Printer Friendly

Medicines By Design: The Biological Revolution in Pharmacology.

What is NIGMS?

The National Institute of General Medical Sciences (NIGMS) is unique among the components of the National Institutes of Health (NIH) in that its main mission is the advancement of the basic biomedical sciences. It supports selected research and research training programs in areas that underlie all medical investigation, such as pharmacology and biorelated chemistry, and cellular and molecular biology. Knowledge resulting from this work contributes directly to the progress of research on specific diseases in the other components of NIH. NIGMS also develops and supports interdisciplinary studies in genetics, biophysics, physiology, and trauma and burn research. Many of the researchers mentioned in this brochure worked with NIGMS support.

A Visit to the Doctor, 2015

September 29, 2015--You wake up feeling terrible. You've been sick for days, and you know it's time to see a doctor. In the office, the physician looks you over, listens to your symptoms, and prescribes a drug. So far, there is nothing futuristic about this scene. But the drugs you'll take in the next century are likely to differ in appearance and action from the medicines you take today.

For one thing, pills and syringes will be joined by a wider variety of drug delivery vehicles. You may sprinkle powdered asthma medicine over your food. If you have diabetes, you may deliver your own insulin by using a magnet worn on your wrist to activate an insulin pump that has been implanted in your side, eliminating the need for injections. Other drugs, perhaps including ones to treat brain tumors, might be implanted directly at the diseased site in a material that will gradually dissolve, releasing the drug where it is needed.

Nitroglycerin for angina and drugs to combat motion sickness are already sold in thin patches that, when stuck on the skin, deliver a slow, steady dose of the drug. In the future, many drugs, including ones that attack the genetic material of viruses and prevent them from reproducing and causing illness, may be delivered via skin patches. Light waves and ultrasound may also be pressed into service as ways to activate medicines.

There will be other changes too. Drug molecules will be rationally designed--with the aid of computers--to fit with the precision of keys into locklike cell surface proteins, called receptors. Proteins of all kinds, including those found on the surfaces of viruses, will undergo high-tech scrutiny. Finely focused, high powered x rays, for example, will give researchers an atom-by-atom picture of viral, bacterial, and human proteins. For drug designers, who need to "know their enemies," such detailed information will help them make drugs specifically aimed at destroying the agents that cause illness.

Recombinant DNA technology (also called genetic engineering) turns microorganisms or modified animal cells into miniature factories and is used today to make large quantities of therapeutic substances for treating diabetes, the anemia of kidney failure, and heart attacks. These techniques, or their improved descendants, will also play an important role in tomorrow's medicines. For example, certain human proteins have a natural ability to fight cancer cells; genetic engineering might be used to make these proteins cheaply and effectively.

Prescribing and regulating drug dosage will become less of an art and more of a science. The current, rather crude methods of deciding dosage based on your weight and age will be replaced by more sophisticated ways to tailor a drug regime to your genetically determined ability to process medicines. In the future, a blood test in the doctor's office could reveal if you have the enzymes you need to process a given drug. If, for example, you do not manufacture as much of a particular enzyme as other people, the doctor will recommend lower--yet still effective--doses of drugs that interact with that enzyme.

In short, the medicines you take in the next century should attack disease organisms and diseased cells more forcefully, while sparing healthy cells. Moreover, better vaccines, pre-symptomatic screening for disease, and a better understanding of how chronic diseases arise will all mean that you may not get sick in the first place. These predictions about the future can be made with confidence, thanks to the incredible strides now being made in pharmacology and other areas of basic biology.

Pharmacology: The Study of Drugs

Pharmacology is a broad discipline encompassing all aspects of the study of drugs, including their discovery, their development, and their actions. Much of the most promising pharmacological research conducted at universities across the country is sponsored by the National Institute of General Medical Sciences, a component of the National Institutes of Health. Working at the crossroads of basic chemistry, genetics, cell biology, and physiology, the pharmacologists described in the following pages are battling disease in the laboratory and at the bedside.

Christine Carrico, former director of the NIGMS Pharmacology and Biorelated Chemistry Program, says, "This is a particularly exciting time in pharmacology. Techniques that were esoteric just a few years ago are now commonplace and have enabled us to understand the essence of disease with unprecedented clarity. For instance, we are beginning to see, at a molecular level, exactly how a cell malfunctions when invaded by a disease organism, or why someone has an adverse reaction to a normally mild drug. Also, expanding knowledge about the shapes of cell proteins is bringing the dream of rational drug design closer to reality. The gap between simple observations of drug actions and applications of therapies targeted to fight disease at the molecular level is narrowing, and we find ourselves on the threshold of a new era in medicine."

This new era is a product of years of dedicated research into the causes of and cures for disease. Because the questions they ask are so fundamental, today's pharmacologists, despite their sophisticated approaches to the study of drugs, are part of a lineage that stretches back to the earliest days of humankind.

Drugs from Nature, Then and Now

Long before the first towns were built, before written language was invented, and well before plants were cultivated for food, the basic human desires to relieve pain and prolong life fueled the search for drugs. No one knows for certain what the earliest humans did to treat their ailments, but, like the nonindustrial peoples of today, they probably sought cures in the plants, animals, and minerals around them.

Ancient Cultures

Drawing on the observations of countless generations, ancient cultures throughout the world developed extensive, and often effective, stocks of medicines that exploited the soothing properties of many natural substances, particularly those from plants. The natives of North and South America, for example, cultivated vast gardens of medicinal herbs. Aztecs in Mexico grew plants used to induce purging, vomiting, and sweating, which were preferred forms of treatment for many complaints. Incas of Peru used cinchona bark (now known to contain fever-reducing quinine) to combat malaria, as well as cocaine-containing coca leaf to both calm and stimulate the sick.

The Sumerians, who built the world's first city in southwestern Asia around 6,000 years ago, invented many things, including wheels and written language. The oldest known medical handbook is a 5,000-year-old clay tablet inscribed in the Sumerian script. It lists both symptoms of illnesses and prescriptions for medicinal plants and animal parts used in their treatment.

Some of the medical knowledge collected by the Sumerians was passed on, by way of the Babylonians, to Egypt. A wealth of artifacts from the time of the Pharaohs gives a good picture of the state of health and the healing arts in the 2nd millennium B.C. Mummies of both rich and poor people show that arthritis, tuberculosis, ear infections, and blindness caused by parasites were all prevalent. Extensive writings preserved on papyrus indicate that the ancient Egyptian physicians administered medications in the form of salves, pills, cakes, and enemas, and prescribed such effective remedies as liver (which contains large amounts of vitamin A) to cure night blindness.

