The President's Address: Clinical Investigation is a Pathway to Discovery

Sydney Brenner was a keynote speaker in a celebration of Max Delbruck held at Vanderbilt University. The advance program listed the title for his talk as “The Next 100 Years of Biology.” Sydney Brenner had won the Lasker Award in 2000 for the characterization of mRNA and elucidation of its function together with Francis Crick. In 2002, he received the Nobel Prize in Physiology or Medicine “for his work on the control of organ development and programmed cell death.” These discoveries were derived from his pioneering genetic manipulation of C. elegans. This work reflected his strategic approach to inquiry that repeatedly placed him in the vanguard of science. Accordingly, in advance of his talk there was keen anticipation of and much speculation about his view of the next century of biology.

It was a brilliant lecture. In essence, he said that the time is ripe for the great discoveries in biomedical science to be made in the investigation of human biology and disease. I was delighted with this prediction, as always is the case when someone agrees with you.

Sydney Brenner's prediction of the future of biomedical research is quite in contrast with the prevailing view of clinical investigation in which it is portrayed as a participant in a one-way flow of scientific progress that originates exclusively from reductionist research at a molecular and cellular level. In that paradigm, the contribution of clinical research is to translate that knowledge into advances in therapy and diagnosis. This unidirectional flow of science is an impoverished concept.

The conceptual framework for biomedical science that fits Sydney Brenner's prediction is depicted in the Figure 1.

Fig. 1.

A conceptual framework for biomedical science.

The nexus of progress in biomedical science is the hypothesis, and the acquisition of fundamental new knowledge that engenders hypotheses is derived from both non-clinical research and from clinical investigation. This is a dynamic conceptual framework for progress in biomedical science in which translational research is bidirectional. We may consider a few of the discoveries that exemplify and validate this concept.

In 1985, the Nobel Prize for Physiology or Medicine was awarded to Michael S. Brown and Joseph L. Goldstein for “their discoveries concerning the regulation of cholesterol metabolism.” The prize recognized their discovery that the LDL receptor was a key regulator of cholesterol biosynthesis. Subsequent to that discovery, they proceeded to elucidate the mechanisms whereby this receptor controlled cholesterol homeostasis. That has led to further discoveries of broad importance to biology, including receptor endocytosis, the sterol regulatory element binding protein, regulated intramembrane proteolysis, and the suite of proteins that bind cholesterol and control regulated intramembrane proteolysis.

It is the inception of this cascade of discoveries that demonstrates the pivotal importance of the investigation of human disease (1, 2). At the time, regulation of cholesterol biosynthesis was being studied in the liver of experimental animals. The strategy of Brown and Goldstein, however, was that the investigation of heritable hypercholesterolemia in humans could elucidate the regulation of cholesterol biosynthesis. Accordingly, they invested in the development of a human fibroblast model for investigation of the regulation of HMG CoA reductase activity, in which they had evidence that cholesterol taken up into the cell controls the activity of this enzyme. Upon learning that a patient with homozygous hypercholesterolemia was about to have surgery in Denver, Mike Brown immediately flew there to obtain the tissue that would yield fibroblast cultures. This young patient had had her first myocardial infarction at age 11. Investigation of fibroblasts from that patient demonstrated that the inhibition of HMG CoA reductase activity by LDL seen in healthy individuals was totally lacking in that patient.

This seminal discovery derived from conception and implementation of a strategy based on the principle that investigation of human genetic disorders can yield fundamental biological insights.

The discovery of DNA by Oswald Avery revolutionized biology. The research leading to this discovery originated in investigations of Avery and Dochez into the basis for the immunologic diversity of pneumococcal strains obtained from their patients in the Hospital of the Rockefeller Institute. They found, to universal surprise, that both the selective immunogenicity and the virulence of pneumococci were determined by their polysaccharide capsule. After Fred Griffith in London found that a substance extracted from a virulent strain of pneumococcus could transform an avirulent unencapsulated strain to a virulent encapsulated phenotype, Avery began research first to isolate and then to characterize this “transforming factor.” Work over an 11-year period (with no publications during this interval) yielded proof that DNA was the factor conferring a virulent phenotype on avirulent pneumococci. Joshua Lederberg, in his paper, “The Interface of Science and Medicine,” (3) stated that the characterization of DNA by Oswald Avery would not have been “performed except in the context of clinical observation.”

