Questions and AnswersProf. Dr. Bruce A. Beutler

How or why did you become involved in infection research, what fascinates you about this subject?
As a child, I read “The Microbe Hunters” by Paul de Kruif.  It kindled my interest in infection research, as it told the dramatic story of the discovery of germs and their role in infectious disease.  In college, I learned about endotoxin (lipopolysaccharide; LPS), from Abraham Braude, a pioneer who sought to use of anti-LPS antibodies to treat endotoxic shock.  And in medical school, I saw serious infections first-hand.  Microbes always interested me, partly because of their terrible destructive power.  But the other side of the coin is equally fascinating:  the tremendous intricacy and beauty of the immune system, which evolved to defend us against microbes.

What are you working on at the moment?
We are trying to characterize the “resistome,” those genes encoding proteins that make a life-or-death difference when one is infected with a particular microbe.  The big question is:  how do these proteins all work together to assure our survival?  We are presently concerned with the resistome for mouse cytomegalovirus (MCMV):  a member of the Herpesviridae family.  It is harmless to mice when given in a small inoculum.  But mutations in many host genes (several hundred or even a thousand or so) can make it deadly.  By making germline mutations at random using the chemical mutagen ENU, we have found many of the genes that are critical to survival during infection, and we can begin to make an inferential “picture” of how resistance is exercised.

What were the turning points in science, in career, in life that influenced your decisions?
There are several that come to mind.  During my teens, I first became familiar with research in the laboratory of my father, Ernest Beutler, and in the laboratory of Susumu Ohno.  Both of them were distinguished biologists, and this was a great privilege for me.  In college, I had an early introduction to classical genetics from Professor Dan Lindsley, also an extraordinary teacher who influenced me greatly.  Medical school clearly shaped my career as well.  In fact, I don’t practice medicine today.  But physiology, pharmacology, and pathology are much more real to me than they would be if I had not been taught medicine.  Most important of all, in the early 1990s, I “rediscovered” genetics in my own research.  This was a major departure from the path I had been following.  If I hadn’t taken the genetic road, I would have gotten nowhere at all with my work.

What was a single most important moment of your career?
There were two related moments, one following quickly upon the other.  For nearly five years, we had been searching for a mutation that made mice of the C3H/HeJ substrain insensitive to LPS, sequencing millions of base pairs of DNA and looking for the homologies within EST databases to identify gene candidates.  The first moment came when I recognized that the Toll-like receptor 4 gene (Tlr4) was in our contig.  This caused instant tachycardia and hyperventilation, because I realized that TLR4 was homologous to the highly inflammatory IL-1 receptor, and to Toll, which had a defensive function in Drosophila.  The second moment came a few days later when I saw the single nucleotide change in Tlr4 that caused LPS resistance.  I went back to look at the trace file over and over again, partly for the sheer pleasure of seeing it, and partly because I almost thought it might be a dream.

What was your most important scientific discovery?
There were two discoveries with tight conceptual linkage to one another.  In 1985, I isolated mouse tumor necrosis factor (TNF) by following a non-classical TNF activity and in so doing, discovered that it was a key mediator of endotoxic shock (and by implication, many forms of inflammation).  I then used TNF production as a readout to positionally clone the LPS receptor, and in 1998, found that receptor to be TLR4.  This was the work that first revealed what Toll-like receptors do.  They act as the innate immune system’s key sensors of infection, and trigger the inflammatory response.

What drives you and carries you on? What do you love about your work?
To be a scientist is to be an explorer and to see things that no one has seen before.  It is also to reach new understandings, never held before.  When I go to work each day, there is a reasonable chance that a new phenomenon or a new understanding will be waiting for me.  A strange exception to the norm may have been observed among our mice, or a mutation causing such an exception may at last have been tracked down.  There is immense satisfaction in this, and it creates a tangible bond to all scientists and explorers in all times. One knows exactly how they must have felt (and how those of the future will feel).

What influenced and impressed you and your life and therefore science?
Music is extremely important for me:  especially the music of Bach.  Here too is a bond:  what we feel when we hear Bach is surely what he felt and intended us to feel.  His music captures all of the moods of science:  the inevitable disappointments; the gratification of honest toil and steady progress; the sheer joy and excitement of sudden illumination.  It surely influences my life, and provides a perfect accompaniment to my work.

Is there a leading motif / a saying that accompanied your life?
“Who dares wins.”  Or “nothing ventured, nothing gained.”  Or “no guts, no glory.”  I have used each of these fairly often.

Idols?
Bach, because he invented (whereas most scientists discover), creating works of great beauty and order out of absolutely nothing.  Mendel, because he deduced the particulate basis of heredity… and why on earth should he even have thought to look into the matter when it was so obvious that inheritance was caused by “mixing of the blood,” and that dogs begat dogs while humans begat humans?  And Einstein, because he too deduced principles that were so far from what was assumed, and because beyond his passionate devotion to science, was by most accounts a kind and gentle person.

What would you recommend to someone starting out in science? What would be your advice for young scientists?

1. Remember who you are:  a scientist and therefore an explorer.  Study a phenomenon that is mysterious and important and do not form a question that is “safe,” promising incremental gain.   To quote Einstein on the subject:  “I have little patience with scientists who take a board of wood, look for its thinnest part, and drill a great number of holes where drilling is easy.”
2. As best you can, avoid hypotheses and their attendant biases.  Much of science is observational, and in biology, great progress can be made by starting with a phenotype and finding its cause.
3. When you must use a hypothesis, do not be afraid to do so, but remember that a hypothesis is only a tool, and does not reflect on you, so you shouldn’t get emotionally attached to it. Try ardently to prove that your hypothesis is wrong.   Never try to prove that that it is right.
4. Further to this last point:  remember why you are a scientist and be irreproachably honest in your work. There is no point to being a scientist if you are not.

What would have been your alternative plan (plan B) if science /your job had not worked out?
I would have been a naturalist, a writer, or both.

What are your dreams for the future?
I hope for a day when a new question will occur to me that no one else has thought to ask, just as it was with my idols. And I dream of answering that question, and seeing the world in a new way.

What do you think is important and should be worked on in the future?
In the field of innate immunity:  what are the protective mechanisms that we have, and what are the mechanisms that we lack?  I refer to the latter category as “latent innate immunity:” host defense mechanisms that can be created through mutagenesis.  These may lead us to new horizons of understanding.

In the wider world of biology:  just why are we self-aware?  Who is watching the television screen in there?  Though I must admit I have no real insight into the answer.

What do you do when you are not working?
I enjoy hiking (often with one or more of my three sons), listening to music, and talking with friends and family: sometimes with a cup of coffee, a bottle of wine, or a nice dinner.  But science is never out of my mind for long; it is really my life.

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