A Little More Space to Play

Marc Kirschner's closing remarks at the first annual Systems Biology Symposium

kirschner

Full remarks as prepared for delivery by Marc Kirschner, the HMS John Franklin Enders University Professor of Systems Biology, at the first annual Systems Biology Symposium on Nov. 6, 2018. Read more here.

Let me start by thanking all of you who came today from afar and from not so afar to share your ideas and accomplishments and to help inspire us with the broad opportunities in science. I would especially like to thank Galit Lahav, our new chair of systems biology, and Becky Ward, who has been the administrative leader of our department, for conceiving this symposium and working hard to make it happen.

Finally, last but not least, I want to thank George Daley, the dean of Harvard Medical School, who supported this idea from its inception and urged us to do it right, whatever the cost. Thank you. All of you who spoke challenged us today to think beyond our narrow interests. As a result, we have much to ruminate on after this day of ideas.

A sense of history

I thought I would give you some sense of history about the beginning of systems biology at Harvard Medical School. It started with my previous position as chair of cell biology here, and what seemed like an innocent request by the former dean, Joe Martin, that I address a retreat of all chairs, clinical and nonclinical, of Harvard Medical School and all of the hospitals on the subject of the future of science in medicine.

Talks on the future of anything make me queasy. I pleaded with Joe not to demand this of me. He was in no mood to compromise. I went into seclusion to contrive some short address that would hide my embarrassment. In the resulting talk, I looked back 100 years, roughly when the old buildings on the Quad were built.

At that time there was real ferment in basic science and optimism that it would ultimately transform medicine. It ended up being true in many fields: embryology, pathology, biochemistry, pharmacology, neurobiology and genetics.

But the more I read the more aware I became that the greatest excitement in 1900 was not in these subjects, but rather in physiology. The seminar room that the departments of cell biology and biochemistry share was named for Walter Cannon, who was the originator of the concept of homeostasis and feedback inhibition, which today is a tenet of systems thinking.

Why had physiology faded in esteem? In the early part of the 20th century, stand-alone courses in physiology were commonplace even in high schools. Any biology major in college would have had to take at least one course in physiology and many took two courses, one in invertebrate and another in vertebrate physiology.

The problem of respect that physiology faced became clear to me. These other subjects had made firm connections on the chemical level, while physiology was still, at that time, about the heart as a pump, the transport of nutrients in the gut and the filtration of the kidney. The triumph of genetics is a good example. It was the chemistry of DNA that ultimately explained all the major features of heredity and then unraveled genetic diseases in terms of the structure of molecules. This was not true in physiology.

But there was no reason to believe that it could not be, sometime in the future. That was 15 years ago, but now physiology is more alive and there is hope that it will play a big role in forging the connection between genotype and phenotype on a molecular level—this is where much of the action is today.

Physiology, by whatever name, is the heart of neuroscience, immunology, developmental biology and much else. All this would have certainly happened without our department, but we were poised to be part of the effort.

Systems foundation

Two months after Joe Martin’s "invitation" to speak on the future, he totally surprised me by asking me to consider starting a new department based on principles of bringing mathematical, chemical and computational approaches to the genotype-phenotype question.

I told Joe that it was very easy for me to say yes, because I knew it would never happen, at least under terms anyone would accept. We all knew that Joe had repeatedly told the preclinical chairs that there was no extra money, there was no extra space and there were no unfilled positions. So, I was confident that this would go nowhere.

But I did not count on Joe’s gritty determination honed on the frontier of Alberta, and his creativity coupled with the farsightedness of then-president of Harvard University, Larry Summers. Larry was prepared to violate the second law of thermodynamics of universities by showing that money could, on rare occasions, be made to flow spontaneously from the central university administration to the medical school. If Larry Bacow were within earshot, I would tell him that if Harvard wants to retain or maybe regain its international leadership, he should open up the endowment and invest wisely in science at HMS. I also want to acknowledge the ingenuity and hard work at that time of Eric Buehrens, who was the administrative dean, and again, Becky Ward, who would become our new administrative leader.

As we began planning the new department, I wanted to be honest and lower expectations. I repeatedly told everyone I met that the course of basic science cannot be predicted and certainly not directed, or rather, should not be directed.

Results often take a long time. If one was expecting big practical advances like cures of disease from systems biology in the short run, it was a foolhardy expectation.

I am reminded by Ham Smith, who won the Nobel Prize for his discovery of restriction enzymes, which enabled, and still enables, all of the recombinant DNA revolution. In his Nobel address, he simply said that no one could have foreseen the application of his discoveries, and that included Ham Smith himself.

Today, eerily, we have the same story replaying in the discovery of CRISPR. I pointed out that the department would justify itself by investigating the principles of complex systems, which most often happens in simpler settings. Mendel did not start with human genetics, even though human heredity stared him in the face. Ilya Metchnikoff discovered innate immunity in the water flea. Pasteur discovered fermentation in yeast.

