Why Do Basic Research?

Why This Brochure?
Why Do Basic Research?
Untargeted Research
Research Models
What Makes Good Research?
Basic Research Pays Off
Some Early Returns
Cost
Unfinished Agenda

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Why This Brochure?

A 1983 Harris poll found that 82 percent of those surveyed believe that "even if it brings no immediate benefits, scientific research is an endeavor worth supporting." This public enthusiasm is matched by tremendous excitement in the research community. Scientists are amassing new information about life processes and developing sophisticated tools and technologies at an increasingly rapid rate. The research horizon is expanding, as are the benefits and applications of research results.

This brochure describes the goals, nature, and some of the advances made possible by basic biomedical research. While it is intended primarily for high-school and college students and their teachers, we hope that it will be of interest to many others as well.

Why Do Basic Research?

Why make bigger mice? After all, as a clever editorial on gene transfer experiments with mice pointed out, we already have rats. Why change the color of a fruit fly's eyes? Why train sea slugs to react to certain stimuli? Why would anyone devote a lifetime to the study of specialized chemical reactions in one-celled animals?

In short, why do basic biomedical research? Why not just concentrate on treating sick people? How can experiments with animals so different from people or experiments with extracts in test tubes possibly have relevance to us?

The answer lies in what we don't know. With some diseases, we don't even know enough to begin a treatment that might be successful. Often there aren't adequate models for the study of a disease, or we know so little that the design of experiments is impossible.

Smallpox, polio, pneumonia, and many other diseases are no longer the terrible cripplers and killers they once were. Science has made great strides in finding ways to prevent or cure some illnesses.

Modern medicine has also made a quantum leap technologically. Hundreds of incredibly complex machines and surgical procedures stand ready to help the physician diagnose and treat patients--once they become sick, and often at great cost. If we knew more, if we could prevent a disease entirely or cure it in its early stages, there would be tremendous savings of both money and misery.

This, in fact, is what basic biomedical research is all about. In order to attack such major diseases of today as cancer, heart disease, AIDS, arthritis, and diabetes, we need a broader base of knowledge. We need to know more about the specific cellular and molecular changes involved in the development of these conditions. By providing this knowledge, basic biomedical research such as that supported by the National Institutes of Health forms the foundation for advances in the diagnosis, treatment, and prevention of such diseases.

Untargeted Research

Untargeted basic biomedical research is usually seen to differ from other types of basic and applied or clinical research by its lack of a direct connection to a specific disease. The latter forms of research are easier to understand. Very simply put, an investigator sets out to develop a means of treating or preventing a particular disease. Extensive laboratory studies often lead to tests in animals to assure the safety and usefulness of the therapy. If it appears to be safe and to work, tests are then performed on humans in a carefully controlled clinical trial.

The researcher doing basic, untargeted studies is looking for answers to more general questions. He or she is seeking to add to the store of knowledge about how living things work. These basic researchers' experiments add pieces to the immensely complex puzzles of life. It may take time to see significant advances; "miracle cures" are not the goal of this work. Sometimes, of course, the pieces come together and a real clinical breakthrough occurs. But the scientists' main purpose is to keep following the leads that appear most likely to yield missing pieces of information, even if the exact applications of the new knowledge are not immediately evident. The National Institute of General Medical Sciences (NIGMS) encourages and supports just such untargeted studies.

From the body of knowledge and understanding amassed by basic researchers, clinical investigators can construct more rational and systematic ways to approach the problems presented by the diseases plaguing us today. Untargeted basic research thus provides the fundamental theories and concepts for more disease-oriented investigations.

Research Models

Human beings are very complicated creatures, but our cells contain the same fundamental materials as those of all living things. Researchers can therefore learn much about the way our cells work by studying simpler organisms. Since cells vary in size, shape, and function, scientists can select cells with special characteristics that make it easier to examine a given problem or process. The goal of using such models is always to gain a general understanding of biological events that occur in or affect humans.

Researchers study a bacterium called Escherichia coli (E. coli) because it is well-suited for research: A bacterium consists of only one cell which is simpler than the cells of higher organisms. As a result, much is already known about E. coli, and since all genetic material is similar, findings in bacteria have relevance to humans and other higher organisms.

Scientists study the fruit fly, Drosophila melanogaster, because it is more complex than E. coli but can still be easily maintained in the laboratory. Fruit flies have easily studied chromosomes and reproduce rapidly, so the effects of genetic changes can be determined relatively quickly. Equally important is the fact that like E. coli, these flies have been studied for many years and a great deal is known about their genetics, biochemistry, and behavior.

Mice are valuable research animals that are genetically much more complicated than flies. Many mutant strains of mice that have been specially bred for research are available today. Breeders provide investigators using the mice with information on the animals' genetic background, diet, and other characteristics so that variables which might confuse the research results are minimized. Scientists can also select animals that are particularly prone to developing certain tumors, metabolic disorders, or other conditions.

