GETTYIMAGES, TODD DAVIDSON
It is a tribute to Eugene Garfield’s vision and insight that The Scientist is still, after 25 years, a flourishing magazine “for the science professional,” as he put it in his inaugural editorial. The magazine’s primary focus is no longer on the political and economic affairs surrounding science, however, but on the heart of the matter: the rapid advances in methodology and the consequent torrent of new findings in the life sciences, lucidly explained both to the broader professional community and to the scientifically literate public. This special anniversary issue features six topics, including several areas of research that did not exist when The Scientist first went to press: omics, neuroscience, nanomedicine, synthetic biology, biodiversity and conservation biology, and science funding. I contributed an opinion article to the first issue of the magazine advocating that the human genome be sequenced. At the invitation of the editors, I now reflect on the huge strides made in the life sciences in the last quarter century and offer some thoughts about how to conquer some of the outstanding problems in the future.
The birth of the omics revolution
By 1986, recombinant DNA techniques were sufficiently well advanced to make the Human Genome Project a realistic possibility. And given the already huge increase in detection of human genetic variability at the DNA level, it could be predicted that the molecular understanding of most clearly inherited diseases was achievable. PCR technology had just been developed, the first automated DNA sequencers were around the corner, and transgenic and knockout mice derived from embryonic stem cells were becoming available. Since then, siRNA has been developed as a major tool for the study of gene function, circumventing the continual need for knockout mutations, and GFP has become an indispensable tool for visualizing gene activity in living cells and organisms.
Undoubtedly, however, by far the greatest advances have come from the continuing computer revolution and its electronic applications. While the extraordinary rate of advance in DNA sequencing, exceeding even that in computing, has depended on clever innovations in approaches to sequencing and automation, none of this would have been possible without concurrent developments in computing.
The real challenge of all this omics is intelligent data analysis that derives decisive, qualitative insights from a mass of interrelated data—not only from DNA sequences but also from all the other types of omics measurements, which have yielded a staggering amount of data. I believe it is very important not to give in to complexity by doing only broad, sweeping analyses, but to continue to see the individual trees in the forest. There should always be a place for the individual creative mind, however complex the data.
Major conceptual advances over the last 25 years have included a more realistic estimate of the complexity of the human genome, now that it is fully sequenced and known to include just over 20,000 protein-coding genes. This lower-than-expected level of complexity may, however, turn out to be deceptive, given the existence of multiple splice products and, especially, the discovery of many noncoding, but functional, RNA-determining DNA sequences. Another key advance is the ability to make induced pluripotent cells that are analogous to embryonic stem cells. This raises the possibility of eventually making differentiated tissues and even functioning replacement organs from and for any given individual. Continuing improvement in the understanding of the control language for complex patterns of differential gene expression during development and differentiation will be essential for the success of such translational developments.
It should now be possible to solve the genetics of essentially all inherited human diseases, whether in a single family or a population—including complex mental diseases such as schizophrenia, whose inheritance is probably explained by independently acting rare variants at many different loci.
Single-cell analysis and cellular manipulation at a level of sophistication comparable to alterations in DNA, RNA, and proteins seems to me to be a key to further developments in the fundamental understanding of higher-organism functions, enabling translational advances in disease prevention and treatment. Perhaps it will be through this better understanding at the molecular and cellular level of higher organism functions, and a better understanding of the genetics of human behavior, that inroads will be made into that most difficult problem: the relationship of mind to brain function.
Nanomedicine and synthetic biology: the newest fields
Nanomedicine is another extension of previous technologies, such as the use of liposomes for drug delivery or quantum dots for antibody detection. However, when combined with new advances in chemistry and microelectronics, it could provide totally new ways of, for example, continuously monitoring metabolic activity or doing automated microsurgery.
It is a tribute to Eugene Garfield’s vision and insight that The Scientist is still, after 25 years, a flourishing magazine “for the science professional.”
Synthetic biology is essentially a sophisticated extension of recombinant DNA technology made possible by advances in computing and automation of DNA manipulation and sequencing. The synthetic creation of genomes is often coupled with natural selection in the test tube, as foreshadowed by Sol Spiegelman’s phage Qß self-replicating “monster.” Applied to appropriate microorganisms, this technology has many potential applications, as emphasized by Craig Venter. Its extension to multicellular organisms may substantially improve our ability to study the functions of higher organisms in animal models, and could also provide much better animal models of human diseases.
For the benefit of all
Advances in genome sequencing have revealed not only heretofore unknown phylogenetic relationships, but also the mind-boggling biodiversity of microbial life on land and in the oceans. These microorganisms may utilize alternate metabolisms that can inform biotech solutions to environmental problems and may harbor potentially valuable pharmaceuticals. As more is learned about how all life on Earth is interconnected, the value of conserving biodiversity will become obvious to all.
Whatever the scientific and technological advances, achieving the social acceptance of their applications will remain a key problem. But for all this, the alpha and omega, as can be seen in both the first and 25th-anniversary issues of The Scientist, is adequate funding. We must be able to persuade our decision makers that even in times of financial constraint, supporting scientific research and education must remain a high priority for the future benefit of all mankind.
Walter F. Bodmer heads the Cancer and Immunogenetics Laboratory in the Department of Oncology at Oxford University.