One of the world’s experts on human stem cell research, and in particular its relevance to heart disease, Professor Robert Roberts, has made a huge contribution to the elucidation of the genetic make-up, not just of humans, but of viruses and bacteria. The latter is vital, because it provides targets on the germs at which new medicines can be aimed. For example, in the few short years since the technology has been available, all the genes that make up the syphilis bacterium have been identified. In an exclusive interview with the JCN, Professor Roberts confidently predicts that this knowledge will lead to its being wiped out as a disease within the next ten years.
Marker systems
The human genome project was supposed to be completed by 2005: new ‘marker’ systems to identify genes will ensure that it is completed two years ahead of schedule. However, Professor Roberts stresses that genes are not so important in themselves, they are merely a template to make proteins, and it is these and what they do, that matters. It will be years before we know everything about which gene makes which protein, and, even more important, which mutated genes produce the proteins that cause disease.
Professor Roberts’ team is using new techniques to identify 100,000 new DNA base sequences (the building blocks of genes) per day. Already more than 9.5 billion DNA sequences in 38,000 species of animal and microscopic life have been recognised, and can be traced to their origins 1.5 billion years ago, close to the beginning of life on earth. Bacteria and viruses have many gene functions in common with man, so that study of genes in these less complex life forms can be extrapolated to their function in man.
The human body calls upon the activity of around 30,000 genes in the brain just to keep conscious. Just the action of standing from sitting involves the coordination of the action of 30,000 genes.
Already 1039 human genes associated with disease and 21,591 mutations have been identified - an avalanche of new information that will lead to much better knowledge of diseases and how their causes may be reversed. By 2008, Professor Roberts predicted, we could all have available to us a CD ROM with a map of all our genes. Let us hope we will not need one as part of a package for job interviews.
All this knowledge has huge practical implications for health in the next century. Eighty per cent of all deaths are caused by only 20 diseases, mainly infections, heart and blood vessel degeneration, and cancer.
Gene ‘engineering’ of microbes will produce highly effective vaccines against all known infections. Already 115 genes have been identified as being responsible for heart defects and 88 for other blood vessel disorders such as strokes.
Professor Roberts’s group is part of a team seeking ways of manipulating genes and their products to form new hearts. It was formed eight years ago, when the research groups in heart (of which he was the leader), lung and blood at the US National Institutes of Health in Bethesda, Maryland, decided that this was a practical aim over the following 20 years. Then, it sounded ambitious, to say the least. Now, they have the technology to cultivate new heart muscle cells and are close to understanding the processes by which they can be shaped into a functioning heart-like organ. Professor Roberts sees no insuperable obstacle to fulfilling their aim within the next ten years.
However, along the way he has come across a more pressing problem. A heart can ‘hypertrophy’, in which case the heart muscle cells overgrow, so that the heart thickens and enlarges. This puts up the blood pressure and eventually causes heart failure as the overgrown muscles outstrip the ability of the coronary arteries to supply them with blood and oxygen. The hypertrophic heart either stops suddenly or more slowly fails. It is one of the commonest causes of sudden death in apparently healthy young adults.
30,000 people in the United States (about 600 in Scotland) die each year of this form of cardiac hypertrophy. Nine genes for it, carrying 150 different mutations, have been identified. They give families that carry it different degrees of lethality: in one family there was an average life-span of 28 years, in another, 62 years. A simple blood sample will soon be able to identify them.
The affected heart muscle overgrows because it is programmed to do so by the gene that makes a particular muscle molecule called heavy chain myosin, so it has been labelled HCM disease. Labelling it is one thing, offering families with it hope is another. Yet that is what Professor Roberts is doing. The way forward lies in the new discovery that the heart muscle completely replaces all its proteins within three weeks - that we all grow a new heart every 21 days. In essence the plan is to ‘knock out’ the gene that makes the abnormal HCM. The abnormal muscle proteins will then be replaced naturally by normal proteins - and the heart will turn from a hypertrophic heart to a normal one in three weeks.
In effect it is a medical heart transplant. Sounds fanciful? Cats and rabbits can have the same HCM disease, due to exactly the same gene mutations as humans. The Houston team has already found ways to change abnormal into normal heart muscle in the laboratory in rabbits. They see no reason why they cannot be successful in humans, too.
This will only be the start. Professor Roberts’ team and similar genetic researchers are working on many other illnesses that are turning out, often to doctors’ surprise, to be genetic. He predicts that the advances in medicine in the last 50 years will be as nothing to those we will see in the next 20.
The other problem is religious opposition to gene research. Since the papal announcement against the use of cells from human eggs, he has received thousands of letters of withdrawal of support from schools and individuals. Somehow a balance has to be struck, but despite many meetings with the American church hierarchy, the block remains. Perhaps it is up to the families of people who are ill, and who are personally involved in the outcome of research, to get the message across. And when that relates to heart disease, it means nearly all of us.