Professor Michael Ashburner 23 May 1942 – 7 July 2023

By Ann Stocker

Michael Ashburner died last year at the age of 81. Most researchers know his 12-volume collection on the Genetics and Biology of Drosophila and his encyclopedic “Drosophila A Laboratory Handbook” with its accompanying Laboratory Manual. Michael was not just interested in his own work. He was passionate about genetics as a whole and Drosophila was one of his loves. He was a living encyclopedia on Drosophila.

Michael’s life was spent working with Drosophila from the late 1960s to 2011, when he retired due to his health. Even then, as Professor Emeritus at Cambridge, he kept up his interest in Drosophila work and bioinformatics. Michael’s scientific work can be divided into two main parts. The first part, beginning in the late 1960s, involved cytogenetics and gene mapping. Later, seeing the increasing amount of biological information and the need for computer analysis to compare results, he was drawn into bioinformatics. Ultimately, he became involved in the development of the Gene Ontology Project, which aimed to provide a framework for the description and organization of biological information (vocabularies or ontologies) so that biological processes could be compared across species.

Early career in Drosophila

Michael began his long involvement with Drosophila genetics in the late 1960s, before the modern era of gene cloning and sequencing had begun. Michael’s PhD and post-doctoral work was an examination and description of the changing pattern of puffs during development of Drosophila melanogaster. These puffs, observed in the salivary gland chromosomes of Drosophila and other diptera, showed changes during development that were believed to indicate increases and decreases in gene activity and were thought to be controlled by ecdysterone.

Chromosome photograph. One of 90 or so figures from Michael’s PhD thesis.

I first met Michael at a Drosophila conference in 1968. I was a beginning PhD student looking at developmental changes in the puffing patterns of Drosophila pseudoobscura. He had just published photographic maps of changes in the puffing patterns of Drosophila melanogaster during development, the result of his doctoral studies at Cambridge. Michael had come from Cambridge to do a post-doctoral fellowship at Cal Tech in the laboratory of Herschel Mitchell and was speculating on controls for the puffing changes he had observed. He had become acquainted with a number of well-known-scientists during his time at Cal Tech and had obviously impressed them. He was very outgoing, conversing with everyone at the conference (even spending quite a lot of time talking to me) and generating enthusiasm and excitement for his own and other scientists’ work.

When Michael returned to Cambridge, he began to do experiments with the hormone, hydroxy-ecdysone, on control of the puffing changes he had documented. Hydroxy-ecdysone was known to be involved in molting and the question Michael sought to answer was how a very complex temporal program was controlled by this hormone. Experiments with the hormone showed that it was essentially a trigger that started the genetic changes in the salivary gland which were then self run. This was the subject of his speech at the Cold Spring Harbour Symposium in 1973 and was published as The Ashburner Model for the temporal regulation of gene activity. His invitation to the Symposium and the requirement for a paper was the impetus for him and his graduate student, Jeff Richards, to go into a period of intense intellectual activity to analyze their data, come up with the model, and write the manuscript.

Control of a D. melanogaster puff by hydroxy-ecdysone. M. Ashburmer, Chromosoma (Berl.) 38, 255-281 (1972).

Ashburner’s Model for the regulation of Gene Activity by Hydroxy-ecdysone.

At that time, none of the transcription factors involved in this process had been discovered. This occurred later, when researchers in David Hogness’s lab discovered that the genes encoded transcription factors, just as the Ashburner Model had proposed back in 1973.

These were the experiments that initially caused Michael to become well known. After this, he and his group worked on several other problems in Drosophila melanogaster, discovering heat shock proteins and genetically analyzing the alcohol dehydrogenase (Adh) locus. Michael had initially begun to study heat shock when he was at Cal Tech, looking at the curious phenomenon of the heat shock puffs; a few large puffs that appeared in the polytene chromosomes when the larvae were exposed to high, but still viable, temperatures. After he returned to Cambridge, he and his research assistant did double labelling and gel separation experiments to see whether these puffs coded for proteins. They did, but a visiting researcher, whom Michael had told about his preliminary results, used better techniques and put out the first paper.

Michael’s laboratory then began to work on the Adh gene and the region around it. They spent 20 years genetically analyzing and sequencing almost 3 Mb of this region. The region they sequenced encompasses 69 bands on the polytene chromosome 2L map.

