NATIONAL INSTITUTES OF HEALTH 
MAINTAINING THE INVESTMENT IN RESEARCH 

Applications, Opportunities, and Potential for 
Drug Discovery and Development

A strong federal investment in basic biomedical research has played a major role in developing effective drug agents and experimental therapies that aid in the treatment of many diseases and afflictions. Most recently, three pharmacologists were awarded the 1998 Nobel Prize in Physiology or Medicine for their research on nitric oxide (NO). Their work led to the discovery that the body uses NO to regulate blood vessels. The basic underpinning's of these investigations helped in the development of the anti-impotence drug Viagra, and have wide ranging implications in drug discovery for the treatment of heart disease and bacterial infections that can lead to sepsis and circulatory shock. 

The knowledge gained from our investment in basic research has led the biotechnology industry to develop more than 65 drug products helping more than 100 million people. Additionally, there are 300 more drug products and vaccines in human clinical trials and hundreds more in preclinical development. Continued strong increases in biomedical research will help us to understand the underlying biochemical causes of many afflictions and allow for the development of novel pharmacological agents. This investment can help play a role in, for instance, identifying individual genes that determine individual variations in drug responses, increasing a drugs efficacy and safety. The American Society for Pharmacology and
Experimental Therapeutics supports a 15% increase for the FY 2000 NIH budget. The bipartisan support in Congress for biomedical research is critical to the nation’s health and economic well being. 

Some examples of federally funded basic research that lead to actual or potential therapeutic benefits include: 

• NIH funded research and advancements in genetic chemistry, computer science, and genetics will make it possible to develop potential cancer drugs in weeks or months instead of years. Combinatorial chemistry allows researchers to produce and screen many molecules for anti-cancer activity instead of one at a time. This will allow biologists and chemists to manufacture and test potential anti-cancer drugs hundreds of times faster than with older techniques. 

• Researchers are investigating the development of a novel drug delivery system that would increase drug absorption by "sticking" bioadhesives to a target instead of flowing through the body. This type of delivery system would be used to administer cancer chemotherapy, hormones, vaccines, gene therapy, and could be used to deliver drugs orally instead of by injection. 

• In the past five years, NIH sponsored research has led to the development of two new drug therapies for treatment of glaucoma, a disease that if left untreated leads to blindness. These drugs reduce eye pressure with fewer side effects. 3 million Americans have glaucoma and as many as 120,000 are blind. Glaucoma is the leading cause of blindness among African-Americans. 

• Diabetic retinopathy affects nearly half of all people with diabetes and will blind as many as 25,000 each year. The cause of this blindness is the growth of new blood vessels in the retina that are stimulated by the lack of oxygen. The NIH is involved in several clinical trials with the pharmaceutical industry to develop novel drug therapies that would inhibit the growth of these new blood vessels.

• Innovative medicines have helped cut the death rate from AIDS significantly. NIH funded basic research on HIV pathogenesis contributes to and supports comprehensive drug discovery and development efforts in HIV research. Protease inhibitors are compounds that block the protease enzyme of HIV, preventing the production of infectious viral particles. Future research in therapeutics can focus on easier to use "second generation" protease inhibitors and the development of drugs targeted against other enzymes critical for viral replication. 

• NIH funded research led to the development of Angiogenesis inhibitor drugs that block the development of new blood vessels. Tumors cannot grow without creating new blood vessels to supply the tumor's nutritional needs. By blocking the development of these new blood vessels, researchers hope to "starve" the tumor and prevent its continued growth and spread to other parts of the body. Drugs that control for the angiogenesis process in other life threatening diseases may be effective in treating a wide range of cardiovascular, pulmonary, and other diseases. 
  NIH basic research found that an antipsychotic drug is highly effective in treating patients with severe schizophrenia. It is estimated that the use of this drug saves $1.6 billion annually, primarily from reduced need for hospitalization. 

• NIH funded researchers are investigating the effects of drugs of abuse on nerve cells and the physiological properties of tissues and cells affected by dopamine, the chemical associated with the euphoric effects of drugs. These findings could lead to therapeutic alternatives such as the development of medications to treat addiction by blocking the effects of dopamine. The economic cost of drug abuse in the U.S. was estimated at more than $276 billion. 