As we went along

But despite the distance from practical application to human disease, these new ideas of how complex systems function would have an important immediate human application—education.

So, from the beginning, the formulation of a field and department of systems biology at Harvard was intimately connected to education. We always wondered of course if that was enough to justify it, but we got resounding support from our colleagues here and from advisors around the world.

There was no escape. I was trapped, but for myself, the term systems biologist was a slight misfit. I thought of myself as a biochemist and a cell biologist. It was only when I realized that I could dispense with labels and simply call myself a biologist that it all felt comfortable again.

So, I started with two friends from cell biology: Tim Mitchison and Lew Cantley, with the strong help of Jeremy Gunawardena. And soon we hired four faculty: Galit Lahav, Vamsi Mootha, Roy Kishony and Walter Fontana, and not so long after, the two people who spoke here today, Angela DePace, Johan Paulsson and several others.

And we made it up as we went along. We were helped by the students and postdocs who never gave us a free pass. And there were disappointments as well. The financial collapse hit Harvard hard and we lost some good friends in high places.

But we were here to stay, and we had great support from the other departments and individuals. I sometimes miss the heady beginning, so full of hope and experimentation, but I am glad just the same that success is now not so shaky as it once was.

In that sense, Dean George Daley, who himself is a distinguished scientist, provided strong reassurance. In addition to his general interest in systems biology, he asserted his support by enabling this symposium. We are confident that systems biology has a firm place at Harvard.

That fundamentally is what we celebrate today, not just for our little group, but for a cadre around the world who believe that quantitative thinking, experiment, mathematical analysis, physical and chemical principles can generate new physiological understandings, such as the ones I alluded to 15 years ago at the chairs retreat.

We had begun to believe our own ideology. In the novel Mother Night, Kurt Vonnegut writes, “You are what you pretend to be, so you better be careful what you pretend to be.” So, let’s all pretend to be systems biologists, and I assure you the world will be a better place!

Education mission

I want to move on to a more general note—not just about systems biology, or Harvard Medical School or American science. I would like to think of systems biology as a form of culture as much as a scientific discipline. Like all human cultures, it has its customs and beliefs, and it is very concerned with perpetuating its population—its children.

The perpetuation of science was deeply in the thoughts of Vannevar Bush, the architect of US science policy during World War II, when he wrote to FDR about future science policy after the war.

He described to the president that the most important advances in warfare, perhaps responsible for saving western civilization, such as penicillin, the atomic bomb and radar, all came from universities. That, despite the huge amounts of money lavished on army and industrial activity, it was disappointing compared to what unregimented university science accomplished.

This experience was the basis for the National Science Foundation, which Bush headed after the war, and for establishing the principles under which the NIH functioned. In his report, Bush quoted James Bryant Conant, the former Harvard president on the renewal of our scientific talent. Conant was a transformative president of Harvard University, perhaps the greatest at seeing science as central to Harvard’s core educational mission.

Conant wrote, and Bush quoted, “in every section of the entire area where the word science may properly be applied, the limiting factor is a human one. We shall have rapid or slow advance in this direction or in that depending on the number of really first-class men who are engaged in the work in question.” Conant did say men, but under Conant the first women were admitted to Harvard Medical School and Harvard Law school.

So following Conant and Bush, I believe that the future of science in this country will be determined, not by our industrial or high-tech or our national labs, but by our basic educational policy.

Science is a playground

Still, I worry that we are neglecting science education at the highest levels. The early years of systems biology at Harvard taught me to see the problem more clearly. I believe that science at its most creative is more akin to a hunter-gatherer society than it is to a highly regimented industrial activity, more like a play group than a corporation.

In hunter-gatherer societies, as I have learned from my good friend the psychologist Peter Gray, there are no chiefs. Play is the principal form of training, a lack of adult responsibility continues often into the child’s twenties and children are not forced into molds by persistent, intrusive attention of their elders.

Playfulness is associated with learning to be an adult. In the end, hunter-gatherer children voluntarily focus on what they each do best: fishing, hunting, dancing, peacemaking, art, music or as repositories of information on healing, navigating, building.

What does this example have to do with science? Peter Medawar, who won the Nobel Prize for his work on the immunology of transplantation, captured the diversity of talents that scientists exhibit and should exploit.

“Scientists are people of very dissimilar temperaments doing different things in very different ways. Among scientists are collectors, classifiers and compulsive tidiers-up; many are detectives by temperament and many are explorers; some are artists and others artisans. There are poet-scientists and philosopher-scientists and even a few mystics. What sort of mind or temperament can all these people be supposed to have in common?" he wrote.

Instead, our courses, our hiring, our promotions, the criteria for papers being published in Nature or Science, our NIH grants, our PhD mentoring, our fellowships, even our awards and honors, are built on adherence to a constrained model.

