The big nanoparticle story behind the COVID-19 vaccine

What is From Here Forward?

From Here Forward shares stories and ideas about amazing things UBC and its alumni are doing around the world. It covers people and places, truths, science, art, and accomplishments with the view that sharing better inspires better. Join hosts Carol Eugene Park and Jeevan Sangha, both UBC grads, in exploring solutions for the negative stuff out there — focussing on the good for a change, from here forward.

[00:07] Carol: Hi. Welcome to From Here Forward, a UBC podcast network podcast. I'm Carol and she's Rumneek.

[00:14] Rumneek: That's me. Hello. Today we're doing another one of our Changemaker episodes. This is where we profiled different UBC faculty and alumni that are out there doing their amazing thing to change the world. Hence the title.

[00:26] Carol: Now, I don't know about you, Rumneek, but I love this Changemaker episode. I know academics get a bad rep sometimes for being nerds, but every now and then you do meet someone who's both smart and kind of funny. And you know me, Rumneek, I love it when men laugh at my jokes. That's all to say that in today's episode, Johal and I… Wait, do people like you’re Johal?

[00:48] Rumneek: Only you call me that and people who don't know my name and address me that way in emails.

[00:54] Carol: Okay. Well underway. Johal and I talked to or rather learned from Dr. Peter Culliss from UBC about his revolutionary work with delivery systems and DNA and RNA based drugs. His work was and is essential for the COVID 19 vaccines that we have today. A literal change maker, if you ask me. Without further ado, here is our conversation.

[01:18] Rumneek: My name is Rumneek and somewhere on your screen is Carol.

[01:22] Carol: Hello, good morning.

[01:23] Rumneek: So why don't we just start off with you giving us a brief intro. Tell us who you are and what you do.

[01:29] Dr. Culliss: Sure. My name's Peter Culliss. I'm a professor in the biochemistry department… Biochemistry Microbiology Department at UBC. And for the last years, coming on 50 years I've been working on…. they're called delivery systems or nano medicines but it's basically systems that will… take cancer drugs, for example, and the think of them a little bit more specifically to tumors to where you want them to go.

[01:57] And for the last 25 years, I've also been working on encapsulating nucleic acid-based drugs, DNA and RNA based drugs. So this has resulted in… we've had over the years 55 drugs approved by the FDA and other regulatory agencies and three of those four to do with cancer and as complications and two that we're using them to take acid-based drugs, one of them to cure a rare disease known as translating induced [?] doses, which is a mouthful. And the other the one is something up you're quite familiar with which is the Pfizer BioNTech COVID 19 vaccine where we developed the lipid nanoparticle that encapsulates the messenger RNA and allows to get inside the target cells. Without the delivery system, the mRNA vaccines wouldn't work.

[02:57] Carol: So we heard that you started at UBC or like 1964 which my math says is like 60 years almost. So what has it been like to know that you've spent six decades at one institution?

[03:09] Dr. Culliss: This is a pretty good feeling. Yeah. I enrolled in undergraduate physics in 1964 and graduated with a Ph.D. in 1972. And then from ‘73 to ‘77, I spent three years in Oxford in the U.K., doing post-doctoral work research, and then subsequently in Holland that was there for a year as a postdoc. And then I came back in 1978 to a position in the biochemistry department. So it's been a long-term association, that's for sure. It's been a very rewarding one. And in many ways I mean people can go to different institutions but it's really good when you're in a place that … where you I must say the word, the resources are there. Obviously family plays a role as well.

[04:10] And as a result as a result of that, what I've managed to do is not only from an academic point of view, I have a very successful career, but also and I played a big role in doing a lot of startup companies. I've done 12 startups which now employ about four to 500 people in the Vancouver area, all of my students or many of my students would end up in the US at one company or institution or another. And I said, we got to stop that. And the only way I could figure out stop it was to start a company where we wanted people that were in my group and we kept them local.

[04:53] And that has grown into… as I said we're now the global hub for these lipid nanoparticles which is having a huge impact worldwide. But now the world is coming to us to use this technology not just for vaccines but for many other pharmaceuticals calls for many other drugs. And so it's a very exciting time, but it's been vital to have been here over a long-term basis. And UBC has played a huge role in that.

