Chain-Florey workshop 2015: of mice and men and haploid cells

 11 December 2015   Events
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Amanda Fisher (Director, MRC-CSC); Harry Leitch; Harpreet Lota; Antonio de Marvao; Jennet Williams; Eleanor Sandhu; Amit Adlakha; Pratheeban Nambyiah; Parvin Begum; Julie Glanville; Gavin Screaton (Dean, Imperial College Faculty of Medicine); Josef Penninger (Keynote speaker); Mark Ungless (Director, CSC Postgraduate studies)


By Susan Watts

Basic research and human medicine have “never been so close” according to professor Josef Penninger, keynote speaker at this year’s Chain-Florey workshop.

His view is that science is technology driven, and as scientific director of the Institute of Molecular Biotechnology of the Austrian Academy of Sciences in Vienna his plan has been to create “a playground of technologies”

In an hour-long address at the MRC Clinical Sciences Centre (CSC), professor Penninger took his audience on a whistle-stop tour of his laboratory’s latest work. His philosophy, he said, has been to “hire the best brains and let them play, like little girls and boys.”

He described his work with fly and mouse models and how he has striven to learn his biology from evolution. He ranged widely – from a description of mice models he’d created to model motor neuron damage research, to genetic links to obesity to work on the creation of a cardiac map, a guide to the network of pathways that might allow a better understanding of how best to repair damaged hearts. He described his “latest toy” in Vienna – powerful microscopy that he combines with optogenetics.

He went on to discuss current work on osteoporosis and links with cancer in an ageing population, drawing together what we know of the role of sex hormones in the development of breast cancer. “Half of my salary comes from the Pentagon to study breast cancer. Personally I think that’s the best way to spend defence money,” he told his audience.

He then described what he sees as the enormous power of whole-genome screening, using haploid cells – those with only one set of chromosomes.

Haploid cells are valuable tools for finding genes essential for susceptibility to specific challenges, such as drugs or toxins. The approach involves saturating the genome with transposons, pieces of DNA sometimes called “jumping genes” that can move around the genome inserting themselves and causing mutations in the process.

The transposons inactivate one or more genes in each cell. The key is to use a large enough population of cells that each gene will be hit at least once. The cells are than challenged, and those that survive isolated to determine which genes have been hit by transposons. To demonstrate that a gene hit by a transposon is the gene responsible for making the cell resistant, the mutation is then reversed. If it all goes to plan the cell will become susceptible again.

The closing section of his talk dealt with the burgeoning field of “organoids” – the creation in a petri dish of tiny versions of human brains, eye or liver, which he said heralds a new direction for human medicine. If the current pace of research continues, scientist-clinicians may one day have extraordinary power to model disease, perhaps even for an individual patient. They would be able to observe the phenotype of conditions such as diabetes or schizophrenia, for example, then model the affected organs, complete with a support system of blood vessels, in a petri dish, and work out how best to treat.

It will be a future, he said, built by clinicians and basic scientists who understand and interact with each other as a matter of course. “Training MDs (doctors) in basic research is key, because basic research has never been this close to human medicine. We have never had the possibility to go from the phenotype to fundamental understanding to doing something about it. I don’t know if this will work, but it is the Grand Vision not only of us, but of many people.”

The lecture met with enthusiastic applause, and Matthias Merkenschlager, head of the CSC’s Integrative Biology section, said he was “blown away” by the talk, which followed short summaries from three of the current Chain-Florey cohort, each of whom described their PhD research.

Dr Eleanor Sandhu, who is close to completing her Chain-Florey fellowship with Mark Ungless’ and Dominic Withers’ groups at the CSC, presented her work on “Exploring the role of dopamine neurons in salt intake.” She described having helped to set up the opto-genetic and chemo-genetic programme at the CSC, and how she has been looking at the effect of exciting and inhibiting dopamine neurons in mice given either salt and sucrose jellies as food. Contrary to her original hypothesis, she’s found that excitation leads to a reduction in intake of the highest concentration salt and sucrose.

Chain-Florey lecturer Dr James Tomlinson described his research on the use of transgenic mouse models in understanding kidney fibrosis. His PhD looked at the role of nitric oxide in chronic kidney disease. He’s now taking that further, including a close look at the role of senescence in damaged cells, in what professor Sir Robert Lechler, Vice-Principal and Executive Director of the Health Partners Academic Health Sciences Centre of King’s College London, described as “elegant work”.

Dr Tomoki Arichi, who is a Chain-Florey alumnus, talked about his work since completing his PhD three years ago, which involved fMRI of the developing brain. He has since gone on to develop novel ways of measuring brain response to stimulus in premature babies – to help understand which parts of the brain develop when, as a fetus matures to full gestation. His goal is to develop a functional atlas of the brain throughout development. “The unique environment of the CSC gave me the tools to continue the work of my career,” Dr Arichi said.

The workshop was rounded off with a lively and wide-ranging panel debate which touched on: the importance of open-ness about the use of animals in research, the junior doctors’ dispute and the impact on biomedical research if Britain were to leave the EU.