However, medicine in ancient Egypt involved much more than treating physical ills. The Egyptians, like the cultures that came before them and the ones that followed, also developed elaborate theories to explain the cause of disease. These theories, in turn, influenced the ways disease was treated. Often, sickness was believed to originate in the supernatural realm, and so healers had the task of restoring an ill person's spiritual as well as physical wellbeing. These dual goals help explain why many ancient remedies combine elements that have physical effects such as lowering temperature, causing vomiting, or inducing drowsiness, with ones meant to drive out evil spirits or appease deities.

Egyptian physicians also subscribed to the doctrine of similitudes--the belief that natural substances which look or function like human organs can be used to treat ailments in those organs. So, for instance, the Egyptians treated some forms of blindness by pouring a mixture of pigs' eyes, red ocher, and honey into a patient's ear.

This doctrine of similitudes appeared in many cultures; the book of Genesis in the Bible relates a story in which the herbaceous root mandrake acts as an aphrodisiac for Leah and Jacob. Mandrake's resemblance to the human body led to its reputation as an aphrodisiac--a reputation that reached its height in medieval Europe. Herbal manuals of the 14th and 15th centuries depict mandrake root in both its "female" and "male" forms, give advice on harvesting (a dog was needed to pull it up because of the potentially lethal shriek emitted by the mandrake when uprooted), and describe its uses as a stimulant and sedative.

Western Medicine

A leading proponent of the doctrine of similitudes in 16th century Europe was the Swiss physician and alchemist, Paracelsus. He recommended St. John's wort for bums and cuts because the translucent spots in the plant's leaves resemble broken skin, while the blotchy leaves of lungwort made it an obvious choice for coughs, hoarseness, and other respiratory problems. Modem analysis of both plants reveals that they contain chemicals which do, in fact, have some therapeutic value for the conditions indicated by Paracelsus.

Paracelsus was unusual in that he advocated using only one agent at a time to treat any given ailment. Most physicians of Paracelsus' day, and later, were adherents of the humoral theory of disease, originally proposed by the famed Greek physician Hippocrates in the 4th century B.C. According to this theory, disease arose when the body's four fluid "humors"--blood, black and yellow bile, and phlegm--fell out of balance. Medical procedures were aimed at restoring lost balance. Bloodletting, for example, was practiced on those who were too "sanguine"--the supposed excess of blood evidenced by sweating, hyperactivity, and ruddy complexion. As refined by the Greek physician Galen in the 2nd century A.D., the humoral theory held sway in the West for 17 centuries.

In the 18th century, new knowledge about the circulatory and nervous systems gave rise to a complementary "solidist" theory that explained disease as the result of "obstructions" in the blood vessels and nerves. Doctors paid careful attention to a patient's pulse, skin temperature, and urine output in order to determine whether the patient was too hot, cold, moist, or dry, or suffered from disturbances in the vessels that carded the humors.

It was generally believed at this time, by both physicians and their patients, that drug preparations with many ingredients were better than those with only a few. One cure-all, Theriac, originated in medieval times and contained well over 100 ingredients by the year 1800. Whereas the hallmark of modern pharmacology is the attention given to discovering the underlying causes of disease coupled with a search for ever-more-specific therapies aimed at particular symptoms, 17th and 18th century physicians sought primarily to restore humoral balance and fiber "tone" regardless of the origin of the imbalance--an approach in keeping with the prevailing views of disease causation.

Also, while European physicians eagerly added plants brought from Asia and the New World to their drug compounds, they did not attempt to compare new drugs with old ones, nor did they study the effects of varying drug doses. The first inkling of change came in 1785, when a doctor named William Withering published An Account of The Foxglove and Some of Its Medical Uses.

Foxglove, a plant with purplish finger-shaped flowers, had been used in medicine for over 700 years when Withering wrote his study. Moreover, the plant's diuretic (urine-producing) property had been noted in the 16th century. Withering's accomplishment was, first, to deduce that foxglove was the active ingredient in the drug mixtures used by his contemporaries to treat "dropsy"--swelling of the limbs now known to be caused when the heart is too weak to circulate the blood effectively. Second, Withering, aware of the dangers of too much foxglove, conducted a large-scale study in which he tried to determine the optimal dose for each patient's condition. Withering's conclusions were accepted by doctors on both sides of the Atlantic, although his methods of determining individual drug dosages were not followed. In the early 20th century, chemists identified the active ingredient in foxglove and named it digitalis. This drug and its derivatives continue to be among the most widely prescribed cardiac medicines.

Led by the German scientist Paul Ehrlich, a new era in drug studies began in the late 19th century. Ehrlich's idea, viewed as quite strange at the time, was that each disease must be treated with a chemical compound specific for that disease. The pharmacologist's task is to seek such compounds by systematic testing of potentially therapeutic substances. Ehrlich's greatest triumph was his discovery of salvarsan--the first effective treatment for syphilis--which he found after screening 605 different arsenic-containing compounds. Subsequently, researchers around the world had great success in developing new drugs by following Ehrlich's methods. For example, testing of sulfur-containing dyes led to the 20th century's first "miracle drugs"--the sulfa drugs, used to treat bacterial infections.

In the following pages, the role synthetic chemists have played in devising new drugs and advancing pharmacology will become apparent. It might seem that such advances make drugs from natural sources obsolete. But this is far from true.

Drugs from Mold and Microbes

For instance, during the 1940's sulfa drugs were rapidly replaced by a new, more powerful, and safer antibacterial drug, penicillin--originally extracted from the soil-dwelling fungus Penicillium. It is difficult to overstate the importance that penicillin has had in improving health around the world--literally millions of people owe their lives to this drug made from mold. Over the past 50 years, chemists have made variations on the original penicillin, and have also made other antibiotics from chemicals produced naturally by certain soil bacteria.

However, disease-causing bacteria often develop resistance to antibiotics, so scientists must continue the search for new antibiotic-producing organisms. In 1984, Japanese pharmacologists, who were searching for new antibiotics and other natural products with therapeutic potential, extracted a substance that seemed to suppress the immune system from microbes living in the soil near their laboratory. Within several years, the raw chemical was developed into a new drug, FK-506. Used after kidney or other organ transplants, FK-506 can prevent organ rejection, even when an older drug usually employed for this purpose fails.