We do not generally value the idiosyncratic, though we occasionally note it after extraordinary success. We consider the successful PhD or postdoc as someone who finishes quickly and uses a set of conventional assays on well-worked problems. In my 50 years of science, the scientific community itself has become more intolerant, more conservative. 

Yet, as I look back at the best scientists from my own lab or in the departments or Universities I have been in, or the great innovators in the scientific fields I know, the element that characterizes these people is playfulness, independence and nonconformity.

Lately, we have somehow become entranced with the industrial model. It is ironic that Vannevar Bush began his analysis of the needs of science in the mid-20th century with a harsh criticism of industry, and with deep appreciation for the operation of academic science.

Today, the fascination seems to have reversed. As industry and academia have been more closely entwined, we are in danger of undermining what has made us so great.

There is much more I could say here, but with regard to systems biology, I would say that I am most proud that we created a little more space to play here. It is hard to monetize this idea of play, but I hope the scientific world gives us enough time to spin off a few remunerative artifacts so we can still retreat into a corner to think broadly about the world, focusing on the obscure, the unknown and the under-appreciated.

No regrets

I know it is trite to say this, that the rewards of science are largely internal, but I will say it anyway. Like art, science is the realization of something that is both new and beautiful. It is the aha moments, perhaps not shared with anyone, that best illuminate the paths of scientific progress. I can imagine that this was the case when Galileo lifted the first telescope and saw mountains on the moon and envisioned another world. Or when Francisco Mojica, at the University Alicante in Spain, saw specific repeat sequences in the DNA of various bacteria, and then saw them again in the DNA of bacterial viruses and imagined for the first time a bacterial adaptive immune system.

As we have seen today, some of the biggest questions lie in the most modest systems. Today was a day of wonder that celebrates originality and discovery. Sometimes the techniques were sophisticated and sometimes not, but the secret was mostly to ask original questions or to try original approaches, or simply to, by theory or experiment, grasp the simplicity that we all believe lies under the unfathomable complexity of life.

I want to end this on a more personal note. I did not want to say that corporate culture is always unoriginal, or for that matter, that academic culture is invariably creative. We know of industries that were immensely creative, for example, Bell Labs, where the transistor, the solar cell, the laser and satellite communication were invented, or Xerox PARC, where the laser printer, the mouse and WYSIWYG were created.

My experience at UCSF, where a small number of basic science faculty, whom I count among my closest friends, created an interdisciplinary, creative culture. We worked as hard to recruit people in departments other than our own as we did in our own departments, and this led to populating struggling departments like the anatomy department with people like Cori Bargmann and Marc Tessier-Lavigne, or pharmacology with people like Tim Mitchison and Ron Vale.

The secret of UCSF and Bell Labs was the willingness of institutions to delegate responsibility. Although Harvard was different, HMS Dean Tosteson also built this place by delegating responsibility and building strong independent research and teaching centers. I took my inspiration from Phil Leder, Gerry Fischbach, Chris Walsh and Bernie Fields. Joe Martin, as I mentioned, firmly believed in finding people he could trust and then trusted them. The confidence he and Larry Summers put in me was what it made it possible for me to start systems biology and the systems biology graduate program. It is my hope and expectation that Dean Daley will do the same.

Contrary to the view that I stepped down because I was exhausted, I stepped down simply because I believed that others could now do it much better than I. And Galit will. I knew I had depleted my own store of institutional creativity.

And of course, I am looking forward to putting my energy fully into being as resourceful as I can be in experimental science in the years that good health and the NIH afford me.

In fact, my 25 years of building and chairing cell biology and systems biology were extremely pleasant, relatively easy, and very rewarding, and I don’t think undermined my ability to run my lab, write books and enjoy my family. I think a great deal of credit is due to the faculty of both departments. In cell biology and in systems biology the faculty and staff were very respectful of my time and were remarkably undemanding, collegial and stimulating people. I mentioned Becky Ward and it is the truth that we could not have succeeded without her insight, hard work and commitment. She deserves at least as much credit as I do for what we built here.

The students who came through here were the only real time measure I had that we were succeeding, and as time passes I see them as tenured professors winning honors. I realize the world knows what I have known for years, that they are our greatest products. Fail in education and a strict limit is placed on your own success.

Finally, although my wife, Phyllis, will cringe at my bringing her into this picture, she figures large into what has happened here. She made it possible for us to leave our beloved San Francisco and move with our three children to Boston to start a new life and restart her own career. She brought her energy, opened our house to countless parties and faculty and student recruitments and advised countless students and postdocs on everything from schools to jobs to medical care.

When I look back at the 25 years here, I have no regrets. In fact, change, adaptation, even a little stress, can be a good thing. But you have to have the right people and you have to trust them and give them a chance to succeed and make mistakes. If you are as lucky as Phyllis and I have been, then the only response to all the hard work and occasional frustration is gratitude for the opportunity.

Oh yes, and one more thing. If you haven’t voted there is still time to do so.