Lab Meeting: Peter Zandstra
“Asking the big question is always worthwhile.”
On the back of his father’s motorcycle, zipping between rice fields in the Philippines, a young Peter Zandstra bore witness to the power of engineering.
His father, well-known agronomist Hubert Zandstra, worked to breed indigenous crops (in regions like Peru and the Philippines) to create more nutritious and sustainable strains. Engineering these “super crops,” requires deep understanding of genetics, plant biology and ecology—not to mention economics and climate change: “This type of childhood taught me a lot about not only the impact science could have on communities across the world, but also the excitement that [scientific] discovery brought,” reflects Peter Zandstra, now a Professor at UBC and former Director of the Michael Smith Laboratories.
This early exposure planted a seed in Zandstra, which would germinate into a desire to understand science deeply. He feels that only rigorous understanding, will facilitate future discoveries and translational application: “we are often interested in not just observing what happens, but understanding why it happens…and how we can use our findings to build technologies,” says Zandstra when describing his scientific philosophy.
After a childhood spent living in Canada, Peru and the Philippines, Zandstra attended McGill for undergrad. As a chemical engineer, he took a course with Professor Thomas MS Chang, who pioneered the development of artificial blood systems: “that course got me really excited about how engineers could contribute to health problems and biotechnology.” Drawn to the idea of using engineering principles to rigorously understand biology, Zandstra pursued graduate training with Connie Eaves and Jamie Piret at UBC: “A high point early on for me was the realization that the tools of engineering and physics—mathematical modeling, bioprocess engineering, synthetic biology—could make incredible contributions to human health.” Following a post-doc at MIT with Doug Lauffenburger, Zandstra started his own lab at the University of Toronto in 1999.
Over the past couple of decades, the Zandstra lab has made fundamental contributions to understanding how functional tissues form from stem cells. They specialize in applying engineering principles and mathematical modeling to map immune cell differentiation and design novel cell therapies: “[Our work] is really about understanding how cells make decisions. We try to engineer those cell decisions for either fundamental understanding and discovery or therapeutic outcomes.”
In July 2017, Zandstra joined the University of British Columbia as the Founding Director of the School of Biomedical Engineering, and Director of the Michael Smith Laboratories: “I am so impressed and excited about the types of work at the [Biomedical Engineering] School; it highlights our philosophy of taking complex biological systems and overlaying engineering control. [We] use this engineering control to advance our fundamental understanding of biology.” For his academic work, Zandstra has been elected a fellow of the Royal Society of Canada (Engineering), the Canadian Academy of Health Sciences, the American Institute for Medical and Biological Engineering and the American Association for the Advancement of Science. In 2021, Zandstra was appointed to the Order of Canada for his significant contributions to stem cell bioengineering and regenerative medicine.
In addition to his academic roles, Zandstra has been on the founding team of ExCellThera and Notch Therapeutics. He is currently CSO of Notch, where he leads a team focused on developing iPSC-derived T cell therapies: “it's been wonderful to see the company grow, both in its footprint and in terms of the scientific depth with which it challenges the problems in the cell therapy field.” In 2019, the company signed a collaboration with Allogene to develop cell therapies for blood cancers like Non-Hodgkin lymphoma and multiple myeloma. In 2021, Notch raised an $85M series A with participation from Allogene, Lumira, the Centre for Commercialization of Regenerative Medicine (CCRM), EcoR1 Capital, Casdin Capital, Samsara BioCapital, and Amplitude Ventures.
Whether it is a novel crop or cell therapy in question, rigorous science is required to create technologies that improve human health. Throughout his career, Zandstra has leveraged advances in engineering to do good science: “I got many things from my mentors, but one thing that has stuck with me is the importance of asking a good question and finding the answer in a rigorous way.” Now at the helm of a new inter-faculty School of Biomedical Engineering and a promising cell-therapy biotech, Zandstra has ample opportunity to ask and answer such questions: “I've never been as excited about where the field is going, as I currently am at this point in my career.”
Below is an interview with Dr. Peter Zandstra Professor, School of Biomedical Engineering and Michael Smith Laboratories at UBC:
1. What was your first taste of science? Briefly, what about this initial experience drew you in? Who was your first great scientific mentor?
I come from a science family. Recently, I've been thinking a lot about my father [Hubert Zandstra] who was an agronomist and had a really big impact on agricultural research—especially in the developing world. As a kid I used to get on the back of his motorcycle, and we would go the rice fields where he would show me gene edited rice, or wheat, with higher yields of different vitamins or other nutrients. This type of childhood really taught me a lot about not only the impact science could have on communities across the world, but also the excitement that [scientific] discovery brought. So, learning from my father was probably my first “scientific experience.” After that I have been lucky to have mentors from undergraduate research programs, to two graduate mentors at UBC [Connie Eaves, and Jamie Piret], and then my postdoctoral mentor Doug Lauffenburger
We traveled a lot as kids—I was born in Saskatchewan, Canada but lived in the Philippines for five years, Colombia for five years, and then eventually made it back to Canada. This was because my father was in agricultural development research. He often needed to work in the region where the given crop he was studying was indigenous. In Philippines, there is the International Rice Research Institute, and there is a Peruvian Potato Research Institute. As a child, it was great to see how one could use science and genetics to take wild versions of these domesticated crops and create long term sustainability for both large farmers and small subsistence farmers in the developing world.