Drugs from Green Plants

Despite the contributions that soil microorganisms have made to health care, green plants, a source of drugs for millennia, continue to be the major storehouse of potential therapeutics. Over 120 currently prescribed drugs were first extracted from plants. These include digitalis (from foxglove), aspirin (from willow bark), codeine (from poppy), the relaxant atropine (from belladonna), and the anticancer drugs vinblastine and vincristine (from a species of periwinkle). It is not surprising that so many plant-derived chemicals cause physiological effects in animals. Plants cannot run away from predators, and so have both mechanical defenses, such as thorns, and chemical defenses to avoid being eaten. In nature, of course, these chemicals are intended to cause sickness in would-be predators, but in small doses or when altered through appropriate chemical procedures, the same molecules can have therapeutic effects.

There are about 300,000 different plant species, but, according to Norman Farnsworth of the University of Illinois College of Pharmacy, only about 5,000 have been studied for their possible medical usefulness. In 1989, the National Cancer Institute (NCI), a part of NIH, began a screening system that will test up to 10,000 potential anticancer agents a year, improving considerably the chance that a newly collected natural product will become a useful drug. In the NCI system, plants brought from tropical rain forests are tested for their ability to slow or halt uncontrolled cell division by placing extracts into cell cultures of more than 100 different types of human cancer. A similar system screens natural extracts for their effect on the virus that causes AIDS.

Drugs from Ocean Life

Extracts from marine plants and invertebrates (animals without backbones, such as coral, sponges, and sea anemones) are also being tested at NCI and elsewhere for their therapeutic properties. Despite difficulties in collecting ocean organisms and in extracting and purifying chemicals from them, certain marine-derived molecules have led to new drugs for human disease. Acyclovir, an antiherpes drug, was modeled on a chemical originally found in a Caribbean sponge. Didemnin B, an antitumor agent undergoing human clinical trials at NCI, was extracted from sluglike sea creatures called tunicates.

Yuzuru Shimizu of the University of Rhode Island is studying a protein extracted from common clams that has shown antitumor activity in mice. Proteins are difficult to use as drugs because they are large molecules and are usually rapidly metabolized and eliminated. If they are not eliminated, proteins are often recognized as foreign by the body's immune system and trigger allergic responses. However, if the active portion of the protein is discovered to be a small string of amino acids called a peptide, it may be possible to synthesize it in the laboratory and "disguise" it so that it can be used as a drug.

Drugs from Frogs

Chemicals originally found in microbes, plants, and invertebrates have all been refined into valuable drugs. A new source of natural product drugs might very well be certain vertebrates that have long been favorite ingredients in folk medicines--namely, frogs. Some frogs produce toxins in their skin to protect themselves from predators. Often, these toxins are alkaloids--a class of chemicals commonly produced by plants, but very rarely made by animals. Alkaloids include such plant-derived drugs as nicotine, caffeine, and morphine, and have wide-ranging effects on the human body. Many frog-derived alkaloids come from tiny poison-dart frogs indigenous to South American rain forests. With continued study, it is possible that frog alkaloids may prove safer or more effective than currently used alkaloid drugs.

Natives of Argentina sometimes tie a certain kind of live frog onto wounds to help them heal. Studies of this frog, called the African clawed frog, conducted by former NIH researcher Michael Zasloff may help explain the frogs' infection-fighting properties. Zasloff identified two peptides made in the frog's skin that have impressive abilities to kill many kinds of bacteria, yeast, amoebae, and protozoa, all of which can cause infections in people. One day, these unusual peptides (called magainins after the Hebrew word for shield) may lead to a whole new kind of infection-fighting drug.

Modern physicians, like their ancient counterparts, are influenced in their approaches to drug therapy by prevailing theories of disease causation. No longer do we believe that illness is the result of visitations by evil spirits. Rather, scientists have shown that disease arises either when the body's defense system is breached by some infection-causing organism or foreign toxin, or when something goes wrong in the cells themselves. Certain diseases (including some forms of cancer) are apparently caused by the combined effects of internal events and external agents. As pharmacologists and other researchers have learned how cells, subcellular components, and genes function, they have seen how chinks in our physical or biochemical armor can allow a disease to begin. Such insights, in turn, are helping them to find new ways of stopping disease.

How Your Body Responds to Drugs

Once, doctors administered therapeutic agents with little, if any, idea of what happened to them inside the patient. In contrast, today's pharmacologists want to predict exactly how and where a drug will act when given to a particular person. To do this, they must know both the characteristics of the drug molecule and also what chemical alterations it will undergo as it moves through the body.

The ability to predict drug actions came about slowly. Pharmacodynamics (how drugs act on the body) and pharmacokinetics (how the body absorbs, distributes, breaks down, and eliminates drugs) did not emerge as subjects of study until human anatomy and physiology began to be carefully explored.

During the "scientific revolution" of the 15th and 16th centuries, people began to study natural phenomena, including the workings of the human body. Over time, the basic actions of various organ systems--including the circulatory, digestive, respiratory, nervous, and excretory systems--were described and, later, were altered by the use of various chemicals. Eventually, the body came to be regarded as a kind of machine in which food (the body's fuel) is converted through a series of chemical reactions into the energy needed to drive the organ systems.

The study of metabolism--how the body uses and stores its fuel--was well established by the end of the 19th century. Aiding the exploration of metabolism were several unifying ideas about the body. One is that the body's basic unit is the cell. Like a miniature body, each cell is surrounded by a skin--the surface membrane--and contains tiny organs, called organelles, that perform specific functions such as the chemical tasks of metabolism.

In this century, a second unifying idea emerged with full force. This is the concept that every cell's activity is directed by a "command center"--the nucleus--in which lie the chromosomes. You have 46 paired chromosomes in each of your body cells; 23 are inherited from your mother and 23 from your father. Chromosomes are made of DNA, the double helix molecule first described by James Watson and Francis Crick in 1953. Some stretches of DNA are genes, which are the coded instructions that a cell uses to make proteins. A cell requires various proteins to build and run its organelles, and certain cells also release the proteins they make into the bloodstream for use elsewhere in the body.

For the most part, your genes are like those of everyone else, but (unless you have an identical twin) your genes also contain enough subtle differences in the order of their subunits to make you unique. Since your genetic instructions differ slightly from those of other people, the proteins encoded by your genes also will differ slightly. Most of these differences have no practical consequences, but, as pharmacologists are now learning, some genetic differences cause the people who have inherited them to metabolize certain drugs in atypical ways. An understanding of these differences and of cell function at its most fundamental level is beginning to offer unprecedented control over the art of drug prescription.

