How 40 years of mRNA research paid off for Hawking Fellowship winner Dr Katalin Karikó
A biochemist and a pioneer in the development of mRNA technology - used in both the Pfizer and Moderna vaccines - Dr Katalin Karikó is the recipient of the 2021 Professor Hawking Fellowship. Adrian Peel spoke to her before delivered the fellowship lecture at the Cambridge Union.
Her research and specialisations include messenger RNA-based gene therapy, RNA-induced immune reactions, molecular bases of ischemic tolerance and treatment of brain ischemia.
Despite the widespread praise she is receiving now, it has not been an easy ride for the Hungarian-born scientist, who has lived and worked in the US since 1985. She spent the 90s collecting rejections, as her work in attempting to harness the power of mRNA to fight disease was viewed as too far-fetched for government grants, corporate funding or even support from her own colleagues.
Dr Karikó is therefore very grateful that all of her hard work has earned her the 2021 Professor Hawking Fellowship.
Speaking to the Cambridge Independent before she delivered the fellowship lecture at the Cambridge Union, she said: “I was working on this for 40 years and for those 40 years I did not get an award – I couldn’t even get a grant and several times I was terminated in my position and also demoted from my faculty position.
“So getting all of this recognition all of a sudden – especially this one... This is a great honour, this special award, and I was really humbled when I learned that I will be the fifth fellow.”
Dr Karikó has been to the University of Cambridge before, in 1977. “That was my first trip seeing what was behind the Iron Curtain,” she recalls, “because I was in Hungary and that was the first time I could get a passport to leave the country and see what was in the West. I went to London, Oxford, Cambridge and Windsor.”
She returned, not in a professional capacity, to cheer on her daughter, Susan Francia, who was competing in the 2012 London Olympics. It seems success runs in the family as Susan, representing the United States, won a gold medal in rowing.
Dr Karikó, who came from very humble beginnings, says she originally wanted to develop mRNA for therapy, not for vaccines.
“At the beginning, everybody thought that the conventional RNA made a good vaccine because it induced an immune reaction,” she explains, “but it turned out that it was not a good immune reaction. You don’t get enough antibodies and it is quite toxic as well in humans.
“So it was developed, this non-immunogenic RNA, for another purpose – for therapeutic protein encoding mRNA – but eventually it was good for vaccines.”
mRNA – or messenger ribonucleuc acid – is a single-stranded molecule that plays a key role in protein synthesis. It carries the genetic code from DNA in a cell’s nucleus to ribosomes, which are the cell’s protein-making machinery.
Through the process of transcription, an RNA copy of a DNA sequence for creating a protein is made. The copy – mRNA – then travels from the nucleus to the cytoplasm, where ribosomes are found. They ‘read’ the mRNA instructions through the process known as translation and create the protein. The cell expresses the protein so that it can carry out its function.
The use of mRNA for vaccines and therapies relies on creating mRNA sequences that cells recognise as if they were produced in the body. These are delivered to specific cells so that the required proteins are made.
In the case of the Pfizer and Moderna vaccines, mRNA instructs cells to create a harmless piece of the Covid-19 virus’ spike protein, which provokes the immune system into
It is ingenious, but many hurdles had to be overcome to get mRNA technology to where it is today.
Asked why she was convinced it was worth pursuing, Dr Karikó says: “Because I thought that most diseases are not genetic.
“Most people don’t have genetic diseases; you more likely have aches and pains and burns, or something. I thought that you just have to reapply something – like the RNA – which will temporarily give you a protein that is beneficial for the wound to disappear and heal faster.
“You don’t need to change some kind of genome in your body, but everybody concentrated on DNA because, in 1990, the Human Genome Project started and, as they discovered new genes, realising mutations caused certain diseases, people tried to introduce the corrected genes and gene therapy was in the spotlight.”
One of the challenges to overcome was the body’s immune system reacting to synthetic mRNA. Dr Karikó says that at first she thought that synthetically-made RNA was the same as what is inside our cells.
“But when we got this immune reaction, I thought that maybe RNA had some difference – but it turned out that actually, in our cells, if it comes out and you put it in immune cells, meaning that you have an injury, you also get an immune reaction.
“But what was interesting was that when we tested out different RNA, the transfer RNA was not immunogenic, and it was known that transfer RNA has a lot of modification in it. The molecules were modified and those were not immunogenic, so we thought, ‘OK, maybe we have to put these kind of things in our mRNA and it will not be immunogenic and not cause inflammation’.
“Then there was the big headache as to how we should do that, because nobody had ever done it. We always make our RNA from four basic nucleotides, and when the RNA is made, after synthesis these enzymes will change the molecules.
“But these enzymes were not known – it was not available commercially – so we had to purchase the building blocks and make this molecule differently.
“We incorporated the already-modified building blocks, but the enzyme didn’t like that... so there was a lot of struggle and trial-and-error and then we found that we could make several mRNA this way.”
Dr Karikó continues: “Then we found that at least one of them translated very well, and three of them which all contained modified uridine were not immunogenic. So we discovered somehow that the uridine is what the human immune cells are recognising as a foreign, invading material, and generate an inflammatory response.
“If we take out the uridine and use a similar molecule called pseudouridine, then there will be no inflammation – and 10 years later they discovered that our natural mRNA in our body also has pseudouridine and everything is naturally present in our human body. So there is nothing foreign in the vaccine.”
There is a great deal of potential to the mRNA technology.
“A lot of people didn’t know that messenger RNA was already in clinical trials in many, many different applications,” notes Dr Karikó.
“It is just right now that it’s got to the front and this accelerated the process but, for heart failure, for example, injecting the messenger RNA code for a protein which helps more blood vessels inside the heart was already in a phase II trial.
“Also for diabetic patients with necrotic wounds that cannot heal, they apply that kind of mRNA code for a protein, accelerating new blood vessels so that the healing is accelerated.”
Dr Karikó adds that a cancer vaccine using mRNA has also been in development for 20 years.
“Of course the challenge is much larger because it is difficult to identify what should be the target,” she says. “For the virus it’s easy; they have 30 proteins and one of them on the surface so you can neutralise whatever is on the surface – that should be the target.
“But for cancer it’s different, and for cancer you don’t need antibodies; you need cellular immunity, you need cells which will recognise and kill the cancer cells.”
Dr Karikó delivered her lecture last Monday (November 1) and left no one in doubt that she was worthy of the fellowship. Prof Hawking would surely have approved.
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