Molecular and Experimental Medicine

Chairman's Overview

Ernest Beutler, M.D.

Having completed 25 years of service at TSRI, I view this silver anniversary Chairman's Overview as an appropriate time to look back to see what has changed -- both for the better and for the worse.

I arrived at the end of 1978 to chair the Department of Clinical Research of The Research Institute of Scripps Clinic (RISC) and to head the Division of Clinical Hematology at Scripps Clinic. At that time both the Scripps Clinic and the Research Institute were components of Scripps Clinic and Research Foundation. The Department of Clinical Research was staffed by less than a dozen faculty members, distributed into research groups in hematology, immunology, and endocrinology. They seemed to me to be quite dispirited, and at the time of my first meeting with the existing faculty I could not help but be aware of the disappointment some of them felt when I did not agree that more frequent faculty meetings was what the department needed. Yet, there were some excellent scientists in the Department or soon to join it, and all they needed was encouragement and support. Among them were Dennis Carson, Frank Chisari, and the late Ted Zimmerman. The quality of our faculty was further enhanced when the then existing Departments of Biochemistry and Cell Biology were amalgamated with the Department of Clinical Research to form a new department, designated Basic and Clinical Research. There were some, of course, whose fortunes lay elsewhere. Dr. William Vanderlaan received a substantial gift from the Whittier Foundation, and was able to form his own Institute, which today functions on the grounds of the Scripps Memorial Hospital. Shortly thereafter we had the opportunity to recruit Dr. Floyd Bloom, now chairman of the Department of Neuropharmacology. At the end of last year our Department faculty consisted of 44 full-time faculty, 15 of them full professors; there were 54 adjunct faculty. Six of our faculty members (four of them full-time) had been elected to membership in the National Academy of Sciences.

While our Department was changing there were major changes in science as well. Powerful new techniques became available. Whereas 25 years ago milligrams of protein had to be purified laboriously to obtain partial sequence information, a speck of protein on a filter or gel now suffices for complete identification. Twenty-five years ago the key to finding the mutation in a protein was to isolate the protein and to sequence it. Now, DNA from peripheral blood or any organ provides that information using largely automated techniques that high school students can perform. Any gene can be destroyed in a mouse, or a new gene placed into its cells. And, partly as a result of application of these techniques, some of our notions of unity and order in biology have been shattered. Nature, it turns out, is even more complex than we had imagined. Long before I came to Scripps I harbored the idea that as we better understood biologic phenomena they would become simpler to comprehend. Perhaps some are, but as more knowledge accumulated it became clear that biologic systems were even more complex than had been anticipated. The reason, it seems to me, is that evolution drives organisms to an optimal state, but a state that can be achieved in many different ways, and chance does not always choose the simplest or even the best route. Often it may simply be that one road was started to solve a problem, and it was more favorable to the species to remain on that road than to take another possibly better one. Any mechanism that works may be chosen. A central paradigm of biology avers that all information required to make an organism is encoded in DNA, and that this is then transcribed into RNA, which , in turn, serves as a template for protein synthesis. But we are beginning to realize that this is only a part of the answer -- a simplification. Genes may be modified, for example by methylation of DNA or changes in histones, so that transcription is either enhanced or is blocked. This modification may differ from individual to individual, and may be influenced by environmental factors or may be stochastic. Moreover, RNA may be spliced in different ways. It may be "edited", changing its sequence. Even the code is not sacred. Under some circumstances "stop" codons may encode selenium cysteine and translation does not always start with an ATG codon.

The recognition of increasing complexity of biologic processes has spawned a fundamentally new approach to attempting to understand the phenomena that confront us. Instead of the hypothesis-driven research with which all of us grew up in science, "fishing expeditions," once derided and non-fundable, have come into fashion. Modern technology has now made collection of vast amounts of data possible. Used properly, of course, tools such as microchips that can measure the transcription of thousands of genes simultaneously can facilitate research, and are becoming widely used in our Department and by scientists throughout TSRI. For example, in our study of the apparent stimulation of hepcidin transcription by HepG2 cells, we needed to know whether the effect depended on the stability of the mRNA. A chip-based experiment using cells incubated with and without an inhibitor of transcription gave us an answer in a fraction of the time that would have been required using the conventional techniques of molecular biology. But careful experimental design is still essential. Mixtures of different cell types are sometimes used, but are unlikely to yield results that will be useful. Some scientists hope or even believe that some sense can be made out of vast amounts of data, pinning their hopes on the skills of a biomathematician to bring order from chaos. Perhaps some such ventures will pay off, but the old principle GIGO (garbage in, garbage out) is still valid.

And, of course, transcription is not the whole story; translation and post-translational modifications may orchestrate regulation of cellular processes. This is where the modern proteomic approaches may prove extremely useful. Enormous advances in the recognition of proteins using minute and often impure starting materials have been made in the past quarter century, but much still needs to be done. We have established a proteomics facility in the department that is being used to solve a variety of problems. For example, Bruce Torbett and colleagues have used this technology to delineate the role of the PU.1 transcription factor in regulating monocyte and macrophage development and function, identifying 47 proteins that were differentially expressed and regulated and tied to development and function.

The advances in our ability to perform laboratory research have progressed on many fronts in the last 25 years. But progress in clinical research has been much less even. One of the great impediments has been the establishment of unnecessary barriers to the performance of clinical studies, based on ill-conceived attempts to rectify isolated abuses. Particularly burdensome, and, in my view unnecessary, are the many regulations regarding issues of privacy and consent in situations where there should no real concerns. For example, it requires months of paperwork to collect a urine sample from a patient, no matter the reason or the disease, or even from a normal subject. Surely there are ordinarily no privacy issues here. I dealt with this issue in some detail in my 2002 Chairman’s Overview, and matters are no better now. Another problem is the congressional mandate that requires research subjects to reflect the national balance of ethnic groups and of gender. These regulations are particularly inappropriate because they do not take into account the fact that some groups are under-represented because they do not wish to participate in clinical research. That, of course, is their right. But investigators are, nonetheless, exhorted to be all-inclusive in their patient distribution and threatened with loss of grant support if they do not achieve the proper quota. Moreover, even a novice investigator understands that a homogenous group of treated subjects and control subjects is more likely to give a useful answer than two heterogeneous groups. Yet, national politics has decreed heterogeneity.

The regulations that have proliferated in the last 25 years tend to discourage those individual clinical scientists who could perform important clinical studies. Companies have the resources to comply with complex regulations. Individual investigators and with non-commercial motivation and meager support do not. The fear of litigation, all too common in our society, makes institutions like ours think twice before allowing potentially valuable products made in our own laboratories to be tested in a clinical setting. Finally, the changing economic circumstances of practicing physicians has made it increasingly difficult for them to participate in clinical research. In the latter regard, we are fortunate that the Skaggs Clinical Scholar Program has helped us overcome this problem, and at Scripps we are again seeing more practicing physicians involved in investigator-initiated clinical research. But looking back over the past 25 years, I must confess that what we have achieved in furthering clinical research has fallen short of my hopes.

The future is more important that the past, for the past is over. I believe that over the next quarter century basic biomedical research at TSRI and elsewhere will flourish. The new technologies now available will be improved, others will be developed, and importantly, scientists will attain a more realistic perspective of how they should best be applied. It is difficult to predict whether the ever-growing base of knowledge can be applied more successfully to humans in the next quarter century than in the last. To do so will require society to achieve a better balance between the protection of the individual and the good of society. Perhaps, as the public begins to realize the scope of the impediments that prevent application of science for the good of man, a reasonable balance will be achieved and more progress will be made.