[05:20] Rumneek: Wow. That's quite a trajectory. Carol, I feel like we need to go back to school because 12 startups and all that seems really, really impressive. So thank you for kind of tracing that. Your revolutionary work through the years have helped make MRNA COVID vaccines possible, so we're very unscientific people, Carol and I. So could you please kind of explain how that came to be?

[05:47] Dr. Culliss: Sure. A part of that has to do with some of the startups, some of the companies that we co-founded. Because it was really been very much of a joint endeavor, a collaboration between UBC and my lab and these companies. But way back in 1985, as I was saying, I had a very good team in my lab and we developed an instrument to make lipid nanoparticles… it turns out other people want that. I get a talk in New York at one time and so one of the people in the audience called me up after and said of course in those days there is no internet or anything and said I want one of those instruments. And so I said, well fine. And I gave him the contact information for a machinist who had made the rounds for us.

[06:43] Well, a couple of months later, I got this very irate phone call from this scientist in New York, say, well, I got this thing but it doesn't work. And of course, the machinists had no idea what the apparatus was used for. It was called the extruder, which we discuss what he calls it later on. And so, there was no quality control or could it actually make the nanoparticles? And so that's when we decided, okay, here's an opportunity to start a little company where we would get machinists to make it with quality tests and make sure the thing worked and then ship it out. And so this was one of the people in my lab. It would be in his garage that we assembled these things.
[07:30] And you saw we sold them hundreds over the years, a couple of thousand dollars each. And this funded parties and other things was really a lot of fun. And so that was the beginning of our entrepreneurial efforts. Somewhat later, we started to work with a company in Princeton, New Jersey, that was called the Liposome Company. And so, again, I wanted to keep the team together here. And so I said, okay, in order to keep on working with this company in Princeton, they needed to form a subsidiary here in Vancouver so we could keep the team in the same the same place, which is what they did.

[08:17] And so for five years, we formed the Canadian Liposome company as was termed. And this is all leading up to into the vaccine in the end. But the after five years, the new CEO came in and basically said, well, you should all move down to Princeton and you offered us high salaries and all the rest of it. We said no and start their own company at that point call INEX pharmaceuticals. This was about 1992 and we were working on delivering cancer drugs using lipid nanoparticles. But in 1995 the CEO that I hired, he came to me and he said, well, I really can't raise money for the company. I'm putting these cancer drugs and these old cancer drugs in liposomes.

[09:12] We need to be doing gene therapy and he felt that it had a lot more appeal to investors. So then we had to switch to that, to trying to get these big molecules. In terms of drugs, they're are big molecules. Trying to get these big molecules into cells in the body. And that was work that we for about five or six years, we worked on trying to get systems that were not too toxic because a lot of the ways of introducing DNA or RNA can be quite toxic. Anyway, so the middle of about 2005 we were contacted by a company in Boston called Mylan Pharmaceuticals.

[10:00] And they said, we want to deliver something called small interfering RNA, a piece of RNA that will… very specifically its causes, a particular protein not to be made. That's because silence is the expression of that particular protein. And so we worked with them for about seven years, which resulted in the drug that went into the clinic in 2012 that was to treat the disorder that I mentioned a little while ago.

[10:30] Transferees induced amyloidosis. That was very successful. But in 2012 another company that I co-founded called [10:36], we decided okay if we can deliver the small interfering RNA or sRNA, maybe we can deliver messenger RNA in the same lipid nanoparticles. And that turned out to be the case. And so we were trying to express these proteins in the liver so that being an intravenous injection and then we would be getting proteins made in the liver. Those proteins that were made were coded for by the messenger RNA that we were putting into the lipid nanoparticles. So that all kinds of diseases, I mean a child is born with some hereditary disease.
[11:15] They're not making the particular protein. Maybe it's involved in blood clotting, so they're hemophiliacs or maybe it's Tay-Sachs. There's a whole there's many, many disorders, these rare diseases. And so the notion was and still is that we can get the liver to make those proteins. And so therefore I rescue the child. But then about 2014 we got contacted by a scientist at the University of Pennsylvania, a guy named Drew Weissman. He's an immunologist and he said, I really want to try your system as a vaccine. And so instead of having messenger RNA coding for a protein that was being made in the liver, in this case encapsulating messenger RNA coding for a protein that was associated with the virus. In his case he said, okay, let's try Zika virus. And so we put the messenger RNA in coding for a surface protein on the Zika virus and sent it to him.

