Alfonso Martinez-Arias

Alfonso Martinez Arias

Alfonso Martinez Arias

Lab Leader

ama11@cam.ac.uk
Department of Genetics,
Downing Street, Cambridge
CB2 3EH,England
Telephone: +44 1223 766595
Fax: +44 1223 333992

As an undergraduate I studied Biology at the Universidad Complutense, Madrid (Spain). After graduating in 1977, I obtained a Fullbright scholarship to study in the US. Having developed an interest in Developmental Biology, though at the time I am not sure that this is what my interest was called, and the possibility that biological processes could be explained in terms of the physical Sciences, in 1978 I went to the Department of Biophysics of the University of Chicago, Chicago (USA). There I realized quickly that at the time, there was not enough Biology known to deal with at the interface with the physical Sciences; particularly in the realm of Developmental Biology. I also realized then the importance of genetic analysis as a first approximation to the solution of biological problems. My PhD, with Malcolm Casadaban, was an exercise learning Molecular Biology (Beta galactosidase fusions for the analysis of gene expression in yeast) and, in my spare time, learning as much classical Developmental Biology as possible. In 1983 I moved on to do a postdoc with Peter Lawrence at the MRC Lab of Molecular Biology in Cambridge, UK. These were interesting days for developmental Biology and the LMB an excellent environment to develop my curiosity in these fields. In Cambridge, Peter Lawrence, Michael Akam and Michael Bate helped me develop a framework to think about developmental problems that complemented the questions I had taken from Madrid to Chicago and which have stayed with me all along.

In 1987 I was awarded a Wellcome Senior Fellowship which I held until 2002 when I became a member of the University and since 2003 I am Professor of Developmental Mechanick . During this time, first in the department of Zoology and since 2000 in the Department of Genetics I have pursued my interests in the logic of animal development. Below you can find a summary of my current interests and views on the subject which, naturally, are also represented in the pages of the lab. I believe that Biology is about Living Matter and that organisms are not the result of cocktails of genes and proteins whimsically shuffled by Evolution. Instead I believe that there are constraints and principles which determine the reproducible behaviours that we observe. One question that has become important to me is derived from the realization that at the molecular (and probably at the multicellular) level, there is a lot of stochasticity in the workings of the cell and yet the macroscopic level (tissues, organs, organisms) is very deterministic. How this transformation occurs is something that intrigues me very much.

Developmental Biology has witnessed a very fruitful period at the end of the 20th century. The application of Genetics to a wide range of problems in Caenorhabditis elegans and Drosophila melanogaster, and the extrapolation of the results and methods from these studies to vertebrates and other invertebrates, has yielded two very important results. The first one is a comprehensive list of the genes that configure the make up of many organisms and, associated with this list, an ever increasing account of what each gene is required for. This results in a part list of sorts. The second result is that these genes, and in many instances their functions, are conserved across species. The conservation is such that it is possible to exchange genes (parts) between organisms without altering their function (as long as we understand function in a broad way and as long as we can keep the regulation in the host) e.g the genes that instruct eyes in a vertebrate instruct eyes in a fly and genes encoding signals in a fly work well and signal efficiently (are recognized by the signal processing machinery of the new environment) in a mouse. The message from these observations is that genes are elements of a programme, of a genetic piece of software, that is used to build organisms. Much work today goes into decoding these programmes. Some perhaps not surprising similarities arise: making a lung is similar to making the airways of an insect and all hearts, from a fly to a human, use a similar piece of software. A cottage industry has emerged from these observations that comes in various flavours, particularly in the form of large scale screens to identify ‘all’ genes involved in this or that process, or genes that ‘do’ this or that.

There is no question that some dose of this cottage industry is necessary for it yields information that, when of high quality, is useful. However I have doubts that this is the way to understand how an organism makes itself.

Making an organism requires the integration of three processes: making enough cells, making them different and organizing the different cells in space. Knowing the list of parts does not get us nearer to answer any of these questions in a satisfactory manner. Furthermore, I would say that the emphasis on the gene has created the mirage that we understand because we can put together long lists of names joined by arrows of dubious meaning. The problem is that at the moment this way of proceeding is getting things messier and messier and us farther and farther from getting near any answers to how the system we are interested in works. To get nearer to answers we have to ask questions at the Systems level, good questions. Unfortunately much of what lies under Systems Biology is, as S Brenner has put it: low input, high throughput and no output. Output, I hasten to add, in terms of understanding. If, to paraphrase R Feynman, we only understand what we can build, we are far from understanding the development of an organism and, I believe, the way forward is change perspectives, approaches, questions.

If the making of an organism is all about information processing, it is important to bear in mind that genes only encode proteins which, within the context of a cell, are the workhorses of the cell. In many ways cells are just macromolecular aggregates with a very big protein core which is the heart of the information processing machinery. Although in the last few years it has become apparent that regulatory RNAs are an important component of the regulatory toolkit of the cells, proteins, remain at the center of the information processing activities of the cell that lead to the generation of tissues and organs. Thus in the making of an organism different scales are woven into a functioning unit: genes into proteins into cells into tissues into organs into organisms. A most interesting principle of this hierarchical organization is that when the elements of one level are put together to generate the next level up, properties appear which cannot be predicted from the sum of the component elements i.e. there are ’emergent’ properties, These properties are the basis for the next level up but also feedback on the level down. Thus, proteins organize themselves into networks which are the basis for the cells but also organize genes into gene regulatory networks. Then when proteins arrange themselves into cells, they acquire properties that can never appear when they are in solution and which will influence the activity of their networks.

My main interest lies in understanding the principles that govern the development of organisms. For some time I have felt that this is all a problem of information processing and recently I have realized that this has a framework that links it to Physics: Biology is about Living Matter and what I am interested in is the principles which I believe exist that govern the behaviour of Living Matter. I have also come to appreciate two important gaps in the way we work. The first one is that we do not have quantitative understanding of the processes we study and that much of what happens in the cell happens within a parameter range which we do not understand. The second thing is that the processes we want to understand are dynamic and can be described as emergent properties from particular sets of elements. A consequence of this realization is that in order to understand these properties and how they impinge on specific biological processes we need models, quantitative models, that describe the processes, highlight their dynamics and quantitative underpinning and make predictions. In this framework, genetics is a way to perturb the system.

The pages of the lab and its members reflect this interest as well as highlighting our small community in which projects develop from our shared curiosity on topics of common interest. Most of the projects in the lab (hopefully all within two years) are associated with a collaboration with a physicist or an engineer. I think that this is the way forward for Biology. We have to measure, we have to model and we have to find the principles that clearly underlie the behaviour of cells when they make organisms.