Investigations of the circulatory system by many scientists have revealed that blood is a rich melange consisting primarily of oxygen-carrying red blood cells, along with infection-fighting white blood cells and a liquid, called plasma, that carries proteins and hormones such as insulin and estrogen, nutrient molecules of various kinds, and carbon dioxide and other waste products destined for elimination. Many drugs, too, travel in the bloodstream. This presents a challenge to those pharmacologists whose aim is to deliver drugs exclusively to diseased areas.

The knowledge that the blood carries substances to and from all parts of the body, thereby linking widely separated tissues and organs, paved the way for later scientists to propose that the nervous and endocrine (hormonal) systems behave similarly. Physiologists (scientists who study the body's functions) developed the idea that all internal processes are integrated so as to keep the organism in a balanced state. This concept, called homeostasis, was more fully developed by the 19th century French physiologist Claude Bernard.

Bernard contributed to many branches of science in his long career. His finding with the greatest impact on pharmacology was probably the discovery, made in the 1850's, of the site of action of curare. Curare, a plant extract that causes muscle paralysis, was used for centuries by Native Americans in South America to poison the tips of arrows.

By careful experimentation, Bernard proved that curare has no effect on isolated muscle fibers or on individual nerve cells. Instead, the drug produces paralysis only when applied at the junction between nerve and muscle cells. Bernard's discovery contained two important insights. First, it revealed that certain drugs are exquisitely specific in terms of their sites of action, and, second, it suggested that chemicals could serve as message carriers between nerve cells, or neurons, and between neurons and other types of cells.

Over the years, researchers have identified many different nervous system messengers, now called neurotransmitters. All the transmitters are "agonists," a generic term indicating that they cause a response in an adjoining cell. One of the first neurotransmitters to be described was acetylcholine, which causes muscles to contract. Contraction is the culmination of several steps, the first of which is the binding of acetylcholine to proteins, called receptors, that stud the muscle cell's surface.

Receptors: Links in Cellular Communication

The surface of almost every kind of cell in your body is sprinkled with a variety of receptors. Like guarded gateways, cell surface receptors usually do not permit message-carrying substances to enter directly. Rather, they "accept" the message and pass it into the cell, where it causes other reactions. Like a lock, each kind of receptor is bent into a three-dimensional shape. An approaching molecule, such as acetylcholine, must, like a key, have a shape that "fits" the receptor's crevices in order to attach and be accepted.

But what if another molecule, shaped very much like acetylcholine, were to come in contact with an acetylcholine-accepting receptor? Can the receptor be "fooled" into binding with the foreigner? The answer is yes. In fact, this is precisely how curare works. By fitting into the acetylcholine receptors on a muscle cell, curare prevents the receptor's usual agonist--acetylcholine--from binding and delivering its message. No acetylcholine means no muscle contraction. The result--paralysis.

There are many drugs that, like curare, compete with natural agonists for receptors. Collectively called antagonists, they include drugs that act on neuronal receptors as well as ones that bind to receptors on other cell types. Certain antagonists have very broad effects because they bind to receptors on many different kinds of cells. The side effects of some drugs, such as a dry mouth or changes in blood pressure, can be the result of the drug's binding to receptors in places other than the desired site. One goal of pharmacology is to reduce these side effects by developing drugs that bind only to receptors on infected or malfunctioning target cells.

In the past, scientists were limited to randomly testing natural or synthetic substances in animals to see if they were either agonists or antagonists to some type of receptor. This method is being replaced by more rational, directed searches in which the pharmacologist first clones (makes numerous copies of) a particular receptor. Next, tiny quantities of potential drugs are added to the receptors in test tubes. Robotic screening, radioactive signal detectors, and other rapid, highly sensitive detection methods are then employed to search for signs of binding. Any candidate drug that passes this initial test can be further studied for its therapeutic effects.

G Proteins: Key Players in Cell Talk

Other cell membrane proteins deserve mention because of their importance in cellular communication and because they may provide a target for drugs in the future. These are the G proteins. Like a relay runner handing off a baton, a G protein reacts to a receptor-bound incoming chemical message, converts it to a different kind of message, and sets off a chain reaction in the cell, which eventually results in a response to the original signal.

More than a dozen distinct types of G proteins exist, and they mediate the responses of many kinds of cells to many different incoming stimuli. In the heart, for example, one sort of G protein passes on a hormonal signal that ultimately speeds the heart rate, while another G protein is involved in transmitting the hormonal message that slows the heart. Conceivably, abnormalities in G protein function could play a role in heart rhythm irregularities. The symptoms of cholera, traveler's diarrhea, and pertussis (whooping cough) are known to result from G protein breakdowns, and diseases with suspected G protein involvement include diabetes, hypertension, and some cancers.

Your body has many other message carriers that coordinate intercellular activities and respond to incoming information. Drugs can influence these substances as well, often by inhibiting or enhancing their production. A major quest in pharmacology has been to find--and exploit--these connections. Usually, a drug's effect is noted first and the way it influences message transmission is discovered later.

The Liver: The Body's Detox Center

But before pharmacologists can study what effect, if any, a drug has on the body, they must first predict how it will be changed as it passes through the body's chemical processing plant--the liver.

The liver is a site of continuous and frenzied, yet carefully controlled, activity. Everything that enters your bloodstream--whether swallowed, injected, inhaled, absorbed through your skin, or produced by your own cells--is carried to this largest internal organ. There, substances are chemically pummeled, twisted, cut apart, stuck together, and transformed. Thus, a drug can enter the liver with one set of properties and leave with quite a different array of characteristics, which may alter its usefulness. The "biotransformations" that take place in the liver are, like metabolic processes throughout the body, performed by the body's busiest proteins, its enzymes.

Every one of your cells has a variety of enzymes, drawn from the body's repertoire of about 100,000. Each enzyme specializes in a particular job. Some break molecules apart, while others link small molecules into long chains. Enzymes are catalysts, which have the special ability to do a chemical task over and over without themselves being permanently changed.

Enzymes act on chemical bonds. It does not matter if the bond is in a food molecule, a drug molecule, or some other kind of molecule. For the most part, liver enzymes make molecules that are either more easily absorbed by other body cells or more easily excreted. Many of the products of enzymatic breakdown, called metabolites, are less chemically active than the molecules from which they are derived. Thus, the liver is properly thought of as a "detoxifying" organ. Over the past several decades, however, pharmacologists have become increasingly aware that drug metabolites can have chemical activities of their own--sometimes as powerful as those of the original drug.

