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The first known human cases of COVID-19 occurred in December 2019. It took about a month before the virus was identified and the full genome sequence was identified. This year’s Nobel Prize in Physiology or Medicine honors a 25-year struggle to identify the virus we now know as hepatitis C.
The AB C
Hepatitis viruses are a bit confusing. Five of them are now known, and although they are linked by their ability to attack the liver, they are very different in most other ways. The most important viruses are hepatitis A, hepatitis B, and hepatitis C, and they are caused by three largely unrelated viruses, some even differing in their genetic material, using DNA versus RNA, with vastly different properties.
One of the first differences recognized by the medical research community was how viruses spread. Hepatitis A infections can start from contaminated food or water; on the contrary, B and C are usually transmitted through contaminated blood or needles, making them a threat to the blood supply. Hepatitis A virus was the first to be identified, leaving researchers focused on bloodborne B’s and C. B was the next to be identified, which is when this year’s Nobel laureates enter the scene.
In the early 1970s, Harvey Alter was at the US National Institutes of Health, working with a group trying to improve the safety of the blood supply. That group went on to confirm that hepatitis infections continued to occur even after the blood was tested for hepatitis B. This led to the obvious inference that there must be yet another virus. A new search was started.
The long search
The search was not easy. Unlike many other viruses, including SARS-CoV-2, hepatitis C does not infect any of the small mammals that we use for immunological research. In fact, to this day, the only other species that we know of infecting hepatitis C is the chimpanzee. Furthermore, it is an RNA virus, and RNA is easily degraded unless great care is taken when collecting and handling samples. The enzyme that we now use to make DNA copies of RNA, which greatly facilitates studies of the virus, was not even discovered until the 1970s, and was not commercialized until much later.
Therefore, we have to wait until the late 1980s before a candidate virus for hepatitis C is described. The work that found it was truly heroic. Michael Houghton, then at the biotech firm Chiron (later bought by the pharmaceutical giant Novartis), isolated fragments of RNA from the blood of an infected chimpanzee, converted them into DNA, and inserted them into a virus that infects bacteria. The infected bacteria would produce proteins encoded by these fragments, which should include fragments of the virus. Then, antibodies from hepatitis C patients were used to identify which fragments were actually of the virus.
In the end, Houghton and his team managed to identify a single fragment of a previously unknown virus. But that was enough; using the fragment, they finally described the virus in full length.
However, proving that this virus was the one that caused hepatitis C turned out to be another hurdle. The initial virus identified by Houghton did not cause infections when transferred to chimpanzees. No other RNA sequences have been identified since then. But Charles Rice, then at Washington University in St. Louis, acknowledged that RNA copy systems are often very error prone. So he scanned multiple sequences of the virus and discovered which DNA base (A, T, C, or G) was most commonly present at each position, building what is called a consensus sequence. A virus made with this consensus sequence was shown to cause symptoms of hepatitis.
Incremental but important
Some general thoughts on the award. On the one hand, hepatitis C may not seem like a major health problem, but that’s because the initial infection usually has relatively minor symptoms. Instead, the problem is that the infection often persists at low levels and will lead to cirrhosis of the liver and liver cancer. Many of those infected require liver transplants and, without the discoveries of these new laureates, the infection would still be spreading through blood transfusions or the use of blood products. Those discoveries potentially include antibodies that are currently being tested as a treatment for COVID-19.
Despite the general importance that makes the work of Rice, Alter, and Houghton Nobel-worthy, they are not really responsible for any cases of sudden breakthroughs or mind-blowing ideas that people like to associate with the Nobel Prize. The award is more a matter of a lot of hard work by great teams and the participation of many collaborators, which is the kind of incremental progress that characterizes biology.
In this regard, it is again informative to consider the COVID-19 pandemic. While progress has been faster (we have better tools and a much easier virus to work with), that progress has also come in the form of many interim and incremental results. These, over time, will be essential to build a complete picture of the virus, its spread, and the symptoms it causes. The nature of biological research does not change much simply because the world attaches much greater importance to it.
Editor’s Note: In the wake of last year’s awards, we started a discussion about the awards. The end result was that we decided to do a quicker coverage on award day and see if there were any facets of the work that deserved deeper coverage that could be done later. At this time, we don’t see anything about this year’s Medicine award to suggest that more detailed coverage would be informative for our readers.
