Stefan Mundlos is director of the Institute for Medical and Human Genetics at the Charité and group leader at the Max Planck Institute for Molecular Genetics in Berlin, Germany.  He will be giving the ESHG Award lecture on Tuesday, May 24, 2016 at 14:15 hrs. He talked to Mary Rice about his life and work.

Stefan Mundlos is clearly happy with what he does.  He’ll retire when he is forced to, not before, he says. And if you ask him if there’s anything he regrets in his career, the only thing he can come up with is not starting his scientific work earlier. “I started my scientific career fairly late, when I was in my early thirties. Although I did some research during my time as a paediatrician, it was relatively little.”

Mundlos’ interest in science began in the forests and ponds near his home.  “As a boy I was always interested in nature and the secrets it holds. I was interested in reptiles, amphibians and fish – I caught them in the ponds in our neighbourhood and kept them and watched how they developed, how they caught prey and so on. I was certainly always very interested in the way nature presents itself. We lived in a suburb of a larger town, but were right next to the forest, and so I spent a lot of time exploring nature there, looking at animals and trying to work out why they behaved the way they did.”

This interest led him to medical school in Göttingen, where they had an exchange programme with the University of California leading to a year spent in a San Diego laboratory working on a breath test for pancreatic function in rats.  He finished his studies in Marburg and Heidelberg before beginning his training in paediatrics.  A specialism in paediatrics holds a particularly happy memory. “When I started my training we had a very sick new-born child with life threatening diarrhoea. Through trial and error, I managed to work out what the problem was. The child had an intolerance of the sugars found in milk [glucose and galactose], and once we removed these and substituted with fructose, she was completely fine. This was an important and very rewarding experience for me, both on a professional and a personal level.”

Another highlight, once he had moved into science, was the discovery of the disease gene for cleidocranial dysplasia. “The gene mutated in cleidocranial dysplasia turned out to be a transcription factor essential for bone formation and chondrocyte differentiation,” he says. “This finding was a breakthrough in the bone field, once again showing how the identification of rare disease mutations can provide major insights into biology.”

More recently, his group has been working on gene regulation and the non-coding genome. “I think that the interpretation of the non-coding genome, which after all makes up more than 98% of our genome, holds one of the major future challenges in human genetics,”,he says.  The effect of structural variations on gene regulation has been another major interest of his group. A highlight of the more recent work has been the discovery that structural variations (deletions, duplications, inversions) can interfere with the 3D folding of chromatin, thereby influencing gene regulation.

Of course he has concerns for the future. He is not alone in bemoaning the importance attached to high impact publications. “The publication of an important paper in a low impact vs a high impact paper can ruin a career. This is getting out of hand, and it has a big effect, especially for young people.”

Outside work, Mundlos still enjoys nature. “I very much like my garden and I enjoy gardening. I grow my own vegetables.  I also like to work with wood, and I build furniture. And I listen to a lot of music – being in Berlin, there’s a wide variety of classical music and jazz to be enjoyed at concerts.

He’ll be talking to the conference about the importance of genome folding. “These are very exciting new developments; how our genome is folded in a three dimensional way and its importance for gene regulation. I want to open eyes to a part of the genome that has not been well studied, the non-coding part of the genome. Most studies have focused on finding the genes, finding mutations in genes, but the big question now is “What is the rest doing?”

It seems that Mundlos’ insatiable quest for new knowledge will continue to shed new light for a long time to come on the way in which changes in the genome cause diseases.

Professor Sir Adrian Bird is Buchanan Professor of Genetics at the University of Edinburgh in Scotland. He will be giving the Mendel Lecture on Tuesday, May 24, 2016 at 13:30 hrs. He talked to Mary Rice about his life and work. 

DNA has fascinated Adrian Bird since he was in his teens. “Like many children of my generation, I grew up interested in growing frog spawn and watching birds, etc. But it was a black and white TV programme about science that really caught my attention. On Sunday mornings, scientists like John Kendrew or Asher Korner would stand behind a lectern and talk about proteins or DNA. If there were illustrations, I don’t remember them – it was just a man giving a lecture aimed at the general public. I have no idea why I started watching those programmes, but they appealed to me.”

No-one in Adrian’s family had been a scientist before. His father was a public relations officer and journalist, and most of his relatives work in publishing or journalism. “When I retire – and I don’t know yet when that will be – I’d quite like to write, though that sounds a bit boringly obvious, like a Miss World candidate saying she wants to travel,” he laughs. “But I do have quite strong opinions about certain aspects of science and indeed biology that I would like to write down. Sometimes I think I should take a sabbatical to do that, but I am not sure that I ever will.”

His strong opinions look to be well-founded. “My research has focused on DNA methylation and its associated binding factor MeCP2. We found that the MeCP2 protein binds specifically to methylated CpG sites and we now know that disruption of this interaction caused Rett syndrome. At that time Rett syndrome was considered to be a neurodevelopmental disorder, the implication being that the condition was irreversible. We decided to make a mouse model of the syndrome to try to understand things better.

“We then put back the gene in an adult mouse that was terminally ill, and it got better. In other words, we showed that this wasn’t strictly a neurodevelopmental disorder – though people still call it that. That was really exciting, because it was completely the opposite of what everyone thought would happen. Even we expected that, once you had this disorder, it would probably be too late to do anything about it. But that turned out to be wrong.”

The fact that there is, as yet, no effective treatment for humans with Rett syndrome is frustrating to him. “There’s a huge amount of interest in labs around the world in trying to get therapy to work. Our work arguably had an impact beyond Rett syndrome in the sense that people are now conscious that a neurodevelopmental disorder they are working on might end up being curable. So it’s not considered crazy to consider trying to cure autism or other profound neurological disorders, although in most cases reversibility has not been demonstrated.

“For Rett syndrome itself, there are several clinical trials under way now that people realise that you can reverse this condition rather than having to catch it before it starts, but no therapy is yet imminent.

“I’m not a mouse geneticist, even though I’m a professor of genetics – I’m really a biochemist. It’s somehow exhilarating that we got into an area where genetics and neuroscience were the dominant approaches and were able to show that some prevailing views were incorrect.

“But working out how MeCP2 works turns out to be rather more difficult to disentangle than we had hoped. It looks as if it affects a lot of genes subtly rather than affecting a few genes in a switch-like manner. The trouble with subtle effects is that they’re quite difficult to study. But that’s what we’re doing and I think things are steadily getting clearer with time.”

Although Adrian hopes he’ll continue working for a long time to come, he has had some thoughts about retirement. “In addition to writing, I could spend more time cooking – I find it therapeutic. I enjoy watching football, like cycling, and used to run in a hill-running club. Unfortunately I’ve lost the cartilage in my knee so I can’t do that anymore. A regret about the state of science today is that not enough people work on knees! It’s particularly disappointing that stem cell scientists haven’t yet managed to grow me new knee cartilage.”

More serious concerns about the state of science today include the hegemony of certain journals. “I do think that science is pretty fashion-conscious at the moment. I would like to see a literature that more accurately reflects the scientific process, rather than the cross between science and journalism that we sometimes appear to have. I don’t want to sound cynical though, because there’s fantastic science going on now, and technologically it’s never been better. But it’s somewhat frustrating when unfounded studies making flashy claims get published.”

He will talk to the conference about his work on Rett syndrome. “We’re manipulating the MeCP2 gene to see if the parts that we thought were important really are. I’ll also discuss reversibility, because this still needs explaining at the molecular level.”

Even though Adrian describes himself as ‘no spring chicken’, it looks as he’ll be intriguing us with his strong opinions for some time yet.