Three other facts make the activities in the liver even more complicated. First, drugs can alter the innate activity of some liver enzyme systems, often with unpredictable results. Second, nondrug substances, particularly foods, interact with drugs and liver enzymes and can sometimes cause very unpleasant reactions.

Third, genetically determined variation in liver enzyme activity causes different people to be either "fast" or "slow" metabolizers of certain drugs. For example, Asians tend to metabolize certain blood-pressure-lowering drugs more quickly than do Caucasians. Since less of the active drug gets into the bloodstream, some Asians need a larger-than-standard dose to get a therapeutic result. Scientists have identified many other drugs, including anticancer drugs, muscle relaxants, and antimalarial drugs, whose metabolism is genetically influenced. Better screening techniques are gradually permitting physicians to take these genetic subtleties into account and to identify slow or fast metabolizers before drug treatment begins.

Drug prescription that includes attention to genetic variations illustrates just how far physicians have come since the days when drugs were given with a "fingers crossed" attitude. Although today's drug regimens are both more rational and more likely to bring about a cure than ever before, the quest for new drugs, and new ways to deliver them, is still being vigorously pursued.

What's Happening in Pharmacology Today

The most important goals in modern pharmacology are also the most obvious. Pharmacologists want to design, and be able to produce in sufficient quantity, drugs that will act in a specific way with minimal side effects. They also want to deliver the correct amount of a drug to the desired site. Fulfilling the twin challenges of drug design and drug delivery is, however, more easily said than done.

By some estimates, it takes $231 million and a dozen years to get a therapeutic agent from the drawing board to the pharmacist's shelf. These numbers are less surprising when you consider just a few of the steps that are usually needed to develop a new drug. Many drugs are developed by screening tens of thousands of candidate compounds. Finding a drug from a natural source may require searching rain forests, oceans, and even mud puddles for substances with bioactive properties. For this reason, many therapeutic agents have been stumbled upon in a more or less random fashion, although research in cell physiology, the causation of infectious diseases, and biochemistry gives pharmacologists a base of knowledge that helps them make educated decisions about which therapies are promising.

Identifying potential therapeutic agents is crucial, but it is equally important to develop a means of manufacturing the agents in quantity. Many natural therapeutic substances are produced only in tiny amounts, making it necessary to process huge quantities of plant or animal matter to extract the drug from its natural source. Thus, it would be much more efficient either to synthesize the chemical in the laboratory and develop a means to manufacture the synthesized drug or to genetically engineer a fast-growing organism, such as a bacterium, to produce the substance. Today, much progress is being made in both areas. Chemists are developing many creative ways to synthesize and manufacture organic molecules and biotechnology firms are learning to use genetic engineering techniques to produce large quantities of certain drugs.

New Drugs Through Biotechnology

The term biotechnology refers to any process that uses living cells to make useful products. (Under this definition, processes such as baking and brewing, in which yeast cells are used to convert raw foodstuffs into bread or beer, are biotechnologies.) Medical biotechnology got under way about 20 years ago, when scientists discovered an enzyme, called a restriction enzyme, that cuts DNA strands into bits and another enzyme that joins cut strips together. Using these enzymes as a chemical tool kit, researchers gradually became adept at splicing together DNA from two kinds of organisms to form hybrid, or recombinant, DNA molecules. Organisms containing this recombinant DNA could then be used to manufacture large quantities of valuable proteins.

The first drug to be produced through such genetic engineering was human insulin, which appeared on the market in 1982. The hormone insulin is a small protein required for the metabolism of sugar that is deficient in people with diabetes. To make recombinant human insulin, scientists first had to identify the gene that codes for insulin--not an easy matter. Once this was accomplished, the human insulin gene could be enzymatically cut out of the rest of the human DNA and spliced into the DNA of a common intestinal bacterium called E. coli. When huge numbers of E. coli containing the recombinant molecule are grown in fermentation vats, they pump out large quantities of human insulin along with their own protein products. After purification, the human insulin is ready for use. The basic technique that is used for making insulin can be used to make many other drugs as well, and it is now the foundation of a rapidly growing industry. In 1991, there were 14 medicines available to physicians that were made through biotechnology, and more than 130 additional drugs and vaccines were in various stages of the testing and approval process.

Among the biotechnology products approved for use are erythropoietin, a hormone that stimulates red blood cell production (used to fight the anemia caused by kidney dialysis); tissue plasminogen activator (TPA), an enzyme that dissolves blood clots (used in the early stages of a heart attack to prevent permanent muscle damage); and a vaccine against hepatitis B infection.

Developing New Therapeutic Proteins

Therapeutic agents are also being produced by another biotechnology that utilizes immune system proteins called antibodies. Antibodies are spectacularly specific proteins that seek out and mark for destruction anything they do not recognize as belonging to the body. They are one of our body's main lines of defense against a host of disease-causing microbes and other foreign agents.

Ordinarily, antibodies ignore healthy cells, but attach to proteins on disease-causing organisms or on body cells that have been invaded by such organisms. Now, scientists have discovered how to fuse antibody-making cells with cells that grow and divide continuously. This creates tiny cellular "factories" that work around the clock to produce large quantities of single kinds of antibodies, called monoclonal antibodies, that bind to single kinds of targets.

These monoclonal antibodies have potential use for many purposes, including the delivery of toxic substances to destroy cancer cells that have spread. "Engineered" antibodies could also be used to deliver radioactive signals--thereby flagging cancerous cells for destruction. Since many cancer cells make proteins that act as chemical messages to stimulate rampant cell division in other, vulnerable cells, monoclonal antibodies are also being developed that will specifically thwart the multiplication of cells dependent on these proteins.

Antibodies, which are produced by one type of cell in the immune system, are only a small part of the body's arsenal of specialized immune cells and proteins. The different cells of this system cooperate and communicate with each other via many proteins. Some of these proteins, such as interferons, interleukins, and tumor-killing substances like tumor necrosis factor (TNF), are of great interest to scientists and to the biotechnology industry because of their potential therapeutic value.

For instance, scientists have used interleukin-2 to enhance the tumor-killing ability of a kind of white blood cell. This has resulted in significant tumor shrinkage in some cancer patients. In an effort to improve on this success, the scientists are now seeking to increase the tumor-fighting ability of another type of white blood cell, called a tumor infiltrating lymphocyte (TIL), by inserting into it a gene that codes for TNF. The hope is that, when returned to a patient, the genetically engineered TIL cells will invade the tumor and produce TNF, which will help destroy the tumor.

