Defending the Nation's Health: Building on the Basics

by Harold Varmus, M.D.
National Institutes of Health
March 14, 1995

In late 1940, as our nation braced itself against a world descending into war, President Franklin Roosevelt dedicated the new National Institute of Health (NIH) campus in Bethesda.

"The total defense," he said, "...Involves a great deal more than building airplanes and ships, bombs and guns. We cannot be a strong nation unless we are a healthy nation."

In the intervening fifty-five years, we have prevailed against many military foes. But most enemies of health remain, and new ones continue to appear. How can we build new and more effective defenses against them?

The agency I represent, the NIH, is dedicated to the advancement of health through science. This is a daunting task, for there are many threats to health. Some of these are intrinsic to us as organisms that inherit thousands of genes, some of which are likely to be faulty; as organisms that undergo complex developmental events that sometimes fail; and as organisms that inevitably age, often too quickly. Other threats are external: an ever-changing sea of bacteria, viruses and other parasites, polluted air, high fat diets, dysfunctional families, traumatic accidents, and a variety of other environmental influences.

I will argue here that defenses against the diseases that result from such threats to our well-being depend upon many elements, most of which were identified at an earlier National Science and Technology Council forum that addressed a broader issue, the status of fundamental science in our country. The participants in that forum--a diverse group including physicists and sociologists, biologists and geologists--proposed several broad goals that became the five principles of Science in the National Interest, a policy statement issued by President Clinton and Vice-President Gore. Those principles pledged to do outstanding science in many fields; to link science to national objectives; to work together to conserve resources; to train the next generation of scientists; and to improve the scientific literacy of the public.

I will illustrate the importance of these principles to the defense of health by describing four examples of recent progress in the biomedical sciences. The stories I have chosen show that success is usually built on many components, decades of dedicated work, and generous, nonpartisan Federal support. Important advances usually begin with basic research, in the laboratory or the clinic, in the U.S. or abroad. The research requires talented investigators, including a steady supply of new minds, and vibrant institutions in which to work and learn. Fundamental discoveries of potential clinical value need to be brought into medical practice, usually through lengthy collaborations with industry and health workers. In addition, news of progress must be transmitted efficiently to patients and doctors. We neglect any of these ingredients only at our future peril.

The medical advances that have occurred in my life time have been staggering. A sampling of those that come readily to mind are listed in the Table at the end of this article. But in selecting success stories, I have chosen to reach beyond these to four examples that are less well-known. Each case illustrates how research delivers practical benefits in unexpected ways, reducing morbidity and mortality, and often costs. The science is sometimes serendipitous, sometimes targeted, but strong partnerships among the Federal Government, academia, and industry are inevitably required to fulfill the promise of improved health.

Lead poisoning and neurotoxicity

The evolution of Homo sapiens occurred in a world in which exposure to lead was minimal. Archaeologic evidence suggests that lead was used as early as 6500 BC, but lead levels in the bones of pre-Columbian Americans show that a typical body's lead content was hundreds of times lower than that of modern North Americans. With the advent of the Industrial Revolution, exposure to large amounts of lead posed a serious problem for workers in the mining and smelting industries, and the acute and sometimes fatal consequences of lead poisoning--encephalopathy, abdominal colic, kidney damage--became well-known. In modern times, the general population has been exposed to lead mainly through two sources, house paint and automotive fuel, but it has been difficult to define the levels of lead that can be tolerated chronically without any subtle impairment of neurological function.

Recognition of lead's dangers produced Federal legislation during the 1970's to remove lead from the two major environmental sources. Today, 99% of U.S. cars burn only unleaded fuel, and ambient concentrations of lead in the air have been reduced by 97%.2 Unleaded gasoline is, however, still not widely available in Europe, Mexico, and Southeast Asia. More important for the health of Americans, lead residues still exist in many homes that were built prior to the bans of lead-based household paint. The Agency for Toxic Substances and Disease Registry has estimated that 3 million tons of old lead-based paint line the walls and homes of 57 million housing units occupied by approximately 12 million children.3 These children, often poor, minority, urban-dwellers, are at high risk of exposure to lead, especially when unsupervised.

