Founder Q&A with Tim Springer, PhD
A catalyst for biotech innovation and recent Lasker Award honoree
Timothy A. Springer, PhD
Latham Family Professor
Professor of Biological Chemistry and Molecular Pharmacology, Professor of Medicine, Harvard Medical School
Principal Investigator, Program in Cellular and Molecular Medicine, Division of Hematology/Oncology, Department of Medicine, Boston Children’s Hospital
Seismic Founder Tim Springer, PhD, is a world leader in structural biology and immunology. He was recently honored as a co-recipient of the 2022 Albert Lasker Basic Medical Research Award for discoveries concerning integrins, key mediators of cell-matrix and cell-cell adhesion in physiology and disease. He is a founder and private investor in numerous biopharmaceutical companies, including Moderna, Tectonic, Scholar Rock and Morphic Therapeutic, and his research and company formation has led to six FDA-approved drugs, including antibodies for treating cancer and autoimmune diseases. We’re proud that Dr. Springer is also a founding investor and scientific founder of Seismic Therapeutic.
To launch our Founders Q&A Series, Seismic Chief Business Officer Maude Tessier had a wide-ranging discussion with Dr. Springer about his work, his recent Lasker Award and how his research led to Seismic.
Maude Tessier:
You were recently honored with the prestigious Lasker Award, for your discovery of a family of proteins – integrins – and their essential role in cell trafficking in health and disease. Can you offer your perspective on what it feels like to have this work recognized and its potential impact?
Tim Springer:
It’s a real honor for me to be recognized by my scientific peers and superiors, because many of the people on that committee are Nobel Prize laureates and they have a very good taste in science.
We are just now being recognized for discoveries that Erkki Ruoslahti and Richard Hynes and I made about 40 years ago. My discoveries date from 1979 when I identified the first molecule that became an integrin, up to 1985 when we published amino acid sequences, and then in 1986 when others recognized that the sequences they had determined for extracellular matrix receptors were homologous to the sequences we published, and the integrin family was recognized as being quite broad in scope. I think that one reason this recognition took so long was that integrins are interdisciplinary and important players in many, many fields of science, but they don’t dominate a single field uniquely like some of the other scientific contributions that have been recognized by the Lasker award.
Can you further elaborate on how your work recognized by the Lasker Award opened up new therapeutic strategies that are being used in the clinic today – especially for the challenging area of autoimmune diseases?
I think what really became important over the many years was the therapeutics that were discovered to target integrins – two came directly from my research. I first reported on LFA-1 in 1981, and now there is a small molecule that is directed to LFA-1. This molecule was approved for dry eye, and it’s estimated that it treats over a 100,00 patients a year who have this autoimmune disease.
The second big success is Entyvio or vedolizumab, an antibody that is directed to the integrin alpha4/beta7 that is responsible trafficking of cells to the intestine. I founded a company based on this work, called LeukoSite. LeukoSite was acquired by Millennium Pharmaceuticals, who then in turn was acquired by Takeda. Entyvio prevents trafficking of lymphocytes from the bloodstream into mucosal tissues, and reduces the inflammation that causes ulcerative colitis and Crohn’s disease. These are both very successful therapeutics.
With the Lasker Award coming 40 years after your first discovery of integrins, you’ve been able to see this discovery translated into approved drugs. Did you somehow know that you had made a meaningful discovery, and how does it feel to now see drugs on the market that are derived from your work?
I thought alpha4/beta7 – which ultimately became the target for the drug Entyvio – could be very important because normal anti-inflammatories at the time were just broadly active on many kinds of cells. I thought that targeting integrins would be much more selective, because it could achieve specificity for certain subtypes of leukocytes that were going to be trafficking to the gut and that it could reduce the potential risk of side effects that can occur if you block the whole immune response.
What I didn’t fully appreciate at the time – because I’m a PhD and I’d never treated patients – is how impactful a drug like Entyvio can be to patients with ulcerative colitis or Crohn’s disease, which is pretty remarkable.
Throughout my life, I’ve met many people who’ve benefited from drugs that I had a role in developing, either through basic science discovery or from starting companies. That’s been incredibly gratifying. For example, there’s a person who works for the Lasker Foundation, who shared with me that Entyvio had made a huge difference. He’s had ulcerative colitis all of his life, and he divides his life into pre-Entyvio and after Entyvio – it’s that big of a change in the quality of his life.
You have accomplished so much, from your illustrious academic career and biotech startups to drugs in the clinic and approved. What continues to drive you? What keeps you engaged and motivated?
There are so many new technologies now, and so much more to come – it’s very exciting. When I started out in my career in 1971, I there was no biotech industry. Genentech, Biogen, and Genetics Institute were all founded between 1976 and 1980. Those companies were working on recombinant proteins that could replace natural proteins, like erythropoietin and human growth hormone. No one then was thinking about synthetic proteins.
