DIP 2

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Between 1985 and 1988, Karikó was a postdoctoral fellow at Temple University in Philadelphia. Karikó participated in a clinical trial in which patients with AIDS, hematologic diseases, and chronic fatigue syndrome were treated with double-stranded RNA (dsRNA). At the time, this was considered groundbreaking research, as the molecular mechanism of interferon induction by dsRNA was not known, although the antiviral and antineoplastic effects of interferons were well-documented.^[38]

In 1988, Karikó accepted a job at Johns Hopkins University without first informing her lab advisor Suhadolnik of her intention to leave Temple, as recounted in Gregory Zuckerman's 2021 book A Shot to Save the World. Suhadolnik told her that if she went to Johns Hopkins, he would have her deported, and subsequently reported her to U.S. immigration authorities, claiming that she was "illegally" in the United States. In the time it took her to successfully challenge the resulting extradition order, Johns Hopkins withdrew the job offer. Suhadolnik "continued bad-mouthing Karikó, making it impossible for her to get a new position" at other institutions, until she met a researcher at Bethesda Naval Hospital who "had his own difficult history with Suhadolnik".^[39] Karikó subsequently confirmed that the incident had happened as Zuckerman described, but emphasized that "more importantly I was always grateful to [Suhadolnik for] sending me the IAP66 form in 1985, for the opportunity he gave me to work in his lab", noting that "when I gave a lecture [at Temple, a] couple of years later, I thanked him for the science I learned from him."^[40] From 1988 to 1989, she worked at the Uniformed Services University of the Health Sciences in Bethesda, Maryland^[41] where she worked with signal protein interferons.^[32]

In 1989, she was hired by the University of Pennsylvania to work with cardiologist Elliot Barnathan on messenger RNA (mRNA).^[27] In 1990, while an adjunct professor at the Perelman School of Medicine at the University of Pennsylvania, Karikó submitted her first grant application in which she proposed establishing mRNA-based gene therapy.^[8] Ever since, mRNA-based therapy has been Karikó's primary research interest. However, in the 1990s, mRNA fell out of favor as many researchers, biotechs, and pharmaceutical companies doubted its potential. Though supported by Elliot Barnathan (who left UPenn in 1997) and David Langer (who then hired her), Karikó found it difficult to gain funding.^[42][43] She was initially on track to become a full professor, but after repeated grant rejections the university demoted her in 1995.^[20][44] Nevertheless, she chose to remain and continue her mRNA research.^[42][45]

In 1997, she met Drew Weissman, a professor of immunology who had recently arrived at the University of Pennsylvania.^[46] They began to exchange ideas and then to collaborate. Weissman's funding was critical in helping Karikó to continue and extend her research^[42][45] and the combination of Weissman's immunology and Karikó's biochemistry was extremely effective.^[43] They began to move the technology forward, solving problems one at a time, and eventually gaining recognition. Weissman has commented "We had to fight the entire way."^[42][45] Karikó's persistence was noted as exceptional against the norms of academic research work conditions.^[47][32][4]

Kate was really just unbelievable... She was always incredibly inquisitive. She read voraciously. She would always know the latest technology or the latest paper, even if it was in a totally different area, and she'd put two and two together and say, 'Well why don't we do this?' Or, 'Why don't we try this formulation?'

— Elliot Barnathan^[42]

Before 2005, a major problem with the proposed therapeutic use of mRNA was that in vivo use led to inflammatory reactions.^[3] A key insight came about when Karikó focused on why transfer RNA (tRNA), used as a control in an experiment, did not provoke the same immune reaction as mRNA.^[1] A series of landmark studies beginning in 2005 demonstrated that while synthetic mRNA was highly inflammatory, tRNA was noninflammatory. Karikó and Weissman determined how specific nucleoside modifications in mRNA led to a reduced immune response:^[45][3] by replacing uridine with pseudouridine.^[48] Their key finding of a chemical modification of mRNA to render it non-immunogenic was rejected by the journals Nature and Science, but eventually accepted by the publication Immunity.^[49][16]

Another important achievement by the researchers was the development of a delivery technique to package the mRNA in lipid nanoparticles, a novel pharmaceutical drug delivery system for mRNA. The mRNA is injected into tiny fat droplets (lipid nanoparticles) which protect the fragile molecule until it can reach the desired area of the body.^[26][50][51] They demonstrated its effectiveness in animals.^[52]

Karikó and Weissman founded a small company, RNARx, and in 2006 and 2013 received patents for the use of several modified nucleosides to reduce the antiviral immune response to mRNA. Soon afterward, the University of Pennsylvania sold the intellectual property license to Gary Dahl, the head of a lab supply company that eventually became Cellscript.^[53] Weeks later, Flagship Pioneering, the venture capital company backing Moderna, contacted her in an attempt to license the patent, at which point Karikó had to tell them it was no longer available.^[8]

In 2006, Katalin Karikó reached out to biochemist Ian MacLachlan to work with him on the chemically altered mRNA.^[54] Initially, MacLachlan and Tekmira turned away from the collaboration. Karikó wanted to team up with Ian MacLachlan because he was the leader of a team that helped advance mRNA technology. Karikó was working on establishing the formulated lipid nanoparticle delivery system that encapsulates mRNA in a dense particle through a mixing process.^[55][56]

In early 2013, Karikó heard of Moderna's $240 million deal with AstraZeneca to develop a Vascular endothelial growth factor mRNA. Karikó realized that she would not get a chance to apply her experience with mRNA at the University of Pennsylvania, so she took a role as vice president at BioNTech RNA Pharmaceuticals^[8] (and subsequently became a senior vice president in 2019), while maintaining an adjunct professorship at the University.^[57]

As of October 2023, Karikó is a professor at University of Szeged in Hungary.^[11]