2004 Award Winner Prof. Dr. Patrick Cramer Gene Center, University of Munich, Germany
The work of Prof. Dr. Patrick Cramer
Good science means good answers to good questions. Some of the latter are more fundamental then others. In July of this year, when Francis Crick, the co-discoverer of DNA, died at age 88, some of us were reminded that he not only worked on the structure of DNA, but also on other fundamental questions surrounding the newly founded field of molecular biology. One of them was the question of how the information flows from DNA to protein, the main component of every living cell, besides water. In several publications between 1955 and 1958 he proposed the so-called central dogma of molecular biology according to which genetic information flows from DNA to RNA to protein. Sometime it is called "DNA makes RNA makes protein". With some notable exceptions, all living cells conform to this rule.Pondering about this rule it becomes clear that genetic information flow occurs in two steps, the first one from DNA to RNA and the second one from RNA to protein. The first one is called transcription, the second translation. It is transcription with which we will deal today. DNA, the genetic material, is a template for two copying steps, one for the copying of itself and one for producing a copy of a related molecular, called RNA, with a similar chemical composition. The major difference between the two is a functional one. While every cell contains the same amount of DNA, cells can contain much larger amounts of RNA and, even more, of RNA which does not represent the entire genetic composition of a cell. DNA thus is read or transcribed in a very selective manner. The RNA content of a liver cell is different from that of an endothelial cell or of a neuron. For this to happen, the copying enzyme must know where to start reading, i.e. how to find the genes which it has to read in a certain cellular surrounding. In addition, a mechanism must exist which prevents undesired gene not to be read. Otherwise hair would grow in the liver and finger nails in the brain.The solution to this dilemma is two-fold. Gene transcription requires specific sequences ahead of the genetic information to be read which is called a promotor region. This region is recognized by specific proteins, called repressors or transcription factors. How can this mechanism be understood! Basically, it works like the railway system. If one thinks about it, it contains tracks with two types of properties. In general, tracks are used for trains to drive on. However, there is a small proportion of tracks which is used to regulate the train traffic. They are characterized through a system of signals which decided whether a train can continue or whether it has to stop. Similarly, a stretch of regulatory sequences decides whether a gene is turned on or turned off.Interestingly enough such a stretch does not contain only one repressor binding site but several, if not many. A gene thus can be activated differently in differently cell types or at different times in a given cell type. This fact permits us to understand, for example, why humans and chimpanzees on the hand have the same kind of genes and why they, one the other hand, look so differently. The answer to this question was provided just about two years ago, when scientists at the Max-Planck-Institute of evolutionary anthropology in Dresden found that certain genes are far more active in the human brain than in the chimp brain. Thus the key to what makes these two species different lies in where and when those genes are active. This also means that genes and gene mutations are not necessarily the answer to evolution but rather variations in the regulatory activity of genes and genomes.These regulatory sequences around the beginning of coding sequences are hard to find. The first ones were identified many years ago but not more than 100 have been identified so far. Since the completion of the human genome, it has been possible to look at this problem more carefully. Thus, it is now estimated that upstream regions of genes are peppered with such binding sites, their number being estimated to exceed 100.000. While a full search on these binding sites is on, scientist already try to understand their function and interactions. The vision in front of everybody is to understand the evolution of body plans by changes in network structures of regulatory elements. The work of Patrick Cramer is quite significant in this context because he works on the enzyme which, by interacting with these regulatory signals, reads a DNA sequence into its RNA counterpart. For this to happen it has to find the correct start site and it has to know when and where to start. One tool to analyze such question is X-ray crystallography. This field was pioneered more than 90 years ago by Max von Laue and adapted to proteins for the first time by Kendrew and Perutz who solved the structures of hemoglobin and myoglobin in the 1950ies. This was quite surprising at the time because nobody could envisage that something like eggwhite could crystallize like salt crystallizes. As counterintuitive as this may sound, it does happen and this possibility has opened the door to a structural analysis of hundreds of proteins. Not everybody can crystallize proteins since it requires something which a gardener would call a "green thumb". The "green thumb" in crystallography can be replaced to some extent by robots who can portion and mix liquids in precise ratios, but nevertheless matters remain quite difficult. Prof. Cramer achievement in crystallizing RNA polymerase thus cannot be overestimated. He not only managed to crystallize the RNA polymerase itself, a complex structure consisting of 10 subunits, but in addition together with some of these transcription factors. He then could show, how this structure manages to signal the initiation of transcription as well as other aspects of the transcription process, namely when to end the reading process and how to indicate this to the reading machinery.Patrick Cramer started this work as a postdoctoral fellow at Stanford University in the laboratory of Roger Kornberg. Prior to this he obtained a Ph.D. at Heidelberg University. He has made an amazing career since his work has earned him one of the first if not the first tenure-track professorships at a German university. We wish him all the best for his future work at the Gene Center of the University of Munich where he recently succeeded R. Grosschedl as a director.