Monoclonal antibodies hadn’t been invented when I started my PhD. I was fortunate to do a postdoc with César Milstein, who had just discovered monoclonal antibodies. And now monoclonal antibodies are a mainstay of currently approved therapeutics. Then biotech evolved further and now we have new modalities, like messenger RNA. Who would’ve thought that messenger RNA could become an important drug product – so that, like millions of people, I just got my latest COVID booster. Also, there’s cell therapy, gene therapy, virally vectored vaccines, and genetic CRISPR. And there’s just more and more on the horizon.
What perspective or advice can you offer others – in academia or industry – who are working on novel areas of discovery, looking back on lessons learned in your career?
Do something that is just very new biology, but so important and so unknown that many new receptor ligand interactions or other new conceptual advances are likely to come from it. Understand the scientific basis for everything you’re doing, and don’t be a specialist. If you’re working on other tools or proteins that people have given you, understand how they work so you can put the big picture together. And keep on learning and keep on challenging yourself. And then if that works out, start a company.
This is currently my model for starting companies: do something in your laboratory that has big potential. And then if you think it is much more than you can do in your laboratory to translate the science into products, start a company.
For example, along with Eugene Butcher’s laboratory and Uli von Andrian, Mike Lawrence and I discovered the three-step model of how leukocytes leave the circulation to accumulate in tissues because they perceive a signal that something is awry. After we published it in 1991, I said, “Well, this is an area that is way bigger than something I can really address in my laboratory, and so we need to start a company to truly address this.” And the company LeukoSite was born.
This process is also how Seismic Therapeutic came about.
Immunology and autoimmune diseases have been a challenging area for drug development. What makes you most excited about Seismic?
At Seismic, we have new vistas on biologics. We are using machine learning to improve the biologics discovery process and have a virtual cycle between structural biology, protein engineering, translational immunology and then machine learning to evolve better and better proteins. The tools that are available now are just so powerful and it continues to evolve.
And it’s really wonderful to collaborate with people who are on the same track with you at a peer level. Often in academics, people find themselves in silos, working in their own area. It’s so nice to have a close collaboration with a company and be all on the same team.
You were the driving force in getting Seismic started. How did the concept of the company come to be? How did these foundational ideas emerge?
Well, we had come across new types of molecules to modify proteins including antibodies, and these modifications could change their properties very dramatically – but would require a lot of optimization, that could be enabled by machine learning, to create medicines. And I thought that would have huge therapeutic implications and in many different kinds of diseases including autoimmunity. I did a lot of research on it and discovered the breadth of what was known, which was staggering, and what the range of diseases was that could be affected, which was also quite wide.
So I put together a set of slides and I presented it to Polaris. And I particularly wanted to attract Alan Crane because he’s such a wonderful person to work with. We started to put together the company, bringing together some scientific leaders and others that I had worked with in the past. And then Jo Viney had some other ideas that she’d been incubating. So she became a co-founder. Jo’s perspectives broadened our platforms, and I’m excited about the drug discovery engine and the very talented team.
At Seismic, we’re integrating machine learning with structural biology and translational immunology to create novel biologics that we hope will transform how autoimmune disease patients are being treated and their quality of life. How do you see the integration of all these different disciplines making an impact in the field? And why did you think this was the right time to start Seismic?
It feels like the field of applying AI to biologics for drug development is just starting. And I think Seismic is really at the forefront of this new area by applying machine learning to biologics drug discovery in several key ways.
First, the new ways we’ve found to optimize protein therapeutics have gained lots of traction. And, with a lot of genome sequences out there, we can explore a lot of sequences through bioinformatics, and then we’ve used machine learning to improve those sequences guided by structural biology. The goal is to use machine learning to get to what we hope is an optimum protein sequence, more quickly.
Second, structure prediction can be done more broadly and easily with machine learning because it enables the ability to make many iterations for new protein modifications simultaneously to change effector functions and yet maintain drug-like properties. And this opens possibilities to make other new kinds of drugs, as well.
Third, the Seismic team is marrying this effort with ‘invisibilization’ where we can design a biologic to avoid immunogenicity, which is a major challenge in the field. So, the idea is to rationally decrease immune responses to any proteins that we would give to patients. I think this is just becoming a reality at this moment. And I think it can have an enormous benefit in a large percentage of patients who receive protein therapies.
You have seen so much happen in the past decade or two in the field of proteins and biologic medicines. In addition to what we’re doing at Seismic, where do you see the field going in the future?
Well, I think we can engineer protein therapeutics much better than we have in the past. And I think machine learning will contribute a lot to that and allow us to get to the right drug product much more quickly. Machine learning must be done in concert with structural biology and the reality of testing designs both in vitro and in vivo, and we are doing that, and I think that it will have a huge impact. We’re ready for great things at Seismic, with a strong plan and stellar team. I think it’s going to be an outstanding company.