Sequencing Drosophila: a career in bioinformatics

While Michael was sequencing the Adh locus, he became interested in using computer analysis to compare the Adh sequence of D. melanogaster with that of several other Drosophila species that his group was working on. The internet was still in its very primitive stages then and communicating internationally was difficult, since the UK and the US were using different information systems. Also, there was no software to easily carry out the analysis that Michael wanted to do. Walter Bodmer, director of the Imperial Cancer Research Fund, gave him the use of a computer that could be accessed by dial-up, which gave him access to the early network. This allowed him to do some analysis by hand, which was further improved by accessing the MOL-GEN software program that was just being developed by Doug Brutlag at Stanford University in the US. There was an interface between these two computer systems at University College, London, and they gave Michael 5 KB of disk space (ridiculously small in today’s terms). Furthermore, Michael had a computer terminal with no memory so had to capture all the information on a printer in parallel. However, he persevered with his comparisons. His analysis showed the number, type, and distribution of the genes and other genetic elements in the Adh region as well as the relationship of the gene products to proteins in other organisms. The sequencing of this region was used to further the understanding of how Drosophila and other organisms work and how Drosophila evolved. It allowed testing of methods that would be used in whole-genome sequencing of D. melanogaster in which Michael was also involved.

At about that time, the first nucleotide sequence libraries were released by the European Molecular Biology Laboratory (EMBL) in Heidelberg and GenBank in the US. Ashburner and his colleagues set up one of the first bulletin boards, called BioNet, to keep scientists informed of changes to the library and to analysis software. From this, the field of bioinformatics grew and the need for an institution to house data and conduct research increased. So, in 1992, the EMBL decided to set up an institute of bioinformatics that would have this function. Michael was one of the main drivers supporting its development and an important promoter in establishing it in the UK. It became known as the European Bioinformatics Institute (EBI) and was finally based in the small town of Hinxton near Cambridge. Ashburner and John Sulston had led the UK bid to host it and Michael was then persuaded to become its first program coordinator. Cambridge gave him half-time leave for this. He eventually took over as joint director, a post he held until 2001.

Michael had also become interested in the organization of Drosophila information, which had been increasing so rapidly that it was no longer sufficient to put out a printed update every 25 years. In 1989, he and some other researchers at the 30^th annual Drosophila research conference in New Orleans, discussed the development of an online data base for Drosophila. Michael had seen that the power of computer processing engines was increasing and their cost decreasing. Thus, the development of FlyBase began, funded by the National Institute of Health in the USA and the National Research Council in the UK. Four groups were involved: three in the USA and one in the UK (Michael at Cambridge). FlyBase includes all possible genetic and molecular information on Drosophila and is continually being updated.

The sequencing of the Drosophila melanogaster genome began in 1998. The first publication of this sequence appeared in 2000 in the journal Science. The sequencing was funded as a precursor to the Human Genome Project and the sequencing of the human genome. Drosophila melanogaster was chosen by Craig Venter, the founder of Celera Genomics, to test the new sequencing machines and the shotgun sequencing technique because it was a smaller, although still complex, eukaryotic genome (∼180 Mb in size). It had historical importance, with a large research community who had developed extensive genetic tools. 

Michael and other Drosophila researchers wanted the results of the melanogaster sequencing to be open access; freely available to all researchers. They were suspicious of Venter because he had founded Celera to copyright and sell sequence data. However, Venter had assured Gerry Rubin, the main Drosophila sequencer at that time, that the Drosophila sequence would be freely available online. He only wanted to practice the sequencing methodology. However, when the sequencing was finished and Rubin was travelling, Michael suddenly learned that Celera had released the fly data under restricted access. Venter was evidently trying to see if the Drosophila people would notice; if Celera could quietly ‘get away with it’. Michael exploded and urgently contacted Rubin and Francis Collins, director of the National Human Genome Research Institute. The result was that Venter backed down and the Drosophila sequence became freely available on GenBank. Drosophila geneticists celebrated at a large jamboree organized by Michael to try and make sense of the sequence. Venter also attended with no hard feelings shown on either side.

In 1999, Michael was the first winner of the Genetics Society of America’s George W. Beadle Medal for his service to the field of genetics and the community of geneticists. The Medal seems to have been established for him. He was a repository of fly information and an organizer of meetings and workshops. He was an excellent teacher and, at that time, was still teaching the Cold Spring Harbour Advanced Drosophila Genetics course that he had organized 15 years before.

In 2006, he won the Benjamin Franklin award for making fundamental contributions to many open-access bioinformatics projects, including FlyBase, the Genome Annotation Assessment Project, the Gene Ontology project, and the Open Biological Ontologies project. These latter projects sought to make gene comparisons between species. He continued working in bioinformatics and participated in genome organization and evolution in Drosophila. He became interested in chromosome structure and contributed data to a paper on how inversions were formed. A few years later, however, he found that he had lung cancer, and went through an operation that resulted in the removal of a lung.

In 2011, he won the International Society for Computational Biology award for Accomplishment by a Senior Scientist. The chair of the awards committee said that Michael had been one of the pioneers of computational biology in the 1980s and ‘‘His work is now seen as a landmark and an achievement in technology.’’ On receiving his award, he gave a long talk about his life, showing his usual humor. He became an emeritus Professor at Cambridge and continued with his interest in the development of comparative ontologies, despite a decline in health in recent years.

Michael had a very full life in which he was an inspiration to thousands of scientists. He was always generous with his time and information and would go out of his way to help others.