Piecing together the biological jigsaw
The challenge for SULSA Director Mike Tyers is not just to pursue his own specialist interests (focusing on systems biology and cell division) but also to tie together different institutions, scientists and scientific disciplines as biology embarks on the next phase of its own evolution… …
Yeast may not be the most complex organism in the universe, but according to Professor Mike Tyers, the study of yeast could be one of the keys to the human condition – at least biologically speaking. In other words, if we can understand a simple organism like yeast, then we are on the way to understanding far more complex species like ourselves.
Tyers is best known in scientific circles for his work on cell division – or what has been described as his “cell-cycle-centric view of the world.” And at the Tyers Lab in Edinburgh, his team of researchers is pursuing a number of ground-breaking projects including systematic cell size analysis in yeast and mammalian cells, protein recognition in the ubiquitin proteolytic system, and another which involves screening yeast bioactive compounds to identify specific chemical fingerprints for diverse species, including human stem cells.
Yeast has played a major role in Tyers’ academic career, and will also be a focus of attention in the future, he says, as researchers contemplate synthesis of the entire yeast genome – refactoring the genome – to systematically modify the DNA sequence so they can study effects on yeast behaviour under different conditions.
Tyers’ interest in the mechanics of biological systems first developed in graduate school in the early 1980s, when the revolution in molecular biology was just beginning. At that time, he also developed an interest in signal transduction – how cells respond to their environment and communicate – but realised the limits of doing experiments with mammalian signalling systems. “Twenty-five years ago,” Tyers explains,” there were no transgenic mice.” Although Tyers managed to clone an important signalling protein (pleckstrin) as a graduate student, there was no way to analyse its function in a living organism. Yeast, however, was very amenable to genetic manipulation and therefore the ideal subject for experiments when studying fundamental processes like cell division, which happens much the same in yeast as in human beings. Tyers also studied key regulators of division – proteins known as cyclins – whilst a postdoctoral fellow at the Cold Spring Harbor Laboratory in New York.
Another big advantage of using yeast was that it was the first eukaryotic genome (an organism with a nucleus containing the chromosomes that make up the genome) to be sequenced, enabling biologists to manipulate genes on a genome-scale level, including “knocking out” every one of yeast’s 6,000 genes to study their functions and interactions. Subsequently, Tyers has spent the last few years developing cutting-edge systems-biology approaches to fundamental questions such as how cells control the balance between growth and division. This can lead to breakthroughs in various other fields – for example, some of the pathways that control growth in yeast can provide insights into the growth of a tumour – or the genesis and maintenance of tissues and organs.
Over the past few years, Tyers has focused on three large-scale systems biology approaches, all involving yeast, and all of which have led to high-profile discoveries. The first project used genome-scale screening to study how genes control cell size and revealed a complex network of new genes that ensures cells are the right size when they start to divide. Another project probed genetic interactions, systematically combining 6,000 yeast gene deletions with other mutations to see which genes interact with each other.
The result has been a detailed “roadmap” of yeast genes that will help explain how different biological processes cooperate. For example, Tyers explains, dozens of genes are involved in the development of a disease like diabetes, and it is hard to find even one of the genes responsible in human beings. By using yeast to “map the genetic landscape of the cell,” however, scientists can begin to analyse the complex interactions of multiple genes, accelerating their understanding of human diseases, at the same time as taking a lot of the serendipity out of the process.
The third project in Tyers’ lab involved the systematic mapping of protein interactions. In the past, says Tyers, scientists did one-off, ad hoc studies of pairs of proteins, but recent approaches use the latest high-throughput mass spectrometry technology to accelerate the process, which Tyers compares to piecing together a mind-bogglingly complex jigsaw. “If you can only see two pieces at a time,” says Tyers, “it would be difficult if not impossible to solve the puzzle. The added complication is that the jigsaw is not two-dimensional, it’s n-dimensional.” And Tyers’ approach allows him to see many of the pieces simultaneously and how they link together.
Most recently, Tyers has extended these approaches to the problem of how small molecules – chemicals such as drugs, industrial compounds or natural products – affect biological systems. According to Tyers, the ultimate aim is “to try to understand how small molecules influence all aspects of a biological system,” and having mapped the complex networks, use chemical biology to control different processes such as the development of different disease states. Most drugs have “promiscuous interactions” with biological systems and the reactions to different drugs vary from person to person, including side-effects. Tyers explains: “The bottom line is that if we can understand the complete response of a biological system to a drug, then we will understand the biological system itself.”
“I strongly believe that chemical biology will re-invigorate drug discovery,” says Tyers. “When we study biological systems now, we don’t just study one gene at a time; the same principle applies to the use of small molecules to interrogate and control networks of interactions between genes.”
For Tyers, SULSA is an excellent environment in which to pursue this research since it draws together so many themes, with an emphasis on interdisciplinary activities. In fact, Tyers believes that biology will be a major driving force of science in general, taking physics and computing in completely new directions, as scientists grapple with phenomena like the individual behaviour of cells as highly complex self-replicating machines. SULSA, says Tyers, is one of the first initiatives of its kind, pooling the resources of several institutions in the same country, and is also a leading example of what can be achieved through close collaboration and the open exchange of ideas.
One of the factors that makes Tyers different is his “systematic mentality” and the fact that he has always been quick to embrace new technologies and apply them to complex biological problems. “Scientists don’t yet fully understand the simplest biological systems,” says Tyers, “and we now know that knowledge of all of the parts encoded by the genome is just the beginning of putting together the puzzle of life.” Yeast has played a critical role in his work until now, and Tyers believes that this will continue as he and others move into the “brave new world” of synthetic biology.