Lab Meeting: Tim Springer
"Never stop learning. Never stop challenging yourself."
Philanthropist. Visionary entrepreneur. Savvy investor. Rock collector.
From Boston to Guangxi province, Professor Timothy Springer is known for his many accomplishments and passions. Yet first and foremost, Springer is an elite scientist—part of a select group of immunologists whose findings have had profound basic and translational impacts.
As medical students, we learn of Springer’s work mapping the steps by which leukocytes move from the blood into tissues—and how this molecular machinery can be exploited for therapeutic potential. As graduate students studying basic immunology, we learn of Springer’s discovery that integrins, such as LFA-1 and ICAM1, interact to promote antigen presentation and adhesion of leukocytes to the wall of a blood vessel.
These findings are just a slice of his work, represented in over 500 publications, 30 patents and several drugs currently prescribed to patients. A graduate student under the legendary immunologist Jack Strominger, Springer learned to tackle the “big questions” and earned his PhD from Harvard in 1976.
About a year later, he became an assistant professor at Harvard Medical School—where his laboratory remains to this day. In the decades since starting his independent laboratory, Springer’s work has centered on studying how conformational change and tensile force activate integrins, von Willebrand factor, the transforming growth factor-β family, and adhesins on malaria sporozoites; as well as discovering novel binding partners that modify the function of these molecules. For his contributions to science, Springer is a member of the National Academy of Sciences and has won the Gairdner Award, Crafoord Prize, the American Association of Immunologists Meritorious Career Award, and the Stratton Medal from the American Society of Hematology. Since 1989 Springer has been Latham Family Professor, and is currently a Professor of Biological Chemistry and Molecular Pharmacology and of Medicine at HMS and the Program of Cellular and Molecular Medicine and Division of Hematology at Boston Children’s Hospital.
As an entrepreneur, Springer is best known for founding LeukoSite in 1993, which was responsible for development of several medications, including vedolizumab (Entyvio), alemtuzumab (Lemtrada) and bortezomib (Velcade). LeukoSite was acquired by Millenium Pharma in 1999 in a stock deal that was worth over $3 billion by 2001. More recently he has founded Scholar Rock and Morphic Therapeutic, which have both gone public. Springer is also an early investor in Moderna and Editas Medicine.
Springer has created endowed Chairs at Harvard Medical School and Children’s Hospital, was on the Children’s Hospital Boston Board of Trust and founded the Institute for Protein Innovation, a non-profit bringing cutting-edge antibody and protein engineering to bear on complex and under-resourced areas of research.
Below is a short interview with Dr. Timothy Springer from July 2022:
1. Name an overlooked scientist, whom you feel strongly that every grad student (or med student) should know and be able to describe their major findings. What were the killer experiments?
Alan Williams. An immune cell biochemist who died too young. Antibody kinetics and affinity are too often ignored in functional experiments in immunology. He found that typical high affinity antibodies only bind through one Fab arm to cell surface antigens. Only low affinity antibodies have kinetics that are rapid enough to equilibrate and bind through both Fab arms to cell surface antigens, and they often have different functional effects.
[Alan Williams also purified and characterized Thy1, and in collaboration with Cesar Milstein helped identify CD4 and create antibodies that recognize CD8. Williams passed away in 1992 at the age of 47 after a brief battle with cancer.]
2. What are you reading in your free time?
I recently read Outside Looking In by T.C. Boyle and Gilead by Marilynne Robinson. I read Cell, Nature, and Science in print.
3. What was your first taste of science? Briefly, what about this initial experience drew you in?
Some enzymology as an undergraduate. We had an antibody to an enzyme [I was studying], and I had lots of fun with it.
4. What has been your scientific high point? — What do you consider to be the most exhilarating discovery or set of discoveries you have been involved in throughout your career?
I am currently at the high point. But I get prizes for old stuff- discovering the first cell recognition (adhesion) molecules of the immune system, the first relationships among integrins, and the three-step model for leukocyte immigration from the bloodstream (rolling through selectins, cell activation by the TCR/kinases/GPCR, firm adhesion and migration through integrins).
5. What set of research questions or projects has you most excited about coming into lab today?
How integrins communicate with and are activated by the cytoskeleton at the molecular level. We found that two integrins that have identical beta subunits and only differ in their alpha subunits assemble actin cytoskeletons with very different architectures and that these cytoskeletons exert different levels of force. And we developed elegant techniques for measuring the kinetics of integrin conformational change and will be able to do this with single molecule pulldown of intact integrins and measure influence of associating cytoskeleton adaptors. We will also be discovering with new techniques the molecules that associate with integrins in real time. We also have lots of new data on how TGF-beta is activated by integrins and there are lots of surprises!
6. Who are a couple up-and-coming scientists (lab < 10yr old) in your area, or more broadly, whom you think we should watch? Why is their work so exciting to you?
Andrew Kruse. He works at the cutting edge of cell surface receptors including GPCR and always uses new technology.
7. What is one piece of advice for a young scientist aspiring to be a have a career in academia, and make some important discoveries?
Never stop learning. Never stop challenging yourself.
8. How have you been able to balance running a busy lab with company formation, and what advice would you give to young scientists with an interest in entrepreneurship?
My advice is to go into science to make discoveries. It requires total commitment. To try to also make money at the outset is to set yourself up for failure. I aimed to make discoveries of fundamental importance, and doing so, put myself in a position to later be an entrepreneur. That involved additional learning and challenges, which made it fun.