Translation of a text to be published by the King Baudouin Foundation of Belgium and used as the basis for a presentation at a conference organised by the King Baudouin Foundation, Brussels, April 20, 2002.

Dr. Erik Tambuyzer, Chairman EuropaBio

Vice-President Corporate Affairs Europe, Genzyme Corporation

Text written by Marleen Finoulst, M.D. based on an interview

The word biotechnology is a cross between the Greek words 'bios' (everything to do with life) and 'technikos' (involving human knowledge and skills). Biotechnology makes use of biological systems to manufacture products and provide services. The biological systems that have traditionally been used are organisms such as yeasts, fungi or bacteria. Examples of biotechnological processes "avant la lettre" include beer brewing or wine and cheese making.

In recent decades biotechnology has gained considerable momentum and has developed at a fast rate in response to increasing knowledge of biological mechanisms. The great breakthrough arrived when scientists discovered how hereditary material, DNA, is stored in cells and functions. This knowledge made it possible to change the DNA of a cell in such a way that the properties of a cell could be steered in a certain direction. Armed with this ability, scientists succeeded in using biological processes for applications that are useful to people, animals and the environment, which opened up markets to them... Some new technological developments such as the large-scale production of human proteins as medicines via biotechnology yield better forms of treatment for diseases such as multiple sclerosis and some types of cancer, and for the first time in history have made it possible to treat patients with rare genetic diseases. Other applications have found their place in the agricultural sector.

The charting of the human genome, the Human Genome Project, is also extremely interesting to the biotechnological industry, not least from a medical perspective. This knowledge opens up possibilities for the development of new medicines, vaccines, diagnostics and the detection of hereditary abnormalities and perhaps even gene therapy. There are currently nearly a thousand hereditary diseases that can be identified using genetic tests, and this number will continue to rise. Most genetic tests are intended to identify a hereditary disease (diagnostic), or to detect their carriers, while others are aimed at predicting whether a certain hereditary disease will manifest itself. A genetic diagnostic test can also contribute to selecting a successful therapy. Or it can indicate appropriate preventative measures or help people to make the right decision.

A well-known example is the PKU test, which all newborn babies are subjected to. The drop of blood taken from the baby's heel is tested for the presence of the gene defect for phenylketonuria, a metabolic disease that, without the correct diet, will result in mental retardation, which could be avoided by taking appropriate dietary measures.

Genetic tests developed by geneticists have already given the medical world much-needed support. Gene therapy is not yet as advanced. In essence, gene therapy involves the transfer of new hereditary information to the cells of an individual with the aim of correcting a hereditary defect. Theoretically, this is an attractive option, but in practice there are still many obstacles to be overcome. One of the main possibilities is to insert the therapeutic DNA into precisely the right place in the human genome. As is the case with many new medical technologies, it takes a great deal of time, usually twenty years or more, to convert a promising technology into practical, commercial applications because the safety of the patient and the effectiveness of a new treatment must first be irrefutably proven. To give an example, the technology involving monoclonal antibodies, which was discovered at the end of the nineteen-seventies, has only resulted in new medicines during the past few years, such as medicines for the treatment of Crohn's disease, breast cancer, rheumatoid arthritis and cardiovascular diseases.

Biotechnological knowledge and the derived procedures are presently being applied in approximately one in four new medicines, in increasingly more medical instruments, in diagnostic products and in genetic tests. Biotechnology has not only led to the foundation of biopharmaceutical and biotechnological companies, but contributes to a restructuring of the existing health care sector as well. It also affects the way in which we see health structures because prevention starts to play a more prominent role.

Since the nineteen-nineties more and more use has been made of molecular genetic tests in order to identify abnormalities and genetic defects in the human genome. These genetic tests are sometimes complimentary to the existing cytogenetic tests, and in some cases may even replace them. Monogenic diseases are caused by the absence of an important protein or by the presence of an abnormal protein. Mucoviscidosis, muscular dystrophy, Gaucher's disease, Fabry's disease and Huntingdon's diseases are all examples of monogenic diseases. There are often several variants or mutations of genetic defects of this nature. For mucoviscidosis, for instance, more than nine hundred mutations have been found up to now, most of which are extremely rare. Unlike the monogenic diseases, there are many more diseases that are caused by a combination of environmental factors and one or more hereditary factors.

