MEET THE DMDD TEAM – DAVID ADAMS

Dr David Adams.In a series of interviews we’re hearing from members of the DMDD programme. Who are they? What inspires them? And what do they hope that DMDD will achieve? This month we hear from David Adams, who oversees the production of embryonic lethal knockout mouse strains for the project.


What has been your main area of research in your career so far?

I lead the Mouse Programme (MGP) at the Wellcome Trust Sanger Institute, which generates around 200 genetically modified mouse strains each year. The MGP explores the role of genes in a range of biological processes including in development, immunology and infection, and in metabolism and cancer. I am primarily a cancer geneticist interested in how the immune system controls tumour growth and the genetic wiring of cancer cells. Remarkably this had led me to explore aspects of developmental biology as we try and understand what these genes do.

 

What inspired you to devote your career to developing animal models of human disease

In all areas of medicine and biology, animal models have contributed significantly to our understanding of disease processes. For example, our understanding of the fundamentals of how the immune system recognises pathogens and cancer result from experiments in mice. The development of induced pluripotent stem cells, which appear to have huge potential in regenerative medicine, was also pioneered in mice. If that’s not enough, the role of literally thousands of mammalian genes in development has been elucidated in mouse model systems. The contribution has been huge. Further, virtually every drug approved for treating patients was tested in rodent models.

 

What do you think is the most exciting recent development in your field?

This has to be CRISPR. The ability to rapidly alter the genome with unprecedented precision makes generating new animal models significantly easier. In particular, we are able to introduce point mutations found in patients to essentially humanise the mouse genome.

 

What is the biggest outstanding problem in your field that you wish could be solved?

There are still many many genes where we don’t have even the most basic understanding of their role in development or disease. Cell culture systems will undoubtedly contribute to further understanding, as will the analysis of human tissues, but to really understand what a gene does you need to manipulate it in the context of the whole organism and see what happens. We call this the post-genomics era but in fact we are still very much living in a time where we don’t know how the genome works and how individual genes function. I think there are many surprises and delights still to be found.

 

Why did you decide to become involved with the DMDD programme?

My role is to represent the Sanger Institute as a member of the DMDD programme. The DMDD is a group of world-leading investigators using cutting edge technology to explore processes involved in development and embryonic lethality. I find the idea of contributing to such a large-scale co-operative endeavour very compelling. It is also wonderful that the data is released to the research community to facilitate further discovery.

 

What do you hope the DMDD programme will achieve?

So far there have been some big surprises. In particular, the significance of the placenta in development and the high frequency of cardiac malformations in developmental disorders have been a surprise to me. Large-scale programmes such as the DMDD that make no assumptions about how genes work or what they do have the potential to challenge dogma, and that’s what I think the DMDD is achieving.

 

If you could have been a fly on the wall during any scientific discovery, which would you choose?

I have a particular interest in how the immune system regulates the growth of cancers. In the last few years there have been substantial advances in understanding how T-cells control tumour growth. I would love to have been involved in, or seen first-hand, the development of T-cell checkpoint therapies because these are truly changing people’s lives and a proportion of patients with advanced disease are being cured.

 

What are you most proud of achieving outside of science?

I have two delightful children, which is a surprise given my genetic contribution. I am also a keen runner like other members of the DMDD (Tim Mohun and Jim Smith) and routinely run 20 km a week. I am currently training for the Cambridge Half Marathon.

 

Tell us a surprising fact about yourself

I used to breed, raise, and show chickens as a child. I guess this was probably the basis for my interest in genetics. Like everything I do I was extremely competitive.

 

David Adams is a Senior Group Leader at the Wellcome Trust Sanger Institute, and a joint grant holder for the DMDD programme.

NEW PHENOTYPE SCREEN EXAMINES CAUSES OF NEONATAL DEATH

Around a third of targeted gene knockouts in mice are embryonic-lethal. But not all deaths occur during gestation – a significant number of gene knockouts result in death at or shortly after the time of birth. Mice from these knockout lines provide a valuable animal model of human neonatal death and are the focus of a new systematic screen by the DMDD programme.

The study, to be carried out by consortium members at the Wellcome Trust Sanger Institute, will offer new insights into the genetic basis of death in neonates, complementing the efforts of large-scale human gene studies such as the DDD and UK10K.


UNDERSTANDING LETHALITY IN NEONATES

The DMDD programme studies embryonic-lethal knockout mouse lines, where lethal means that no pups are observed 14 days after birth (known as postnatal day P14). Detailed phenotyping of these lines can provide important clues about the genetic basis of human developmental disorders.

Our phenotyping efforts so far have focussed on in-utero development at embryonic days E9.5, E14.5 and E18.5 since, for the majority of embryonic-lethal lines, the embryos die well before birth.

In 5-10% of cases, however, the embryos die at the time of birth or shortly afterwards, and can provide an animal model of neonatal death due to genetic mutation. The pilot neonatal screen will study 20 of these lines during the period E18.5 to P14, gathering systematic phenotype data.

Nesting wild-type pups.
Nesting wild-type pups on their day of birth.

Common causes of lethality for neonates can include problems with partuition, breathing, suckling and achieving homeostasis. To understand the likely cause of death in each case, the neonatal screen will assess the pups’ gross dysmorphology, breathing, milk spot morphology (a test that reveals whether they have been able to feed), weight, measurements, locomotive skills, righting reflex (ability to correct their own body position) and blood glucose levels.

The first data is expected at the end of 2016. For more information about the DMDD programme, visit dmdd.org.uk.

JOIN DMDD AS A POSTDOCTORAL FELLOW

The Wellcome Trust Sanger Institute is now hiring for a Postdoctoral Fellow to join the DMDD (Deciphering the Mechanisms of Developmental Disorders) programme. Based in the Vertebrate Genetics and Genomics group at the WTSI, the successful candidate will use RNA-seq and a range of high-throughput sequence analysis tools to identify genes and regulatory networks perturbed as a result of gene knockout.

The role will involve running the DMDD sequencing workflow, from sample preparation and sequencing pipeline submission to sequence analysis and interpretation. This will include following already established protocols, but it will also require the development of new applications. The post is an excellent opportunity to learn next generation sequence analysis, and there is also scope for learning and further developing lab techniques.

The closing date for applications is 22 September 2016. View the full job description on the WTSI website.