In 2009 we are still comparatively near to the beginning of an era in which biomedical research is revolutionizing our understanding of inherited human diseases and providing the first effective treatment for at least some of them. This new knowledge will offer benefits that are at least as great as those from past biomedical research which has dramatically reduced the devastating effects of many infectious diseases. The powerful new tools that will bring this about are those for molecular genetic analysis and stem cell biology.
Human health and lifespan in the more fortunate parts of the world has improved dramatically in the past 1,000 years, but in the main this is because we became better at meeting the everyday needs for survival. Over this period humans became more effective at collecting or producing adequate supplies of food. On this timescale it was only comparatively recently that communities recognized the need for clean water and effective sanitation to prevent infection. More recently still, methods have been developed for immunization against potential infection and compounds identified as being powerful antibiotics. While the authors of these essays, and the vast majority of those who read them, can take all of these benefits for-granted it is a sad commentary on us all that this is not true for many millions in the less fortunate parts of the world, but that is another matter.
The coming together of emerging techniques in cell and molecular biology will change our entire approach to human diseases that are inherited, rather than acquired from an infective agent, such as a virus or bacterium. “Inherited diseases” are those in which run in families because of errors in the DNA sequence of some family members. For the sake of simplicity, this essay will concentrate upon diseases inherited through chromosomal DNA, while acknowledging that there is DNA in mitochondria which is also error prone and the cause of other inherited diseases.
While the proportion of diseases for which the precise genetic cause has been identified is increasing because of the power of modern molecular analysis, it is still small. Even more important, is the fact that, the way in which the genetic error causes the symptoms of the disease is known in very few cases. This has been a major limiting factor in the development of effective treatments because the objective with present treatments is not to correct the error in the DNA, but rather to prevent the development of the symptoms.
One advantage of the new tools is that it is not necessary to have identified the genetic error to be able to identify compounds that can prevent the development of symptoms. This new opportunity arises from the revolutionary new technique, by which stem cells able to form all tissues of the body are formed from cells taken from adults. Shinya Yamanaka of the University of Kyoto was the first to show that a simple procedure could achieve this extraordinary change and named the cells “induced pluripotent cells” in view of their ability for form all tissues.
Many laboratories are now using induced pluripotent stem cells to study inherited diseases, such as ALS. Pluripotent cells from ALS patients are turned into the different neural populations affected by the disease and contrasted with the same cell population from healthy donors. Discovery of the molecular cause of the diseases will involve analyses of gene function in the diseased cells in many ways. There is then the practical issue of devising a test to discover if potential drugs are able to prevent the development of the disease symptoms. This can be used as the basis of tests that can be carried out by robots able to screen thousands of compounds every week. Many further studies will then be required before any new medicine can be used to treat patients.
In addition to the prospect of understanding and being able to treat inherited diseases it is also likely that these therapies will be effective in treating related cases for which there is no evidence of a genetic cause. In the case of ALS it is estimated that less than 10% of cases are inherited. ALS should be considered as a family of diseases because it reflects errors in several different genes. Recent studies have revealed an unusual distribution of a particular protein within the cells of many patients. This was the case in inherited cases associated with all except one of these genes and in addition occurred in several patients for which there was no evidence of an inherited effect. While this pattern may not occur with all inherited diseases the observation lends encouragement to the hope that treatments developed through research with inherited cases will often be equally effective for the cases in which there is no genetic effect.
While I have separated infectious and inherited diseases, in reality there is a considerable overlap. New understanding of the molecular and cellular mechanisms that govern normal development and health will also provide the basis for novel treatments for infectious diseases. In this way for example, an understanding of the development and function of the immune system may reveal new approaches to the treatment of diseases such as HIV.
It is always impossible to predict the future and scientists above many others should know to expect the unexpected. Sadly this leads one to be cautious and fear that it will not be possible to develop effective treatments for some diseases, but it also suggests that there will also be joyous surprises in store. I certainly find it very exciting indeed to think that in my lifetime effective treatments will be available for some of the many hundred inherited diseases. The devastating effect of these diseases on the patients and their families will be greatly reduced or even removed, in just the same way that earlier research banished infections such as polio, TB and the childhood diseases such as measles or mumps.