Patenting genetic material

It goes without saying that it costs a lot of money to bring about the necessary biotechnological innovations via research and development and supply them to our society as products or services. It is also mandatory that industry will invest in this R&D, but there must be a return on that investment to prevent companies from closing down, which would result in no more innovations being developed. After all, the industry is the only group at global level that places commercial products and services on the market. To prevent competitors from gathering the fruits of the research into which a lot of money has been invested, the inventor can apply for a patent on his or her invention. A patent is a form of intellectual property right that is issued for inventions that are new, contain and inventive step and have industrial application. The purpose of a patent is to protect such invention against unfair competition from third parties, so that it remains an attractive option to continue investing in innovation. In the health sector a new invention can only culminate in a commercial product following in-depth research that takes many years. A patent ensures that the patent holder has the exclusive right to ultimately manufacture and sell the products based on the invention for a period of twenty years from the time at which the patent was issued. It is often the case only a few years are left, when the products are finally approve to market, to earn back the investments that have been made. During that time the invention has however been published in detail by applying for the patent (otherwise a patent will not be issued) so that other scientists can make use of the published knowledge and try to improve on it. To return to the example about monoclonal antibodies, the first commercialised therapeutic applications arrived after twenty years of research and further development, at the time the patent period for the first technology patents ended. Fortunately, diagnostic applications based on monoclonal antibodies were applied in practice much earlier, so that it was possible for funds to flow back to the original patent holders.

Investing in biotechnology calls for significant sums and patents are therefore an absolute must when it comes to attracting investors. On the other hand, questions can arise regarding the patenting of genetic material. Each living organism has only one genome. If an inventor (an institute, a company or an individual) takes out a patent on hereditary material, this implies that he has a license on a certain gene or genome fragment, albeit for a limited period of time. To patent these materials, the basic rules for patenting outlined above have to be followed: the item being patented must be new, must be an invention rather than a discovery, and must have industrial application. That is why the inventor must also provide extremely detailed information that provides the required proof when making the application for the patent, otherwise the patent will be rejected. This makes it impossible to patent living material that is found in nature. The patenting of genes therefore evokes ethical questions, because without the exclusivity and the protection of a patent it is not possible for the inventor to convert his research result into a commercial product and obtain a return on his investment. In other words, the medical innovations that are currently being placed on the market would not have seen the light of day if it had not been possible to patent the original inventions.

The path that has to be followed between promising research results and a commercial product runs from identifying an active component, in vitro safety and effectiveness tests, determining the correct dose and other product specifications, in vitro studies, in vivo clinical studies, validation and setting up production processes. Cost price: on average 800 million EURO'S per therapeutic product. Without the protection of a patent, this type of investment would be inconceivable, because no investor on earth (and that includes many of us who invest on the stock market) would risk his money in something that could be copied the next day by another company! Copying is possible once a patent has expired, and a company therefore has to try to earn back its investment during the period covered by the patent protection. Consider, for example, the rise of generic medicines.

The patenting of genes whose function is known has been done to a significant extent by academic laboratories on the one hand, which licence them out to companies for royalties and other payments, and by the industry on the other. Some companies have also attempted to patent gene fragments. A consensus has been reached that patenting is only possible if there is detailed knowledge of its function and usage. There are some universities that speak out against the patenting of human genes in public, but at the same time offer licences to the industry for the use of some gene patents or technology. This attitude cannot be described as a logical one.

Development of genetic tests

The development costs for genetic tests are lower than those for the development of new medicines, but are none the less rising. Before considering developing a genetic test, it is first necessary to perform epidemiological and other research to establish whether a test of that nature could be useful within the scope of public health. And there is more: many technologies or procedures have been patented. To use these, it will be required to negotiate with the patent holder. And a licence of course has to be paid for, which means that the cumulation of licences on patents for genes, mutations, procedures and materials result in the development costs for genetic tests increasing still further.

