Prof. Dr. Bruce Beutler, Nobelist, Founder and Director of the Center for Genetics of Host Defense at Southwestern Medical Center, University of Texas
There will certainly be many opportunities for treatment as complex interactions between genes become apparent to us. The therapeutic approaches available to us at the moment are quite non-specific, for the most part. We try to treat inflammation using steroids, or cytotoxic drugs that eliminate immune cells indiscriminately. There is certainly much room for improvement.
Professor Beutler, as early as teenage you had clearly shifted your interest in research and science since during your summer recess you had been working in your father’s laboratory. How did the great scientific progress of your father as well as your involvement from an early age to research affect your future course?
My father was an inspiration and role model for me. He was someone with whom I could discuss science, and he gave me a chance to find out how much I enjoyed working in a laboratory. One might think his prominence in science would have been an impediment; that I would find myself perpetually standing in his shadow. However, I never felt that way about it. I was lucky to have such a teacher; one who clearly wanted me to succeed. From my pre-teenage years until I was fifty years old, my father and I often spoke about evolution, disease pathogenesis, genetics, and the history and philosophy of science. And we occasionally collaborated during those years.
In 2007 you undertook the post of chairman of the newly established Department of Genetics at the Scripps Research Institute. Tell us about the research you led to this important center. In which areas did you focus your interest?
My primary focus, then and now, was to use unbiased mutagenesis to discover genes of key importance in immunity. We began to perfect our use of mice as model organisms for this purpose during the years 2007 to 2011. New technologies for massively parallel sequencing began to make it possible to find the mutations responsible for immunodeficiency and inflammatory diseases more quickly. Indeed, we identified many genes with previously unrecognized roles in the immune system. We also found genes needed for regulation of iron absorption, hearing, vision, and neurobehavioral function. These findings were exciting, foremost because every one of them was a surprise. We could not have guessed the affected proteins had the functions they did. We learned by randomly damaging genes in the mouse seeing new diseases, and determining which mutation was responsible for each disease.
In 1986 you founded your own laboratory at Howard Hughes Medical Institute of Southwestern Medical Center of University of Texas. However, in 2000 the funding of your laboratory by the Howard Hughes Institute stopped. How important is funding for a researcher? To what extent did the lack of funding had an impact on your later research?
Funding is critically important, of course, and I was concerned at the time that my research might come to a halt. I was also dismayed that HHMI had failed to recognize the importance of what we had accomplished. We had discovered the LPS receptor, which many other investigators had sought over the decades without success. And by implication, other receptors in this family might be responsible for sensing most infections. Fortunately, many others were more insightful. Our work received accolades far and wide, and our discovery ultimately led to the Nobel Prize. I submitted a number of proposals to the NIH, and ultimately received far more funding than had been provided by HHMI. What did I conclude from this experience? The facts are all that matter, and one must not be perturbed if others don’t seem to grasp them right away.
Being the founder and director of the Center for Genetics of Host Defense at the Southwestern Medical Center of the University of Texas, please tell us about the purpose and goals of this important center which is in the forefront of the basic biomedical science.
We have sought to take ENU mutagenesis to an entirely new level. The search for mutations that cause phenotype used to be a slow and arduous process. Typically five years might go by between the observation of a phenotype and finding the mutation that caused it. In our laboratory (and at present, only in our laboratory), solving genetic problems of this kind has become an instantaneous process. When a phenotype is detected, its cause is discovered at the same time. We are also able to know precisely how much damage we have done to the genome over time. The rate of gene discovery has accelerated several thousand folds. Much more effort can therefore be dedicated to understanding mechanism: the issue of how and why a certain protein is essential for a given biological function.
Which are the factors that help a research center distinguish on a worldwide basis? How important is this distinction for the research center?
Leadership, the use of synergizing technologies, concentration of talent, strong institutional support, and not least, adequate funding all help to make research Centers excel. Those centers that steadily pursue an important problem, rather than trying to cause a sensation in several different areas, are also likely to make the greatest impact in the long run. Success begets success. The brightest trainees are likely to be attracted to a Center that is making real progress and opening a field. This falls under the heading of concentration of talent. So certainly, being known as the “best” in a certain area is something to strive for.
Why do you think the center’s orientation in the understanding of genetics can help in the treatment of infections and the understanding of disorders of autoimmune diseases?
Every living organism is a complex biological machine, and genetics gives us a list of the parts of that machine, or the smaller interacting machines that contribute to it. Genetics can give us a list of the parts of the immune system, for example, which is a machine within a machine. Those “parts” are proteins, and are the very cogs and wheels that make the machine function. When a person succumbs to an infection, it means that the immune system has failed in its primary function, which is to protect us from infection. Often, there is a clear reason for failure: a mutation that diminishes the efficacy of immunity, or a microbe that has evolved to exploit a vulnerability. On the other hand, when a person has an autoimmune disease, it means there is a failure of tolerance to self. Again, this may be caused by a mutation. Perhaps by more than one mutation. Perhaps by a particular environmental condition in conjunction with mutation(s). Understanding precisely what went wrong; i.e., why an infection killed the host, or why the immune system did so, is the first step in devising a truly specific treatment for either condition.