To gauge the public health problems associated with lead, we need to be able to measure two things accurately: the bodily content of lead, even at relatively low levels, and the subtle neurological changes that might be produced by chronic, low-level exposure. Several sophisticated detection methods, including atomic absorption spectroscopy and mass spectroscopy, have been applied to the determination of lead levels in whole blood, red blood cells, teeth, and bones, thereby allowing estimates of the amount of lead in the whole body. In recent years, these methods have been greatly improved in accuracy and sensitivity.4,5

Results from several NIH-supported studies indicate that levels of lead once considered safe have significant detrimental effects on cognition and behavior. For example, developmental indices are significantly poorer over the first 24 months of life in children with comparatively high levels of lead in their blood at birth, and reading disability is more common in young adults with higher amounts of lead measured in their teeth.6,7,8 There is further evidence that chronic exposure to lead can create IQ deficits of up to eight points in children without overt symptoms of classic plumbism (lead poisoning).9,10

In response to such evidence for subtle deleterious effects on neurological function, the Centers for Disease Control and Prevention has gradually lowered the acceptable levels of lead from a blood lead concentration of 40 ug/dL established in 1973 to 30 ug/dL in 1978, to 25 ug,/dL in 1985, and to 10 ug/dL (the current recommendation) in 1991.11

The new findings of neurological impairment from low levels of lead and the more stringent safety standards create an immediate need for instruction in lead-avoidance, especially for children in our urban centers. But these new findings also impel us to ask what can be done for those children, estimated to number six million, who already have excess lead in their bodies. 12

The traditional drug for promoting excretion of lead, the chelator known as EDTA, has recently been replaced with a new drug, called succimer, which is easier and safer to administer.13,14 This chelator forms stable covalent bonds with lead, resulting in a water-soluble, renally excreted complex. But we will not know whether the drug is truly effective until the completion of a controlled clinical trial. This trial, involving over 1300 children between 12 and 32 months of age with blood lead concentrations from 20 to 44 ug/dL, is now underway in four American cities: Philadelphia, Newark, Baltimore, and Boston.

Vaccination against Hemophilus influenza Type B

Hemophilus influenza Type B (HiB) is a common gram-negative bacterium that causes a variety of childhood infections, most notably meningitis. Until the late 1980s, HiB caused over 10,000 cases of meningitis per year in children under the age of five. 15 Despite treatment with antibiotics, about five percent of infected children die from HiB meningitis and about one-fourth of the survivors are left with significant neurologic damage, ranging from hearing loss to mental retardation.

Efforts to reduce the mortality and residual morbidity associated with HiB meningitis have focused on the prospects for developing an effective vaccine that would prevent childhood infections. It was recognized over sixty years ago that the rarity of clinically significant HiB infections in adults was related to high levels of serum antibodies against the organism. In contrast, after an initial brief period of protection by maternal antibodies, children are at high risk untiI about age four or five, when the incidence of disease falls to very low levels as antibody levels rise. 16

Despite the development of successful vaccines for many infectious diseases of childhood and despite the inference that people naturally acquire protective immunity to HiB, it has been difficult to prevent infection of young children with the usual vaccine strategies. The apparent explanation for this problem is intrinsic to the chemical nature of the important HiB antigen. H.influenza Type B is encapsulated with a polysaccharide, composed of ribose, ribitol, and phosphate, that serves as the point of attack for the protective antibodies found in adult blood.17 But immunization with capsular polysaccharides produces only weak antibody responses in young children, particularly those under the age of two. 18

In response to the problem with immunogenicity, scientists working at the National Institutes of Health and the Food and Drug Administration (FDA) have shown that conjugation of HiB polysaccharide to proteins, especially to strong antigens, such as diphtheria or tetanus toxoids, generates immunogens that induce high titres of antibodies against the polysaccharide component, even in very young children. 19 The effectiveness of the conjugated antigen seems to depend upon the protein-promoted involvement of T cells in the production of antibodies, since the T-cell-independent antibody response to polysaccharides is generally poor in children younger than two years of age.20

Several pharmaceutical firms have recently developed and field-tested conjugated HiB vaccines, and four have been licensed for use in infants as a result of successful trials. In Los Angeles County, for example, a traditional polysaccharide vaccine, introduced in 1985 for use in two-year-olds, had no apparent effect on the incidence of HiB meningitis in children under one year of age. In contrast, use of a conjugate vaccine at the age of 18 months dramatically reduced the incidence of disease, even in younger children, presumably by what is often called a "herd" effect; the vaccinated children were unlikely to bring the organism home to their younger siblings.21,22,23 After the conjugate vaccine was shown to be safe and effective at inducing antibodies in two-month-old infants, immunization of the younger population, beginning in 1990, drove the incidence of serious HiB infections to near zero. These findings, which have been replicated in other urban areas, bode well for the elimination of HiB meningitis and its sequelae in the U.S.

The obvious payoff of government research on HiB vaccines is healthy children. But there are economic benefits as well. Use of the vaccine has been estimated to produce a twenty-fold annual return to the public on its relatively small investment. In the past, each annual cohort of brain-damaged survivors of HiB meningitis cost the country as much as $470 million for long-term institutional care; the conjugate vaccines can be expected to save most or all of that expense.

Despite significant progress in development of new and improved vaccines against HiB, pertussis (whooping cough), and other childhood maladies, we still lack an optimal, simplified vaccination schedule, and compliance with existing schedules remains embarrassingly low in many parts of the country. Even an excellent vaccine is of little value if it is not widely used. It is therefore important to move our nation towards a coherent, nonpartisan plan for universal immunization.

