by Piyush Nanda
figures by Shreya Mantri

Gravity has been apparent for thousands of years: Aristotle, for example, proposed that objects fall to settle into their natural place in 4th century BC. But it was not until around 1900, when Issac Newton explained gravity using mathematical equations, that we really understood the phenomenon. Why didn’t thinkers before Newton think about gravity the way he did? Scientific history is riddled with examples of phenomena that have been observed way before they were understood, explained or utilized – bacterial plates had been contaminated with fungus before Alexander Flemming observed them and diversity in the physiology of living beings was known before Charles Darwin characterized it – but it took different kinds of scientific thought to really elucidate these observations. Today, such different kinds of scientific thought often come together to solve a single problem. 

In this article, we will see how three kinds of strategies used in scientific explorations of nature can be combined to elucidate one of the biggest issues facing our world right now: the COVID-19 pandemic. From the fundamental description of messenger nucleic acids (mRNA), to the development of the lipid nanoparticle delivery system, to the technological advances allowing for the description of the viral antigen, the coexistence of diverse  scientific approaches allowed us to quickly develop defenses against the SARS-CoV-2 virus. 

The global response to the COVID-19 pandemic demonstrates how “basic science” can be turned into usable knowledge for the fight against a disease. “Basic science” refers to scientific work aimed at understanding the processes of life at a fundamental level, regardless of immediate applicability to the world of medicine or technology. The development of mRNA vaccines can be traced back to two papers led by Sydney Brenner and James Watson in 1961, in which scientists demonstrated the presence of  molecules known as messenger RNA (or mRNA) in living cells, that relay genetic information from the archives in the cell’s command center (the nucleus) to the cell’s factories (the ribosomes) (Figure 1). This fundamental mechanism of informational relay within cells allowed us to understand how the genetic code is translated to protein molecules, the building blocks that perform most biological functions, from digesting food to fighting diseases. 

Figure 1: Sydney Brenner, James Watson, and colleagues figured out that mRNA is the molecular messenger that relays information from the nucleus, the command center of the cell, to the ribosomes, the cell’s protein making factories. 

Curiosity fuels search for cure

The discovery of mRNA gestated in the scientific community for about 30 years until, in the 1990s, Katalin Karikó and Drew Weissmann got fascinated by the idea of using mRNAs to express therapeutic proteins in the human body. If the body uses mRNA to tell the cell which proteins to make, can’t we artificially introduce an mRNA that will instruct the body to make a drug by itself? Decades of scientific work led Karikó to figure out that natural mRNA originating from outside the organism triggers the immune system and therefore isn’t suitable for injection into the human body. But another kind of RNA involved in protein synthesis, transfer RNA (tRNA), does not trigger an immune response. A tRNA is made up of modified molecules known as pseudouridine that are not recognized by the immune system, thus evading an immune reaction. Karikó and Weissman synthetically changed mRNA to contain pseudouridine instead of its usual molecular make-up so that the modified mRNA does not trigger an immune response (Figure 2). By understanding how mRNA functions in normal cells, Karikó and Weissmann were able to apply this knowledge towards therapies for human diseases by turning mRNA into a platform that can instruct our bodies to express molecules, such as those in vaccines, that are able to “train” our immune system to fight against diseases. 

Figure 2: Katalin Karikó discovered that tRNAs escape immune response and, along with Drew Weissmann, was inspired to utilize the modified molecular makeup of the tRNA to engineer an mRNA molecule that can produce drugs (vaccines) directly in the body. 

From lab to clinic

A key hurdle to the actual application of Karikó and Weismann’s mRNA technology to the real-world fight against diseases was that mRNAs are unstable and susceptible to degradation by enzymes in our body. Scientists hypothesized that encapsulating the mRNA in lipid nanoparticles could protect them from degradation and allow safer delivery to the cells in our body. To that end, a game-changer in the mRNA vaccine war against COVID-19 was the lipid nanoparticle that was used to deliver the vaccine-encoding mRNA to tissues in our bodies. 

Interestingly, the history of lipid nanoparticles as delivery systems can be traced back even beyond mRNA vaccines. In the early 1990s, even when mRNA vaccines were a developing subject, scientists, including Pieter Cullis, started working on lipid particles called liposomes to deliver drugs to tissues in the body. When discussions on using DNA and RNA as drugs gathered momentum, researchers started testing if lipid nanoparticles could be used to deliver DNA or RNA. But there was a problem: RNA and DNA are negatively charged, so the lipid particles would need to have a positive charge in order to stay together. However, positively charged lipids are not often found in nature and synthetic positively charged lipids are toxic to our bodies. Despite this, Cullis and his colleagues figured out a way to make lipids that can switch their charge based on their surrounding environment, enabling the lipids to become neutral within the human body. Cullis’ team developed ‘ionizable cationic (positive) lipids’ (Figure 3). This technology was ultimately used to deliver mRNA vaccines during the COVID-19 pandemic. The technological advancement of drug delivery methods combined fundamental scientific knowledge and translational research to bring usable mRNA vaccines to the world of medicine. 

Figure 3: Peter Cullis developed ionizable lipids, which have a positive charge to strongly interact with the negatively charged nucleic acids (mRNA) and shield the mRNA from degradation, but become neutral when inside the body to prevent toxicity.

Seeing the mRNA vaccine development as a collection of discoveries derived from diverse lines of scientific inquiry is an excellent example of how knowledge comes from integrating different schools of thought and directions. Some scientists research to uncover how the world works in detail, some are passionate about developing cures for the most significant health challenges facing mankind, and some love developing new technologies that aid the advancement of scientific research. This diversity in scientific methods propels scientific progress and helps us tackle some of the biggest problems facing life on earth. 

Gravity, penicillin, and evolution, some of the biggest scientific discoveries, have come not from observing something completely new to the world, but from applying a fresh framework to an observation that has always existed in nature. There are parts of our world that would have remained concealed from our understanding if scientists didn’t think of approaching problems differently. Importantly, as scientific problems become more refined and complex, integrating different scientific approaches and disciplines will become more important in moving science forward. 

Piyush Nanda is a third-year PhD student in the Biological and Biomedical Sciences Program working in Andrew Murray’s lab. He studies how cells regulate metabolism in fluctuating environments. You can find him on Twitter as @NandaPiyush.

Shreya Mantri is a PhD student in Biological and Biomedical Sciences at Harvard Medical School.

Cover image by chenspec on pixabay

For More Information:

  • Interested about how basic science has played a role in drug development? Read Mark Fishman’s article on ‘Curiosity brings cures’ here.
  • For more information on how mRNA was discovered to be the key material that transmits information in cells, check out this essay
  • This article gives an account of how lipid nanoparticle invention helped  mRNA vaccines be delivered correctly.
  • mRNA vaccines can be gamechanger for a variety of diseases. Check out the diseases currently being targeted with mRNA vaccines on this webpage.

This article is part of our special edition on diversity. To read more, check out our special edition homepage!

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