Bruce Beutler and Jules Hoffman: A monk and a gambler

It all started with their fathers’ interest in science and nature.

“My father was a researcher and often took me to his lab. I was very comfortable in that environment and conducted my first scientific experiment when I was in my teens. Then I just kept on going, first I went to medical school and then on to conduct biomedical research,” says Bruce Beutler.

He goes on to explain that he has always been intrigued by the endotoxin receptor, which triggers the immune system. “That interest has gotten me where I am today,” he says, leans back and smiles. 

Jules Hoffman also worked as a student with his father, who was an entomologist, and he became fascinated by insects. “Do not forget that they comprise 80 percent of all species, destroy one third of crops annually and put one third of the human population at risk by transmitting diseases,” he says, emphasizing the importance of the creatures that many might find a strange choice for studying the immune system.

On to something big

Both Laureates claim that their research was entirely curiosity driven. Jules Hoffman was intrigued by the fact that insects are resistant to most microbial infections and wanted to identify a weak spot in order to find a way to defeat them. Bruce Beutler had noticed a particular mutant mouse strain that could not recognize the endotoxin LPS and wanted to identify the responsible genetic region. In the early days neither of them had any idea that they were about to discover the principle behind innate immunity.

“We just worked our way through the system. When we got to the signaling cascade we started to think that we were on to something,” says Jules Hoffman. 

Bruce Beutler gives an account of the endless sequencing experiments in the late 80s and 90s when the technology was still in its infancy.

“We ran everything manually, from casting gels to reading and comparing the sequences. When we were done with about 90 percent of the region we got really scared – this is the kind of project where human error is common.”

On top of the feeling of having missed the needle in the haystack the funding for the project was also running out. Nevertheless Bruce Beutler and his colleagues felt the pressure to continue and finally found what they were looking for.

The power of evolution

Beutler and Hoffman were surprised when they noticed that they had basically identified the same mechanism, but in quite different species, namely in the fruit fly Drosophila Melanogaster and in the mouse.

“We really did not expect these so completely different organisms to be so alike. I guess we were ignorant to the power of evolution,” says Hoffman and laughs.

Since almost all genes in mice have an orthologue in humans they quickly understood that the same mechanism must also exist in man.

Molecular methods past and present

Bruce Beutler’s approach to sequence the region of interest took five years, from 1993 to 1998. Sequencing methodology has undergone rapid development and nowadays he could get the same results within a week at most. If the precise region to look at is know, results could even be available within a couple of hours.

“As we are speaking one million base pairs are sequenced in my laboratory per second,” he says proudly, referring to his newly build lab at UT Southwestern in Dallas. Hoffman also points to the development of molecular methods during the last 50 years.

“The techniques now are so powerful. There is almost no question that you cannot attack methodologically. The key to success is instead to have a good idea, ask a good question and have the courage to tackle it. Then you need the right funding of course,” he says and almost immediately adds that despite the common complaint of the scientific community, there has never been more money for science than now. “But more people are in the system and not everybody will succeed.”

Bruce Beutler nods and shapes a triangle with his hands. “The academic system is a pyramid and not everybody will make it to the top. Things are tough, the reaction should be to work harder and not complain about it.”

A monk and a gambler

Long hours, bad pay and months without reasonable or – even worse – contradictory results. What made the Laureates stay in research?

“I think that conducting science is very much like entering a monastery. You have to believe, be ready to accept difficult times and work hard. It is a lot about believing, working and maybe even praying,” says Jules Hoffman.

Bruce Beutler uses another analogy. “I would rather think of researchers as gamblers. You just get addicted to it and cannot give up. After having made certain investments you just have to continue, whatever impossible thing it is that you have set out to do.”

Big groups lead to big achievements

Intellectual brilliance and hard work are not enough. These need to be placed in an environment where they can perform to best effect. Both Laureates believe that their big research group has been one of the key factors in succeeding.

“We have been up to fifty people working together on one central goal simultaneously – to find out what makes the insect resistant. Everybody has contributed with their specific competence. None of them could have made it on their own,” explains Jules Hoffman. 

Bruce Beutler was inspired by the group dynamics of the Hoffman lab and built up a similar team. His new lab was inspired by his long experience and over time he has also adjusted to the new requirements. The fast development within sequencing technology imposes demands for computational competence, for example. Beutler is currently building up a centre for the genetics of host defense, extending his group instead of cutting down. Hoffman describes his plans as a little less ambitious, but nevertheless aims at interaction and association of groups that have the same scientific interest but different approaches.

“I will put some energy into helping the next generation,” he says, looking modest.

Life after the Nobel Prize

Although having received several scientific prizes during the last few years neither of the two Laureates saw the Nobel Prize coming.

“Of course, in hindsight one could say that I should have suspected this,” says Bruce Beutler.

Jules Hoffman emphasizes that the Nobel Prize rewards the work of a whole laboratory – over the years some 200 people have contributed. “I would really like to diffuse the prize back to the field. That is one of the reasons I want to make an effort to help the next generation.”

Bruce Beutler picks up on Hoffman’s notion that while the Nobel Prize does not change you, it changes the way people look at you and gives a different weight to what you say. “Getting the Prize was never the goal. You should go into science to explore and discover something and because you feel understanding nature to be deeply rewarding, not to get the Nobel Prize.”