Researchers who modify the genes of test animals to produce, for example, especially large mice or red-eyed flies are attempting to learn vital facts about gene expression and control. Knowing how genetic processes are regulated may someday have relevance to a host of human diseases which develop when normal function goes awry.

What Makes Good Research?

We are all familiar with that favorite science fiction scenario: The scientist knocks over a test tube or accidentally puts two solutions together and suddenly discovers the secret of eternal life...or possibly produces a huge cucumber that tears out of the laboratory and starts eating the neighborhood. In fact, the history of science is sprinkled with anecdotes of accidental discoveries that do turn out to have a dramatic impact.

For example, major efforts are made searching for new anticancer drugs, but sometimes beneficial drugs are discovered by researchers working on other problems. Cisplatin is a case in point: This drug was discovered by chance by an NIGMS grantee who was studying the effect of electrical fields on bacteria. He noticed that in some situations the bacteria did not divide as usual, and traced the cause of this phenomenon to the platinum electrodes he was using. Further investigation revealed that the platinum compounds also prevented certain normal cellular functions and had specific antitumor effects in animals and humans. Today, cisplatin is a key drug in the treatment of testicular, ovarian, and bladder cancers.

A number of other important advances have come about almost by accident, and even achievements that occur based on a specific plan, after years and years of hard work, still seem a little miraculous when they finally happen.

But of course, most scientific advances are not accidental. Most findings are not made by one lone scientist either. They are products of years of intensive labor by teams of researchers that include many graduate students and postdoctoral fellows. These teams, in laboratories all over the world, are often working in the same or related areas, each contributing a little bit to the eventual "discovery" or answer to a problem.

"Chance favors the prepared mind," said Louis Pasteur. Basic researchers are seeking to prepare minds, to provide the knowledge necessary to make and use important discoveries. For every accidental discovery that was immediately recognized as important, there are many whose significance was not fully realized for years. Today, frequent scientific meetings, computer listings of published articles arranged by subject, and generally improved communications help convey the results of experiments to a large number of interested scientists.

Some of the ingredients that make good research happen are lucky combinations of stimulating personal interaction, adequate funds to buy instruments and pay personnel, and other factors that add up to the right scientists being in the right place at the right time. Not all of these ingredients can be planned for or predicted.

However, one thing seems increasingly clear: Too many efforts to direct untargeted research toward specific goals may reduce the chance that something really interesting will emerge. As Lewis Thomas, the biologist and writer, observed,"It is hard to predict how science is going to turn out, and if it is really good science it is impossible to predict." Scientists benefit from working in a relatively unfettered environment in which they can shift the direction of their research to follow promising leads.

Basic Research Pays Off

It is not really possible to document the many "payoffs" of basic biomedical research. Often new facts and theories become generally known and accepted quickly. The influence they have is far- reaching and not immediately traceable to the source.

However, in an effort to examine the process by which medical advances are made, in the mid-1970's Julius H. Comroe, Jr., formerly of the Cardiovascular Research Institute at the University of California, San Francisco, and R.D. Dripps, then professor of anesthesia and vice president for health affairs at the University of Pennsylvania (both are now deceased), asked 90 physicians to list the top 10 developments in cardiovascular-pulmonary medicine. Such improvements as open-heart surgery, blood vessel surgery, and drug treatment of hypertension headed the list.

Comroe and Dripps then traced the roots of these medical breakthroughs. They found that 42 percent of the conceptual steps in the development of the 10 most important medical treatments in this field came from the work of biochemists, endocrinologists, physiologists, and other basic scientists who were not working specifically on that disease area. Clinical progress was reaped from their work because they boosted understanding of the heart, lungs, muscles, and other components of the human body, as well as of hormones and drug receptors.

When scientists were unraveling the mysteries of heart and lung cells, they may not have realized how their discoveries would apply to the use of surgical implants for coronary artery disease or to treatments to reduce high blood pressure. They may simply have wanted to understand how cells contract or how hormones enter cells and change cellular activity.

Based on their findings, Comroe and Dripps recommended that a generous portion of the Nation's biomedical research dollars be targeted to identify and provide long-term support for creative scientists whose main goal is to learn how living organisms work, without regard to the immediate relation of their research to specific human diseases.

Some Early Returns

Basic research in genetics has led us to the beginning of a new era in medicine. More than 40 years ago, James D. Watson and Francis H.C. Crick determined and published the structure of the hereditary material, deoxyribonucleic acid (DNA). Since then, scientists have decoded many of the gene segments contained in DNA molecules. They can now remove a gene from one cell and manipulate it so that it can be inserted into another cell.

This work, called recombinant DNA technology, grew out of years of research--much of it supported by NIGMS--on the genetics of simple creatures such as viruses and bacteria. Gene-splicing techniques now make it possible to produce previously scarce biological or chemical agents such as human insulin, growth hormone, and interferon by placing genes that direct their formation into the cellular machinery of fast-growing bacteria and yeast. Scientists are working on ways to manufacture many more biological compounds that are difficult, impossible, or prohibitively expensive to produce by other methods.

