The first known human cases of COVID-19 occurred in December 2019. About a month went by before the virus was identified and its complete genome sequence identified. This year’s Nobel Prize in Physiology or Medicine honors a 25-year-long struggle to identify the virus we now know as hepatitis C.
The A B Cs
The hepatitis viruses are a bit confusing. There are now five of them known, and while they’re united by their ability to attack the liver, they’re very different in most other ways. The most significant of the viruses are hepatitis A, hepatitis B, and hepatitis C, and they’re caused by three largely unrelated viruses—some even differ in their genetic material, using DNA versus RNA—with very different properties.
One of the first differences recognized by the medical research community was how the viruses spread. Hepatitis A infections can start due to contaminated water or food; in contrast, B and C are typically spread through contaminated blood or needles, making them a threat to the blood supply. The hepatitis A virus was the first identified, leaving researchers focused on the bloodborne B and C. B was the next identified, which is when this year’s Nobel Laureates enter the picture.
Back 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 bloods supply. That group went on to confirm that hepatitis infections were still occurring even after the blood was screened for hepatitis B. This led to the obvious inference that there must be yet another virus around. A new search was begun.
The long search
The search was not an easy one. Unlike many other viruses, including SARS-CoV-2, hepatitis C doesn’t infect any of the small mammals we use for immunology research. In fact, to this day, the only other species we know hep C infects is the chimpanzee. In addition, it’s an RNA virus, and RNA is readily degraded unless a great deal of care is taken when obtaining and handling samples. The enzyme we now use to make DNA copies of RNA—which making studies the virus so much easier—wasn’t even discovered until the 1970s, and it wasn’t commercialized until much later.
Thus, we have to wait until the late ’80s before a candidate virus for hepatitis C was described. The work that found it was truly heroic. Michael Houghton, then at the biotech firm Chiron (later bought by the pharma giant Novartis), isolated fragments of RNAs from the blood of an infected chimp, converted them to DNA, and inserted them into a virus that infects bacteria. The infected bacteria would then produce proteins encoded by these fragments, which should include fragments of the virus. Antibodies from hepatitis C patients were then used to identify which fragments were actually from 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 eventually described the full-length virus.
Showing that this virus was the one that caused hepatitis C turned out to pose another hurdle, however. The initial virus identified by Houghton didn’t cause infections when transferred to chimps. Neither did other RNA sequences identified since then. But Charles Rice, then at Washington University in St. Louis, recognized that RNA-copying systems are typically very error prone. So he scanned multiple sequences of the virus and figured out which DNA base (A, T, C, or G) was most commonly present at each position, constructing what’s called a consensus sequence. A virus made using this consensus sequence was shown to cause hepatitis symptoms.
Incremental but important
A few overall thoughts on the award. For one, hepatitis C may not seem like a major health issue, but that’s because the initial infection typically has relatively minor symptoms. The problem instead is that the infection frequently persists at low levels and will cause cirrhosis of the liver and liver cancer. Many of those infected go on to require liver transplants and, without the discoveries of these new laureates, the infection would still be spreading via blood transfusions or the use of blood products. Those discoveries potentially include the antibodies currently being tested as a treatment for COVID-19.
Despite the overall significance that makes the work of Rice, Alter, and Houghton Nobel-worthy, they really aren’t responsible for any instances of sudden breakthroughs or mind-bending insights that people like to associate with the Nobel Prize. The prize is more a matter of lots of hard work by large teams and involving many collaborators, which is the sort of incremental progress that typifies biology.
In this sense, it’s again informative to consider the COVID-19 pandemic. While progress has been more rapid—we have better tools and a far easier virus to work with—that progress has also come in the form of plenty of tentative, incremental results. These will, over time, prove essential to building a complete picture of the virus, its spread, and the symptoms it causes. The nature of biological research doesn’t change much simply because the world is attaching much greater importance to it.
Editor’s note: in the wake of last year’s prizes, we started a discussion about the prizes. The end result was that we decided to do quicker coverage on the day of the award and look into whether there were any facets of the work that merited deeper coverage that could be done later. As of right now, we don’t see anything about this year’s Medicine prize that would suggest more detailed coverage would be informative for our readers.