A great deal of attention has to be paid to the development of genetic tests. It is not enough simply to consider the possible ethical implications: there must also be quality control so that the result is correct. At the time of writing, that quality is still not guaranteed. The laboratories that analyse and interpret genetic tests must have sufficient know-how and trained personnel to provide a correct test result. That is not always the case in Europe. A study into genetic tests for mucoviscidosis revealed that one third of the voluntarily co-operating European laboratories provided incorrect test results, often as a result of the incorrect use of the technology, insufficiently trained personnel, interpretation errors, and so on. There is a growing awareness in the European Commission that rules must be put in place to guarantee the quality control of genetic tests at a European level. The Organisation for Economic Co-operation and Development (OECD) is also working on this issue.

If a party is considering developing a susceptibility test, a genetic test that shows the risk of a person getting a certain disease, this may call for a substantial investment. That party must not only address the technology, but must also establish the number of mutations, perform epidemiological research (what is the division of mutations in the population, what are the clinical implications of having the mutation), and so on. Without clear answers from this research, it is unclear whether the susceptibility test will show any usefulness, which increases the risk of the research. It was recently proved, for instance, that people with an abnormal gene for hemochromatosis, a disease that results in an increased iron level in the blood, suffer far fewer problems with this disease than was previously thought. Not all carriers develop symptoms by any means. The group that would have to be tested for this defect (in this case a diagnostic test) proved much smaller than was originally thought.

Another case in point is the genetic susceptibility test that identifies carriers of hereditary breast cancer. A number of mutations or defective gene variants have been identified for the breast cancer gene BRCA1. Those mutations have been brought together in the BRCA1 test. A BRCA1 test can be used to establish whether a person carries a defective gene for a certain type of familial breast cancer. If that proves to be the case, it must be possible to tell the carrier the extent of the risk of breast cancer. At the time when the BRCA1 test was first introduced, there was insufficient information available to do just that. People simply did not know the extent of the risk of breast cancer was for a BRCA1 carrier because not enough research had been done on that question. The initial research indicated that the risk was close to fifty per cent (fifty per cent is the average between zero and a hundred, i.e. the same as not doing the test). Much more epidemiological information is now available, and more accurate predictions can now be made about the risk of breast cancer based on BRCA1 testing (the risk is between 50 and 80%).

Such result remains an approximation, because it is impossible to totally validate a test. To achieve this, you would first have to screen the entire risk group for BRCA1. Only then would you be able to make an accurate prediction about the predictive value of the test. But then you would no longer need the test, because all of the existing BRCA1 carriers would have been charted. It will however be clear that it is necessary to know in advance the clinical utility of a test before offering it. Clinical utility can be defined as the moment at which a doctor is supported in making a diagnosis or recommending a treatment or lifestyle to one of his patients based on a test result.

Genzyme developed a susceptibility test for certain forms of colon cancer. Before starting the development programme, epidemiological research was performed and the clinical utility of a test of that nature was confirmed. Only then was a start made with developing a test for commercial use. Before using the colon cancer test, data about the person for whom it would be used, were needed (family risk, ...). Unfortunately, a decision was made not to continue offering this test because it was too expensive. This again underlines the fact that those developing these tests run a risk because they cannot be sure of earning back their investment.

The industry's role in developing genetic tests

The industry could play an important role in the development of genetic susceptibility tests. First and foremost, these tests are extremely expensive and industry could find the necessary financial resources for their development subject to the condition that there is a market for them. The fact that there is not always a market for clinically useful tests, but there is for more frivolous tests, was recently demonstrated once again. A book was recently published in the United Kingdom with the title "The Seven Daughters of Eve". The publisher was confronted with a tidal wave of rich Americans, hundreds a week, who wanted to be tested to find out which of Eve's daughters they were descended from. For this type of useless information they want to pay more than 150 EURO's... It's a strange world we live in. The developer of a genetic susceptibility test must be able to create a rigorous protocol to establish a test's clinical utility and to repeatedly use that protocol. We know from experience that the industry generally succeeds better in this than academic research laboratories because the laboratories generally have insufficient structure to work with protocols and do not always succeed in working in a standardised manner because their staff are accustomed to performing research rather than working in a routine manner.

