Photo illustration by Kelvin Li
When the first COVID vaccines appeared at the end of 2020, they didn’t just shift the course of the pandemic. They also changed how scientists think about creating vaccines in general. A years-long development marathon had been turned into a months-long sprint thanks to advances in mRNA technology. Less appreciated was the fact that the work leading to mRNA vaccines stretched back 40 years — and that most researchers had viewed it as a dud.
Hungarian-born scientist Katalin Karikó, who is now a senior executive at BioNTech, was not among them. In the late 1970s, she began working on mRNA, a molecule used by the body to make proteins. By manipulating the mRNA code, cells can be made to produce different proteins, such as antibodies against infectious diseases. Though Karikó was convinced of mRNA’s potential — first as a treatment for genetic diseases and later in vaccines — most other scientists considered it impractical for medical use as it was fragile and tended to degrade quickly in experiments. Funding dried up and Karikó was left to keep the candle of research largely by herself throughout the 1990s.
mRNA’s rescue from scientific purgatory came around a decade ago in the form of tiny blobs of fat. Pieter Cullis, a biochemistry professor at the University of British Columbia, helped devise lipid nanoparticles that could surround drug molecules. This protective casing proved an effective delivery mechanism for getting mRNA into the body in one piece. This technology formed the basis of the Pfizer-BioNTech vaccine, which has now been administered more than 58 million times in Canada alone.
At MaRS Impact Health, a recent conference on medical innovation, Karikó and Cullis discussed how the COVID shot was developed, where this technology goes next — and why funders should be careful before writing off lines of inquiry as fruitless. They were joined on stage by Janet Rossant, president of the Gairdner Foundation. Here’s what they had to say.
Janet Rossant: Kati, you were the person who was convinced that mRNA could become a therapeutic. How did you start?
Katalin Karikó: It was not overnight; it was decades of hard work. In ’78, I started my graduate course getting my PhD and then I moved to an RNA laboratory. We were trying to develop an antiviral compound, which was a short RNA. And then I moved to the United States in 1989-90 and I started to write grants about mRNA therapeutic applications.
Rossant: But you didn’t have an easy task, right? Grants were hard to get, and you had to fight to make people believe that this was going to work.
Karikó: Yes, because everybody was focusing on DNA. It is permanent and everybody considered RNA just had problems. Only a very small amount of protein could be produced because RNA is so quickly degraded, and everybody thought it would not be enough to treat any disease. In addition, we learned from work we did with Drew Weissman [a professor at the University of Pennsylvania], RNA was extremely inflammatory in human immune cells. So, in the ’90s, many left the field because they couldn’t get funding, or they had run into other problems.
I was lucky to have always at least one person who felt sorry for me or who believed in RNA and provided at least the salary so I could keep going. Constantly the RNA got better. The RNA improved in a way that more protein could be produced from it.
Rossant: Then things start to come together with the lipids and the RNA. Let’s go back to the beginnings of Pieter’s story then. At what point did you start seeing what you’re doing as fundamental research that could have applications?
Pieter Cullis: In the mid-’80s, I was trying to keep a very good team that I had together at UBC. We started a company to deliver cancer drugs more accurately to where they’re needed in the body. Then of course you run into the realities of companies — the CEO came to me and said, “Look, putting these old cancer drugs into liposomes is all very well, but I can’t raise money on that. I need to be doing gene therapy,” which was coming into vogue by the mid-’90s.
This meant we had to encapsulate DNA or RNA into these lipid nanoparticles. That was a huge problem because you needed a lipid with a positive charge to associate with the negative charge on the RNA or DNA. But those molecules are really toxic — so we couldn’t use the available positively charged lipids.
Well, as luck would have it, we’d synthesized a lipid as part of our studies that was positively charged at low pH, whereas at neutral pH it wasn’t. And so, we could encapsulate the nucleic acid at low pH, and then bring the pH up. So, we now had a system that was much less toxic, but where we’ve managed to very efficiently encapsulate the nucleic acid.
