Researchers often work hard in the laboratory for many years, but there is no promise that their research will produce any meaningful results for society. But sometimes this work leads to breakthroughs with global impact. This is the case with Katalin Karikó. Together with her colleague Drew Weissman, she helped develop messenger RNA (mRNA) technology, which is used to produce highly effective COVID vaccines produced by Pfizer and Moderna.
Current senior vice president and head of RNA protein replacement therapy Karikó of BioNTech (a company that co-developed a COVID vaccine with Pfizer) and Weissman, professor of vaccine research at the Perelman School of Medicine at the University of Pennsylvania. They just received a $3 million Life Science Breakthrough Award in recognition of their work in modifying genetic molecular RNA to avoid triggering harmful immune responses. The Breakthrough Prize was founded by Sergey Brin, Priscilla Chen, Mark Zuckerberg, Yuri and Julia Milner, and Annie Wojcicki to recognize the fields of fundamental physics, life sciences, and mathematics Breakthrough discovery. Despite suspicions and lack of funding, Karikó spent several years conducting this research. However, in the end, her efforts paid off-laying the foundation for extremely effective vaccines, which may be the most reliable way to escape the COVID pandemic in the world.
Kaliko was born in an ordinary family in Hungary. She began to study RNA modification during her PhD. To study and believe in the prospects of RNA-based therapies, he came to the United States to engage in post-doctoral research. She later became a professor at the University of Pennsylvania. Interest in mRNA therapy declined, and she was told to pursue other research directions or risk losing her job, but she persisted. In a conversation on the Xerox machine, she met Weisman, who was interested in developing vaccines at the time. They started to cooperate.
When foreign mRNA is injected into the body, it causes a strong immune response. However, Karikó and Weissman found a way to modify RNA to reduce inflammation by substituting one DNA “letter” molecule for another. Next, they researched how to deliver it. After testing many different delivery vehicles, they decided to use lipid nanoparticles as delivery vehicles. The results prove that these methods are very effective: the nanoparticles act as adjuvants, and this substance can enhance the expected immune response to the vaccine.
At the end of 2019, when a mysterious pathogen was spreading among people in Wuhan, China, Weissman and his colleagues had been working on influenza mRNA vaccines. Weissman quickly realized that this virus was a perfect candidate for an mRNA vaccine, and Pfizer-BioNTech and Moderna quickly turned to a job. The rest is history.
Scientific american Discussed with Karikó how she started researching mRNA, why it is a great fit for a COVID vaccine, and what other exciting medical applications it might have.
[An edited transcript of the interviews follows.]
What was your initial reaction to the award? Are you surprised, or did you expect this?
KARIKÓ: No, I never thought I would get any prizes. For decades, I never got anything. I am very happy to do this work. I received a letter from a nursing home in New York, where they celebrated. With the vaccine, no one died during the infection—for me, these are the real prizes. I know this breakthrough award-it is very famous. But, you know, I never thought about prizes of any kind. So this is a very, very pleasant surprise.
As far as the COVID vaccine is concerned, did you expect this technology to have such a big impact on the world? Or is it just your work for this pandemic at the right time and place?
KARIKÓ: I never thought about developing a vaccine. I made this modification in RNA because I always wanted to develop it for treatment. In 2000, when we learned about adding messenger RNA (which I made) to humans, they made inflammatory molecules — cytokines — and I thought I had to do something. I try to make sure that when we use it for treatment—you know, for example, to treat a stroke patient—we don’t add some extra inflammatory molecules. At first, people thought that this form of RNA immunity would be a good vaccine. The first paper published in 2017 showed that the modification we found to make mRNA non-inflammatory can produce a good vaccine, and both Moderna and BioNTech-Pfizer vaccines have this modification.
At BioNTech, I am responsible for the protein replacement program. We use modified mRNA for cancer treatment. This is not a vaccine. This is mRNA that encodes cytokines and injects them into the tumor to “warm up” the tumor so that immune cells know what to observe and eliminate the metastatic tumor. We don’t know there will be a pandemic, but I know this is a good way to make a vaccine, because my colleagues at the University of Pennsylvania and I have used it not only for Zika virus, but also for influenza, HIV, and herpes simplex. ——It has been proved in animal studies to be an excellent vaccine.
Therefore, when the pandemic begins, are you immediately aware that this may be a useful technique for developing a COVID vaccine?
KARIKÓ: Since 2018, we have been cooperating with Pfizer to develop influenza vaccines. We are ready to start clinical trials for this. But switching to COVID, this is just a technical issue. So it is ready.
If the pandemic happened 20 years ago, you will need to have a part of the virus in your body. So this will be a big delay. But commercial gene synthesis started about 20 years ago. Now you can order a gene.You order DNA and then insert it into [typically circular molecule of DNA called a] Plasmid, and then you make RNA. But getting the nanoparticles to deliver mRNA is a bit of a challenge.
Lipid nanoparticles are a key part of the technology, making it useful for vaccines, right?
KARIKÓ: In my opinion, yes. Lipid nanoparticles protect the mRNA outside the cell because there is a large amount of human RNA in the blood and everywhere. Second, it helps it to enter, because the cell picks up particles.Then in the inner body [a membrane-bound compartment] In immune cells, then this lipid nanoparticle helps to escape from the endosome to the cytoplasm [the solution inside cells] In this way, protein can be made. This is a very clever particle.
Do you think this technology can be used in many other types of applications, such as the cancer treatment you mentioned earlier?
KARIKÓ: It is already. My first job at BioNTech was to inject messenger RNA encoding cytokines… Human trials have been conducted for many years. Then another program using nucleoside modified mRNA is already underway. For example, Moderna is producing antibodies against Chikungunya virus. [In a collaboration with AstraZeneca] They have already conducted a phase II trial [led by the latter company] Inject mRNA into the heart [that] Code [a protein that] Create new blood vessels. They are still conducting clinical trials on wound healing. So the data is there-you have seen these ongoing mRNA therapy trials-but those who are not in the field don’t know. They thought, “Oh, this is the first time.” No, there are many, many other applications.
Has all this new interest in mRNA changed the field? Do you think this will accelerate the development of mRNA vaccines for other diseases, such as influenza?
KARIKÓ: Yes, if you read Wall Street Journal article [interviewing] Albert Bourla, the CEO of Pfizer, you know, he said Pfizer will seek mRNA vaccines against other diseases. They will do autoimmune diseases.We published on BioNTech this year [exposing someone to an antigen, or substance that provokes an immune response, until they can tolerate it]We used an animal model of multiple sclerosis, and we showed that if the mRNA encodes an autoantigen, you can use tolerance to autoimmune diseases. In the past, like CureVac, Moderna, BioNTech-these are small companies that cooperate with RNA. And now, all of a sudden, you can see that Sanofi is acquiring other companies, and Pfizer is doing the same, so big companies realize that they can get many products very quickly.
Do you think this mRNA technology can be a good candidate for a universal coronavirus vaccine?
KARIKÓ: I think it applies to all vaccines except vaccines against bacterial diseases. [It could work for vaccines against] Viruses and parasites, such as [those that cause] Malaria, and of course cancer-but we must better understand the target.
What are you going to use the bonus for?
KARIKÓ: Maybe, I will use it for research. I want to start a company. When I got a smaller reward, I gave it back to those who needed it more-for the education of poor children. I am 66 years old and I am not used to having a car. I have never had a new car, and I don’t think I will own one now.