Identifying the pathogen: Chiron, the CDC, and the NIH

Unveiling this pathogen would require both the long-term efforts begun by the NIH on ‘non-A, non-B’ hepatitis as well as new breakthroughs in the field of molecular biology. A private pharmaceutical company Chiron used these breakthroughs, the long-term tracking work by the NIH, and collaboration with another government agency, the CDC, to crack the code behind the mystery pathogen.

In the years after the 1975 identification of a ‘non-A, non-B’ form of viral hepatitis,

government scientists sought first to prove that the causative pathogen was indeed transmissible (Tabor et al. 1978b). At the NIH and Food and Drug Administration, scientists proved that the virus taken from patients in tracking studies could be transmitted to chimpanzee, resulting in similar liver abnormalities as in humans (enzyme elevations as well as histological changes) (Alter etal. 1978a; Tabor et al. 1978b). These experiments proved the infectious nature of the pathogen. NIH scientists also elucidated the pathogen’s structure through a series of studies to determine that it was likely a virus, given its small size, and had a lipid-based outer envelope structure (Feinstone et al. 1987).67 Despite these crucial findings in the late 1970s and early 1980s, the pathogen remained elusive on a molecular level: absent its key identifying features, such as its genetic code, foreign structures that induced the body’s immune response (antigen), or the proteins making up the body’s defense against the invading agent, there was no way to detect the pathogen until it was already infecting liver cells. No one had pieced together the precise identity of the pathogen.

In 1983, a small biotechnology company, Chiron68, became interested in this mysterious form of viral hepatitis as a potential business opportunity: by identifying the virus, the company believed they could develop diagnostic tests soon afterwards and generate millions in potential

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They used filtration and extraction-based methods to elucidate its size and viral nature. Filtration studies pass molecules through small, microscopic pores to identify potential size of pathogen, whereas extraction- based methods use a form of detergent to understand what kinds of chemical configurations compose the pathogen structure.

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Founded by three university scientists from Berkeley and University of California-San Francisco, the company represented an early wave of biotechnology companies using new molecular biology techniques and corporate partnerships (Fischer 1993).

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sales to blood banks and transfusion services (Fischer 1993; Houghton 2009). Chiron’s research program into identifying non-A, non-B hepatitis occurred over six years, until 1989, with the company reportedly investing approximately $5-6 million each year which they had garnered from an initial public offering in 1983 and revenues from partnerships with larger companies (Fischer 1993). 69

A stark challenge lay before any scientist pursuing the pathogen: the blood of infected patients was not teeming with virus, making the search tantamount to finding the proverbial needle in the haystack (Alter and Houghton 2000; Houghton 2009). For the effort, they recruited a scientist fresh off his post-doctoral thesis that had involved new techniques from the rapidly evolving breakthroughs from molecular biology, Michael Houghton. After initially experiencing several rounds of failure in identifying the “needle in a haystack”, Houghton’s team turned to a) pivotal collaboration with the Centers for Disease Control and b) new tools in molecular biology developed through public funding (Houghton 2009).

In their early experiments, Chiron’s scientists relied on old biological techniques, in which pathogens were identified via a direct discernment of ‘viral structure’.70 But with the virus not abundantly present in the blood stream, these approaches failed (Alter and Houghton 2000; Houghton 2009). Searching for blood more abundant with non-A, non-B pathogens, Houghton’s team began working with Dan Bradley, a scientist at the Centers for Disease Control. In 1977, Bradley had started work on viral hepatitis when a company that produced blood clotting

proteins for hemophiliacs became concerned that non-A, non-B hepatitis could be transmitted via its product (Bradley et al. 1979). After being approached by the company, Bradley began to test the hypothesis in chimpanzees. Upon confirming the company’s suspicion, Bradley continued to develop the chimpanzee model and determined which chimpanzee samples had the highest levels of infection coursing through their blood plasma and liver.

