Goose that lost the golden egg

Twenty-five years ago, two Cambridge scientists won the Nobel prize for medicine for a paper on monoclonal antibodies. But their technique was not patented and US drugs firms reaped the billion-dollar rewards. One of the pair, Cesar Milstein, explains what happened

When I started my research in immunology at the Laboratory of Molecular Biology in Cambridge 37 years ago, it never crossed my mind that my work had potential practical applications. Indeed, the atmosphere was of complete unconcern about such matters, not withstanding the underlying belief that advances in basic science inevitably open opportunities for practical applications.

It was in that healthy environment of scientific curiosity that, following Fred Sanger's suggestion, I decided to find out how animals learn to recognise all sorts of foreign substances such as microbes, viruses and toxins, even when they have never encountered them. To do so they are capable of producing thousands of millions of different structures, indeed many more than the coding capacity of the whole genome.

The paper (written with George Kohler) consisted of two parts. In the first, we showed that the expression of the immunoglobulin - a class of antibody proteins - remained valid in hybrid mouse-mouse tumour cells. It was our success with this experiment and our need for our own antibody-producing cell in culture, that led to the second part. We showed that by substituting a tumour cell with a pool of spleen cells from an immunised donor, it was possible to immortalise cells secreting an antibody of a pre-defined specificity.

Monoclonal antibodies made it possible first to target unknown molecules almost at random, and subsequently to establish their function. This was a fundamental change in the analysis of biological problems.

The use of this technology opened new vistas in basic research. Although their importance as diagnostic and therapeutic tools is now recognised I believe we are still looking at the tip of an iceberg.

What made the approach particularly powerful and attractive was (and still remains) that monoclonal antibodies were at the same time a fundamental tool for functional as well as molecular biological studies. They were used to study expression of substances that cause antibodies to be formed, called antigens, in different tissues and cell types, and to isolate and further analyse cell sub-populations. Monoclonal antibodies also became standard tools for purifying target antigens and were used for DNA cloning for the genetic characterisation of the target antigen.

As time goes by they are becoming the vehicles for clinical diagnosis and/or therapy. In these days of genomic analysis, monoclonal antibodies are a tool to define the function and potential usefulness of the host of unknown genes uncovered by the genome project.

While the above application of the monoclonal antibody technology was the basis for a new market that neither we nor early market analysts had expected, other applications were easier to predict. The most obvious was in the area of immunoassays, well exemplified by the introduction of the home-based pregnancy test. Equally obvious was the use of monoclonal antibodies in passive immunotherapy.

For this, however, it was necessary to derive human monoclonal antibodies and this proved to be very difficult. A new technology was born as an experiment to give us the tools to analyse the genetic origin of antibody diversity and specificity. Further academic developments opened vistas well beyond immunology, transforming the way we try to investigate and analyse biological phenomena. These purely academic pursuits had a spill-over into the world of commerce to feed the emerging biotechnology revolution. A few of those applications became very obvious by the time we wrote our 1975 paper, which ends with the sentence: "Such cultures could be valuable for medical and industrial use."

Yet the procedure was not patented. A considerable number of ill-informed opinions have been given, including some from official sources such as the Spinks report on biotechnology by a joint working party of the Advisory Council for Applied Research and Development, the Advisory Board for the Research Councils and the Royal Society. This report, published in 1980, stated that: "We are concerned that a lack of appreciation of National Research Development Corporation (NRDC), particularly by young scientists, may continue to result in situations such as that which occurred over monoclonal antibodies."

I am afraid that I did not quite see things in that way, perhaps because I was better informed. The facts are that before the paper was published I sent a pre-print of the paper for consideration for patenting purposes, but nothing happened. Even one year later, the NRDC felt unable to identify the patenting features presented in our paper.

Furthermore, as late as in 1993, at a meeting organised by the Wellcome Institute for the History of Medicine, entitled "Technology Transfer in Britain: the Case of Monoclonal Antibodies", the NRDC submitted a document suggesting that a patent based on our 1975 paper was premature and that considerable further work had to be carried out in secrecy to develop the invention to a state when it could have been patented.

Scientists saw things differently. We not only resented secrecy but also considered that it should be possible to reconcile our scientific interests with benefits to the public at large and indeed with legitimate commercial exploitation. New approaches were required and an early example was provided, by the exploitation of the monoclonal antibody to interferon.

Today it is difficult to appreciate the scientific as well as entrepreneurial atmosphere prevalent at the time. In those days, neither employees nor the Medical Research Council, itself were allowed to register patents. This was reserved to the NRDC, a separate government organisation. There were no incentives to patent inventions because neither the inventor, the laboratory nor the MRC itself could expect financial returns.

In any event, given the nature of entrepreneurs in 1975, it is dubious that they would have been willing to develop the discovery. It was not only a question of patenting but also of how to exploit inventions. Time proved that it was scientists who changed the approach to commercial exploitation.

The aggressive approach taken by American entrepreneurs to commercialise monoclonal antibodies took considerable time to materialise in the rest of the world, including the United Kingdom. It seems that the major problems arose largely because of the conservative nature of local entrepreneurs and venture capitalists and not because of the reluctance of scientists and the scientific community. On the contrary, scientists were, at least in the monoclonal antibody saga, often the ones who pushed for novel and imaginative ideas for the commercialisation of further developments.

The prevailing atmosphere both in academia and in industrial and financial circles has turned a full circle. Young scientists are increasingly keen to take initiatives at a level that goes well beyond their pure scientific curiosity. Although many consider this a salutary state of affairs, I am concerned with the consequences. Perhaps this is a good occasion to pause and remind ourselves of the story of the goose and the golden eggs. The golden eggs of industry arise from fundamental discoveries and these in turn usually come from scientists left free to pursue their own curiosity.

This is a summarised version of a speech to the Medical Research Council conference to mark the 25th anniversary of the paper.