06 Sep 2021
Issue 73: The monoclonal antibody story part 4: mAbs and the end of the age of innocence
Written by Nobel Laureate Professor Peter Doherty
Following Kohler and Milstein’s discovery (#71, #72) of how to make lots of an identical monoclonal antibody (mAb) by fusing immune B cells from a mouse to a mouse myeloma cell line, a new industry became established that was soon providing a spectrum of defined reagents. We now had standardised, very specific, commercially available products that allowed us to identify, say, viral and cell-surface proteins in both mice and humans with ease and precision. The mAbs immediately became a gold standard for both research and clinical laboratories.
An example is that, from the outset of the AIDS pandemic in 1981, staining white blood cells with mAbs told us straight off that there was a selective loss of the circulating CD4+, but not the CD8+ T cells. Losing the CD4+ ‘helper’ T cells was soon found to be associated with massive immune compromise and death from other infections, like Pneumocystis or the lethal lymphomas induced by Epstein Barr Virus (EBV). In western medicine, those disease problems were generally seen only in people (including kids) who were massively immunosuppressed due to treatment with highly cytotoxic anti-cancer drugs.
Then, after Francoise Barre’ Sinoussi and Luke Montagnier isolated (1983) the causative human immunodeficiency virus (HIV) we could show, by double staining with mAbs to HIV protein and to CD4 (#34), that the T cells were dying because they were being selectively infected with the virus. Further analysis using mAbs to CCR5, a chemokine receptor associated with innate immunity and the inflammatory cascade, showed that it was the principal cell-surface receptor that (like ACE2 for SARS-CoV- 2) allows HIV to enter the CD4+ T cell and ultimately destroy it. As an aside, a very silly mantra that was around for a while was that ‘HIV doesn’t kill people’. In fact, it just destroys the immune system so that other pathogens take you out.
The great clinical breakthrough for HIV was, of course, the development of specific anti-viral drugs that stop virus growth and allow people to live normal lives. Maybe in the future we’ll see a solution based in molecular technology – perhaps the CRISPR-Cas9 strategy – that might achieve the same result without people having to pop pills all the time. For some years now, advances in molecular science have been moving medicine forward with enormous speed. An obvious example is the mRNA COVID-19 vaccines, and the genomic approaches that facilitate the tracing of SARS-CoV-2 lineages in an outbreak. As we’ll discuss in more detail later, that has also been true for the progression of the mAb revolution which, among other points highlights the operation of the ‘law of unintended consequences’.
Back in the 1970s when the mAbs first emerged (#71), medical scientists lived in an open environment with regard to the interchange of reagents. If we knew, for instance, that another investigator had made a hybridoma cell line that might move our experiments forward fast it was, after they had published their initial research paper, often just a matter of calling them and they would send the cell line so we could grow-up our own supply of the mAb in question. Soon though, both what was happening with the mAbs and with molecular technology, convinced institutions like universities that they were sitting on a goldmine (#72) of unexploited intellectual property (IP). In hindsight, that was often overrated, though there are major exceptions.
First, all universities had to develop an IP policy that laid out how the institution and the people who did the work would benefit from any financial gain. Then, it wasn’t just a matter of calling a friend to get that latest reagent. First, ‘our people’ had to negotiate an IP agreement with ‘your people’ before anything, no matter of how little commercial value, could be supplied. In my case at least, we’d often lost interest in doing the experiment before all this was finalised.
In a sense, it was the end of the ‘age of innocence’ for discovery science in medicine with, in a few cases, that change bringing considerable wealth to some long-term colleagues. There were stories about the Ferraris in the university parking lot and medical science entrepreneurs were soon a familiar subset within the academic community. Meetings with lawyers and venture capitalists became part of university life and many of us who were not directly involved in developing new ‘products’ found ourselves serving on scientific advisory committees for biotechnology ‘start-ups’ initiated from within the ranks of researchers.
The reason for highlighting this change in culture is to point out to any who are embarking on continuing education now that a good grounding in science can be a significant plus for a career based in finance, the law and so forth. And, for the sciences, that loss of innocence/naivete and the opening out to a broader perspective has enhanced community interactions and led to the development of new industries and dollar earnings that contribute to national budgets. The ‘ivory tower’ is history.
Many of us continue to learn a great deal from encountering new ways of seeing the world through the eyes of colleagues who come at problems from a very different perspective. When I started in science, a much-admired elder observed: ‘great researchers are perpetual adolescents’. Some of us had to grow up!