Breaking Through: My Life in Science

Breaking Through: My Life in Science by Katalin Karikó, Ph.D., was published on October 10, 2023, 8 days after the announcement that Dr. Karikó and her colleague, immunologist Drew Weissman, M.D., Ph.D. (1959–), had received the Nobel Prize in Physiology or Medicine. This inspirational book recounts the innumerable obstacles and intransigent skepticism that biochemist Karikó was forced to overcome while pursuing her ultimately successful goal of developing messenger ribonucleic acid (mRNA) technology for preventive and therapeutic purposes. Katalin “Kati” Karikó was born in 1955 in Szolnok, Hungary, to a butcher and his bookkeeper wife. The family lived in modest surroundings in rural Communist Hungary, during an era when the Party rationed basic goods, confiscated private property, filled communities with secret police, and encouraged neighbors to spy on neighbors. Kati resided with her loving parents and older sister in a tiny home without running water, indoor plumbing, or heat. Nonetheless, she was happy; she felt loved and supported by her family and had enormous gratitude for the few material comforts the family shared. From an early age, Kati loved school, had a voracious appetite for learning, and worked indefatigably to satisfy her boundless curiosity. She dreamed of contributing “my own small part to the grand mosaic that is human knowledge.” Despite its many bleak challenges, life under Communism was not total misery. One positive aspect was the government’s determination to give children of blue-collar workers access to a world-class education. Under this program, Kati was able to attend the excellent University of Szeged during summer in high school. She eventually matriculated there as a college student, graduating with a B.Sc. degree in biology in 1978 and a Ph.D. degree in biochemistry in 1982. Dr. Karikó has often remarked, “These years in Szeged were among the happiest in my life.” Hungarian culture is vastly deeper and richer than goulash, paprika, and gypsy violinists. Hungarian luminaries in music and literature include Franz Liszt (1811 to 1886), Béla Bartók (1881 to 1945), Attila József (1905 to 1937), and Péter Esterházy (1950 to 2016). Among several eminent Hungarian physicians and scientists are Ignaz Semmelweis (1818 to 1865), an early pioneer of antiseptic procedures who is often described as the “savior of mothers,” and Albert Szent-Györgyi (1896 to 1986), the first (1937) Hungarian Nobel Laureate in Physiology or Medicine, who isolated vitamin C, discovered many of the components and reactions of the citric acid cycle, and described the molecular basis of muscle contraction. The innovative Hungarian-Canadian endocrinologist, János Hugo Bruno “Hans” Selye, M.D., Ph.D. (1907 to 1982), conducted seminal work on the response of an organism to stressors. Although initially nominated in 1949 for the Nobel Prize in Physiology or Medicine, he never received the award. Nevertheless, Dr. Karikó read The Stress of Life by Selye when she was a teenager, and she writes in her memoir, “For the rest of my life, no book will affect me quite as personally, or as meaningfully, as this one.” The book helped her understand that stress isn’t exclusively a negative physiologic experience; it can also have positive forms that include motivation. With the proper attitude, we can transform negative stress into positive stress by focusing on the things we can control, rather than the things we can’t. We can respond to misfortune by learning more, working harder, and being more creative. In other words, what matters is not so much the particular nature of tribulation, but how one responds to it. This insight was to be invaluable to Kati in future years. From 1978 until 1985, Dr. Karikó continued her postdoctoral research at the Institute of Biochemistry, Biological Research Centre (BRC) of Hungary. In 1985 her lab at the BRC lost its funding, and Kati immigrated to the United States with her husband and 2-yr-old daughter, whose teddy bear clandestinely contained the family’s total financial assets of £900. From 1985 to 1988, Dr. Karikó worked at Temple University (Philadelphia, Pennsylvania) as a postdoctoral fellow focusing on interferon. She then conducted her research at the Uniformed Services University of the Health Sciences (Bethesda, Maryland) from 1988 to 1989, investigating signal protein interferon. In 1989, Kati was hired by the University of Pennsylvania (Philadelphia, Pennsylvania), where she changed her focus to mRNA-based therapy. She struggled unsuccessfully to attract outside funding and, after multiple grant rejections, the university