From Skin Cells to Brain Cells


#1
From Skin Cells to Brain Cells

A presentation by Dr Maeve Caldwell, University of Bristol, organised by the Newark branch of Parkinson's UK on 17th February 2012.

Tricia Butt told us, as she introduced Dr Caldwell, that this amazing afternoon, attended by over 80 people from 15 Parkinson's UK branches and groups, was inspired by the attendance of her and her husband, Michael, at the World Parkinson Congress in Glasgow in September 2010. The excitement of that occasion made them determined to learn more about what was going on in research into Parkinson's and to redouble their fundraising efforts. One result was the invitation to a prominent scientist – Dr Maeve Caldwell – to come and explain her work and its significance to people living with Parkinson's. Dr Caldwell is engaged in an intensely promising field: induced pluripotent stem cells.

Many Parkinson's symptoms – tremor, stiffness, slowness of movement – occur because certain nerve cells in the brain have died off. So what if these cells could be replaced so that proper functioning is restored? And what if, instead of using ready-made nerve cells from foetuses or human embryos - which clearly has raised ethical questions - cells from the patients own body could be coaxed into playing this role?
Dr Caldwell told us that the body possesses cells called stem cells that can turn into one of a range of types of tissue depending on where they are found. Unfortunately, there are not many in the brain and no way has been found to persuade them to migrate to the right place nor to turn into the sort of dopamine-producing cells that are lost in Parkinson's.

Yet the promising development is that scientists in different laboratories and in different countries have been discovering that ordinary body cells such as skin cells can be extracted, turned into stem cells and persuaded to divide and grow almost indefinitely. These are called induced pluripotent stem cells, or iPS cells. What's more, Dr Caldwell's lab have managed to get them to develop into cell's that appear to be no different from the right kind of dopamine-producing nerve cells.

There is a lot of work to do before transplantation of cells like these into the brains of Parkinson's patients becomes a practical possibility. (A word of warning was given that there are various companies offering stem cell treatment right now but their techniques have not gone through rigorous testing for safety and the scientific community is highly sceptical of their claims for which scant evidence is ever given.)
Scientists must be sure that substances used to induce skin cells to become stem cells in the first place are completely eliminated from the resulting nerve cells. A modified virus is used to get the original skin cells to switch on the necessary genes to transform themselves into iPS cells that can divide indefinitely. So at the end of the process the viral particles have to be removed and the genes turned off again otherwise tumours could result. Preliminary results suggest that Dr Caldwell's lab has achieved this. They have also checked that they have not inadvertently allowed some cells to turn into other kinds of tissue – stem cells always have the potential to differentiate into other types of cell such as heart, lung or muscle.

The work that they are currently engaged in is to check that all the characteristics of true nerve cells in the relevant part of the brain are present in the nerve cells that they have produced. They must produce dopamine and a variety of other so-called markers which confirm that they have the right make up and are functioning properly. Later they will carry out equivalent experiments in rats and see whether cells transplanted into their brains can restore function when their brains have previously been injected with a toxin to give them a Parkinson's-like condition.

Experiments like this should show how well the new cells can connect up with surrounding cells and begin to function properly to restore movement disorders. A great advantage of being able to produce nerve cells from a person's own skin cells is that there are likely to be minimal problems of tissue rejection – the body should not reject what it recognises as its own.

But there are other benefits from having a laboratory method of producing iPS cells and from them dopamine-producing cells.

It is not known whether there is intrinsically any real difference between cells, especially dopamine-producing nerve cells, from persons with and without Parkinson's. Is there any reason why a nerve cell in a person with Parkinson's should be any more vulnerable? Being able to grow nerve cells in the laboratory from skin cells from different people will enable this to be tested. Some people with Parkinson's have particular genetic variations – for instance LRRK2, PINK1, triplication of the alpha-synuclein gene – that pre-dispose them to Parkinson's. For many people without such variations their Parkinson's is due to an unknown cause. It is possible that studying nerve cells derived from all of these will reveal why for some people the dopamine-producing cells are particularly vulnerable. That could gives clues as to what might be an effective therapeutic intervention. An enormous amount of work has been done on animal cells, but the obvious new advantage is that now living human cells from affected individuals can be used.

Having cells derived from Parkinson's patients could also allow testing of potential drugs that might protect against the progression of the disease. At the moment such substances can only be tried out in animals and promising drugs are too often found not to be effective in humans.

In her presentation Dr Caldwell gave many details of the process of transforming skin cells into stem cells and then into functioning neurons. While laboratories around the world have spent years developing effective protocols – i.e. 'recipes' and methods that work well – they have now got the process, from skin biopsy to iPS cells, down to seventy five days and from iPS cells to nerve cells producing all the right substances down to a similar period! A remarkable achievement. We'll skip the technical details here, but it must be said that Dr Caldwell explained the processes with great clarity, much to the pleasure and relief of the largely lay audience.

She paid tribute to the excellent work of her team and collaborators and to the Ph D student funded by Parkinson's UK who is working with her. She then patiently and expertly answered questions from the audience on topics which went quite beyond the subject of her talk.

Newark Branch is a leader amongst groups interested in research and it is hoped that through the Research Support Network which is starting up in the East Midlands region more people can pursue their interest through similar events to this and be enthused to raise funds for more vital work like Dr Caldwell outlined. There are several centres doing Parkinson's research within and near to the East Midlands.
The Newark Branch is also clearly expert at baking as evidenced by the excellent and delicious range of cakes and cookies! Shame on the person who remarked that they only came for the cakes, but I see his point.

John Telford
Chair, E Mids RSN Steering Group.




References
Induced pluripotent stem cells are also being researched by groups in Edinburgh and Oxford funded by Parkinson's UK. See:
Can stem cells cure Parkinson’s? Dr Tilo Kunath, http://www.parkinsons.org.uk/pdf/F-0902_Kunath_stem_cells.pdf
Oxford Parkinson's Disease Centre Newsletter, http://www.parkinsons.org.uk/pdf/monument_discovery_award_newsletter_sep2010.pdf
See also the Wikipedia page: http://en.wikipedia.org/wiki/Induced_pluripotent_stem_cells

#2
My understanding is that the cells in the Substantia Nigra that have died have long axions that reach through to the Striatum. If you plonk new cells in the SN is there really any chance that they will grow these axions to the same place that the original ones did? Or have I got it wrong? Or doesn't it matter?