Cisplatin and cancer therapy

In 1965, Dr. Barnett Rosenberg, a biophysicist at Michigan State University (MSU), made an unexpected observation. When an electric current was generated with platinum electrodes in a continuous culture of Escherichia coli, normal cell division was inhibited, and the bacteria grew into long filaments. The inhibitory effect was not due to the electric current, but to a small amount of a well-known chemical, cis-dichlorodiammineplatinum (II) (cis-platin), which was produced by electrolysis of the platinum electrodes in the presence of ammonium chloride.24

The story could have ended at this point, but it occurred to Dr. Rosenberg and his students that cis-platin might have the ability to arrest the doubling of other kinds of cells, including animal cells and, in particular, cancer cells. Encouraged by initial tests with mammalian cell lines grown in tissue culture, the MSU group teamed up with the cancer drug screening program at the National Cancer Institute (NCI) to carry out a more provocative test in mice. A standard inoculum of L1210 leukemia cells produces a large tumor and ascites fluid in the abdomen of control mice, but growth of the tumor and development of ascites were dramatically inhibited by treatment with relatively low doses of cis-platin. Additional experiments showed that other platinum complexes were also effective and that these drugs were effective against a broad spectrum of cancer cell types.25,26

These encouraging initial results were the products of two kinds of academic-government relationships. The award of an NIH grant led to a fundamental discovery by a university investigator, and a clinical application was then identified through collaborative experiments with government scientists. The results fostered further collaborative work, some also involving industry. University chemists synthesized new platinum derivatives, e.g., carboplatin, for tests of anti-cancer cell activity. A pharmaceutical firm, Bristol Myers-Squibb, developed cis-platin for human use, working with the National Cancer Institute in early clinical trials to determine efficacy and toxicology, learning to avoid the drug's renal toxicity by vigorous hydration of the patient, and then conducting large scale clinical trials at academic medical centers under the supervision of the FDA.

The results have been spectacular. Early in the search for possible therapeutic targets, it was recognized that testicular cancers responded dramatically to cis-platin. While testicular cancer is a relatively rare cancer, afflicting approximately 5000 men annually, these individuals are usually young, 20 to 40 years of age. Before cis-platin, the death rate in advanced testicular cancer was high; less than 10 percent of patients survived for five years. Now, using cis-platin, usually in combination with other drugs or radiotherapy, over 90 percent of even advanced cases are cured. Equally important, cis-platin, in combination with other drugs, has been found to be beneficial against many other cancers, including carcinoma of the ovary, bladder, lung, head and neck, and esophagus.27

Progress in the development of anti-neoplastic drugs is useful only if the news is efficiently transmitted to those who deliver and consume the drugs. But how can the typical cancer patient or a busy oncologist expect to keep up with the flood of new and potentially helpful information about drugs such as cis-platin? The NIH now provides up-to-date results through the Physicians' Data Query (PDQ) system, available over the Internet, or through a telephone service (1-800-4-CANCER) provided by the National Cancer Institute. By accessing PDQ, for example, the potential user of cis-platin can find current recommendations, results of completed clinical trials, and lists of ongoing trials in language appropriate to either the general public or health care professionals. Our ability to maximize the benefits of biomedical research now depends on efforts to teach these consumers of medical information how to get appropriate information quickly through computer networks.

Surfactant and respiratory distress syndrome

During the first few moments of a newborn's life, a startling transition is made from floating in the liquid world of the womb to breathing air. Although infants born after a normal gestation adapt readily to the new environment, the transition is difficult for the half million infants who are born prematurely in the U.S. each year. Consequently, as recently as 1970, about ten percent of premature infants developed the respiratory distress syndrome (RDS), causing over 10,000 deaths per year.28

The lungs of premature infants are structurally underdeveloped and function poorly in the exchange of oxygen and carbon dioxide between blood and air. Examination of lung tissue from RDS infants by light microscopy reveals collapse of the alveoli. Early attempts to understand RDS focused on the possibility that immature lungs lacked elasticity. Then in the 1950s electron microscopists noted an unusual cell type, known as the alveolar epithelial cell type II,29 containing swirls of lamellar material destined for secretion into the lung alveoli. At about the same time, physiologists had begun to suspect that the basic problem was not lung elasticity, but a failure of immature lungs to maintain a low surface tension and hence prevent the collapse of alveoli. 30,31

This confluence of new observations and ideas led to the isolation in 1959 of an active substance, called surfactant, that reduces surface tension when it naturally coats the alveolar lining or when it is infused into immature lungs. Surfactant is produced late in gestation by type 11 epithelial cells, but inadequate amounts are present in the lungs of premature infants, accounting for RDS.32,33,34 By the early 1970s surfactant was found to be composed of phospholipids and a few proteins. Natural surfactants can be extracted from cows, pigs, and human beings and used for therapeutic application. Since 1989, synthetic surfactants composed of active lipids have also been available.35,36