• Lymphangioleiomyomatosis (LAM) is a rare lung disease that affects women of childbearing age. An unusual type of muscle cell that invades the tissue of lungs, blood, and lymph vessels characterizes LAM. NIH researchers are currently looking into the mechanisms of lung destruction in LAM, understanding the role of and rationale for hormonal therapies, and developing alternative therapies based on the unique presence of tumor antigens in the smooth muscle cells of LAM patients. 

• Osteoporosis is characterized by a breakdown of the cells that build strong bones. Postmenopausal osteoporosis and other types of bone loss are the causes of fractures and significant disability and expense, over $10 billion annually. Current treatments, such as hormone replacement and anti-resorptive drugs are not appropriate or effective in all instances of bone loss, necessitating continued investigations into novel therapies.

• Epidermolysis Bullosa (EB) is a devastating childhood skin disease afflicting one out of every 50,000 infants. The EB child's skin is extremely fragile and the slightest friction can cause painful blistering. Patients with severe EB have blisters covering their body that resemble serious
  burns. After three decades of studying the molecular biology of skin membrane, new clues and insights into the disease were discovered.  Industry was attracted to the study of EB when patients with EB wounds were used in a drug study approved by the FDA and now widely used as a prescription antibiotic for skin infections. EB patients continue to face many challenges while scientists seek new therapies, including gene therapy, to make advances in conquering this disease.

• Von Hippel-Lindau Disease (VHL) is an inherited disorder affecting one in 32,000 people worldwide. There is no cure. Adults with VHL have frequent recurrent tumors. VHL disease is caused by mutations in the VHL tumor suppressor gene. NIH researchers are working to find drugs that will mimic key activities of the normal VHL-protein to neutralize the effects of the defective protein produced by the mutated VHL gene. 

• Tuberculosis infects almost 2 billion people worldwide and it is estimated that over 30 million will die from it within a decade. New drugs are needed that are not resistant to the disease-causing microbe. NIH funded researchers discovered that the drug commonly used to treat TB will not work on some TB strains. The mutation in the gene that codes for a protein makes TB cells invulnerable to the drug. This results in antibiotic-resistant TB strains. Now that scientists know that the protein is critical to TB growth, they can begin designing drugs to specifically attack the protein. 

• Identification of microbial toxins and the methods to deactivate them led to the development of vaccines for tetanus and diphtheria; and new tissue culture techniques led to vaccines for measles, mumps, rubella, and polio. Today, Basic research on the biology and genetics of resistance among bacteria and fungi will lead to the development of new tests for detecting resistance, identification of new classes of antimicrobial agents, and evaluation of alternative treatments for drug-resistant infections. Scientists hope to develop rational approaches to drug design and development to fight drug-resistant malaria that affects 300-500 million and kills 3 million people worldwide; and some cases of penicillin-resistant Streptococcus pneumoniae which causes thousands of cases of meningitis and 7 million ear infections in the U.S. annually. 

• The increase in antibiotic-resistant micro-organisms is necessitating doctors to once again prescribe an older but still effective class of antibiotics called aminoglycosides. However, these antibiotics can impair kidney function and cause injury to nerve cells in the ear, leading to hearing loss. NIH funded research showed that nutrients known as antioxidants play a significant role in mediating the toxicity of aminoglycoside antibiotics, allowing further research with the goal of developing new approaches to prevent the toxic effects of these powerful antibiotics.

• The identification of BRCA1 and BRCA2 genes and their role in familial breast cancer provides an opportunity for new therapeutic tools for a disease that kills over 40,000 American women each year. Systemic hormone therapy and new drugs that are more effective with less toxicity are being introduced with our expanding knowledge of the basic biology of the disease. 

• Multiple Sclerosis is a chronic, progressive disease that attacks the central nervous system. Scientists now report that damage and loss of nerve fibers following inflammation in specific regions of the brain affected by MS are extensive. This finding suggests that early treatment with drugs that fight this inflammation may help prevent or stall nerve fiber loss and disability. Over 70 therapeutic substances are in various stages of testing to fight MS. The annual direct and indirect economic costs of MS exceed $9 billion making it the second most costly neurological disease.