When we at Genzyme take out a licence on an innovation for the development of a genetic test, we have up until now been doing so on a non-exclusive basis, but we can well imagine that in certain specific cases it may be necessary to work on an exclusive basis. Also, when we have developed a test and introduced it to the outside world, we usually do this under non-exclusive conditions, in such a way that others can perform the test. That may be the rule, but there are possible exceptions. In view of the high investment costs involved in developing a genetic test, it is conceivable that companies want to have the testing on the samples performed in a single laboratory in order to reduce costs. It is perhaps for this reason that Myriad Genetics, the licence holder of the BRCA1 test, recently decided to have all samples analysed in its own laboratory. As the licence holder, Myriad is entitled to do this, but the question remains whether this was the right decision in this case. The decision certainly meets with little understanding in the media.

The general public is under the impression that the industry is earning a fortune by developing genetic tests. This impression does not match with reality. People forget that addressing innovations of this nature calls for substantial investments and the investors, including us, expect a return on their investment, as we discussed before. In the case of Myriad, its website however shows that the company is still suffering considerable losses, in the area of 10 million EURO's a year. Moreover, it is not Myriad, but an American university that has taken out the patent on BRCA1, and another university holds the patent on BRCA2. The first university granted Myriad an exclusive licence on BRCA1.

Pharmacogenomics & pharmacogenetics

Once a sound diagnostic test that can clearly and unequivocally determine that a person has a certain disease has been obtained, the next stage may be to develop a therapy. One of the big problems when it comes to searching for medicines is that various genes can be involved in a certain disease or syndrome. If we take Alzheimer's disease for example, we now know that there are various subgroups of patients with the involvement of various genes. We have to be able to identify the group to which a patient belongs in order to develop a treatment, and also to be able to offer the right treatment as soon as that exists. Once the subgroups have been clearly delineated, the search can start for medicines for a certain subgroup of patients. An example of such customised medicine is Gleevec® of Novartis, for the treatment of a certain type of leukaemia.

Medicines of this nature are gradually placed on the market. Herceptin® of Roche, for instance, a medicine for the treatment of breast cancer, is accompanied by a genetic diagnostic test. Before starting the treatment, one first establishes whether the patient belongs to a certain subgroup of breast cancer patients and could benefit from the medicine. In the future, more and more medicines will be linked to such preliminary genetic test. Biotechnological and genetic knowledge will be combined to develop medicines. This is a new field that is known as pharmacogenomics.

On the other hand it is possible using current knowledge to establish whether a patient qualifies for an existing medicine or one that is under development by finding out which subgroup of the disease the patient belongs to and whether the medicine works better with the one subgroup than the other. This approach forms the basis of another new area, i.e. pharmacogenetics. More and more patient groups are being tested with pharmacogenetic markers (SNPs). This makes it possible to categorise people with a certain pathology in subgroups so that they form a more clearly delineated target group for a certain medicine. The same tests can subsequently be used as diagnostic tests to establish the subgroup to which a patient belongs before starting the treatment.

And the cost price borne by the patient? Innovative medicines based on biotechnology are more expensive in terms of their development, but do not necessarily have to lead to higher costs to society. As soon as it becomes possible to prescribe medicines to a patient in a more targeted manner and automatically rule out less suitable medicines and reduce side effects to a minimum, the benefits will compensate the costs. It is however necessary to think over the long term, and unfortunately that is not always done. Health is our greatest asset, on that everyone agrees, but we are not always willing to pay for it. Belgium spends ten per cent of its gross national product on public health. Whether this is enough is a matter of debate.

Genetic counselling

The biotechnology industry supports strongly that people who undergo or are considering a genetic test should receive proper counselling before, during and after the test. Counselling is an absolute necessity, both for negative and favourable results. The test must therefore be offered within a professional medical framework. In Belgium this is well organised, because genetic tests belong exclusively to the domain of human genetics centres. The only question mark is whether the current genetics centres (eight in Belgium) will be able to meet the growing demand for tests and counselling. Another sticky point is the cost. Our society must be willing to pay for the counselling, because without it genetic tests are potentially harmful. The American government has set up an advisory council for genetic tests in response to the anticipated social debate on these tests. That advisory counsel is presently establishing whether the legal regulations for genetic tests need to be altered.