Recent advances in molecular biology by 1985, however, allowed Bradley and another Chiron scientist, George Kuo, to propose an alternative, and ultimately fruitful route: cloning many, many copies of the virus, and then assessing its structure through indirect methods such as matching these copies with potential viral antibodies (Houghton 2009). By this strategy, called blind immuno-screening, cloned copies of genetic material from the infectious samples developed

A decade later, Chiron would use this investment as a justification for its wide-ranging and contentious intellectual property claims on the Hepatitis C virus which I briefly highlight in the following chapter.

70 _{For example, they tried to bind genetic material from infected livers with those of known viral genomes}

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by the CDC’s Bradley would be tested against antibodies from infectious patients. Rather than trying to find the needle directly, in other words, they came up with a ‘magnet’ – the antibody – and then attempted to find out whether the antibody would detect one of the cloned copies of the ‘needle’ (the virus) taken from Bradley’s infectious chimpanzees (Houghton 2009). The approach worked: one of the cloned copies from the chimpanzees bound to the antibody. These molecular biology techniques were made possible through breakthroughs in manipulating genetic material made in the 1970s, These advances, pioneered by scientists Stanley Cohen and Herbert Boyer and funded by the National Institutes of Health, laid the technical basis for Chiron’s strategy and an entire new sector of biotechnology (Cohen et al. 1973; Pisano 2006; Vallas et al. 2011).73

One more major step remained in confirming the identify of the pathogen: testing

whether this antibody would detect the virus not just in chimpanzees but in the infectious human patients that the NIH’s Harvey Alter had tracked for over two decades. Multiple groups had approached Dr. Alter to see whether they had correctly identified the pathogen. Alter reflected, “By 1989, many different laboratories claimed to have developed a non-A, non-B assay and asked to test the panel. None were able to break the code and by 1989, the score was viruses, 20; investigators, zero” (Alter 2013:10). But at this point, Alter received a call from one of Chiron’s scientist, asking Alter to trial Chiron’s antibody test against the panel of blood he had carefully tracked over decades. To Alter’s surprise, the Chiron test worked. He tested the pre-transfusion and post-transfusion samples, and found that the antibody tested negative in the pre-transfusion group, and positive in the post-transfusion group, just as would be expected from the right test. Fifteen years after identifying a non-A, non-B pathogen, scientists working across Chiron, CDC, and the NIH had solved the puzzle in 1989 (Choo et al. 1989).74 They called the virus hepatitis C.

In sum, the post-war period to 1989 required an ascendant National Institutes of Health and a series of public sector organizations (including the Centers for Disease Control and Veterans Affairs) to pursue an unknown pathogen through patient investments. First, through

73 _{Cohen and Boyer were able to use a kind of protein called ‘restriction enzymes’ to cut small, circular}

pieces of bacterial DNA called plasmids at specific, known sites, and then insert DNA from another organism into those gaps. The bacterial DNA then replicated in large numbers, proliferating the newly manipulated DNA and its proteins. This technical foundation was elucidated and developed through significant federal funding from the NIH, with the seminal studies by Boyer and Cohen along with Paul Berg conducted in the early 1970s. Their research paved the way for further experimental possibilities, with 123 NIH-funded projects funded by 1976 (Vallas et al. 2011).

74 _{In a major award for the discovery of the virus, the Gairdner Prize - all three – Houghton from Chiron,}

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long-term tracking studies of infectious patients, scientists at the NIH were able to identify the existence of a unique pathogen leading to a chronic but infectious form of hepatitis, which they dubbed non-A, non-B hepatitis. Second, by applying biochemical and histological analysis to these long-term tracking studies, publicly funded scientists across the NIH, CDC, and VA revealed that this form of hepatitis was not a benign entity, but rather the cause of a serious disease

process that could end in mortality for a significant number of its human hosts. Finally, critical collaborations between Chiron and the CDC and NIH, along with new publicly funded advances in molecular biology, enabled the discovery and identification of the precise pathogen. Yet this early stage research would only mark the beginning of the scientific effort behind hepatitis C: further advances would rely on patient public capital to overcome a major technological hurdle posed by the virus.