Effective drug therapy ranks high among the scientific advances that have changed our lives over the past century. Cures of infectious diseases and treatments of chronic illness, such as cardiovascular disease, diabetes, central nervous system disorders, and cancer, have dramatically changed our lives. Yet, we are still at the beginning of truly effective therapies. Complexity of disease, and hence of the necessary treatment, increases dramatically with an aging population, and drugs are only partially effective or even cause serious side effects. Moreover, drug costs begin to place an increasing burden on the patient.
Recent advances in understanding the human genome--i.e., all genes combined--have revealed much new insight into human disease. We frequently read about exciting findings on the molecular and genetic cause of disease. Invariably, commentators add that these developments surely will lead to unprecedented novel therapies of thus far untreatable illness. Yet, we have not seen the expected flood of new medications as promised by such profound advances, a direct result of the complexity of biological systems, and humans in particular. Whereas new information arises at a breathtaking speed, our ability to interpret the results and translate them into effective therapies is lagging.
Herein lies the promise and excitement for students who want to partake in a new era of medicine. An entire industry depends on the timely discovery and development of new medications--an outstanding and growing opportunity for young scientists.
This article lays out some of the scientific fields that all must come together for a successful translation of basic biomedical sciences into drug therapies. The culture of today's science changes rapidly. We move from the small laboratories that originate and pursue their own ideas--an exceedingly successful process over the past decades--to large interdisciplinary groups working together. We experience this transformation at many levels--through Ph.D. curricula that enable students to have broad exposure while still maintaining a strong area of emphasis, preferred funding for consortia that can tackle the main health problems we face today, and an emerging spirit of teamwork among scientists from different disciplines.
Consider what is needed to bring a new drug to clinical use. First, we must understand the underlying molecular, biochemical, and genetic mechanisms that contribute to disease. Together with the use of bioinformatics and genomics, this leads to potential drug targets that might play a critical role in disease. Chemists can then design compounds that interact with these targets to avert disease (medicinal chemistry).
However, at this point we only have a candidate drug, which then undergoes a complex evaluation process referred to as drug development. Only a fraction of drug candidates eventually survives the preclinical phase, and even less go all the way to final approval by the Food and Drug Administration (FDA). Fields of science germane to the drug development process include pharmaceutics (physical chemistry, pharmaceutical technology, and biotechnology), pharmacokinetics and pharmacodynamics, pharmacology, pharmacogenetics and pharmacogenomics, regulatory sciences, and clinical sciences.
Whatever specialization you choose, keep in mind that the greatest advances can only come about if these disciplines coalesce into a continuum, encompassing all necessary steps in creating a new drug therapy. The medicinal chemist must understand the biological system, and also the physico-chemical properties needed for a useful drug formulation. Pharmaceutics deal with the optimal drug delivery as a function of the disease to be treated. Pharmacogenomics is pertinent to all phases from drug target validation to final approval for clinical use. For an aspiring scientist to enter this arena, possibly the most enticing aspect is the ability to choose an area of specialization in drug discovery and development while maintaining a broad perspective and multiple career options.
Moreover, anyone with a sound knowledge of drug development can adopt alternative careers outside science, such as working in government agencies, patent offices, investment firms, and more. Few fields offer a similar spectrum of choices for aspiring scientists with a passion to contribute to an important issue--our health.
The main areas relevant to drug discovery and development include the following topics, each of which I will survey briefly. (See the sidebar for Web links to more details on each topic.)
Molecular drug targets, proteomics, bioinformatics, and drug design
No single area has undergone a more dramatic transformation than biology. It cannot escape anyone's attention that the sequencing of the human genome has ushered in a new era. Yet, translation into effective therapies is even more challenging than sequencing--a task considered impossible less than 30 years ago. Today we attempt to unravel how the gene products, the proteins, work together to determine the status of a cell. Similar to genomics, this spawned a new field termed proteomics--i.e., the study of all proteins together.
The underlying theme is pervasive--we are beginning to see an outline of all components, but now we wish to understand their combined function, of the whole. This is a highly integrative process, and it is the primary driving force for scientists from multiple fields to work closely together. By measuring all mRNA messages in a tissue, or all proteins, we obtain an immense amount of data that need to be sorted out and processed. For this, we need computer scientists, mathematicians, and scientist in informatics, bioinformatics, and even linguistics; after all the human genome sequence is compared to a book having a molecular language.
The goal is to identify the key nodes in a complex network of genes and proteins (and small metabolites, i.e., the metabolome) that can serve as legitimate drug targets--an extremely valuable concept for subsequent drug discovery. Given a protein target, chemists can thus embark on the quest for chemicals that bind to the protein and affect its function in a favorable fashion. Alternatively, if the protein is defective because of a genetic mutation, one can consider the use of replacement therapy using the same protein, generated by recombinant technology.
