From mould to man. Edward Lewis Tatum’s vision of the future of medicine.

"If I have seen further, it is by standing on the shoulders of giants." (Sir Isaac Newton)

Over 40 years ago – in May 1966 to be more precise – Edward Tatum, whose hundredth birthday will be remembered in December this year, gave a remarkably farsighted talk on the future of medicine. Tatum was one the founding fathers of the newly emerging field of molecular biology. In 1958 he had won the Nobel Prize for Medicine for his work in the 1930s and 40s with George Beadle on radiation-induced metabolic changes in the mould Neurospora crassa. They demonstrated that genes control metabolic processes by determining the function of specific enzymes. This discovery led to the "one gene one enzyme" hypothesis. The double helical nature of DNA had been discovered only 5 years beforehand, and 1958 was also the year in which everything was pulled together by Crick’s formulation of the central dogma of molecular biology.

Tatum had probably been thinking since then about the impact these new biological concepts would have on the "health and the welfare of man." With the cautious disclaimer that he is not in the business of fortune telling he tries in his talk to predict how these discoveries might change medicine in the "next 10 to 20 years."
To us, who enjoy the benefit of hindsight, it is fascinating to see the outcome of his predictions. Omitting immunology and neuroscience, which were covered in other talks of the same meeting, Tatum is remarkably precise with regard to the directions this new knowledge would lead medical science and also in outlining the therapeutic goals medicine would aspire to reach. Other predictions are less accurate, mostly concerning time scale and complexity.

Certainly, Tatum’s urgent warning at the beginning of the talk about world population growth and the limitation of natural resources has not been heeded. With today’s knowledge, we should also add climate change to these dangers. Even if the dire consequences he predicts have not yet taken full effect we are already seeing them emerge. Unfortunately, the political reactions such as military adventures to secure resources, failed developmental policies not primarily aimed at increasing self sustained and competitive economies in the developing world, and indecisiveness or even simple denial of climate change, have been grossly inadequate responses to these challenges. These warnings are if anything even more urgent today and changes in the political approaches to deal with the underlying problems are more desperately needed than ever.

As he predicted, molecular virology has led to an enormous insight into the biology of many viruses, and consequently to novel and effective therapeutic strategies against viral disease. However, we are still far away from conquering "most if not all" viral diseases. The high mutability of viruses, enabling them to avoid initially effective therapies, could not have been predicted; even less foreseeable was the emergence of new viral diseases, such as HIV, Ebola, or SARS, some of which evolve from animal pathogens. The lesson to be learned is that virus-human interactions are part of our genetic makeup and evolutionary inheritance and will probably always keep us busy and pose new challenges, although constant accumulation of molecular understanding will increase our ability to fight back via prevention and treatment.

Viruses have also become important research tools and, as Tatum anticipated, they can be used to carry therapeutic DNA into affected cells. Long before the techniques of human cell culture and cell expansion had been established, he suggested an ex vivo hepatocyte gene therapy protocol. His presentation is often referenced as one of the very first published predictions of human gene therapy. However, it still took until the early 90s for the first clinical trails to be conducted, and almost 10 years more for the first curative success on X-SCID patients in 1999.

Similarly, without ignoring the great progress in cancer research and therapy which confirms the trend of Tatum’s prediction, the predicted level of understanding of the basic causes of cancer within his timescale appears over-optimistic, despite his recognition of the great complexity of this group of diseases. The emergence of cell biology, which reintegrates the discoveries of molecular biology at the level of the smallest unit of life, the cell, is one of the reactions of biomedical science to reach the aspired goals in the understanding of cancer and other diseases. Today, about 40 years later, the knowledge of molecular and cellular biology, immunology and molecular pharmacology, including gene therapy, all combined in the basic science arsenal of molecular medicine is indeed beginning to provide the anticipated first effective preventive measures and curative therapies.

Despite knowing that mutations are the molecular basis for genetic diseases, it took about 20 more years to develop a strategy for discovering the individual genes and mutations responsible for the majority of these conditions in which the phenotype does not immediately point to a known defective protein. This "reverse genetics" or "positional cloning" strategy was first applied to Chronic Granulomatosis Disease and Duchenne Muscular Dystrophy in 1986, followed in 1989 by Cystic Fibrosis, and in 1990 by Neurofibromatosis I. These gene searches took an international effort over more than 10 years. Nowadays, based on the completion of the human genome project and a battery of genome spanning markers, such gene searches can be done in months or even weeks. These enormous steps forward have only become possible through the earlier development of the in vitro DNA-recombination and molecular cloning technologies in the mid–1970s and 80s.

Tatum’s vision of applying the knowledge of molecular biology to detect disease-causing gene mutations in carriers was realized in the early 80s by DNA diagnosis for many monogenic diseases. Tatum is, no doubt, motivated by a deeply humanistic responsibility in his aim to "improve man’s life, heritage and health". However, the social concept of "eugenic engineering" to make a "conscious effort to decrease the prevalence and expression of undesirable genes" through "most important … general acceptance by individuals of their social responsibility not to perpetuate these genes" should not go unchallenged. Besides the unfortunate use of the historically tainted expression "eugenic", the idea of societal or moral pressure to interfere with individual reproductive decisions for the perceived "greater good of mankind" in the fairly distant future cannot be accepted without comment. We are already seeing that individual genome sequencing is able to provide information on a multitude of undesirable genetic traits. It is likely that every human individual can be shown to carry one or several of them. As is nowadays broadly accepted good practice in DNA diagnostics, great care must be taken to ensure that these data are handled confidentially and that professional genetic counseling is provided to avoid stigmatization and undue anxiety as well as to allow the tested individual to make informed reproductive and/or lifestyle decisions in accordance with their personal choices. Such individual decisions will of course be largely influenced by the prospects of effective or even curative treatments and advances in reproductive medicine. Further improving these fields of medicine is our responsibility in fulfilling Tatum’s humanistic legacy.

Edward Lewis Tatum was one of the scientific giants on whose shoulders we stand in the further development of molecular biology and its application for human health and welfare. The advances in medicine over the last 40 years, as he predicted, have offered and continue to offer new solutions, including gene therapy. Even his vision of curing genetic disease by mutation correction appears now as a realistic goal. If achievable and safe it will be for future generations to decide if this may be a medically justifiable and ethically acceptable approach to correct adverse sequences at the germ line level.