Jonathan Kagan: A cell biologist’s view of immunity

When I finished my studies in Craig Roy’s laboratory, I was becoming more interested in the host immune response to infection, and Yale was the place to be. Medzhitov’s research group was systematically analyzing the ability of TLRs to promote inflammation and adaptive immunity in mice. However, we knew almost nothing about where TLRs and their associated signaling proteins were localized and my initial goal was to create a map of the intracellular sites of TLR signal transduction. In my own lab, we have continued these efforts and we have recently expanded our work to include Drosophila melanogaster. In this system we provided the first in vivo evidence for the importance of our cell biological map of signaling for host defense. Perhaps most importantly, we identified the first example of a broadly used cellular response to bacterial lipopolysaccharide (LPS) that proceeds independently of TLR4. TLR4 was thought to be the sole receptor for LPS capable of controlling downstream cellular responses to this cell wall component. Other LPS receptors were presumed to function merely as chaperones delivering LPS to TLR4. However, we found that TLR4 does not promote its own endocytosis but requires signaling triggered by a distinct LPS receptor called CD14 and TLR4 is merely cargo for this pathway (4). Once TLR4 enters endosomes, it induces the expression of hundreds of immunomodulatory genes. The importance of CD14-inducible endocytosis for TLR4 signaling highlights the amazing connection between trafficking and signaling pathways. Our findings were quite timely for the field, as subsequent studies from other laboratories identified additional TLR4-independent cellular responses to LPS. We now face the challenge of understanding how several LPS receptors operate to control distinct and overlapping cellular responses that are collectively important for host defense.

How the immune response operates in complex environments is a question that excites us. We recently identified how the innate immune system uses coincident detection of microbial products and tissue damage to “hyperactivate” immune cells. We are interested in understanding how these cells promote host defense (5). We are also studying the biochemical basis of innate immune signal transduction at distinct intracellular sites. Many proteins operate at these locations but we are just beginning to understand how they are organized. For example, we have identified the endogenous myddosome in macrophages, a receptor proximal protein complex that is the principal site of TLR signaling (6). The myddosome is just one example of several large oligomeric protein complexes that control inflammation, which we have dubbed supramolecular organizing centers (SMOCs). Similar SMOCs control inflammasome and RIG-I–like receptor signaling events, and we are interested in defining the mechanisms and consequences of SMOC activation as these organizing centers are the decision-making organelles of the immune system.

My approach to our projects is very much concept driven. We often discuss questions in the field that may be overlooked based on current dogma or experimental methodologies. In other words, we try not to initiate projects that are obvious, as these projects are usually highly competitive. Rather, I prefer to work on questions that others may not (at the time) find noteworthy. The hope is that whatever we learn may shift the perspective of our colleagues and spur them to follow up our observations.

I learned how to be a scientist, in every sense of the word, during my graduate and postdoctoral studies. I believe the hardest part of being a group leader is maintaining high standards of work performed by several trainees. By working with such excellent mentors and laboratory-mates, I learned the best way to design experiments, to truly test a hypothesis, and to communicate these findings to a broad audience. I try very hard to pass these lessons on to my trainees. I was unprepared for how hard it is to judge talent when considering postdoctoral applicants. There is no perfect way to determine who is going to be a star, and it is a constant struggle for me to make such decisions when hiring new people. After all, you meet an interviewee for a single day, and decide whether you want a years-long relationship with him/her. It is almost like speed-dating . . . no, speed-marriage! For this reason, I hire very few postdocs, and the ones I do hire are selected very carefully.

The biggest challenge of my career has been to stay true to my interests in basic science. These days, there is a tremendous push to work on translational aspects of biology, with the goal of identifying clinical significance. The incentive to shift our research focus into one that is less basic and more translational is huge, as it is easier to obtain grants, publish papers, and establish oneself in the community by following this path. However, I did not get into science to cure a disease. I got into science to understand life. I look at the human body as a clock, and I just want to take it apart and see how it ticks. I have tried very hard to stay true to my interests in basic science, and this approach allows me to truly love all the projects in my laboratory.

The best advice I ever received was from my parents. I was encouraged to focus on my passions and to work hard. My parents led by example and their day-to-day choices made it clear that they valued hard work and consistency. There was rarely a discussion of finances as a critical determinant of career path, but there was often a discussion of doing what you liked and hoping for the best. Students often feel that they need a path to success that is more tangible than “be happy, work hard, and hope for the best.” But I believe that my mentors, and most successful people I know, lived by this mantra in their formative years. Of course, it is good to plan for the future, but never let that plan come at the cost of doing what you love. Because without that passion for your work (or your life), you will be unhappy.

These days, my hobbies are to play with my three wonderful kids (ages 7, 4, and 2) and spend time with my beautiful wife, who is also a scientist. We are a very active family, with much laughter and craziness. Most of my free time is spent embracing the joys that come with early parenthood. Prior to having children, my hobby was poker. I have many fond memories of driving to the local casino near Yale on a weeknight, talking about experiments and card games, and then doing the same many hours later on the way home.

Follow your heart, meet lots of people, stay excited about your work, and never, ever, get complacent. There is always a new challenge ahead, and the fight is what keeps life interesting.