[12:13] And it worked extraordinarily well. And so that resulted in a collaboration between the company in Germany called BioNTech and [12:25] cured is the start of 2017, 2018. And the objective there was to develop a vaccine for influenza. Now, it turned out that BioNTech was also working with Pfizer on an influenza vaccine. And so in January, February of 2020, when the pandemic hit all the efforts were switched of course to making a vaccine for COVID 19. And so the lipid nanoparticle that we had been supplying for the influenza virus was moved over to encapsulate the messenger RNA for the spike protein on the SARS-CoV-2 virus which is the virus that causes COVID 19. And the Pfizer BioNTech took that into the clinic and of course the rest is history.

[13:17] In November 2020, the results were announced that this vaccine was 95% effective for preventing infection or preventing COVID-19 and across all ages and ethnic groups etc.. And so I think last year there was over 3 billion doses delivered in this year. And it's a heck of a lot of it too. I think 4 billion people in the world have felt the benefit of this vaccine. So it's had a huge impact that one could never prophesied based on what we were doing, say, about three or four years ago. So it's been a great surprise to us as you can imagine. Because we've been working to show that these lipid nanoparticles can be important delivery systems. But to have it kind of validated or proven in response to the global pandemic is really quite a startling situation.

[14:22] Anyway, so it's really changed the… this is now an established therapy for vaccines. But even more exciting is the fact that… so the same approach can be used to treat really any disease you care to name, ranging from cancer to heart disease to neurological disorders, Alzheimer's, etc.. And so it's a very exciting time in medicine as we apply the nucleic acid therapeutics using these different nanoparticle delivery systems to treat a huge range of disorders. I hope that's not too scientific.

[14:58] Carol: You brought us along and I said that… so I just kind of want to go back to something that you said a few times, is that you wanted to have your lab kind of local and keep people with you as opposed to them leaving. Why was that so important for you to maintain that locality with your lab and your researchers?

[15:19] Dr. Culliss: As Canadians, we've got to be concerned about the fact that I think 40% of our science, technology, engineering, mathematics grad, the STEM graduates as it's termed, go south. They will take jobs in the U.S. And so what are we doing training people in the Canadian taxpayer a point of view? This is not very good. Training people that are in benefit, say, the U.S. or other countries. So that's certainly one driver for me. But the other is if you got a core of well-trained, highly motivated people who get along together and then you can really build on that in a company environment. If you get that kind of team operating, as you can see from what we've done, you build on that expertise and then you …

[16:24] See, the thing is it's not just the academic or the discovery side of it. You also build, say, the intellectual property portfolio. For example, we have many patents through [16:41] and the other companies on the components of the lipid nanoparticle. The ones that work the best. So [Akudis 16:52] can license that to other companies. Anyway, you build a lot of value in the companies locally. And of course, that has huge benefits in terms of the ability to… right now we're starting up companies to look to go after blood disorders, to go after neurological disorders, skin disorders, you name it.

[17:16] Rumneek: You touched briefly on the connection with Pfizer. Can you explain further how the connection with Pfizer and Moderna came about and kind of did they approach you? How did that come to be and what can you tell us about that?

[17:28] Dr. Culliss: So with Moderna, actually through [17:32], we were working with Moderna. Now this was in the 2013, ‘14, ‘15 time period. But then Moderna decided that… they felt they had intellectual property that allowed them to move forward with their own lipid nanoparticle. The technology was really something we developed with all nine of them and lipid nanoparticle use there for the drug for transfer even induced amyloidosis as was the sRNA. Anyway, so some of the ideas were there. And so as a result of that, Moderna developed their own proprietary version. And so that that relationship stopped somewhere in around about 2016 as I remember. But then with Pfizer BioNTech as I mentioned, we were working with BioNTech on a flu vaccine and BioNTech in turn was working with Pfizer.