Many kinds of cells make special proteins called growth factors that also hold important therapeutic potential. These proteins were first discovered when researchers noticed their ability to stimulate the growth of colonies of certain cells in the laboratory. Growth factors play key roles in wound healing and in immune cell production. Thus, they may have value in treating people, such as those with diabetes, who have impaired wound healing and people whose immune systems have been damaged by disease or by chemotherapy.

Studies of the immune system have led, and continue to lead, to important advances in pharmacology. In the early 1970's the discovery of the drug cyclosporin A, which prevents organ rejection by suppressing the immune system, made it possible for surgeons to save the lives of many critically ill patients through organ transplants. Recently, researchers seeking immunosuppressant compounds with activity equal to cyclosporin A but with lesser toxicity have found another compound, called FK506, that seems to produce the same effects at lower, and less toxic, doses. The researchers found, to their surprise, that the two drugs were chemically quite different. Subsequent studies then led to valuable new information about how the drugs achieve their effects, thus paving the way for the design of other drugs that may either suppress or stimulate the immune system. In addition, the work opens new routes by which to study immune system function.

Drug Delivery

Ideally, a drug should enter the body slowly and steadily, go directly to the diseased site while bypassing healthy tissue, do its job, and then disappear. Unfortunately, the typical methods of delivering drugs--ingestion or injection--rarely attain this goal.

Drugs that are swallowed may not be able to cross the intestinal membrane and so may never enter the bloodstream. Many therapeutic proteins and enzymes cannot be taken orally because they are rapidly digested. If a drug does enter the blood from the intestine, much of it may be inactivated by enzymes on its first trip through the liver. This "first pass effect" means that several doses of the drug must be administered before a therapeutic level is achieved in the bloodstream. Drug injections are also often unsatisfactory, because they are expensive, difficult for the patient to self-administer, and unpopular if the drug must be taken daily. Both methods of administration also result in fluctuating drug levels in the blood, which, besides being inefficient, can also be dangerous, since many modem drugs are more potent than their older counterparts and therefore dosages must be very carefully controlled in order to prevent toxicity.

Delivery dilemmas are being overcome with a variety of ingenious techniques. The now-familiar drug-impregnated skin patches bypass the digestive system altogether. These foil-backed, adhesive patches set up a tiny electric current that draws the drug out of the patch and into the skin. They have been used since the early 1980's to administer such drugs as scopolamine (effective against motion sickness) and nitroglycerin (for angina). Slow, steady drug delivery directly to the bloodstream is the primary benefit of skin patches, which makes them particularly useful when the chemical must be administered over a long period. However, only very small drug molecules can get into the body through the skin.

Nasal Sprays

The mucous membrane of the nose is more permeable than the skin and therefore can act as a gateway into the circulation for proteins, enzymes, hormones, and other larger molecules. A nasal delivery system for insulin is now in clinical trials and may be available for general use by the mid-1990's. The trick that makes this system work is combining aerosol droplets of insulin with a chemical "permeation enhancer" that momentarily opens the junctions between nasal cells. Insulin levels in the blood peak about 15 minutes after administration, closely mimicking the body's normal insulin response to a meal. Nasal delivery systems are currently available for anti-allergy and other medicines.

Drug Implants

Nasal dosing has obvious advantages over injections and oral medications, but, like them, it results in sharply fluctuating drug levels. "Bioerodible" implantable drugs may offer a way to achieve the slow, continuous release of drugs needed to treat chronic problems. Bioerodible implants work somewhat like the solid air fresheners that gradually release fragrance as they melt. One implant being developed by Johns Hopkins University researcher Henry Brem and others is a thin wafer impregnated with an anticancer drug. During surgery, it is placed directly at the site of a brain tumor, where brain fluids cause it to slowly erode. As it does, it releases its drug, killing the cancer cells, but causing no side effects in the rest of the body. Other drugs that are best administered continuously, including contraceptives and the neurotransmitters needed to treat various neurological diseases, can also be put into bioerodible materials and implanted in the body.

A number of researchers, including Robert Langer of the Massachusetts Institute of Technology, are now developing "patient-activated" implantable drugs. Langer has found that insulin-laden plastic implants will release the drug more quickly when exposed to ultrasound or to magnetic fields. If perfected, these methods might allow a person with diabetes to boost insulin levels in the blood immediately following a meal, just as the body normally does. Although much experimental work has been done with insulin, such "patient-activated" implants have the potential for use with other drugs that need to be injected at frequent intervals.

"Pill Pumps"

Another experimental implant system combines insulin with sugar-sensitive enzymes, and would not require the person to do any work at all. Instead, the insulin is released in direct response to rising blood sugar levels, which activate the enzymes and cause the insulin to flow out of the implant. When sugar levels drop, the insulin level does too.

A similar body-activated delivery system is the "pill pump," an improved kind of "tiny time pill" invented by the late Takeru Higuchi of Kansas University. Higuchi coated a powdered drug with a water-absorbing membrane. The pill pump is swallowed, and, as it passes through the digestive system, water gradually seeps through the coating and dissolves the powder, which leaks out of a tiny laser-drilled hole in the pill. The rate of drug release can be regulated with a fair degree of precision by altering the thickness of the pill's coat. Pill pumps that deliver indomethacin (an anti-inflammatory drug) have been developed by a California drug company.

Drugs in Bubbles of Fat

A drug delivery vehicle that has long been viewed as promising is the liposome, a microscopic bubble of fatty molecules (lipids) surrounding a watery interior into which drugs can be placed. One of the benefits of liposomes is their similarity to cell membranes, which makes them nontoxic. However, liposomes have proven to be difficult to direct to desired sites, other than the liver and the spleen. Also, they do not remain in the bloodstream long enough to be useful vehicles for most drugs.

The latter problem was overcome in 1988 by Demetrios Papahadjopoulos and colleagues at the University of California, San Francisco, and Terry M. Allen of the University of Alberta, Canada, who modified the surface chemistry of liposomes so that they can circulate for longer periods of time. In tests directing them to cancer cells in mice, the modified liposomes also showed increased accumulation in tumors and increased antitumor activity.