The event came at the end of a week that saw the Chancellor, George Osborne, protect science funding from cuts in his spending review. But scientist-clinicians in the room with little experience of politics were urged to speak up over the coming few years, to engage parliamentarians and help to persuade them of the value of bio-medical research and preserve science funding from future erosion.

“I think we all breathed a huge sigh of relief on Wednesday 25th November,” said professor Lechler, who this week becomes the new president of the Academy of Medical Sciences. “We’re in a much better position than we might have been. The argument that the academy and others will start to make is preparing for the point when we have a surplus, that’s 2020. That’s when the argument really needs to get traction that the budget for science needs to go up.”

He said there is some worry around aspects of the recently published Nurse Review of UK research, notably on the independence of the person in charge of Research UK with respect to Government. “The question is whether there is a risk now that this is a conduit through which the Government will begin to influence how money is spent. There are people around who want to direct research more than I would say it’s healthy for research to be directed.”

Professor Jonathan Weber, director of the Imperial Biomedical Research Centre and Chain-Florey advocate, said that like everyone he is thrilled that the science budget is being maintained. But he added that in his view the so-called Haldane principle (that Government decides how much money is spent but scientists decide what it’s spent on) is already being eroded, with the advent of the “Grand Challenge” approach to science. He cited the Government’s dementia programme as an example.

“One of the risks is that it is now inevitable with this new structure that there will be more political influence on that process, and as a consequence I think there will be more projects that are ‘human-based’ because these are more politically acceptable, but not necessarily more tractable.”

Professor Weber pointed out that the Government’s current chief scientist, Sir Mark Walport, is a former professor of medicine here (at Hammersmith Hospital), and that he’s adamant that scientists don’t speak to politicians enough – and need to do it more. Professor Lechler agreed. “You need to see issues from the politician’s perspective. What matters to George Osborne is the health of the economy, and he is persuaded that science and innovation is key to the health of the economy.”

“You need to make the arguments in a way that will scratch where the politician’s itching. They are susceptible to sound argument. You need to make compelling arguments in short sound bites and you need to give them sound bites that they can use,” he added. “Being realistic, there will be very few people who have direct access to the politicians. However, what’s really important for everybody in this room is that they polish their skills in communicating the benefits of their science. That’s something we’ve been a bit lazy about.” He cited animal research and the benefits of that as one example.

Junior doctor and Chain-Florey lecturer, Dr Antonio de Marvao, suggested that perhaps scientists might spend some time with the Academy of Medical Sciences to witness at first hand the way the academy works.

On the subject of the junior doctors’ dispute, Dr de Marvao thanked professor Charles Pusey, another advocate of the Chain-Florey scheme, when he said that the great majority of the consultant colleagues he works with are extremely supportive of the junior doctors, and have made that clear publicly.

“We genuinely are supportive, because we work as a team. The term junior doctor is quite misleading I think. Many of you are almost middle aged! have a family and could be running a major company or country. You’re experienced, responsible doctors and you are part of our team. We cannot possibly look after patients without working together as a team. I think there has been an unnecessarily confrontational approach sometimes from Government, with the implication that doctors are lazy and don’t work at weekends when everyone in the profession knows exactly how much we all work at the weekends. It strikes me as inappropriate that we should regard working in the evenings and at weekends as the same as working nine to five during the day – other professions don’t”.

Professor Lechler warned that there are some in Government who feel that doctors are paid too much and others who are uncomfortable that unlike many professionals, doctors are pretty much guaranteed a job on leaving university. “There are probably some basic scientists out there who think junior doctors are paid too much as well. In general I’m inclined to be sympathetic to the junior doctors cohort because they are the future.”

“There are some aspects of the contract that I would absolutely fight to oppose. And categorically I would wade in on any day of any week to protect clinical academic careers. We have to constantly battle to ensure that clinical academic medicine remains a choice that people want to take.” He said an adversarial mood had grown up that was probably avoidable had there been appropriate negotiation. This risked setting a tone for a relationship between doctors and the Government that needs to be maintained.

Current Chain-Florey fellow Dr Amit Adlakha summed up with thanks, adding that in his view the importance of communication had emerged as the theme of the day.

The Chain-Florey scheme brings medical graduates into the basic science laboratories of the MRC Clinical Sciences Centre at Imperial College for three-year PhDs. The scheme is funded jointly by the MRC and NIHR through the Imperial Biomedical Research Centre, and was founded to spur the development of the next generation of world-class academic clinicians. The scheme is named after Ernst Chain and Howard Florey, whose work on antibiotics is a tribute to scientific endeavour plus medical purpose. Since its inception in 2009, 17 Chain-Florey fellowships have been awarded. The first Chain-Florey lectureship came in 2014, with 4 lecturers now in place.

Professor Penninger is one of very few scientists awarded a prestigious ERC Advanced Grant – twice. He is also the first Austrian to have received the Innovator Award from the US Department of Defense for his achievements in breast cancer research. In 2014, professor Penninger received the Wittgenstein Award, the highest science award in Austria.