Even before surfactant was available for administration, methods for intensive care of premature infants had progressed remarkably, especially with the introduction of continuous positive airway pressure for treatment of RDS.37 In addition, a crucial observation was made in studies of newborn lambs. Corticosteroids were shown to induce the production of surfactant in fetal lungs after administration to pregnant sheep.38 The new techniques for pulmonary ventilation, plus the occasional use of steroids to stimulate production of surfactant accounted for the steady decline of RDS mortality rate.39 After a period of little progress, the advent of surfactant therapy in the late 1980s further reduced mortality, from nearly 9000 deaths in 1972 to about 3600 in 1989, and significantly shortened neonatal hospitalization.

Despite these gains, over 2000 infants died from respiratory distress in 1994. Is a new generation of investigators on hand to solve the remaining questions about RDS? Dr. Joanna Floros, an associate professor of cellular and molecular physiology at Pennsylvania State University, illustrates some of the ingredients required to reinfuse scientific disciplines with new minds. Born and schooled in Greece, Dr. Floros had a long-standing interest in practicing medicine. However, exposure to laboratory experience as a college student in the U.S. and through an NIH graduate student fellowship persuaded her that she could also reduce human suffering by studying a clinical problem at the molecular level. She later became involved in RDS research while working at Harvard as a postdoctoral fellow with Dr. Mary Ellen Avery, one of the pioneers in this field. Dr. Floros and her own students are now facing some of the important questions remaining in RDS research. What is the role of surfactant-associated proteins? What are the genetic factors that make some infants more likely to suffer from RDS? Why does RDS occur more often in males and in the offspring of diabetic mothers?

Concluding themes

My purpose in telling these success stories has been to elucidate the elements critical for success. It is not difficult to measure the success itself -- a new ability to prevent disease, to detect it at an early stage, or to arrest or reverse the disease process. But we often fail to remember the ingredients necessary for such achievements: secure funding, collaborations, talent, live research subjects (both animals and patients), many scientific disciplines, and strong communication networks. Current pressures that threaten the support of science now demand that we emphasize these ingredients in various ways.

First and foremost, our country needs to reestablish an atmosphere for research in which well-trained investigators can work productively and confidently, pursuing their best ideas with reasonable prospects for financial support, safe laboratory facilities, modern instruments, and enthusiastic trainees.

Second, the public must be informed about the importance of animals and of human subjects in health research; only rarely does biomedical research have clinical impact without studies involving them. (At the same time, of course, we must continue to protect living subjects of research from unreasonable risk.)

Third, we must acknowledge and seek financial support for the broad sweep of health-related sciences required to make fundamental discoveries and bring them to clinical use, including the physics that underwrites instrumentation, the chemistry required for drug design, and the many relevant forms of biology.

Fourth, we need to paint realistic pictures of the slow tempos and complex modes of health-improving discoveries. The stories I have described were played out over many years and involved universities, private companies, and several government agencies. The consequences of policies that restrict such interactions or impair progress at any step, especially the early steps, may be felt only decades later.

Finally, we must remember that advances become meaningful to the citizens who supported them only if progress is widely enjoyed. As information about health becomes more complex, general use will require scientific literacy, enlightened exploitation of computers, and new ways to motivate our citizens to defend their health.

Fifty-four years ago, with Europe and Asia already at war, President Franklin Roosevelt began his speech at the NIH by saying:

"Nowhere in the world, except for the Americas, is it possible for any nation to devote a great sector of its efforts to life conservation, rather than life destruction .... All of us are grateful that we in the United States can still turn our thoughts and attention to those institutions ... whose purpose it is to save life and not to destroy it."

In the years since FDR's speech, these "lifesaving" institutions have multiplied and prospered, in the Federal, state, and private sectors; collectively they are one of the world's most cherished resources. Now we are largely at peace, but new problems threaten these institutions. Let us again "turn our thoughts and attention" to the preservation of their vitality.

• Vaccines against polio, hepatitis B and many other infectious agents
• Penicillin and many other antibiotics
• Recommendations for health-promoting diet and life-style, including simple means to lower the incidence of heart disease
• Replacements for many hormone- and vitamin-deficiencies
• New methods for contraception
• Tests to protect the blood supply from hepatitis B and C viruses and HIV
• New surgical methods, including organ transplantation and implantation of pacemakers and artificial joints
• Effective therapies for certain leukemias and cancers
• Drugs effective against mental diseases
• New therapeutics, such as blood cell growth factors, from recombinant DNA technologies
• in vitro fertilization methods
• Genetic testing for many inherited diseases

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