In 2005, the Nobel Prize for Physiology or Medicine was awarded to Barry Marshall and Robin Warren “for the discovery of Helicobacter pylori and its role in gastritis and peptic ulcer disease” (4). Before their discovery, medical students were taught that peptic ulcer was the result of stress. This view also dominated the public's concept of peptic ulcer, as exemplified by President Truman's comment that a member of his government was “a one-ulcer man in a two- ulcer job.” Following Robin Warren's observation of curved bacteria in the gastric mucosa of patients with gastritis, Marshall joined him in a series of investigations that fulfilled Koch's postulates in establishing that these organisms, Helicobacter pylori, are etiologic in peptic ulcer and gastritis. They demonstrated that duodenal ulcer was almost always associated with the organism and succeeded in the culture of H. pylori. After great difficulty in creating H. pylori infection in piglets, Barry Marshall ingested cultured H. pylori and developed nausea, vomiting, achlorhydria, and histologic evidence of gastritis which was cured with antibiotics. After their finding that bismuth, a known anti-ulcer agent, killed H. pylori, they then demonstrated that bismuth cleared H. pylori in patients with ulcers and produced sustained ulcer remission. These findings in concert led to several controlled clinical trials demonstrating that antibiotics combined with proton pump inhibitors eradicated peptic ulcer. The clinical investigations of Marshall and Warren provided fundamental insights into the mechanism of peptic ulcers, and led to a paradigm shift in the reductionist research aimed at further understanding this disease and gastric cancer.

John Vane received the Nobel Prize for Physiology or Medicine in 1982 for his discovery of prostacyclin and the mechanism of action of aspirin and the non-steroidal anti-inflammatory drugs. Perhaps an even greater contribution to medicine was the discovery by his group that the venom of Barthrops jararaca inhibited the conversion of angiotensin I to angiotensin II. They isolated and characterized the active inhibitor peptide, which was then synthesized by scientists in the Squibb Institute. However, the prevailing opinion at the time was that a peptide could not be the basis for an orally administered antihypertensive drug and there was doubt that angiotensin II contributed to essential hypertension. This discouraged Squibb management from considering this to be a basis for drug development. John Vane, a consultant to Squibb, encouraged them to make the intravenous formulation of the peptide available for a proof-of-concept investigation in human hypertension, and John Laragh then demonstrated that this inhibitor of the angiotensin converting enzyme lowered blood pressure in 70% of hypertensive patients (5). With this identification of a clear and important therapeutic target, David Cushman and Miguel Ondetti at Squibb proceeded to synthesize captopril (6). This not only opened the field of successful inhibitors of the renin-angiotensin system for treatment of hypertension, but also demonstrated for the first time that a small molecule could be synthesized that mimicked the pharmacologic effect of a peptide. In contrast to the conventional view of drug development in which demonstration of efficacy in an experimental animal was requisite for proceeding to human investigation, this illustrated the paradigm in which investigation in humans could provide the essential evidence upon which drug development was based.

The molecular basis for chronic myeloid leukemia has derived from the discovery of Peter Nowell and David Hungerford in Philadelphia that a “minute chromosome was found in cells cultured from the blood of patients with this particular form of leukemia” (7). Subsequently, Janet Rowley demonstrated that this short chromosome resulted from a t(9; 22) translocation (7).

The discovery of this chromosomal defect provided a hypothesis for studies that have demonstrated that this translocation results in the fusion of the Ableson leukemia virus gene on chromosome 9 with the breakpoint cluster region on chromosome 22, yielding the fusion protein BCR-ABL. This protein contains a constitutively active tyrosine kinase that engenders neoplastic transformation (7). With this molecular understanding, a relatively selective inhibitor of the tyrosine kinase, imatinib, was shown to produce both clinical and molecular remission in patients with chronic myeloid leukemia (8). The mechanisms of the molecular evolution of resistant clones and strategies for overcoming such resistance will be discussed by Charles Sawyers in the Gordon Wilson lecture.

Thus, clinical investigation in patients with chronic myeloid leukemia engendered research elucidating a molecular basis for this disease and a promising approach to its treatment. This development of a treatment for neoplastic disease with agents directed at a specific molecular target heralded the opportunity for novel approaches to cancer pharmacology in general, based on neoplasm-specific molecular abnormalities.

These few compelling examples illustrate the power of clinical investigation to provide fundamental insights into human disease that then generate novel hypotheses for reductionist inquiries, illuminate pathophysiology, and identify rational targets for drug development.

The potential that clinical investigation will yield important discoveries in the future is enormous. This prediction is in the context of the magnitude of ignorance about human diseases and the powerful research tools now available to support the research.

As an example, the prospect for discovery through research on human neuropsychiatric disease is clearly articulated in the perspective article “The Future of Psychiatric Research: Genomes and Neural Circuits,” written by Huda Akil, Sydney Brenner, Eric Kandel, Kenneth Kendler, Mary-Claire King, Edward Skolnick, James Watson, and Huda Zoghbi (9). To address the molecular basis for schizophrenia, autism, bipolar disorder, and depression, they propose analysis of the complete genomes of patients integrated with characterization of modified neural circuitry by approaches such as diffusion tensor imaging. Given the genomic complexity of these diseases, more trenchant understanding is most likely to come from linking the genomic discoveries to pharmacologic tools that address these molecular targets.