The problem of directing liposomes to specific sites has been more intractable. However, it has recently become possible to attach monoclonal antibodies to the surfaces of long-circulating liposomes. The antibodies mark the liposomes for delivery to their target cells. Researchers faced another type of delivery problem in developing a site-specific drug for inflammatory bowel disease. David Friend and his colleagues at SRI International in Palo Alto, California, created such a drug by capitalizing on the fact that populations of normal gut-dwelling microorganisms are not uniform throughout the digestive system. First, the researchers attached a powerful anti-inflammatory drug to a sugar molecule. The resulting compound, called a prodrug, is given orally, but it is not readily absorbed by the stomach or the small intestine. When the prodrug reaches the colon, however, it comes in contact with enzymes produced by microorganisms that live only in that location. The enzymes clip the sugar molecule off the prodrug, liberating the active drug, which is then absorbed.

Light-Activated Therapy

Another targeted drug delivery system, called photodynamic therapy, combines modern transfusion techniques, an ancient plant remedy, and light. Photodynamic therapy has been approved for use in treating a hard-to-cure cancer, and shows promise for treating the skin disease psoriasis and certain immune disorders. The key ingredient in photodynamic therapy is psoralen, a plant-derived chemical with the peculiar property of being inert until exposed to light.

Psoralen is the active ingredient in a Nile-dwelling weed, called ammi, used by the ancient Egyptians to treat skin disorders. They noted that people became prone to sunburn after eating the weed. Modern researchers explained this phenomenon by discovering that psoralen, after being digested, goes to the skin's surface, where it is activated by the sun's ultraviolet rays. Activated psoralen attaches tenaciously to the DNA of rapidly dividing cells and kills them.

Richard Edelson and his colleagues at the Yale University School of Medicine developed "photopheresis," a method in which a psoralen derivative is used to treat cutaneous T-cell lymphoma, a cancer of certain white blood cells. The scientists give the patient a dose of psoralen drug, then remove some of the patient's blood. Next, they separate the white blood cells from the rest of the blood and activate the psoralen by shining ultraviolet light on the white blood cells for several hours. The scientists had expected this procedure to kill the rapidly dividing white cells, and it did, but when they returned the killed cells to the patients, they were surprised at the unexpectedly rapid improvement in some patients. Apparently, photopheresis damages the cancer cells in such a way that the immune system mounts a vigorous battle against them--and against all other identical cancer cells. In this way, the process acts as a sort of vaccine, in that a small amount of material (the light-treated cells) elicits an immune response.

All of these advances in drug development and delivery are reflections of the modern notion that illness, whether inherited or acquired, is the result of molecular malfunction. Today, efforts to treat sickness by focusing therapies precisely on the malfunctioning molecules are increasingly successful. In the future, communicable diseases--including the age-old scourge of the common cold--as well as inherited conditions may be cured, rather than merely treated, with "drugs" that actually repair cells or protect them from attack.

Shaping Tomorrow's Drugs

Today's pharmacologists are in the vanguard of a revolution. Building on foundations laid by researchers in the fields of genetics, chemistry, cell biology, structural biology, and computer graphics, the pharmacologists of the 1990's are constructing a science that would be all but unrecognizable to their predecessors. Rational drug design, protein engineering, and gene therapy are among the techniques being utilized by forward-looking pharmacologists.

Computer-Assisted Drug Design

The best developed of these new approaches to therapy is computer-assisted drug design, which is intended to reduce the number of candidate drug molecules that must be synthesized in the laboratory. Now over 10 years old, it has the potential to completely eliminate the older practice of building unwieldy ball-and-stick models of potential drug molecules. Taking their place are colored, three-dimensional molecular skeletons--with every atom and chemical bond clearly represented--that can be called up on a computer screen by a few keystrokes.

A joystick lets a pharmacologist move models of potential drugs across the computer screen toward a model of the target molecule--usually a protein receptor or an enzyme known to be involved in some disease. Information about atomic interactions drawn from the computer's database allows the operator to modify aspects of the model drug, such as its atomic composition, size, and chemical stability, directly on the screen until the model drug appears to fit snugly into the receptor.

But before computers can help pharmacologists design a drug, the shape of the target protein must be determined. Proteins are made of subunits called amino acids. Deducing the order of amino acids in a protein from a known series of DNA subunits has been possible since the 1960's, when the so-called genetic code that relates DNA to amino acids was cracked. It is also relatively easy to determine the order of amino acids in a protein that has been isolated from a cell. But knowing the order of amino acids in a protein without knowing the protein's folded, active shape is like knowing a person's name, but nothing about his or her personality.

Unfortunately for pharmacologists trying to make computer models of proteins, there are no simple "folding rules" that will tell at a glance how a series of amino acids will bend and the shape of the final protein. Sometimes scientists can infer the shape of the binding site (the place where the protein binds to another molecule) from the shape of a drug known to interact with it. Or, researchers can attempt to crystallize a protein so that its atoms lie in a regular pattern that can then be determined by bombarding the crystal with x rays. A newer technique, nuclear magnetic resonance spectroscopy, detects interactions of atoms in a molecule and can be used to get an idea of the shape of proteins that cannot be crystallized.

Despite the difficulties, computers have been used to design a number of drugs that interact with body proteins. The first was captopril, which combats high blood pressure by interfering with one of the series of enzymes that act together to allow blood pressure to rise. Other drugs being developed include an anticancer drug built to inhibit an enzyme that is present in high levels in the nuclei of rapidly dividing cancer cells. Another potential drug may slow arthritis by disabling an enzyme called phospholipase (which is involved in the release of substances that lead to inflammation), while a third is shaped to block the action of elastase (an enzyme that can bring about the destruction of lung tissue in persons with emphysema).

Viruses: Elusive Targets

Viruses, including those that cause the common cold and AIDS, might also be disarmed by drugs shaped to disable key proteins. Viruses are essentially bundles of DNA--or a related molecule, RNA--surrounded by a protein coat. Viruses use their proteins to stick like burrs to cells. Then the viruses insert their own DNA or RNA into the "host" cells, thus hijacking the cells' own protein-making machinery and forcing them to produce large numbers of new viruses. Pharmacologists would like to design antiviral agents that will either cripple viral proteins so that they cannot get into cells, or strike at the enzymes a virus needs to reproduce once it enters the cell.

In 1985, Michael Rossmann and his coworkers at Purdue University took a major step toward improved antiviral agents, specifically toward the long-sought cure for the common cold, when they crystallized one of the rhinoviruses that cause colds. The three-dimensional map of the virus that the researchers made using their crystallographic information revealed that a deep cleft on the surface of the virus is the site at which the organism attaches itself to human cells. This finding, in turn, explains how an anticold drug, previously developed by a pharmaceutical company, works. Scientists are now working on structural improvements of this drug that will decrease its side effects.

