Spring 2010 Newsletter

The BBSRC, one of the major UK Research Councils, has recently awarded £3.3 million to a single project which is entitled ‘Engineering human neural networks-the iBrain’, which involves Oxford, Cambridge and Aston Universities. This award is important from two main standpoints. Firstly, it supports a project aimed at developing an experimental model of functioning human brain tissue which does not involve any animal usage and secondly, without The Trust’s support for Aston University’s contribution, the award could never have been made.

To appreciate the full significance of this award, some background is required. Work carried out in the late 1980’s in the University of Sheffield produced a cell line which started life as a cancer, but could be ‘retrained’ and lose its cancerous characteristics and develop into real human neurones. A group in Canada showed a few years later that the cells could form astrocytes also, which are essential for the full functioning of neurones in the brain. The potential of this experimental model was somewhat under appreciated for many years and from 2002, The Trust has funded my research group at Aston, mainly to develop the combination of human neurones and astrocytes as the most basic model of the human nervous system for the evaluation of possible human neurotoxins. With The Trust’s support it was found that this model could determine the effects of different toxins on the ‘developing’ as well as ‘adult’ brain neurones and astrocytes without using animal or human foetal tissue.

However, the potential of this model of astrocytes and neurones was still not fully developed; indeed, the work up to 2008/9 was very focussed on toxicity and the functionality of the model was not sufficiently explored. In some ways, you might imagine it was rather like crash testing evaluation for the car industry -

‘instead of driving this complex car into an oblique concrete block today, why don’t we see how fast it will go around our test track…’

So the group started to explore the capability of the neuronal/astrocyte model in terms of what real brain cells can do - such as form networks with each other, respond to chemical and electrical challenges and ultimately - process and store information. We joined forces with top scientists from Oxford and Cambridge who were interested in the same goal - a functional model of human brain tissue which will start to understand how neurones control memory and processing of information.

This enormously ambitious BBSRC award is also a landmark, in that it is evidence that the Research Councils are becoming more prepared to invest considerable resources into non-animal brain modelling - a situation which would not have occurred without credible preliminary data produced at Aston - which in turn would have been impossible without The Trust’s support. In the next five years, it is hoped that the iBrain project will stimulate non-animal research into the human brain. As we all know, there is a huge demand for progress in this area, particularly in terms of neurodegenerative disease, as well as in basic understanding of how our brains store and process information.

Importantly, there is another issue to consider - it has often been said that those using animals are doing so partly because they do not believe that adequate alternative in vitro models exist which can reflect the human situation as well as their chosen animal model. As a result of the farsightedness, patience and belief of The Trust, the BBSRC has now provided us with a crucial and golden opportunity to build a new and highly sophisticated model of the human brain’s most basic functions which will not only improve our understanding of the human brain, but it will also hopefully prevent incalculable animal suffering by offering a credible alternative to animal models in the field of neurobiology.

The Trust has been funding a PhD studentship for Jenny Collins at the University of Oxford, on the development of methods for growing human fat cells in the laboratory. Jenny finished her studies in 2009, has been awarded her PhD and has now published an important paper arising from this research in the prestigious Journal of Biological Chemistry.

We store excess fat in specialised cells called adipocytes (see picture). Most of the early research on adipocytes was done with a particular fat depot (a group of adipocytes) that surrounds the testes (male sex organs) in rats. It is not hard to see that there must be a big question over the relevance of those studies to the function of fat cells in humans! In recent years several groups have used pieces of human fat removed during surgical operations, to separate out the individual fat cells for study. Jenny developed a different approach. She wanted to be able to study the function of fat cells from a variety of people, and not just those who were about to undergo surgery. It is quite easy, and relatively painless, to ‘suck out’ some fat from under the skin using a syringe and needle, but the amount of fat you can obtain in this way is rather small. Jenny developed a method for using these small amounts of fat, and separating out from them particular cells that are a sort of ‘stem cell’ that can be persuaded to develop into true adipocytes. By finding the right conditions, she was able to produce sufficient cells to study in detail the process by which a human adipocyte develops.

Jenny’s particular focus was on the mechanisms by which human fat cells store fat. In rats and mice, it is well known that fat cells can make fat from carbohydrates (sugars) such as glucose, but it has become accepted dogma (based on little evidence) that human fat cells cannot do this. (Instead, the accepted wisdom says, they can only take up fat from the bloodstream and store it.) Jenny showed that this is quite untrue. She was able to grow completely normal adipocytes, nicely filled with droplets of fat, even if the precursor cells were grown only in the presence of sugars and amino acids (picture). Therefore the synthesis of fat from sugars is active in human fat cells, and possibly even essential for their development.