demoted her in 1995, reduced her salary, and removed her from the tenure track. Despite these humiliations, Dr. Karikó remained at Penn and resolutely continued her mRNA research. Autobiography is a genre that offers ample opportunity to settle scores, and the author takes advantage of this option. While academic politics have a reputation for being notoriously vicious, it is only fair to acknowledge that memory is malleable, and autobiographical narrative usually presents only one version of a multifaceted story. That said, many of the behaviors described are disturbing and have been widely substantiated. Importantly, these behaviors might have dissuaded, or at least discouraged, a less tenacious (read obdurate) individual. Without delving into granular details, suffice it to say that the author encountered numerous instances at more than one institution where she felt unheard, invisible, unsupported, and disrespected. Finally, in 1997, Dr. Karikó’s professional life began to change for the better after she serendipitously met Dr. Drew Weissman, a relative newcomer to Penn, when the two scientists vied for access to a photocopier. They began to converse and discovered that their interests and backgrounds were complementary. As an immunologist, Dr. Weissman was interested in the potential for mRNA vaccines, whereas until then Dr. Karikó had been focused on the therapeutic potential of mRNA. They began a collaboration that not only was mutually beneficial but would ultimately save countless lives across the globe. The two conducted innumerable painstaking experiments over the next several years that led to transformative discoveries in mRNA technology. Since the late 1700s, scientists have used a variety of approaches to create vaccines. In the early 1990s, scientists started to investigate a new method that involved delivering genetic material (i.e., instructions) that would enable the body’s own cells to manufacture the virus proteins capable of triggering an immune response. However, several major scientific impediments initially prevented mRNA from being a practical route to vaccination. Not only is mRNA associated with transient longevity, its in vivo administration produced an aggressively deleterious inflammatory reaction. In 2005, Karikó and Weissman demonstrated that nucleoside modification (i.e., replacing uridine with pseudouridine) to lab-transcribed mRNA markedly attenuated the undesirable inflammatory response. Moreover, their later experiments disclosed that these nucleoside modifications also enhanced protein production. Another critical discovery of the research team was an innovative delivery technique involving lipid nanoparticles to protect the fragile mRNA molecule until it reaches the desired site in the host’s body. Sadly, these brilliant discoveries initially were greeted by the scientific community largely with a shrug, if not a yawn. It took the COVID-19 pandemic to expose the true worth of the pair’s meticulous work, which enabled companies to rapidly (and relatively cheaply) develop and deploy mRNA vaccines worldwide. The rest is history. Now, scientists are exploring how mRNA might be used in vaccines for other infectious disease, as well as in cancer vaccines. I enthusiastically recommend this fascinating and accessible volume to the entire medical community, as well as to lay people with an interest in science. Its contents will serve as an effective foil to those patients encountered in preadmission testing clinics who are vaccine-hesitant or resistant because “the vaccine was developed much too quickly.” Just as the mRNA molecule exists temporarily to deliver a message, readers will want to discover Dr. Karikó’s messages about how the conduct of research at academic institutions might be improved, and the necessity to question assumptions that constrain our view of the world. Booklovers will also enjoy the personal vignettes where Kati praises her extraordinarily supportive husband, Béla Francia, and her daughter Susan, who overcame herniated discs and stress fractures of the ribs to become a gold medalist in rowing at the Olympics in 2008 and 2012. It seems that dogged determination runs in the family! Indeed, this memoir is a motivating testament to what can be accomplished when an individual believes in herself and has the requisite resilience and grit to pursue her dreams. Katalin Karikó is now a professor at the University of Szeged, fittingly situated in the office once occupied by Albert Szent-Györgyi. As Friedrich Nietzsche (1844 to 1900) philosophized, “He who has a why in life can tolerate almost any how.”

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