Bengaluru: The 2023 Nobel Prize in Physiology or Medicine has been awarded jointly to Hungarian biochemist Katalin Karikó and American immunologist Drew Weissman for their decades of research into mRNA, which enabled the effective and quick development of vaccines for Covid.
The duo’s research was based on trying to understand how different types of Ribonucleic acid (RNA) — a nucleic acid present in all living cells, structurally similar to DNA — interact with the immune system. They recognised that while immune cells do not react to mammalian mRNA, some become activated with mRNA developed in the lab and lead to inflammation.
This led them to eventually discover that, instead of using unmodified mRNA molecules created in the lab, if they modified the four nucleotides or bases (A, U, G, C), the immune response was averted in cells.
Immediately, the two scientists realised the potential to use mRNA in therapeutics. Soon, biologists around the world began working with mRNA to develop vaccines for other diseases like that caused by the Zika virus, but the duo’s work had been underfunded for decades until the arrival of the pandemic.
Covid became a global pandemic in the early months of 2020, but the impressive speed at which mRNA could work enabled the approval of two vaccines by December of the same year — the shortest time ever taken to develop a vaccine.
Karikó is only the 13th woman to win a Nobel in Physiology or Medicine since 1901, among a total of 227 laureates, including Weissman. The two have jointly been awarded 11 million Swedish kronor (SEK), roughly $980,000.
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History of development
Messenger RNA or mRNA is a molecule carrying a set of instructions that can be understood by ribosomes to produce proteins. Genetic information that is stored in our complex double-helix DNA is first broken down into single-strand RNA and processed with mRNA.
In the 1980s, labs around the world were able to produce mRNA without culturing human or mammal cells by simply producing the molecules. This was called in vitro transcription, and immediately accelerated molecular biology research.
Some scientists also attempted to use mRNA for producing vaccines and therapeutics, but the body’s immune system response was a hurdle. In-vitro mRNA was unstable and broke down easily, and in mammalian immune cells, produced inflammatory reactions.
In the early 1990s, Karikó was a professor at the University of Pennsylvania, where she worked on overcoming these drawbacks while still struggling with lack of funding. Weissman soon joined her at the same university, having worked on immune cells called dendritic cells, which patrol the body looking for foreign objects (antigens) to activate the immune system.
The two collaborated to understand why in-vitro mRNA caused inflammation in cells in the lab, while mammalian-cell mRNA was easily accepted by these cells. It was evident to them that mammalian-cell mRNA that was produced naturally had some properties that were absent in the lab-grown molecules.
It is known that bases in RNA and DNA are constantly chemically changed in the body during cell division, which is also what causes genetic errors or mutations in our code. So, they decided to try various combinations of modified mRNA, and were ultimately successful in not provoking any action from immune cells.
Their breakthrough was published in a paper in 2005, which did not receive much attention outside their niche field at the time.
The two researchers also published follow-up work, in 2008 and 2010, showing that the modified mRNA was able to increase protein production, thus making mRNA technology now viable for clinical applications like vaccines and therapeutics.
In the Covid-19 vaccines, synthetic mRNA molecules carry instructions to produce a protein that is analogous to the spike protein of the SARS-CoV-2 virus, without inserting any component of the actual virus into the human body. Once our body has processed the instructions to produce this protein, the mRNA molecule disintegrates.
Dendritic cells then immediately recognise this newly produced protein as foreign, and calls the immune system to mount a response, thus enabling it to recognise the actual virus when it uses its spike protein to latch on to the human body.
The technology has been a game-changer in vaccine development and a life-saver, helping prevent deaths of potentially millions.
A lone woman’s fight
Karikó grew up poor in Hungary, and had to sell her car on the black market to immigrate to the US. She was with Temple University from 1985 to 1990, when she joined the University of Pennsylvania.
Research into mRNA was so sparse that her work was repeatedly ignored for funding because the world had become focused on genetic engineering of DNA. In 1995, after she was demoted and refused grants, and even threatened with deportation, she accepted a lower-paid research position instead of being faculty to continue her work.
In 2013, when Moderna made a deal with AstraZeneca to develop mRNA-based therapies, she was offered a role in the company but was told that she could be let go without notice at any time. Karikó instead decided to take on the role of senior vice-president at BioNTech RNA Pharmaceuticals, which co-produced the Covid vaccine with Pfizer.
Moderna is now widely credited with putting mRNA therapeutics on the map.
Karikó is set to gain about $3 million from her decades of research, while Moderna’s CEO Stephane Bancel, investors like MIT’s Bob Langer and Harvard’s Tim Springer, and BioNTech’s owner Uğur Şahin had already become billionaires from soaring stock values by the end of 2020.
Future of mRNA
mRNA in vaccines has an established safety profile. Other mRNA vaccines currently in clinical trials are for the human immunodeficiency virus (HIV), Zika, rabies, herpes, and influenza.
mRNA is also used in some forms of immunotherapy for cancer, instructing the body to recognise cancer cells that it normally is not capable of doing.
mRNA technology acts to help our body produce proteins, and does not pass to future generations. As a result, the technology holds a lot of promise to treat medical conditions in a safe manner without modifying human DNA.
Although the technology is inexpensive and easy to produce, it did not win approvals for trials before the pandemic in any drug or vaccine.
However, since the approval of the vaccines, and now the Nobel, the technology is expected to develop rapidly and pave the way for future easier, cheaper, and safer therapeutics.
(Edited by Uttara Ramaswamy)
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