[18:34] And so that's how that relationship evolved. Actually it was kind of funny, in February towards the end of February of 2020, I was invited to give a talk in, so Pearl River which is just north of New York, it was the Pfizer headquarters. And I couldn't really understand that usually when I give talks and say pharmaceutical companies then basically to the scientists that I'm talking, it's not really to the or the business people or some of the people higher up in the organization. But in this talk, there was vice presidents. They all wanted to listen to what I was talking about. And I said I couldn't quite understand that. Turned out so that they were just then making the decision as to whether or not to go forward with the lipid nanoparticle mRNA vaccine. And as you know, they made a heck of a bet there. Because not only did they start the clinical trial which started in March or April of 2020 but they also started scaling up on anticipating that the clinical trial would be would be successful.

[19:48] So in other words, if the clinical trial results were not good, then they would have basically wasted half a billion dollars or some staggering amount of money. And so it was a time that they were the whole company--- it's a huge company but was really focused on whether or not they should go forward with the mRNA vaccine which was a really relatively unproven technology at that point. It's not a classical approach to making vaccines. Obviously, the preclinical results were astonishingly good but was this really going to work in people was still a question. So they obviously made the right decision. But I think the CEO more or less bet his job on that, that if the clinical trial hadn't worked out, I don't think he would be CEO anymore. He took a chance that really had a big impact. It's a guy named Albert Bourla.

[20:55] Carol: I just kind of want to go back to something again that you said about how like this wasn't really something that you anticipated and the success and how many people would be taking part in this technology. What is it like knowing that so many people have benefited from your work? Or is it something that you're just like, cool, it is what it is or is it every day where you're like, Wow, that's so wild?

[21:18] Dr. Culliss: Well, it's amazing. It's absolutely amazing, right? I mean, who would have thought. Because as I said three years ago, nobody knew what lipid nanoparticle was. While we thought this stuff was pretty important, we certainly didn't have the rest of the world convinced of that. And then suddenly we have a global pandemic, and to be playing a bit of a role in that is that is amazing. I mean, really, I just feel very happy that something that I started way back in the 1980s with about four post-docs in my lab has such an impact. So you feel pretty good about that. So occasionally, the four of us will go or a few of us will go out for a drink and celebrate that.
[22:02] But it's still… none of us can really get our heads around the fact of the big impact it's really had. It's quite so it's quite amazing. Obviously a lot of that is just plain luck or whatever you want to call it. We were in the right place at the right time as the pandemic had happened a couple of a couple of years earlier-- there was a bunch of things that came together, such as the messenger RNA. I was mentioning Drew Weissman at the University of Pennsylvania, they wouldn't have been ready for that side of the equation. Then we wouldn't have been ready from the point of view of the delivery system. So, yeah, well, a lot of things had to come together that so you couldn't forecast.

[22:47] The point, so rather than your nature of science, right. I mean, we didn't start out to make a vaccine at all. We were trying to make something that made proteins in the liver and then suddenly get cold up and that's tried as a vaccine. But so my knowledge of immunology is very scanty. And as I say, it turns out that it worked extremely well anyway. So these are the kind of events that can happen if you get involved in something and push it as far as you can and things you don't expect can occur. I always encourage people to take chances a bit because.. For example, my training is in physics, I got a PhD in physics. I said, okay, I didn't want to do physics anymore. The things in the life sciences looked way more interesting. So I took a bit of a chance there after a couple of years, I found I could maneuver in that environments. And then I thought, okay, well I don’t know anything about drugs but let's have a go at that.

[23:53] I don’t know anything about companies but let's have a go at that. And I think when you move out of your comfort zone and do things that you're not exactly all that comfort that you can do, then interesting things can happen that are obviously in my case work quite well. Oh, there's been some downsides as well. I'm not saying it's all been totally linear but it makes for an interesting life. Let’s put it that way.

[24:25] Rumneek: That is great advice, Carol. I hope you're taking notes because we need to… I mean, not that we're going to come up with some great invention that's going to save millions of people's lives but maybe something close. So to backtrack a little bit, you talked about how you spent most of your career at UBC and again, giving back to the local community in terms of providing jobs for people here was very important to you. So, can you tell us a bit about how UBC contributed to your success and kind of… if you see it as unique and special as an institution, what do you feel that's so unique and special about it that differentiates it from other institutions that you've perhaps spent time at?