In the 2000s, we started working with a company in Boston called Alnylam to deliver small interfering RNA to the liver. We managed to get a system where we could silence a gene in the liver with a therapeutic index around about 1,000 — in other words, we could give a thousand times higher dose of the medicine before we saw any toxic side effects.
And this is where Kati and Drew Weissman came into the picture. They contacted us to say, how about you try and see whether they have properties as vaccines? That worked out brilliantly.
Karikó: This is how science works — working on something and you don’t know what it will be useful for.
I accidentally learned about existence of this company. The company had no website, and nobody knew about it. The reason I went there — I could have gone to Moderna as well — but BioNTech had a clinical trial of mRNA in 2013. So, I thought, BioNTech has already an RNA in clinical trial, they know how to make RNA.
The company, at that point, was less than a hundred people. The scientist group was much smaller than today — now it is 2,000 to 3,000 people. I was delighted because we were making a product that would help somebody. That was very uplifting for me.
Rossant: It’s interesting that both of you have taken a discovery and said, I want to take it all the way through. I want to see it translated into something that helps people. How important is it really to develop those kinds of commercialization activities so that the discoveries that we make can be translated in Canada?
Cullis: We need to double down in Canada to get that mindset in place that it’s a good idea to facilitate those discoveries that are made in universities here being the basis of companies in Canada.
Forty per cent of our science, technology, engineering, math graduates go south, taking jobs in the U.S. There are about 5,000 graduates each year, so it means 2,000 are going south. If you say it costs us $200,000 to educate those people in their PhD, and you can do the math — we’re subsidizing the American industry to a remarkable extent. It’s extraordinarily important for us as Canadians to say: This is a real priority, and universities can do much better in encouraging these kinds of endeavours.
Facilitating the movement of intellectual property from the university to startup companies, as well as finding ways to fund things in the early stages — which is where most things die — for me, that’s a real driver. It’s also a heck of a lot of fun. If you’re a part of a team that is trying to do something and you’re in a small company, it’s one of the most enjoyable things you can ever do. That sense of “we’re going to do something big together” and everybody pitching in — it can be a very rewarding experience.
Rossant: What else can we use mRNA and these delivery systems for in the next few years? It seems that there’s now a lot of interest.
Karikó: The news that is coming out is around new vaccine trials that have been initiated, and Moderna has two HIV vaccines. Two different trials are ongoing. And some of the vaccines we already have were not affordable. And so, it makes many other medicines affordable — the shingles vaccine, for example, is 800 Euros. You could see [new vaccines for] not just viral diseases, but intracellular bacterial diseases like tuberculosis and also parasites. The big section of pharmaceutical industry growth is antibodies, which are very expensive, because of the protein. But by delivering mRNA coding for the antibody, patients can make the antibody themselves. It is a passive vaccination for infectious disease, as well as for cancer treatment that is already ongoing.
Rossant: What about lipid nanoparticles beyond nucleic acids? Obviously, you can put all sorts of things in them as well.
Cullis: I think the application to RNA is probably the biggest. We’ve only just touched the surface of this. There’s all the vaccine applications. Then there’s chronic disease, for example, Drew Weissman and some of his associates just published something to treat heart failure. Then, you have all the rare diseases, Tay-Sachs, Fabry. So, if a child is not making a particular protein, you now have the possibility to make the mRNA. Within a very short time — it takes a day to formulate — you have a very focused, personalized therapeutic that is affordable.
It’s a revolution in medicine and we’re seeing billions of dollars go into this area. New companies are being set up pretty much every day, and it’s an amazing time. In Canada, we need seize this opportunity. We were caught a little bit with our pants down by the pandemic. Our pharmaceutical industry has been decimated over the years. Now is the chance to correct that. It’s estimated up to half of new medicines in 10 years’ time may be based on these kind of nucleic acid approaches. We need to be a part of that story.
This conversation has been condensed and lightly edited for clarity.
Watch the full discussion here: