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Overlooked scientific innovation reaps rewards 40 years on

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Recent headlines about therapeutic breakthroughs, such as those to treat advanced skin cancer and Alzheimer’s, involve drugs made from monoclonal antibodies (Mabs). Such drugs now make up a third of all new medicines approved for market and account for six out of ten of the best-selling drugs worldwide. Despite their importance relatively few people understand what Mabs are, where they come from or the major revolution they have brought to healthcare.

The technique for producing monoclonal antibodies was first published 40 years ago, on 7 August 1975, by scientists funded by the British Medical Research Council (MRC). At the time few understood the significance of the achievement and no British patent was sought. The failure to patent fuelled a major political controversy in the late 1970s, resulting in significant reforms of the patenting process for innovations developed by academics funded by UK research bodies.

Invisible to the naked eye, Mabs are laboratory produced molecules derived from the millions of antibodies the immune system makes to fight foreign invaders such as bacteria and viruses. The first viable Mabs were created by César Milstein, an Argentinian émigré, and Georges Köhler, a German post-doctoral researcher, on 24 January 1975 at the Laboratory of Molecular Biology (LMB) in Cambridge. This institution grew out of the MRC Unit for Research on the Molecular Structure of Biological Systems that was attached to the Cavendish Laboratory. Opened in 1962 with MRC funding, the Laboratory of Molecular Biology brought together scientists working towards the development of a new discipline - molecular biology.

Milstein and Köhler started developing Mabs as a research tool to investigate how the immune system produces so many different types of antibodies specifically targeted to the infinite number of foreign substances that invade the body. This had puzzled scientists ever since the late nineteenth century; they had struggled to isolate and purify single antibodies that targeted specific bacteria or viruses from the billions made by the body. Milstein and Köhler finally solved this problem by immunising a mouse against a particular foreign substance and then fusing antibodies taken from the mouse's spleen with a cell associated with myeloma, a cancer that develops in the bone marrow. Their method created a hybrid cell that secreted Mabs.

While Milstein and Köhler's technique marked a significant breakthrough, relatively few people at the time grasped its significance. It was not only missed by the editors of Nature, who cut short their article outlining the new technique, but also by the British National Research Development Corporation (NRDC), who declined to patent the work after Milstein submitted it for consideration. The NRDC said that they could not:

...identify any immediate practical applications which could be pursued as a commercial venture.

They concluded:

Unless further work indicates a diagnostic application or industrial end product which we can protect...we would not suggest taking any further action ourselves. 

The NRDC's inaction became highly controversial in the late 1970s and a rallying point for those concerned about the country's economic future, seeing it as yet another example, alongside penicillin, of Britain's failure to exploit its scientific discoveries commercially. Margaret Thatcher took the non-patenting issue up particularly forcefully after she became Prime Minister in 1979. She was heard to remark that the days of the NRDC were 'numbered'. The bitterness was heightened by the fact that in October 1979 and April 1980 the first two patents on Mabs were granted to American scientists on the back of cells sent to them by Milstein. A report published in 1980 by a government working party headed by Alfred Spinks, a British chemist, largely blamed Milstein who was to feel the brunt of the attack for many years. 

Why wasn’t Milstein more pro-active? Years later when asked whether he was unhappy not to have patented the technique, he answered:

I was not unhappy, Margaret Thatcher was.

He viewed patents as slightly distasteful, best left to lawyers and kept separate from scientific discovery and invention. His attitude reflected the general dislike of commercialisation among scientists in the 1970s. Nobody, for example, considered filing a patent on the protein-and-DNA sequencing techniques developed by Fred Sanger between the 1950s and 1970s.

What was forgotten at the time of the patent controversy was how casual the arrangements were for scientists sharing cell samples in the mid-1970s. Moreover the technique was still relatively untested and fragile. Indeed, soon after their Nature paper was accepted, Köhler and Milstein could not replicate their initial results, a problem that continued for six months. Even after they resolved the issue, researchers struggled to replicate the technique.

Years later, Milstein reflected that the failure to patent his technique was a blessing, allowing him greater freedom to publish and share his results, and get on with his research. Had he received a patent he would have been forced to be more secretive. Many also doubt whether the missed patent resulted in any long-term loss. Royalties would probably have been negligible, as the Köhler - Milstein Mab had limited applications and required considerable refinement to be clinically useful. Milstein played a significant role in the dissemination of the technique, welcoming researchers into his laboratory to learn the methodology and collaborating with others to demonstrate its utility. His efforts were not only fundamental to the rapid adoption of Mabs, but were also highly unusual among scientists at the time.

Many lessons were learnt from the initial failure to patent Mabs and by the early 1980s mechanisms had been established to patent innovations that emerged out of funding from  UK research bodies. Since then the MRC has gained more than £486 million in royalty revenue from patents on techniques to improve the safety and efficacy of Mab drugs that were developed by scientists at the LMB. From the mid 1990s, the LMB began earning just over £1 million per year in royalty income, rising steeply in 2000 to approximately £6 million a year.  

Over the course of the next few years at least four Mab drugs are annually expected to win regulatory approval. Their expansion is one of the fastest in the global pharmaceutical sector, being embraced by many companies in response to dwindling  revenue streams as key patents expire.  By 2020 it is predicted that approximately 70 Mab products will have reached the global market, with combined worldwide sales of nearly US$125 billion. The continuing importance of Mabs is a reminder of the long-term value of government investment in basic scientific work. 

Please note: Views expressed are those of the author.


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