Pieter Cullis, Professor, Scientist and Entrepreneur at the University of British Columbia
Pieter Cullis, Professor, Scientist and Entrepreneur at the University of British Columbia
Pieter Cullis, Professor, Scientist and Entrepreneur at the University of British Columbia
Biography
Pieter Cullis is a Professor at the University of British Columbia (UBC) and a physicist, biochemist and entrepreneur whose research has helped shape the development of lipid nanoparticle (LNP) technologies for nanomedicine and nucleic acid delivery. His work spans fundamental studies of lipid behaviour in biological membranes through to the development and translation of LNP systems for cancer therapies, gene therapies and vaccines.
He and his collaborators have contributed to delivery technologies underlying clinically approved medicines, including the RNAi therapeutic Onpattro and the Pfizer/BioNTech COVID-19 mRNA vaccine, Comirnaty. Over his career, he has published more than 400 scientific papers, is an inventor on over 100 patents, and has co-founded multiple biotechnology companies, including Acuitas Therapeutics, Precision NanoSystems and NanoVation Therapeutics. His work reflects a longstanding focus on translating fundamental lipid science into technologies capable of improving how genetic medicines are delivered to patients.
Interview
NanoSphere: You began in physics before moving into biology. Looking back, which moments or decisions most shaped the path that brought you here? What did you see in living systems that others around you were missing?
Pieter: Yes, this was way back in 1972. I got a PhD in physics doing magnetic resonance on phosphorus-doped silicon, a semiconductor-type material. The problem in physics at that time, which actually still is a problem, is that much basic physics was solved around 100 years ago. People in physics are looking for new physics problems, but there’s only high-energy physics that gets anywhere near that, and that wasn’t really what I wanted to do. And so, I started looking around and looked at the life sciences and realized that everything there was a problem. And so I made a decision to move into the life sciences.
I was lucky enough to get a postdoctoral fellowship to go to Oxford University in England and do nuclear magnetic resonance, studies on biological membranes, although I didn’t know very much about biological membranes. Anyway, so that’s where it all started. I got fascinated by the properties of lipids in biological membranes, spent 20 years trying to understand something called lipid polymorphism, which is the ability of lipids to adopt different structures in water and also a topic called lipid asymmetry, which means that the lipids on one side of a membrane are different than on the other. All of what we did subsequently depended upon those initial studies, which were just completely curiosity-based. I mean, we weren’t thinking that we were going to develop new drugs, that’s for sure.
NanoSphere: In several discussions, you've highlighted collaboration. What separates a truly transformative scientific collaboration from an ordinary productive one?
Pieter: Yeah, I was very lucky when I got to Oxford. I collaborated with a Dutch postdoc named Ben De Kruijff, he had brought a whole library of lipids to Oxford. He was a biochemist. I knew something about NMR, he knew a lot about membranes. A good collaboration really works very well when you have people coming at the same problem, but from very different backgrounds. Subsequently, I met a postdoc from London named Mick Hope, who subsequently came out to Vancouver to work with me. Mick was a biochemist who knew a lot about not just membranes but also general biochemistry. We formed a great team that included four postdocs in my lab in the middle ’80s, all of whom got along very well.
One of the things we invented was something called an Extruder, a device that we used to make liposomes very rapidly and very reproducibly. We started a little company to make Extruders, and we sold quite a few of them. We had a company motto that was “free beer every Friday and parties whenever possible”. We did a lot of good science, but we also had a good time as well. Fun is a very important ingredient in a collaboration.
NanoSphere: You built companies partly to create opportunities for your students. At what point did you realize mentoring people could matter as much as publishing discoveries?
Pieter: Oh, I think that was there from the beginning. One of the problems that we had here in Canada, and it’s true for a lot of countries, is we didn’t have local jobs for people that graduated, say, from my laboratory. I found this rather frustrating. They would go to jobs in the United States or wherever. That was a big driver to say, okay, we have to start companies that employ the people that we’ve basically spent so much time and effort educating. And so that’s been a big part of what we’ve done. There’s now about 500 people that are employed locally in companies that I started.
NanoSphere: When future scientists study this era of RNA medicine, what lesson do you hope they learn beyond the headlines?
Pieter: Let’s go to the headlines first of all. If you can deliver nucleic acids such as mRNA in vivo you suddenly have potential ways of treating most human diseases including rare diseases, cancer, cardiovascular disease and so on. You’re starting to see a lot of that news coming out. First there’s the vaccines — vaccines against most infectious diseases, COVID-19 being the first example. We’re going to see many more LNP RNA vaccines. Secondly, rare diseases. The baby K. J. Muldoon story that came out last year really illustrates the power of being able to modify a baby’s genes to correct a genetic defect. I think that’s going to become a very common therapy. Third, the personalized cancer vaccines ae a very big story with significant success with pancreatic cancer, melanoma and others. Moderna just announced the results of a phase 3 trial in melanoma that are really quite spectacular. Anyway, those are the current headlines.
Beyond the headlines a priority is to be able to transfect extrahepatic tissues. Huge efforts are being made to get to bone marrow, lung as well as kidney, brain, etc., in order to treat everything from Alzheimer’s to cystic fibrosis to sickle cell anemia. In addition LNP mRNA systems must be more potent, must have a larger therapeutic index so that the dose at which we see a biological effect in mice is maybe hundred-fold lower than the dose where you see any toxic effects. Then you have something that might be clinically useful. Another priority is specificity, confining transfection to one particular tissue versus another. Obviously it’s a very exciting time as we are developing new approaches to treat cancer, heart disease, rare diseases, neurological diseases, even aging. An example is to try to rejuvenate your immune system as you get older, 90 percent of all cancers occur after the age of 50. That’s mainly because your immune system starts to not work as well. If we can keep your immune system going, then that’s going to be a major thing to achieve healthy aging.
The main lesson that future scientists should recognize is that the advances that have been made in RNA medicine really rest on basic research that was not aimed at developing new medicines.
NanoSphere: If young scientists entering nanomedicine today remembered only one principle over the next decade, what should it be?
Pieter: One important principle of nanomedicine is the potential for treating disease in a highly personalized way. Developing a therapeutic that will just do what you need it to do and is very rapidly produced. I think this highly personalized, individualized approach that’s very much very targeted and non-toxic is what makes it really exciting. We’re finally using the same mechanisms that your body uses to treat disease. As I always say to students, this is a great time to enter the field of gene therapy because we now have some really good tools to be able to actually do gene therapy and develop new drugs to help people.
NanoSphere: Antibody therapies such as checkpoint inhibitors can work extremely well for some patients, while others see little or no benefit. Do you think gene therapy could eventually offer a more broadly personalized approach - one that can be tailored to individual patients while still working effectively across a much wider range of people?
Pieter: Yes, I think the trial that Merck and Moderna just announced for melanoma is a great example. They are developing an LNP mRNA personalized cancer vaccine. Their results show that the cancer vaccine amplifies the effectiveness of the checkpoint inhibitors. So the two together are proving to be a huge benefit.