In a new series of interviews we’ll hear from members of the DMDD team. Who are they? What inspires them? And what do they hope that the DMDD programme will achieve? We kick things off with joint grant-holder Liz Robertson.
What has been your main area of research during your career?
My lab studies how our body plan is established in the early embryo using mice as a model. We focus on one particular signal known as TGFb, which cells use to communicate with each other. This turns out to be fundamental to why different tissues form in different parts of the early embryo in a predictable and reliable pattern. A consistent theme emerging from our work is that the way TGFb works is to activate master regulator genes in different parts of the embryo. These master regulators then trigger a programme of gene activity that results in differentiation of an individual tissue.
What inspired you devote your career to understanding embryonic development?
I actually started out as a PhD student back in the late 70s, early 80s studying tumour-derived embryonal carcinoma cells in a dish. It was only with the advent of embryo-derived stem cells, and our discovery that they would reproducibly colonise the germ-line, that I became really interested in early embryos.
Back in the days when only a few genes had been identified molecularly, I was fortunate enough to stumble on a mutation that gave a very early post-implantation defect and completely derailed the embryo. The first dissections were a real “wow” moment for me. I knew I was on to something really interesting when I showed the mutant embryos to my good friend the late Rosa Beddington, a card-carrying embryologist, and even she was suitably puzzled about why they were so disturbed!
What do you think is the most exciting recent development in your field?
Most people would probably respond to this by saying CRISPR-mediated engineering but, as a mouse geneticist, I’ve had the ability to manipulate the mouse genome in vivo for decades. So whilst CRISPR has become an incredibly useful tool to manipulate other model organisms, for me it’s just a nice addition to my tool kit. What’s caught my attention the most is the emergence of wonderful imaging technologies and new methods for looking at the organisation of the genome (although my lab are very much amateurs in both areas).
What is the biggest outstanding problem in your field that you wish could be solved?
There are so many I don’t know where to start!
Why did you decide to become involved with the DMDD programme?
Sitting on the sidelines of the international KOMP and EUCOMM consortia over the last decade, I’ve seen the enormous effort and investment that has been put into knockout mouse projects. Given my long-held interest in studying embryo phenotypes, I was delighted to be included in the initial discussions with Jim Smith, Tim Mohun and David Adams to plan DMDD – an in-depth phenotype screen for a sub-set of 240 embryonic lethal lines. In particular, I was interested to see how much new information we could find out about later developmental patterning defects using the High Resolution Episcopic Microscopy (HREM) imaging technique that Tim has developed.
In the long-term what do you hope that DMDD will achieve?
Given that around one third of protein coding genes are now known to be essential to sustain development of the embryo, it’s a huge challenge to understand their many and varied roles. The pipeline that generates knockout mice for DMDD is largely unbiased, and many of the phenotypes we’ve detected are related to previously uncharacterised genes. Hopefully some of the mutations will match up with genes that have emerging associations with human developmental defects, such as those being uncovered by the Deciphering Developmental Disorders (DDD) study.
I also hope that after exploring our phenotype data on the DMDD database, individual investigators will feel compelled to call up specific null or conditional alleles from KOMP or EMMA for further study. We’re carrying out a primary screen, but I hope it will spark further research to determine the roles these genes play at the molecular level, and exactly why they are essential for embryo development.
If you could have been a fly on the wall during any scientific discovery in history, which would you choose?
My lab is based at the Dunn School of Pathology, where the first mass quantities of penicillin were made. It was here that the initial trials on animals and humans were carried out 75 years ago. The dawn of the antibiotic age must have been a very exciting time.
What are you most proud of achieving outside of science?
In my next life I’m going to try and have a life outside work!
Liz Robertson is Professor of Developmental Biology at the University of Oxford and a grant-holder for the DMDD Programme.