industries, outsourcing can be the first step toward moving offshore a more substantial operation that will support all aspects of R&D operations in a lower cost environment where a supportive infrastructure is evolving. This trend is already visible in Singapore. Information-intensive industries like the pharmaceutical industry will always be dependent on sustainable innovation for growth; however, the locations where the opportunities to innovate exist are likely to move to more cost-effective environments.

Although outsourcing and moving operations offshore are serious issues for our chemical enterprise, green chemistry is an area where U.S. science and technology seems to be leading the way. Here, cost savings and innovative science blend in a way that is attractive to the pharmaceutical industry. History has taught us that it is better to eliminate waste in a chemical manufacturing process rather than to dispose of it at the end. New processes for pharmaceuticals are being developed that will allow more efficient conversion of raw material to product. These processes teach us that sustainable living is an achievable goal that makes economic sense.

Telecommunications and electronics have revolutionized the way we work, communicate, and even play. It is now possible to distribute work around the globe to an ever-expanding, scientifically literate workforce. The technical skill and competitiveness of this workforce are on the upswing everywhere. The constant in this sea of change is the power of science and engineering to create value through innovation, which will drive the global economy. Those who continue to invest in this endeavor will benefit the most.

The countries and companies that engage their people in lifelong learning focused on science and engineering knowledge will lead the way. In this country, it is important for us to remember this and act appropriately. A culture that would rather be entertained than be engaged in innovation will not continue to be an economic powerhouse. A society that thinks litigation is on an equal footing with innovation will not thrive. Fortunately, we are a free, open society with enormous capacity for productive change. As scientists and engineers, it is important for us to exercise this capacity for the good of the country and the betterment of the world. The health, prosperity, and security of the nation continue to rest on our ability to create and use new scientific information.

More than 200 years ago, Joseph Priestley's good friend Benjamin Franklin worried that he had been born too soon. He feared that he would miss all of the exciting things that science would reveal in the coming years. He was right.

Franklin's thought is still valid today. Our world is becoming more, rather than less, dependent on science and technology. This dependence will produce many opportunities to create new knowledge and products that will have potential to improve quality of life and make this a safer, healthier, and cleaner world. While we can be proud that chemistry will be central to how this happens, we, as responsible scientists, must work to ensure that high ethical standards are used to define and pursue worthy goals for the improvement of society. This was Priestley's perspective, and it remains appropriate for us in our time.

 
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