When cells make fat from glucose, it is at least initially in the form we call ‘saturated fat’ (like animal fats) and this might not be good for the cell. Jenny went on to show that the production of fat from sugars is closely linked to the development of pathways (enzymes) in the cell that modify the fats produced, making unsaturated fats (as in olive oil, for instance) which enable the cell to remain healthy. In some experiments, Jenny added saturated fat to the cells during their development. These cells actually increased the rate at which they make fat from sugars, we think in order to produce more unsaturated fat to ‘dilute’ the effects of the added saturated fat. In yet further experiments, Jenny used molecular techniques to suppress the key enzyme that makes unsaturated fats, and showed that these cells were less healthy as measured in several ways.

These studies have shown that it is quite possible to grow human fat cells in the laboratory starting with quite tiny amounts of human fat. Detailed studies of these fat cells have shown some unexpected properties. Our laboratory will continue to work with this system, hoping to gain a greater understanding of the functions of human fat cells. We are grateful to The Humane Research Trust for funding Jenny’s studentship.

In September and October 2009, The Humane Research Trust were kind enough to sponsor my medical elective. This is a two month placement before commencing the final year of medical studies in which to experience medical practice outside the standard curriculum.

I spent the first month at the Red Cross Children’s Hospital, a tertiary referral centre in the heart of Cape Town. I began by working on the Short Stay Unit, a fast-paced environment charged with stabilising acute admissions. After this, I transferred to the Paediatric Cardiology unit to further my interest in cardiac physiology and learn about the management of congenital heart disease. A typical day commenced at 8am with a ward round, after which I joined the team in commencing the day’s jobs, which included a detailed review and examination of each patient, chasing test results and arranging discharges.

I was challenged by the variation in disease burden from the UK, including HIV, TB, under-nutrition and anti-retroviral side effects with children often presenting a combination of these problems. Sadly, such was the scale of HIV that all patients were assumed to be HIV positive until proven otherwise. It was heartbreaking at times to witness the shame, guilt and fear felt by the mothers of newly diagnosed children.

My UK training had been thus far largely observational and the responsibility of caring for my own patients taught me the attention behind each clinical decision, which cannot be so easily appreciated from observation alone. Although the responsibility was daunting to begin with, I soon began to develop confidence in my skills, and felt like a useful member of the team.

After an incredibly beneficial four weeks in South Africa, I flew to India to take part in travelling health clinics in the state of Himachal Pradesh with a program called the Himalayan Health Exchange. Our team, consisting of 12 final year medical students and 6 doctors, undertook clinics at six isolated Himalayan villages, delivering primary health care to a total 1140 patients. On arrival at the clinic sites, tents would be erected to form consultation rooms in which two students would work, supervised by a doctor. Students were expected to make a clinical assessment, carry out simple investigations and formulate their own management plan in order to nurture a sense of responsibility. The clinics presented me with all kinds of opportunities, from demystifying complaints of “whole body swelling”, to draining a dental abscess.

Helena treating a patient in an isolated Himalayan village

I undertook a small research project to develop a greater understanding of health-seeking behaviour in relatives of children under - 5, finding that parents responded poorly to symptoms of illness in their children, and that the wider family played an important role in children’s healthcare.

My elective provided me with two very unique experiences through which my medical knowledge has improved unquestionably and I have gained valuable experience in both paediatric and adult medicine.

I would express my utmost gratitude to The Humane Research Trust for their kind support which made this experience possible.

Dr Lindsay Marshall and Anne Bielemeier from Aston University attended the seventh European Cystic Fibrosis Society Basic Science conference in Carcavelos, Portugal on April 7th-11th 2010. They arrived to find the sunshine had reached Portugal and the hotel the conference was based at was on the beach. That was where the fun ended as the conference itself was really intense, with sessions starting at 9am and finishing, on the first day, at 11:30 (at night!).
Anne was selected to give a ten minute talk which she performed brilliantly. This went down well with a very mixed audience, in a session about ion channel activity, quite removed from our focus! We also took a poster; this received lots of interest from post-doctoral researchers and PhD students and we were really glad to be putting our message across. We picked up many tips for the future and offers of support from people working on similar systems. We have to say that we struggled with the presentations on animal models for cystic fibrosis (CF) but we feel that we need to attend these conferences to make our presence felt and to demonstrate that there is another, more valid way to go about these studies. We have taken the first step to getting our experimental methods known and accepted and are feeling positive about the future for CF research without using animal models.




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