Why did you the last years draw your attention to the understanding of the immune system of the human body? How significant is the role of inflammations in the development of several diseases such as atherosclerosis, Alzheimer’s disease, obesity, diabetes, Crohn’s disease, asthma and multiple sclerosis?
Ultimately what we discover in mice is usually relevant to humans. About 98% of genes in mice have human homologues, and while there are occasional differences between human and mouse biology, the similarities greatly outweigh them. Our definition of inflammation has gotten to be quite broad in recent years. It has gone beyond the classical description (rubor, tumor, calor, dolor) to focus on the molecules important to the classical description. Transcription factors such as NF-κB, cytokines such as IL-1 and TNF and the interferons, adhesion molecules, and other components of the classical inflammatory response, have been found to be active in pathologic processes we would not formerly have thought to be inflammatory. Are atherosclerosis, Alzheimer’s disease, and obesity really examples of inflammation? Perhaps yes; perhaps it depends upon one’s definition. In the end, the question will not matter so much: what will matter are the molecular facts.
Is there hope for the treatment of the above mentioned diseases by understanding the immune system? Could we talk about a selective therapeutic intervention in these diseases?
I tend to be optimistic in answering such questions, partly because I am amazed by the historical record of progress in medicine. With that caveat, my answer to both questions is yes. Many of the diseases mentioned above are not single diseases, of course. There may be many molecular defects that present clinically and radiographically as what we call “Crohn’s disease.” But in the long run, knowledge of the causative molecular defects may lead to much more specific therapies than are presently at our disposal. Here too, genetics will influence our progress. Many diseases are fundamentally genetic but complex in the sense that a facilitating (disease-promoting) mutation may operate in one genetic background but not in another. A second mutation, or potentially a certain drug, might suppress disease. There will certainly be many opportunities for treatment as complex interactions between genes become apparent to us. The therapeutic approaches available to us at the moment are quite non-specific, for the most part. We try to treat inflammation using steroids, or cytotoxic drugs that eliminate immune cells indiscriminately. Or we block much of the immuno-inflammatory response with cytokine inhibitors. There is certainly much room for improvement.
The Center mainly focuses in biochemistry, cell biology and molecular biology, to understand the mechanism by which specific mutations produce specific phenotypes. Which are the conclusions you reached? What is newest information available about the study and research of the above data?
We have had many successes in understanding mechanism. One example, recently published, might be a good illustration. We found a mutation that prevented activation of the NLRP3 inflammasome, one of the key protein complexes that causes inflammation in response to many stimuli by processing interleukin-1β, an inflammatory cytokine, to an active state. When our work was initiated, we knew of just three protein components of the inflammasome: NLRP3 itself, a second protein called ASC, and a third called CASP1. The mutation revealed a fourth component: NEK7. NEK7 was formerly known as a protein kinase active in cell division. But it apparently has a dual life. We discovered that it binds tightly to NLRP3, and this is necessary for the inflammasome to assemble. This was one of many instances in which genetics identified a new part of the inflammatory machinery, and mechanistic studies clarified exactly where that new part fit. What can be done with this knowledge? As mentioned above, there is a real hope that one day, perhaps with greater structural insight, we might target the inflammasome with drugs to prevent its activation, and do so much more selectively than we can at present.
Do you think the Center for Genetics of Host Defense at Southwestern Medical Center at the University of Texas operates as a nursery for young researchers and scientists? How important is for the evolution of the center its collaboration with leading scientists and the creation of programs and partnerships with other centers?
Maybe the word “nursery” is a bit more infantilizing than I would like! A lot of independence and responsibility is expected of all the trainees. But most certainly the Center does help young researchers learn, discover, and become creative. A trainee at the Center must work diligently, but he or she will soon be using genetics at a high level, and will make discoveries that can be of great importance. Trainees must also learn to communicate effectively. After all, science is a competition of ideas, and one must be able to express one’s self clearly and sometimes forcefully. Because we can’t be expert in all areas, we definitely collaborate with other laboratories, institutionally, nationally, and internationally. One example that comes to mind is our longstanding collaboration with the laboratory of Professor Dale Boger at The Scripps Research Institute, in the development of drugs that target Toll-like receptors, activating or inhibiting them. A good collaboration is driven by a genuine need, felt by each of the parties.
Professor Beutler, having received significant distinctions and awards throughout the course of your career –the top distinction being the Nobel Prize in Physiology and Medicine which you obtained in 2011 together with Jules Hoffmann and Ralph Steinman for your revolutionary discoveries concerning the activation of innate immunity– we would like you to share with us whether these distinctions provide you with an incentive to continue your research or, do they generate an added stress and a responsibility towards the community.
The Nobel Prize has indeed given me fresh incentive and also greater resources to pursue scientific questions. It also came with added stress and distractions, and greater responsibilities. But for the most part I welcome them. It is good to be in an advocate for science if one has a chance to do so. Who will make society understand the importance of science if we ourselves are silent on the matter?