Researchers are rapidly learning the structures of sites believed to be critical to the infectivity of other viruses. They are also developing new techniques to locate drugs that can disable a virus by binding to it with a high degree of specificity. One of these techniques is a quick computer method to screen candidate drugs for their "fit" with target binding sites. Since this technique is based on molecular shape, not chemistry, it is capable of turning up unexpected fits for many types of molecules. The method promises to be useful for identifying drugs to combat many different diseases.

Made-To-Order Molecules

Considering the difficulties scientists have in determining the structure of natural proteins, especially such critical information as how they fold, it might seem a bit presumptuous that some researchers are trying not only to make natural proteins "better"--that is, more stable, more active, or more specific in what they bind to--they are even building never-before-seen proteins "from scratch." Indeed, protein engineering, as it is called, was generally dismissed as mere fantasy just a decade ago. After all, nature has been making proteins for billions of years, while humans have been at it for relatively few. Nevertheless, protein engineering is beginning to move from small-scale experiments to mainstream techniques that are likely to play a major role in drug manufacturing in the future.

Researchers would especially like to learn how to "engineer" enzymes to provide greater control over chemical reactions, prevent the synthesis of unwanted byproducts, and produce drugs more quickly and less expensively than is now possible. In 1990, Elias Corey of Harvard University won a Nobel Prize for his development of ways to synthesize organic molecules. Corey has developed molecules that he calls "chemzymes," which can catalyze certain chemical reactions quickly and in such a way that only the biologically effective product is made. He starts out by understanding the chemical mechanisms involved in a particular reaction and then engineers molecules with exactly the properties needed.

Chemzymes are designed to help chemists eliminate one of the most persistent roadblocks to efficient, cost-effective molecular synthesis. Conventional chemical synthesis of biologically active molecules usually results in a product that is a mixture of molecules having two different spatial orientations. Molecules of only one of the orientations actually perform the desired task. The opposite form can have no effect or can cause reactions ranging from mild to severe. Chemzymes, in contrast, make every one of their product molecules in the same orientation. This eliminates not only the waste of costly raw materials at the beginning of a synthesis, but also eliminates the need to remove unwanted products of the "wrong" orientation at the end of the synthesis. Potential applications range from basic research on reaction mechanisms to multimillion-dollar pharmaceutical manufacturing processes.

Other researchers are working to make antibodies that can act as enzymes. They call these catalytic antibodies "abzymes," and they hope to develop them as tools that will break peptide bonds, thus cleaving proteins with the same precision as the enzymes now used to cleave DNA. Because of the virtually unlimited diversity of antibodies, abzymes could, in theory, bind to a much wider variety of molecules than natural enzymes or even designer enzymes like chemzymes. Although researchers are now able to produce abzymes that work much faster than before, abzymes are still much slower than enzymes. This may not be a problem for some uses, however, since DNA-cutting enzymes are not particularly fast either.

Gene Therapy

Of all the therapies that pharmacologists see on the horizon, perhaps the most tantalizing are ones that would cure disease by fixing damaged genes. Diseases such as cystic fibrosis, hemophilia, and severe combined immunodeficiency are termed "single-gene" disorders because a single abnormal gene makes an abnormal protein, which, in turn, results in the symptoms of the disease. In theory, "genetic surgery" could cure these single-gene diseases by cutting out the abnormal gene and replacing it with a working one. One might even imagine diseases with more complicated genetic underpinnings, such as certain forms of heart disease, being conquered with more extensive "genetic surgery."

To date, however, scientists have struggled with only mixed success to make gene therapy a reality. Among the many challenges are: identifying the gene or genes that cause the disease; manufacturing a complete, working gene in the laboratory; getting the "good" gene into the patient's DNA; and, most difficult, getting the gene to make the corrective protein in amounts large enough to eliminate the disease symptoms.

In the fall of 1990, approval was obtained for the first human trials of gene therapy. These early trials involved children suffering from adenosine deaminase (ADA) deficiency (a severe immune disorder) and, at present, appear to be yielding beneficial results. Children with ADA deficiency lack an essential enzyme and are therefore prone to life-threatening infections. To treat ADA, the researchers are inserting a copy of the gene that codes for the missing enzyme into blood cells that have been removed from the patient. They then transfuse these modified cells back into the child. If the treatment is effective, the child's immune system should grow stronger. Since this therapy has not been targeted to the bone marrow cells that produce all the blood cells in the body, the treatment will have to be repeated at intervals.

As human DNA becomes more familiar territory, additional possibilities for selectively influencing portions of it emerge. Researchers are working on synthesizing compounds that can interact either with genes themselves or with the messenger RNA that carries the instructions needed to make proteins. These compounds, composed of the subunits of DNA or RNA, are called antisense oligonucleotides. They are mirror images of the target stretches of DNA and RNA, and are designed to bind to DNA to prevent a gene's expression or to bind to RNA to prevent translation of the gene's message.

Theoretically, these antisense strands could be used for a host of therapeutic purposes, including blocking the spread of cancer cells, viruses, or disease-causing proteins. However, many hurdles will have to be overcome before antisense nucleotides can be used to treat disease. Scientists need to find ways to alter the molecules so they can cross membranes more easily and avoid premature degradation by cell enzymes. Moreover, ways must be found to manufacture antisense molecules relatively inexpensively and in large quantities.

Although it is impossible to predict which of the techniques now being developed will yield valuable drugs for the 21st century, it is clear that, thanks to modern pharmacology, physicians of the future will have an unprecedented array of weapons with which to fight disease. As pharmacologists continue to pursue the many leads opened by new research advances, even more exciting approaches to drug therapy are sure to arise.

To order a free, printed copy of this document, please use our Publication List order form.
National Institute of General Medical Sciences
National Institutes of Health
Bethesda, Maryland 20892-6200

Last updated: April 30, 1997
COPYRIGHT 1997 National Institutes of Health
No portion of this article can be reproduced without the express written permission from the copyright holder.
Copyright 1997 Gale, Cengage Learning. All rights reserved.

Article Details
Printer friendly Cite/link Email Feedback
Publication:Pamphlet by: National Institutes of Health
Article Type:Pamphlet
Date:Apr 30, 1997
Previous Article:Parkinson's disease: hope through research.
Next Article:What We Know About Radiation.

Terms of use | Privacy policy | Copyright © 2021 Farlex, Inc. | Feedback | For webmasters |