Scientists are also using the new technology to follow the inheritance pattern of specific DNA sequence differences in families with genetic diseases for which neither the gene nor the biochemical defect is known. If linkage between the occurrence of an inherited illness and a specific DNA sequence (called a marker) is observed, then the general location of the gene causing the illness can be identified. Eventually, this could enable researchers to isolate the specific gene, determine its protein product, and learn more about how it causes disease. Isolation of a marker can also lead to a test that will predict which individuals are likely to get the disease.

Recombinant DNA technology opens new vistas. Scientists hope to use it to find the causes of and cures for many diseases that cannot be prevented or treated satisfactorily today. Although no one can predict the future, it seems likely that the basic research now in progress will eventually have major clinical applications.

Recombinant DNA technology is also an important laboratory tool that has allowed scientists to study the genes of higher plants and animals directly, whereas in the past they were generally limited to studying the genes of bacteria and viruses. Researchers can now isolate specific genes, determine their structures, compare them to the structures of other genes, and relate gene structure to function.

Another tool coming directly from basic science laboratories, the nuclear magnetic resonance (NMR) instrument, promises to improve diagnostic exploration of the body. Before x-ray machines, physicians had to use external signs and symptoms described by patients to try to determine what was happening inside the body. X rays were a great advance, but they posed a radiation risk and were limited to measuring the density of bones and tissues, making fine distinctions difficult. More elaborate scanners combining computers with x rays (computed tomography or CT scans) or radioactively tagged compounds (positron emission tomography or PET scans) are now being used to "see" soft tissues, tumors, and even brain metabolism. But NMR is improving doctors' diagnostic capabilities even further.

Until recently, NMR was used only in research laboratories to study chemicals in test tubes. Now, NMR machines are being used in conjunction with computers to provide detailed pictures of the body's interior. When it is used for diagnostic purposes in patients, the technique is called magnetic resonance imaging (MRI), to remove the ambiguity of the word "nuclear," which has nothing to do with nuclear power in this case. MRI is truly noninvasive: In contrast to x rays and CT scans, it uses no ionizing radiation. Unlike PET scans, it does not require the injection of radioactive material. Rather, MRI uses magnetic and radio frequency energy to reveal new information about the chemistry of the living body.

Because MRI can provide more information about the biochemical state of tissues and organs, it may help diagnose some types of stroke earlier and better, reveal disease buried in dense bone, expose tumors and determine if they are malignant or benign, and indicate whether a heart attack has occurred and how much damage it has caused.

Cost

Basic research is an investment in the future, but it is a relatively inexpensive investment compared to the cost of health care. In 1990, all health-related research and development, including drug development by the pharmaceutical industry, amounted to 3.7 percent of the total U.S. health care costs. It has been estimated that the basic research cost was less than 1 percent of total health care costs.

The cost of treating diseases is high. Contemporary medicine is reeling under the economic burden of expensive, halfway technological fixes that do not cure. The use of kidney transplants and dialysis machines for patients whose kidneys have failed and heart transplants or bypass surgery for those with coronary artery disease illustrates the costly and unsatisfactory methods that result from insufficient biological knowledge.

Such halfway technologies contrast with methods that prevent or cure diseases. Basic biomedical research can provide such methods, as happened with the polio vaccine, whose development depended on basic knowledge of the cause of the disease and the three types of poliovirus.

When such fundamental applications are developed, they show that the investment in basic biomedical research pays off with savings, benefits, and even profits. Selma J. Mushkin, author of Biomedical Research: Costs and Benefits, did an economic analysis of biomedical research conducted between 1900 and 1975. She found that every dollar invested returned $10 to $16, measured in increased productivity due to longer life and less illness.

Basic biomedical research also benefits the economy in more direct ways. Many nonbiomedical industries have been either created or enhanced by biomedical discoveries. An example in the food processing industry is freeze-drying, a method developed by basic biomedical research to concentrate and preserve samples. Similarly, knowledge of the biochemistry of enzymes has enhanced production in the beer and laundry detergent industries. In fact, Mushkin lists 10 industries based primarily on developments transferred from basic biomedical research that boosted the U.S. gross national product by $37 billion in a single year in the 1970's.

Unfinished Agenda

Biomedical science has conquered many bacterial, viral, and parasitic diseases that plagued people for centuries. We now live longer and are healthier. Children do not have to die of polio, diphtheria, smallpox, or pneumonia.

But humankind is still confronted by another type of disease, called intrinsic, which results from failures of basic molecular mechanisms within cells and tissues. Intrinsic diseases, including heart disease, cancer, arthritis, kidney disease, and some forms of diabetes, were once thought to be the "natural" consequences of aging. We now know that these disorders are neither natural nor inevitable. They may be prevented or cured if scientists understand their basic mechanisms and learn to intervene at the initial stages.

Lewis Thomas believed that "the major diseases of human beings have become approachable biological puzzles, ultimately solvable," and that "it is now possible to begin thinking about a human society relatively free of disease"--a notion unthinkable half a century ago.

Humankind awaits the conclusion of an unfinished medical drama that depends largely on the progress of basic biomedical research.