[25:08] Dr. Culliss: Oh, yeah, yeah. No, I mean, it’s had a huge impact. And one that one of the things that's been good about what UBC has done. As I mentioned, I came back here in 1978 as an assistant professor in the biochemistry department, but the opportunity came along to as to say start a company which we did in 1985 I guess, the Canadian liposome company. And so I went to my head of department and said, was it, okay if I go on half time. So I was working half time at university and then half time at the company and of course being…. so I only get paid for half time. He was quite enthusiastic about this because it helped the finances of the department.
[25:59] But anyway, so that was the kind of flexibility that UBC gave me to be able to start up these start-up companies. And of course also assistance with the intellectual property. So things that were invented in my lab then the university would certainly help in terms of patenting, writing, the invention disclosures and the patent applications, and making sure that that side of things was taking care of. And then helping quite directly in some cases with… if you wanted to develop something in my lab then facilitating that process so that we could actually take it to a point where maybe something could actually be commercialized in the case of some of the instruments we worked on. So it's been a very productive relationship in that way. So yeah, that's been a huge benefit that UBC has been stay so flexible. It’s also just an amazing resource in terms of… when you've got a problem, then there's people in the university who can help.

[27:17] Carol: I mean, most of this conversation has just been the fact that you've been very, very successful in your life and you've kind of hinted at certain things. But what is an advice or perhaps a secret that you have gained throughout your life that has taught you about success and how to be successful.

[27:34] Dr. Culliss: Well, it really comes down to moving out of your comfort zone and doing something. I mean, very often these are things you want to do but you sometimes feel held back because you don't know what to do. So the example, I mean, just getting into anti-cancer drugs which we did in the eighties, we didn't know anything about how to develop a cancer drug or anything like that. But it’s surprising if you go and chat with people. In this case, we talked with an investigator, University of Toronto and said, look, we've got this was liposome. It was lipid nanoparticle with the cancer drug in it. And this is a drug called Doxorubicin which is a very common anti-cancer drug but it has a very nasty toxicity that it can cause your heart to… It causes cardiotoxicity. It causes the toxicity of the heart and can cause heart failure. And so obviously, it's not very good if you get cancer and you're being treated for cancer and then the drug can cause your heart to fail. Anyway, so it turned out that with this delivery technology, these different nanoparticle models, they weren't accumulated by the heart.

[28:59] But on the other hand, they did tend to accumulate in the tumor. And so we could have a less toxic version of this cancer drug. And so we went and presented those results to a clinician who would do phase one trials is there in terms of initial trials and people. And yeah, he said, sure, I'll take them to the clinic. And so something where we didn't have any idea of how to do things, but if you reach out enough then something happened and that drug ended up getting approved for metastatic breast cancer some ten years later. So by moving outside your comfort zone as it were, and then trying to make contact with people who might be to help you to go to that next level, can't say it's been a particular linear path, but just by virtue of starting something off, it's amazing.

[29:56] It's amazing what happens. So in terms of advice, I mean, that's probably… the biggest one is to take a chance every now and then if you really want to do something, even though you may not have a clue as to how to do it. Well, have a go and surprising things going to happen. You’re going to have some fun doing it. You always bring things when you change fields of it. You always bring something to the new field and other people don't have.

[30:24] Rumneek: And so just to kind of wrap up, although we may I don't know, Carol, sometimes surprises with the last question. So I'm going to ask my last question. And Carol, I don't know what you're going to do about that. But scientists have alluded to potentially more pandemics happening in the future. I mean, obviously, I don't know if you can predict the future but what does the future hold in store with in your opinion, with the advancement of drug deliveries or this kind of drug delivery? And do you have any kind of thoughts as to where this is going?