This proposed approach to understanding psychiatric illnesses based on research on these diseases in humans merits our consideration in part because of the scientific achievements of the authors of the proposal. Given the scientific accomplishments of the members of the ACCA, our individual views on the opportunities for discovery afforded by the investigation of patients encompass similarly attractive conceptual approaches that take advantage of the scientific tools now at our disposal.

The challenges in the path of the clinical research enterprise are not small. Success in the recruitment, training, and encouragement of the next generation of clinical investigators will reflect the efforts of this group, both personally and in our leadership roles. An inspiring example is Joe Goldstein who, as a medical student, initially aspired to be a neurosurgeon. He was encouraged by Donald Seldin to obtain training that would prepare him for a faculty position in Medical Genetics. He proceeded, as a Clinical Associate at the NIH, to obtain research training with Marshall Nirenberg who had just discovered the genetic code, and subsequently was a Fellow in the Human Genetics program with Arno Motulsky at the University of Washington before returning to the University of Texas Southwestern as Director of the Medical Genetics program in Medicine. Robert Lefkowitz as a medical student also was aiming to practice medicine until he came under the influence of Paul Marks and Dickinson Richards as his Attending Physicians.

When James Shannon first became Director of the National Heart Institute, among his very first acts was to visit several leading residency programs to recruit Clinical Associates for the Institute. Among that group of recruits were James Wyngaarden and Donald Fredrickson, both of whom became Directors of the NIH. It is telling that among the press of responsibilities facing a new Institute Director, the recruitment of physician scientist trainees was a top priority.

I would not venture a recipe for overcoming the current obstacles to recruiting promising physicians-in-training into research. Rather, if we could emulate James Shannon in only one way, it would be to give priority to recruitment and training of future clinical investigators. Placed at a high priority, the creativity and ingenuity of this group certainly can implement strategies for leading a talented group of new scientists into productive clinical research.

Successful clinical research is firmly grounded in the fundamental sciences, both in its conduct and in the training of clinical investigators. The concept of such interdisciplinary research and training is highly touted. However, implementation of this concept in the modern university is unlikely to be accomplished only by articulation of its merits; it requires clear administrative intent and corresponding action. Discovery-oriented research on human disease thrives in institutions that value interdisciplinary research.

Oswald Avery's discovery of DNA took place in the fertile scientific environment of the Rockefeller Institute in which no departmental structures separated the scientists. The concept of the Rockefeller Institute was novel at the time; it was deliberately planned to conjoin a research hospital with the laboratories of a multi-disciplinary group of scientists. The NIH Clinical Center was organized similarly. These models cannot be exactly replicated in a university medical center, but the principles can be implemented by creative planning and leadership. The development of centers and institutes that bring together scientists from across the spectrum of departments and the promotion of cross-disciplinary training are among the strategies. At the heart of these efforts is the recruitment and encouragement of faculty members who view the scientific enterprise with an enthusiasm that knows no departmental boundaries.

Supplementing the efforts of institutions to invigorate interdisciplinary research are the Clinical and Translational Science Awards (CTSA) from the NIH that provide a cross-disciplinary research infrastructure. This includes the Clinical Research Centers that serve a function analogous the Hospital of the Rockefeller Institute and the Clinical Center NIH. The CTSAs have the additional advantage of extending the support of clinical research into the entire scope of university hospitals, and providing the research cores that make available to clinical scientists a range of technology that is beyond the scope of any single investigator's department or laboratory.

The preeminent evolutionary biologist, E.O. Wilson, makes a strong case for building intellectual bridges between disciplines in his book, “Consilience” (10). Consilience, a felicitous interaction between disciplines occurring at the organizational and personal levels, certainly provides a conceptual framework for the fusion of clinical investigation with the fundamental sciences in the university.

Consilience also is the hallmark of the American Clinical and Climatological Association. Bringing together investigators from different disciplines, it engages us with a broad scope of scientific approaches, concepts, and technologies. The scientific enrichment derived from communication between specialized areas of science is clearly one of the attractive features of the association.

In conclusion, efforts to promote clinical science in academic institutions and at the national level will be most successful when conceived within a dynamic conceptual framework that encompasses its central contributions to progress in biomedical science. Vital to translation of preclinical hypotheses into safe and effective therapy, clinical investigation also generates fundamental new knowledge that informs the pathophysiology and treatment of disease and provides novel hypotheses that engender reductionist research. In that paradigm, clinical investigation is a basic science.