[Was your initial goal to be like your father and apply science to agriculture? Or did you have an interest in specifically applying science and engineering to medicine?]
My interest in applying science to medicine came later. I did my undergraduate degree in Chemical Engineering at McGill. Chemical engineering at that time [late 1980s] was predominantly pulp and paper and oil and gas. Very quickly I realized that that [type of engineering] wasn't my interest. The program I was in did have a biotechnology minor. As part of this [minor], I took a course taught by Professor Thomas MS Chang, who pioneered artificial oxygen carrying blood systems. That course got me really excited about how engineers could contribute to health problems and biotechnology.
2. 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 had an unusual opportunity as a graduate student. Though I was working as a “chemical engineer,” most of my work was done collaboratively at the BC Cancer Agency with Connie Eaves. A high point early on for me was the realization that the tools of engineering and physics—mathematical modeling, bioprocess engineering, synthetic biology—could make incredible contributions to biology. Even the first paper we wrote was fairly straightforward from an engineering perspective but had a big impact on biotechnology. I think at that point I realized thinking of biology as engineering systems was a growing opportunity.
[What were some of the low points throughout your training path?]
Interesting question. There were many low points, and in those low points you learn to recognize that failure is a part of doing science. Science is hard. Whether it's having experiments that don't work out, getting papers rejected, grants denied—this all happens with way more frequency than successes. Recognizing that this is the process of doing science, embracing and learning from it, can fuel you to ask better, more specific, questions, and design more informative experiments.
[What were some important lessons you learned from your mentors?]
I got many things from my mentors, but the one thing that has really stuck with me very deeply is the importance of asking a question and getting to the answer in a rigorous way. Perhaps there is an engineering influence—to me [engineering] is about getting an answer with enough depth and rigor that the result is robust so that you really can build on the knowledge and properly ask the next question. All of my mentors were incredible, and sticklers for detail and rigor. Today, [in my lab] we are often interested in not just observing what happens, but understanding why it happens, and how we can use our discoveries to build technologies.
3. What set of research questions or projects has you most excited about coming into lab today?
There are a few areas in the lab that I think are super exciting, and also “keep you up at night” types of questions. One area is about learning to replicate lymphopoiesis—the formation of our immune system—from stem cells. We are starting to combine both cell engineering and niche engineering so that the two systems talk to each other and coordinate dynamic developmental decisions. If you look at T cells—there are all kinds of types of T cells, such innate and effector cells. The timing and dosing of development signals are critical to the emergence of these subsets. This has been a fantastic problem to work on, and one where we are making good progress.
The other problem that we're interested in is more fundamental, which regards collective behavior of cells: how do many cells come together to behave in a coordinated manner? This has emerged very nicely out of the work that people are doing in organoids. This project applies wherever you're starting to model and mimic early stages of development—where cells act in unison and differentiate into different tissue types for different organs. We really don’t yet understand the principles that guide how cells communicate collective behavior with each other. Also, how we can control this behavior to yield specific cell types and tissue structures – whether mimicking nature or specifying an entirely novel tissue-like collective? We have really interesting mathematical modeling underway studies in the lab that integrate gene regulatory networks between groups of cells. We also are exploring more experimental systems that the mimic symmetry breaking events that are so important during early embryonic development and tissue specification.
Overall, both these areas, which may seem very far apart, are really about understanding how cells make decisions. We try engineer those cell decisions using either a computational description of endogenous networks, or by manipulating cells and niches using synthetic approaches. In the end we hope our work provides a foundation for new therapies.
4. Which areas of science, outside of your direct field, are you most excited about seeing develop in the next 5-10 years?
I'm really fascinated by the whole area of lab automation. We’ve had a bunch of discussions in the lab that are centered around the concepts of: can a machine win a Nobel Prize? And how do you start to take automation, artificial intelligence, and experimentation, and bring discovery into it?
Lab automation is currently limited by testing known parameters using available reagents. But how do you automate moving outside that and go into spaces that are unknown? How do you do this in a systematic manner? Given the advances in robotics and analytics, I think it's going to be an interesting place to watch. It’s certainly an area that that merges with computational biology, which is closer to my field, and definitely complimentary.
5. Who are a couple up-and-coming scientists (lab < 10 yr old) in your area, or more broadly, whom you think we should watch? Why is their work so exciting to you?