[30:55] Dr. Cullis: I often refer to what's happening as being the third generation of pharmaceuticals. From the first generation on drugs are these small molecule drugs like cancer drugs or aspirin or basically they go everywhere in your body. And it helps you have some benefits but it can have some downsides to the second-generation drugs or what you might call biologics or like antibodies or certain antibodies that are used for treating cancer and other diseases. But these third-generation, nucleic acid-based drugs from the reform of gene therapy really have an enormous range of applications, not just as vaccines. And so pretty much any disease you care to name, you can treat using an MRNA based therapeutic. And also change the equation as an example, the say, with sickle cell anemia, which is a pretty prevalent disorder, genetic disorder, that requires us to get rid of nanoparticles with messenger RNA. It's a bone marrow where the blood cells are made.

[32:11] Well, we're just starting to be able to do that. We're very good at doing the liver. Anyway, so as soon as we're able to do that, able to deliver RNA that, say, codes for production of proteins that will affect which form of hemoglobin is made, then you can easily see a cure for sickle cell anemia emerging or cystic fibrosis if you can get to the lung. And there it's a protein called it's just the CFTR. It's in this land transport protein. If you can get that corrected, then that disorder will be rectified. And heart disease there is now high levels of high-density lipoprotein or low-density lipoprotein or the so-called bad cholesterol leads to heart disease. We all know you can find ways of turning that on and off or modulating levels in the circulation…

[33:07] --again, using these messenger RNA based techniques. I mean, in the brain, we can transfer certain tissues in the brain and neurological disorders become open territory. So you're going to see really in the next ten years I think an enormous number of new drugs coming along that are based on this emergency approach. The other part of this that people haven't really recognize is that it's so fast because once you know what protein you want to stop making or start making or you want edit and then making the messenger RNA that will perform that function, we'll take maybe a month or so, maybe a little bit longer but not much packaged. Packaging it up takes a day or so. And so then you have this highly targeted drug to perform whatever function you want. And so it's much cheaper and much faster than our current way of making drugs which it can be ten to 15 years in a billion. Well, now we're into a month or two maybe it's true three hundred dollars. So it's a very different equation that's going to revolutionize medicine from what I can see.

[34:34] Carol: So I've heard a lot of successful people have a routine or a thing that they've done consistently throughout their lives, whether it's drinking coffee block or waking up at 5 a.m.. What is something that has been consistent in your life that you've done for a while?

[34:49] Dr. Cullis: I suppose one thing has been that I've always been part of teams, whether it's teams in my lab or teams in these companies. I really enjoy that sort of working in an environment where I'm working with a bunch of other people and we have a common aim. So long as I keep that going then I'm going to keep on going as long as I can. As I try to emphasize that without UBC none of this will happens. Certainly UBC has been very supportive over the years so it's been a good, good relationship, that's for sure.

[35:31] Carol: Well, that was a really great conversation. And as Cullis said, big shout out to UBC. She's really doing her thing and changing the world.

[35:39] Rumneek: Definitely. I mean, I thought I wouldn't have understood a single thing during that conversation but I feel like I learned a lot and it made a lot of sense. And the potential for Cullis’s discovery to treat other diseases, including cancer, heart disease and Alzheimer's is something that cannot be understated.

[35:55] Carol: And I do feel like we get to talk to a lot of really cool people as journalists. But I've got to say Dr. Cullis is probably the most coolest so far in my very objective opinion.

[36:05] Rumneek: Yeah. I mean, the fact that he contributed to something that was so pivotal in our lifetime and honestly likely changed the course of the pandemic and saved lives is wild.

[36:15] Carol: I know I said this last time but I feel like a little luck and a lot of hard work does go a long way. Personally though, I wish I had more luck in my life. But here we are.

[36:23] Rumneek: I mean, just stay hopeful because as Cullis said, if you keep trying, you never know what could happen, Carol.

[36:30] Carol: That is a wrap from us. Your favorite hosts ever.

[36:34] Rumneek: Thanks everyone for listening. Make sure you catch our next episode by subscribing or following our show on Spotify, Apple or wherever you get your podcasts. And if you're feeling your feels, please drop us a review. You can also find me on Twitter @Rumneeek with three E's.

[36:49] Carol: And me at @caroleugenepark.

[36:52] Rumneek: Today's episode was recorded at CTR Radio and engineered by Hannah Imam. From Here Forward is an alumni UBC podcast produced by Podium Podcast Company.