This is a main approach for the biotechnology industry, although small molecular weight drugs are often preferable because of their ease of application. Moreover, we can consider delivering the intact gene, which then generates the defective protein in the target tissues--widely know as gene therapy. All these applications require diverse expertise, energy, enthusiasm, and perseverance, as translation of any of these strategies into clinical therapies proceed along an arduous path.
Delivery systems and formulation design
Imagine you have a promising drug candidate, but testing in animal models reveals no activity at all. One problem may be that the chemical does not even get into the body, or it fails to reach the site of action. Alternatively, effective treatment might require brief application with rapid reversal of the effect (anesthesia), drug delivery over months (birth control), or pulsatile delivery (certain hormone therapies). In the treatment of diabetes, one must provide insulin at optimal levels for a specified time period--a challenging task. Lastly, targeted drug delivery to the tumor--and not to normal tissue--is a central goal of cancer chemotherapy.
All of these questions are addressed in a field termed pharmaceutics and pharmaceutical technology. Material sciences, physical chemistry, and the interaction of drug formulation with biological systems are hallmarks of this critical field in the process of drug development.
Pharmacokinetics, pharmacodynamics, and clinical evaluation
Drugs that successfully interact with the target protein in vitro may never reach it in the body because the drug is not absorbed, is rapidly metabolized and excreted, or removed from the target tissue. Study of these processes is called pharmacokinetics--i.e., what the body does to the drug. In contrast, pharmacodynamics focuses on what the drug does to the body--specifically the nature, magnitude, and time-course of drug effect and toxicity.
These fields combine biological and pharmacological sciences with mathematical modeling. Pk-Pd, it's common abbreviation, has had considerable impact on drug therapy because we can strive to predict drug response, optimal dosage, and adverse events. Moreover, it has illuminated differences among individual patients, alerting us to the need to individualize dosage regimen. Pk-Pd is therefore an intricate part of the drug development process and germane to new drug approval by FDA.
Pharmacogenetics, pharmacogenomics, and clinical evaluation
First awareness of genetic differences in an individual's response to foreign chemicals emerged in the 1930s, showing that some cannot taste a bitter chemical. Over the ensuing decades, this concept has quickly broadened to include variable response to drug therapy--already alluded to in the preceding paragraph. The field of pharmacogenetics has thus emerged with detailed knowledge on genetic mutations in drug metabolizing enzymes--a main cause of variable drug response. The importance of genetic differences is highlighted by the assertion that mutations in drug-metabolizing enzymes may contribute to adverse drug effects--a serious health problem and one of the top 10 causes of death in the United States.
Recently, this field has broadened considerably, reflecting the notion that drugs interact with multiple proteins in the body, each potentially subject to genetic variations. Therefore, we must consider hundreds if not thousands of genes that could affect disease outcome and drug response--leading to the term pharmacogenomics. The eventual goal is to discover a majority of genetic variations in the human population that predispose to disease and permit one to select the optimal treatment.
The concept "one drug fits all" will give way to "optimal therapy for each individual patient." Given the less than optimal therapy we can currently offer, particularly in the treatment of chronic illness of the elderly, much can be gained by fully exploiting our growing knowledge of genetic factors in disease and drug response. However, genetics is only one component, and it must be viewed together with environmental effects and life style. We are just in the beginning of implementing pharmacogenomic strategies, but the impact on health care could be far-reaching.
The role of the FDA/USP in pharmaceutical sciences
This is an example of alternative career goals if one wishes to apply knowledge of the drug discovery and development process to regulatory affairs. This is a science in itself--termed regulatory sciences. Moreover, FDA conducts its own scientific studies in the pharmaceutical sciences so as to set optimal standards for bringing a drug to market. On the industry side, experts in this area are in urgent demand as no drug can go all the way to final FDA approval without a complete understanding of all steps in the process, including regulatory issues.
Standardization of drugs and formulations is specified by the United States Pharmacopoeia (USP), which is continuously updated to new methods and therapeutic entities, another career option. Other examples of alternative careers emerging from the pharmaceutical sciences include patent law, consulting, and investment evaluation. Lastly, many pharmaceutical scientists have founded their own companies, generating new drug formulations or testing drugs in preclinical and clinical trials.
Drug therapy has become a central issue in our nation, in part driven by the extraordinary success in drug discovery and development. However, we are not even close to realizing the potential of revolutionary advances in the biological and pharmaceutical sciences. There is no more exciting time, and few areas with similarly broad career opportunities, than drug discovery and development, whatever your primary interest may be.
Wolfgang Sadée, Dr. rer. nat., is a professor of pharmacology and director of the School of Biomedical Sciences, College of Medicine and Public Health, The Ohio State University, Columbus, Ohio.