Johan Elf is Professor of Physical Biology at Uppsala University. His biggest driving force is the desire to know how things work, such as how a bacterium can duplicate all its parts in a controlled manner in 20 minutes.
“Classifying what we are doing into the traditional scientific disciplines is irrelevant. My interest is based on how the natural sciences are interlinked, and that we can agree on how things work across disciplinary boundaries,” explains Johan Elf and continues:
“I think it is worthwhile to develop cell and molecular biology into quantitative sciences based on quantitative physical models. Without quantitative models, it is often impossible to say if what is measured in the cell is unexpected or not. The experiments must also be so well controlled that you are able to say whether the models are at fault or if you have actually discovered something new. We want to get to a point where we understand the central biological processes so well that we will be glad when an experiment deviates from the models – not disappointed, which is often the case now.”
This is why he has gathered together physicists, microbiologists, computer scientists, engineers, mathematicians and molecular biologists in his research group to work on issues concerning gene regulation, transcription and protein synthesis in bacterial cells.
On a monitor behind Johan Elf, many tiny points of light traverse the screen, apparently irrationally and unpredictably. Sometimes they pause for a brief moment, only to soon continue their restless wanderings. It could be a screen saver on any computer, but what are visible on the screen are in fact transcription factors inside a living bacterial cell. It is these molecules that control a cell's production of RNA and proteins by locating individual genes on the DNA strands, activating the genes, and then continuing on to find new genes to activate or switch off.
Transcription factors have been well studied under artificial forms in test tubes, but, according to Johan Elf, the molecules are faced with completely different challenges in their natural environment. This is why he has chosen to study them in living bacterial cells, and there are these studies that he will advance as a Wallenberg Academy Fellow.
“We are in particular studying the physical limitations for the regulation of various processes inside the cell. It's very much about how molecules find each other in an environment packed with other molecules and other reactive groups.”
Johan Elf and his colleagues are also interested in how, and how quickly, transcription factors find and bind to certain sites on the DNA strands; why they bind to certain sites, and not to others; how long they remain attached when they find a site; how they move; and what happens when they collide with, for example, the replication machinery.
In other words, to find the right site to bind to on the DNA strands, the transcription
factors must therefore, in the throng of hundreds of thousands of other molecules, search through millions of DNA base pairs in just a minute or so. To use a metaphor, one could say that a transcription factor is like a person who has the task of quickly finding one of millions of books in a library when the books are placed randomly and all the shelves look alike. The problem is complicated by the fact that the person looking has such a bad memory that he forgets which shelves he has already looked on.
“There are physical limitations that even apply to living cells, for example, limited access to building materials, energy, time and the randomness in chemical reactions. One strength of quantitative models is that they make it possible to take these physical limitations into account and thus restrict the models to what is possible. An important part of our research, therefore, is to identify the physical restraints that evolution has had to work with. When we understand these limitations, it often explains why nature has designed a biological process in the way that it has.”
Traditional ways of labeling transcription factors by attaching a larger fluorescent molecule do not work because this often leads to the transcription factors moving and behaving in an unnatural way. Part of Johan Elf's project is therefore to develop new technology to replace one of approximately 300 amino acids residues in a protein inside the cell with a fluorescent amino acid. At the same time, it is important to build extremely sensitive and fast optical microscopes that can capture the light from individual molecules, so as to be able to follow the movements of the molecules.
Why then is this research important?
“We are looking for a fundamental understanding of how life works. In the long term, it may be important for the development of new drugs, materials and energy. For now, however, the most important thing is to develop sufficiently accurate methods of measurement in order to be able to determine how well we really understand the most
central biological processes – to begin with, in bacteria.”
Transcription: When genetic information in a cell's DNA is copied into RNA. In eukaryotic cells, that is, cells with a nucleus, almost all transcription occurs in the cell nucleus. The RNA molecule is then transported out of the nucleus to the cell's ribosomes, where it is used as a template for the production of protein. In prokaryotic cells, that is, cells that lack a membrane-bound nucleus, the transcription occurs in the cytoplasm.
Transcription factors: Proteins that control which genes in the DNA are to be transcribed at a given point in time.
Text: Anders Esselin
Photo: Magnus Bergström