How Far Will We See in the Future?

Any attempt to contemplate the next fifty years of cell biology must do so in the context of a past that encompasses roughly three equivalent periods. The first witnessed the discovery that living organisms are composed of cells, that these arise solely from the growth and division of preexisting cells, that an unbroken series of divisions connects us to a primordial cell providing a material basis for heredity and evolution, appreciation of the role of nuclei, the discovery that these divide by an indirect process now known as mitosis, and finally the notion that heredity is conferred by the set of chromosomes that we inherit from our parents’ germ cells. The second period saw proof of the chromosome theory of inheritance, birth of molecular genetics, realization that hereditary information is carried by DNA, development of x-ray crystallography, and the double helix. The third phase was driven by advances in bacterial genetics that gave rise to the notion of differential gene expression and recombinant DNA, an ability to manipulate eukaryotic genomes, development of DNA sequencing, the revelation that molecular mechanisms are astoundingly conserved, and the ability to image macromolecules in real time inside cells. What then will the fourth phase bring? Were the future predictable it would lose its mystery and we would lose our motivation to enquire further. Moreover, the law of unintended consequences will ensure the most important discoveries will be made for quite the wrong reasons or aims. Instead of speculating about future discoveries, I prefer therefore to consider some of the things we would like to do and/or understand. Crucially, because previous discoveries have revealed more ignorance than understanding, we are paradoxically more ignorant than we have ever been. There is no danger of our running out of important questions. I suggest that there will be increasing emphasis on molecular mechanisms, because it is these that provide the tools for ascertaining whether our fantasies are right or wrong. The language of the cell is chemistry, and the language of experimentation, be it biochemistry, structural biology, or genetics, is at the level of atoms. The second reason is that future medical advances increasingly rely on mechanistic information. Sadly, despite huge advances, our ability to observe and manipulate the chemistry of cells remains limited. If only we could see more clearly the “wheels and cogs” that drive cells then there would be no need to study mechanism indirectly, namely by observing the consequences of “throwing a spanner in the works.” High up on our wish list must therefore be development of methods to visualize single macromolecules within cells, with as great precision as possible throughout their biological cycles. Ultimately, one would like to observe collections of molecules simultaneously. Given that such methods will remain limited for some time, it will also be important to develop more sophisticated methods for changing the behavior of macromolecules rapidly and observing the immediate consequences. This will require a move from using purely genetic techniques, which for the most part merely change amino acids, to using ever more sophisticated chemical methods. Another area of profound ignorance is how collections of cells create organs, central nervous systems, or even tumors. There is not a single instance, for example, where we have an even vaguely satisfying explanation for how neural networks give rise to complex behavior. Due to their spatial and temporal complexity, our grasp of the molecular mechanisms that make neurones special lags behind that of other cells. I would therefore like to be surprised by how much we learn during the next fifty years about the chemistry of synapses and the behavior of complex neural networks. I suspect also that advances in cell biology will increasingly be exploited for industrial or environmental causes, but I hope that hubris will not lead to their overoptimistic application to ameliorate current deficiencies in our economies, such as global warming. Seeding the oceans with fertilizers would be madness. Moreover, would a world full of recombinant trees that locked carbon away for millennia be worth living in? My other wishes include a desire that veracity and importance are given greater value than is currently the case in the unenviable task of evaluating each other’s work, where supposed novelty currently holds sway. We must also face up to the fact that our field still lacks rigor concerning what is considered a satisfactory explanation as well as standards of proof for our assertions. I would like to see the contributions of mathematicians move from seeing their goal as making us happy about our state of understanding to making us unhappy. Furthermore, I would like to see the undoubted utility of systematic data collection exploited better to address specific questions and cease to be a goal in its own right. I would like to see greater transparency in discussing our disagreements, in other words a move away from criticism being confined to the anonymity of an unaccountable DOI: 10.1091/mbc.E10-04-0359 Address correspondence to: Prof. Kim Nasmyth (kim.nasmyth@ bioch.ox.ac.uk).