There is tons of exciting science going on all over the place. I've never been as excited about where the field is going, as I currently am now at this point in my career. I would like to take the opportunity to highlight what we're doing in the School of Biomedical Engineering at UBC—this is a new school that we just launched five years ago. We have hired a number of outstanding new faculty, and I'll highlight three young investigators here: Anna Blakeney (also at the MSL) who works on self-amplifying RNA, Carolina Tropini (also at Microbiology and Immunology) who works on microbiome engineering, and Nika Shakiba who works on stem cell differentiation and understanding how lineages emerge out of reprogramming events. I am so impressed and excited about the types of work that these scientists and others like them are bringing to the school, because they are aligned with our philosophy of taking complex biological systems and overlaying engineering control. They are using this engineering control to advance our fundamental understanding of biology. I hope that people get an opportunity to check out their labs and work.
6. As a co-founder and current CSO of Notch Tx, what about the opportunity made you so excited? What is the founding story?
Notch is a really exciting company for me because it allows us to found a company based on the aspects of engineering design and therapeutics I described (Q#4). We are doing this in an area where we can address one of the big challenges facing the space-- accessibility and scalability of immuno-engineered cell therapies. There are a lot of technologies that are being developed, which inordinately expensive or not broadly accessible across the world. Notch is trying to develop these very effective CAR-T cell therapeutics from a renewable source of stem cells that can be manufactured at scale. We're really hoping that these can come together to bring down the cost, increase the accessibility of these technologies and also increase the sophistication of the clinical product.
Notch started through a collaboration with another faculty member at the University of Toronto [where I was at the time], named Juan Carlos Zuniga-Pflücker. At the time, we co-supervised a student--Shreya Shukla—in the lab. Shreya’s project was to look at how we could generate T cells from pluripotent stem cells. The way that it was done at the time was to put cells on a feeder cell layer [OP9 DL4 cells]. Shreya said: “you know, this is ridiculous, I can't control the cell types, I can't control the timing, I can't control the dose, how am I supposed to learn anything about these cells?” Shreya and others along the way have contributed to developing technologies that allow us to control the time and dose in which [development] signals are delivered in these dynamic systems. This IP was a key component that led to the founding of Notch Therapeutics. I was also very lucky that I was able to benefit from good business leadership and business experience. We'd started a non-profit in Toronto a number of years ago called the Center for Commercialization of Regenerative Medicine, now CCRM. One of the goals of this non-profit was to support early-stage companies through their growth and foster initial partnerships required for their success. So CCRM and others supported Notch and mentored it through the early stages. Experienced biotech operators like Ulrik Nielsen, came in early on to help the company’s growth. Since then, it's been wonderful to see the company grow in its footprint and impact under the leadership of David Main and the rest of the Notch executive team.
7. What do you view as the role of scientists/engineers in academia interacting with biotech and industry? Has this role changed throughout the course of your career?
One thing that I've learned over the years is to stick to the things I'm good at—doing these things over and over makes you even better at it. In my role as CSO at Notch, I'm really focused on the science that the company does. I don't take on management and organizational type aspects there. There are great leaders emerging out of that company that will replace me and so my role is really to focus on trying to help ensure the quality, depth and rigor of the science; and that the types of questions we ask are as impactful as possible. If I focus on these sets of questions, then I can use the same mental processes over and over [in academia and lab] as opposed to having to stretch myself too thin.
There have been a number of changes in the relationship between academia, biotech and pharma over the past couple decades. These changes occur with market conditions, government priorities and are very dynamic. Funding in many places [in academia] has been more tied to ensuring a translational element. This translational element, whether we agree that it's a critical aspect of science or not, often facilitates company creation or company growth. Another thing we're seeing is opportunities for deeper partnerships with established industry and academia. Academics have deep expertise in many cutting-edge technologies that are difficult for smaller biotechs or large pharma to equip, execute or adopt. These partnerships that can happen between industry and academia can really benefit both sides—with the goal of just doing better science. Being a part of these relationships has been really exciting for me.
8. What is one piece of advice for a young scientist aspiring to have a career in academia, and make some important discoveries?
I think this is probably a truism you've heard before, but asking the “big question” is always worthwhile. Often our circumstances force us to ask questions that maybe are too focused or incremental in nature. Trying to first understand the field to a level where you can really identify what the big questions are is crucial.
Play the long game. Develop a field that is exciting for you—create a series of crumbs that leads you in that direction. The other thing is to follow your gut. If something doesn't feel right, or doesn't sound right, trust that. We are often in rooms talking to people that have more power than us, or we don't feel comfortable raising our voices—whether it's science or another issue. Every time I haven't followed my gut or raised my hand, I've regretted it. Science is a great equalizer for having conversations because they're often based in scientific knowledge and process. I think it's really good for us to learn to have those conversations openly and always ask questions.
9. What are you reading in your free time?
I just read a book called The Apollo Murders by Chris Hadfield. Hadfield was commander of the International Space Station—and a Canadian astronaut. He’s done a lot of things in his life, but he wrote this book that reimagines a place time in the development of the Apollo program, as if something had gone wrong. It’s a nice combination of insight into what life might must have been like as a test pilot, then an astronaut, but also a little bit of espionage and fiction thrown in for fun. I really enjoyed it.