Private initiatives, a private laboratory for example, in which important genetic tests can be offered are not possible in Belgium because these services would not be reimbursed. In other European countries private laboratories for genetic testing can be set up. These initiatives are often taken by people from the academic world that realises that they can earn money with the knowledge they have gained. They set up private laboratories where they can offer the tests, but not always in a sound manner.

Commercial initiatives such as these are often lumped together with the industry. Sometimes wrongly. A company, certainly if it is listed on the stock market, cannot afford to have its image harmed and simply do just anything. If the company gains a poor image or runs up against public opinion, its share price will drop, reducing the company's financability. Public opinion is the same opinion as that of people who buy shares in a company, in any event a listed company. Such companies cannot take measures that place them at odds with clinicians and patient groups. This is in fact at then end a self-regulating mechanism. Companies with long-term vision must play a responsible role and build ethics into their long-term strategy. Otherwise they will cease to exist. That is the situation as it stands today, also for the biotech-based industry, despite occasional predictions to the contrary in the press.

Self tests in the supermarket?

There are some who claim that our destiny is a future in which all sorts of genetic self tests will be freely available, in the supermarket for example, and where there will be no counselling. In my view, that pessimistic view is not realistic. Firstly, it is not technically feasible in the short term because self-tests have to be simple and the current genetic tests depend on complex technical procedures. Extensive simplification is certainly not something that will be happening soon. But if it did become possible to develop self-tests, we would have to ask ourselves whether public opinion would go along with it. As soon as ethical questions arise on this issue - and they will - there is no industry with a sense of responsibility that will be willing to take the risk of placing self-tests on the market. The chance that the investments made will not be recouped is much too large, and a company that thinks in the long term will not want to burden itself in that way. After all, a company is an inseparable part of our society through its employees, its market, its shareholders,...

Unfortunately, there are also commercial initiatives with little or no sense of responsibility, known as pirates. Piracy cannot be placed on par with the industry: pirates are usually smaller initiatives, which may work for a relatively short time. If pirates were able to earn money with self-tests in the short term, they would certainly do so. What this amounts to is providing regulations that prevent such abuses in good time, but rules such as these must not be too strict or put in place too quickly, otherwise there will be a risk that the baby is thrown out with the bathwater. There is a big chance that any such abuses will remain a marginal phenomenon. A few years ago a company in the United Kingdom offered a genetic test by mail, with advertisements in the free press and so on. However, they never managed to exceed a few dozen tests a month, so that the business quickly sank without a trace.

EuropaBio

As the European bio industry's most representative association, EuropaBio promotes the interests of the biotechnological industry in society, mainly in respect of public authorities. EuropaBio thus sets out to play a role in the discussion about new regulations and strategies. The association has also published a document setting out the 'Core Ethical Values', an ethical statute list. All members have subscribed to this document. Subscribing is in fact a condition for becoming and remaining a member of EuropaBio. In this document the members state, for example, that they find the reproductive cloning of human beings unacceptable. They also state that genetic tests must go hand in hand with professional counselling. The members therefore rule out the sale of human genetic tests via the Internet. The ethical rules that EuropaBio's members impose on themselves can be read by all on the association's website (www.europabio.org).

EuropaBio is of course unable to prevent some private persons or groups of people from setting up irresponsible commercial initiatives. At present, there are a number of groups active in the area of reproductive cloning, and attempting to pass themselves off as members of EuropaBio. The association for the European bio industry emphatically rejects those claims, but is unfortunately unable to prevent such attempts from taking place.

There will not in the near future be a wide range of new genetic risk tests, as some predict. Progress in that direction will be much slower than many people believe. The (epidemiological, clinical and production) research preceding the development of a genetic test is extremely comprehensive and takes many years. This makes the development an extremely expensive and time-consuming matter. No organisation can afford to place tests on the market on a hit-or-miss basis which subsequently turn out to be largely useless and result in substantial financial losses. The Human Genome Project was a starting point for the development of genetic tests, but certainly not an end point.

The biotechnological industry maintains close contact with the other parties, such as clinicians and patient associations, and is a party to the social, ethical debate. If public opinion were to speak out against some genetic tests, against the prenatal selection of 'people à la carte' for example, rules would be put in place with the aim of preventing them. For its part, the industry will not devote its resources to dubious tests that place them at odds with public opinion.