most people don’t think about their liver unless it malfunctions, yet the organ performs crucial jobs in the body. it renders toxins harmless, for instance, and converts food into usable substances that are released when needed. liver inflammation, or hepatitis, causes damage that can provoke serious illness and death. it arises most commonly from microbes, including the hepatitis c virus.
2020欧洲杯在线网址in 2015, about 71 million people worldwide, including 3.5 million in the u.s., were living with chronic hepatitis c infection. the condition leads to almost 400,000 deaths globally each year. no vaccine is available and, without treatment, about 15 to 30 percent of infected individuals develop liver failure or cancer. until 2013, the standard therapy included drugs that often don’t cure the disease and that deliver severe side effects. thanks to major innovations spearheaded by charles m. rice, we now have medicines that cure about 95 percent of people afflicted with the hepatitis c virus. to achieve this feat, rice overcame obstacle after obstacle. for his discoveries, rice received the 2016 lasker-debakey clinical medical research award.
2020欧洲杯在线网址the hepatitis c virus was identified and isolated in 1989, and this advance allowed development of diagnostic tests that can assess whether a person is carrying the virus and protect the blood supply. the next step, in principle, was to grow the virus in the lab. this capability is essential not only to learn about the virus and design vaccines, but also to find chemicals that interfere with its production. such agents provide the basis for antiviral drug-discovery efforts.
2020欧洲杯在线网址the virus did not cooperate with this plan. the known hepatitis c sequence would not multiply inside laboratory-raised host cells.
this observation caught the interest of rice, then at washington university in st. louis. he was studying yellow fever virus, the prototype of the rna virus family to which hepatitis c belonged. he had recently figured out how to make, in the lab, yellow fever virus rna that could produce infectious virus after being placed inside host cells. in so doing, he surmounted numerous technical hurdles and acquired enormous insight into the replication of this viral class. rice’s expertise spurred him to wonder whether the existing hepatitis c genetic sequence was incomplete. by experimentally probing this possibility, he uncovered a novel and previously undetected segment at the end of the virus. its presence among distantly related subtypes of hepatitis c virus implied that it was important. these findings, reported in parallel by kunitada shimotohno, then at the national cancer center research institute, tokyo, suggested that the virus had failed to replicate in the lab because it lacked this feature.
rice constructed hepatitis c virus sequences that included this special tail. hopeful that they would produce infectious virus, he tested them on chimpanzees, but the rnas did not induce hepatitis or other signs of infection. this outcome sparked a second realization for rice: knowing that the virus readily picks up sequence changes not only during laboratory manipulations, but also during growth in people, he recognized that some of these perturbations might compromise the virus’s ability to propagate. by comparing multiple sequences that originated from a single person’s infection, he designed and engineered a virus that contained the most common rna subunit at each position. these choices, he reasoned, would create a “successful” genetic code for the virus—one that facilitates replication.
2020欧洲杯在线网址the resulting rna infected chimpanzees, and the animals developed hepatitis, rice and jens bukh of the national institutes of health reported in separate 1997 studies. scientists assumed that these rnas would duplicate in laboratory-grown liver cells and produce infectious hepatitis c virus. once again, the virus confounded them: replication failed.
in the meantime, ralf bartenschlager, then at the university of mainz, had been wrestling with similar challenges. he replaced portions of the hepatitis c genome—parts that package the virus but are not needed for multiplication once the virus is inside a host cell—with a gene that confers resistance to a lethal drug. bypassing the natural entry step by injecting the rna, researchers thought the replication machinery would amplify the gene that guards against the poison. only host cells that contained many copies of the gutted, protective virus—called a replicon—would survive exposure to the otherwise deadly compound. this approach would identify cells that carried viral rna sequences that could support replication.
the strategy worked, but it was inefficient. only about one in a million cells that received the rna emerged from the procedure. in 2000, rice and bartenschlager independently showed why. replicons in host cells that withstood the treatment had acquired particular sequence alterations. by engineering these adaptive changes back into the hepatitis c viral rna, the scientists dramatically increased production of infected cells. some of the sequence changes increased the efficiency more than 10,000 fold.
2020欧洲杯在线网址finally, researchers could study replication in the lab. the replicons did not generate infectious virus, so high-level safety precautions were unnecessary. they did, however, retain genes that encode components of the replication machinery, and these elements served as targets for potential drugs. the new tool afforded pharmaceutical companies a powerful way to screen for antiviral compounds and thus drove drug discovery. in december, 2013, the first in a new class of hepatitis c therapies with unprecedented potency received fda approval. a panoply of others have followed. the world now has safe oral medications that not only provide symptomatic relief from hepatitis c, but that eradicate the virus from the body.