What is life? Answering this question is one of the ultimate goals of biologists. Since Mendel, SchrÃ¶dinger, Watson, Crick, Jacob, Monod and so many others, the view has emerged that life is programmed by the DNA molecule. This view culminated during the last century through the completion of the “Human Genome Project,” the sequencing of a human genome. Simultaneously, major technical advances for counting RNAs and protein species opened the maws of the OMICS world (transcriptomics, proteomics, you-name-it-omics).
This is essentially when the smoke from our pipedream of a molecular Grail was blown away by the harsh winds of reality. If DNA is the book of life, no one has the slightest idea of how to read it. One major reason for this is that making sense of the huge amount of data is too complexâ€”when one focuses on the small details the complete picture becomes blurred.
The twenty-first century thus begins with the challenging process of converting “data into knowledge”. From 2001 to 2004, the annual “Integrative Post-Genomics” meeting brought together researchers from different scientific areas, all stimulated by this challenge. Biologists, genome experts, mathematicians and computer scientists gathered together to build the concepts and tools that are so badly needed to provide a global understanding of organisms, from genome to physiology.
The fifth edition of this meeting, held from 29th of November to the 2nd of December in Lyon, was an excellent opportunity to listen to and interact with some major scientists in this emerging field, as well as in related fields.
Perhaps one can try to answer the initial question this way: â€œLife is the mysterious transformation from a one-dimensional, inanimate, simple code (the genome) into a three-dimensional, highly complex system (a cell)â€?. One key step in this process is, of course, gene expression regulation.
It turns out that this issue of gene regulation continues to be one of the main issues in modern biology. The question then becomes: â€œWhat is a gene?â€? Letâ€™s try to see how our IPG â€™05 invited guests dealt with this question1.
According to Wolfgang Enard, â€œgood old genesâ€? are what should make the difference between us (the humans) and them (the chimpanzees and the bonobos, our closest relatives on the evolutionary tree). Unfortunately, it seems that neither gene transcriptional regulation nor gene sequences are sufficient for explaining such a difference. Such a conclusion could only be reached recently thanks to the -omics technical advances (including complete genome sequencing and microarrays (DNA chips)), which allow scientists to monitor gene expression patterns at a very large scale.
According to Ken Wolfe, a gene is a â€œunit of loss:â€? It is a memory; it keeps track of the history, and at least part of the evolutionary pressure can be read from it. It can be duplicated, lost, kept, and lead to speciation events. The demonstration for such a role for genes was essentially rooted in the sequencing of numerous complete genomes in various yeast species.
According to Wendy Bickmore, a gene is a three-dimensional dynamic structure that tends to gather together in chromosomesâ€™ territories. Its regulatory properties influence its biophysical and topological properties (and vice-versa). Therefore, time and space should be taken into account, although this will necessitate the development of new technologies for real-time observations at the cellular level.
According to Diego di Bernardo a gene is â€œa good approximationâ€? of all of the gene products (mRNAs and proteins), is a putative target for a chemical compound, and is regulated by other genes. Here again, the possibility to identify target for chemicals is based upon large-scale transcriptomics analysis.
According to Christophe SoulÃ©, a gene is a letter (a vertice in an interaction graph) that has an effect on another one. This oversimplification might be shocking at first for a biologist, but Marcelle Kaufmanâ€™s talks demonstrated that such an approach nevertheless could still give precious insight into the behaviour of a real-life biological problem.
So in the end, can we say a gene is something that is regulated by a gene? (Circular, isnâ€™t it?) Or can we say a gene is a three-dimensional dynamic regulatory unit, the function of which has been evolutionarily shaped, that is a target for other genes and for putative therapeutical chemical compounds, the function of which relies upon its regulation? Fuzzy, isnâ€™t it? And hard to sell to the formal sciences.
So we are in the post-genome era (and all the biologically relevant pieces of information we heard at IPGâ€™05 could not have been obtained by the â€œgood oldâ€? molecular techniques), but we still struggle to come out of the age of genes. It is my personal feeling that a conceptual breakthrough within the years to come will be badly needed to reshape our theoretical view of living systems. I have little doubt that the IPG series will continue serving this cause.
1 This question was not asked beforehand to our guests, but I decided to â€œreadâ€? some of the talks from this very subjective point of view. Furthermore, due to space imitations, not all talks will be discussed here.