Gene genius that cuts out the need for vivisection: Molecular biologists now play a key role in drug research, says Ruth McKernan
Monday 12 October 1992
Five years ago most companies did not have such wizards. Now the gene jockeys are leading the field in three key areas of drug research: brain disorders, cancer and chronic inflammatory diseases such as arthritis and asthma. Before, pharmacologists might have identified an active compound by its ability to trigger a reaction in an isolated piece of animal tissue, or by the compound's effect on mice. Most drugs now coming on to the market will have taken more than 10 years to develop, and so many of them will have been developed in this way. The techniques of the gene jockeys frequently allow scientists to avoid using animals in the process of drug development.
Most drugs act by binding to specific targets on the surface of cells, called receptors. One problem in drug research is that most cells die when they are removed from their natural surroundings in the body - only a very few types can be cultured for study in the laboratory. The gene jockeys have found a way of getting round this problem.
The recipe that a cell follows to make a receptor is carried by a corresponding gene. Once the gene has been identified, scientists can transfer it from its 'natural' host cell into a cell that will grow in the laboratory. The engineered cell will then 'express' the gene, by growing the appropriate receptor.
In this way, the gene jockeys can persuade human proteins - including human cell surface receptors - to grow in cells derived from completely different organisms. Their colleagues intent on the search for new drugs can then try the effect of thousands of chemicals on the receptors embedded in the engineered cells - a process called 'screening' - to search for an active drug.
Leslie Iversen, director of Merck Sharp & Dohme's Neuroscience Research Centre in Harlow, Essex, says: 'Molecular genetics has allowed the drug discovery process to leap forward in many respects. The amazing thing to me is that we can have a protein which doesn't just resemble, it actually is the human brain receptor transferred into a cultured cell that has been designed by scientists.
'Although this is an entirely artificial system, it is a living, immortalised human receptor that we can put in the freezer and retrieve at any time. It is an enormous advance.'
The search for drugs to treat brain disorders has centred on compounds that either enhance or block the action of the naturally occurring 'chemical messengers' or neurotransmitters, one of the means by which cells communicate with each another. For brain disorders, one unexpected advantage of the application of molecular genetics has been the discovery that for each chemical messenger there is a huge diversity of receptors - much greater than scientists had thought.
For example, the Valium-type drugs act on a specific receptor in brain cells. Scientists have discovered that instead of the two types of brain cell receptor identified by the old-fashioned methods, there are now at least 10 times that many. This has encouraged them to believe that by screening compounds on immortalised cells containing various forms of the receptor they will be able to find better tranquillisers, without the side-effects that have dogged the present generation of drugs.
Other companies are adopting the same approach. Glaxo considers the change in research methods important enough to employ a scientist solely to retrain its traditional pharmacologists in current genetic techniques.
In the search for drugs with the potential to prevent chronic inflammatory diseases, scientists at Glaxo have developed a simplified screening procedure that reproduces the critical early stages of inflammation in the laboratory. These initial reactions are common to many disorders, including arthritis, asthma and ulcerative colitis.
Allan Baxter, director of cellular and molecular sciences at Glaxo, and his team have been trying to find ways of preventing white blood cells migrating from blood vessels into other tissues, where they can cause trouble. The first stage depends on specific receptors on the surface of white blood cells sticking to complementary adhesion molecules on blood vessels. The accumulating white blood cells trigger a complex series of events that results in the inflammatory response. In recent years, potential anti-inflammatory drugs have been sought by injecting compounds into a surface blood vessel of an animal and watching the response.
Researchers now use artificially produced adhesion molecules by transferring the gene coding for the human form into a virus or bacteria, which then produces large amounts of the molecule. Scientists coat glass plates with the molecules, then add human blood cells. Potential drugs prevent blood cells from sticking to the plate. Procedures of this type now underlie most of their drug research programmes.
At the Wellcome Research Laboratories, the search for anti- cancer drugs also depends on engineered cells. A cell becomes cancerous when one of the proteins essential for regulating its normal growth is mutated and goes out of control. Instructions for making the aberrant protein are encoded in an oncogene (cancer-causing gene). When an oncogene is put into a normal cell in the laboratory, rather than growing as a smooth flat layer, the cell takes on very different characteristics. Normal cells grow like a smoothly plastered surface, but cells engineered to contain the oncogene would be the equivalent of a badly Artexed ceiling, with large textured swirls and lumps falling off. The Wellcome scientists test chemicals for their ability to convert cells back to their original state.
'We have used this cell system to screen for agents which work against breast cancer and colon cancer, where one of the aberrant genes has been identified. Compounds identified in this way are now in the early stages of development,' says Martin Page, of Wellcome's cell biology department.
Multiple brain receptors, cell adhesion molecules and cancer-causing genes are just three examples whereby molecular biologists have translated new scientific knowledge into real practical advances in the search for better drugs.
'The more we use the techniques of molecular biology, we realise that, in the past, drugs have been developed in the absence of real knowledge about the receptors with which they interact,' Dr Baxter says.
The writer is a senior research neurobiologist with the pharmaceutical company Merck Sharp and Dohme and has been working as the 1992 British Association Media Fellow at the 'Independent'.
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