Q&A: Stem cell research

Dr Rosemary Fricker joined our discussion forum in May 2011 for a question and answer (Q&A) session, answering questions about stem cell research.

Transcript of the session

Rosemary: My name is Dr Rosemary Fricker and I look forward to receiving your questions. I'd like to share just a little bit about my background and interest in Parkinson's disease.

I studied Applied Biology as an undergraduate at Bath University. While there, my grandmother was diagnosed with Parkinson's. She died shortly after I graduated.

I knew that I wanted to be a research scientist and to study the brain, and at the end of my degree wanted to undertake research that would make a difference to people's lives.

I am now a Senior Lecturer in Biomedical Sciences at the School of Medicine and Principal Investigator, Keele University. I am also running a Parkinson's UK-funded research project to investigate whether dopamine-producing nerve cells can be produced from embryonic stem cells.

I hope that I can use my knowledge and background to answer your questions.

A general comment before I begin: There have been no stem cell treatments tried in patients in the clinic to date. Stem cells are being investigated in the laboratory in models of Parkinson's but have not been given approval to be used in any clinical trials.

Therefore any clinical trials I refer to below are done by dissecting out mature nerve cells from foetal brains and implanting them directly into patients.

LA via our website: Could you give a very brief description in lay terms of how stem cells are expected to bring benefits to people with Parkinson's, and what kind of treatments might be developed from them?

Turnip via the forum: If stem cell treatment worked, could it reverse Parkinson's disease?

Turnip via the forum: Would stem cell treatment replace dead cells or would it stop the underlying process?

Geraldine via our website: Could stem cell treatment help somebody who already has Parkinson's or is it only to prevent Parkinson's?

Rosemary: Stem cells offer the chance to replace the dying nerve cells in Parkinson's disease. They will not stop the underlying disease process and the patient's own nerve cells would continue to die. However, stem cells could be able to help people already diagnosed with Parkinson's and it is likely that any clinical trials would use patients who have lost the benefit of drug therapies.

The hope is to convert stem cells into nerve cells that produce the chemical dopamine. These are the nerve cells that are lost in Parkinson's. The new nerve cells would be implanted directly into the brain, and hopefully should connect up with the patient's brain cells and release dopamine to help replace this chemical to normal levels. This would mean that the movement problems that patients experience would be decreased or even disappear.

So the stem cells wouldn't reverse the disease process, but would fix the damage caused in the specific part of the brain that controls movement.

Ribena via the forum: Can you give any idea of how many years it will take for stem cell therapy to be used?

SF via the forum: I heard on the news that the new treatment which injects levodopa-producing cells might be available in 6 years.

Gillian via our website: Is the research at the point of testing on people yet?

Rosemary: This is an extremely difficult question to answer. There are a number of different types of stem cells that show potential for therapies (eg embryonic stem cells and induced pluripotent stem cells), but at the moment we do not understand exactly how these stem cells work.

The aim for stem cells is to convert them into nerve cells that can produce the chemical dopamine. To do this is a complex process and as yet scientists don’t know how to make a lot of nerve cells of the correct type. This is quite a stumbling block, but if it can be overcome we will be a lot nearer to starting clinical trials.

The other major hurdle that has to be overcome is one of safety. The types of stem cells that show most potential are quite primitive cells whose main job is to divide and make more stem cells. If these are put in the brain they form large tumours. Therefore, to develop a safe treatment, scientists will need to ensure that they can make cell mixtures that are totally free from stem cells.

So it is difficult to put a date on when clinical trials may start. The treatment is not yet ready for patients, and a lot more work has to be done particularly using animal models of Parkinson's disease. 6 years is an optimistic estimate. However, if the two issues of converting stem cells to nerve cells and making them safe can be achieved, progress will be rapid.

Ian via our website: What concerns me about stem cell therapy is stem cells could produce new dopamine producers, but the underlying problem with Parkinson's disease is the dopamine producers are dying. What is to stop the new ones dying too?

Question via Facebook: How are the stem cells supposed to survive when the usual resident ones don't in the same conditions?

Rosemary: We have some clues to the answer to this question from previous clinical trials that have used dopamine-producing nerve cells to transplant into patients with Parkinson's.

Doctors and scientists have found that in a few patients who had transplants more than 10 years ago, their transplant cells do show hallmarks of the disease process, in the form of Lewy bodies which are clumps of abnormal proteins that are found in dying nerve cells in many Parkinson's patients.

While this suggests that the transplanted cells are at risk from the disease process, it is thought that only low numbers of cells have a problem, and also that it takes a fairly long time for the Lewy bodies to develop. So a transplanted patient could expect their transplanted nerve cells to last a good number of years and provide good brain function.

There haven't been any studies yet using stem cell-derived nerve cells transplanted to animal models, which specifically investigate whether in the long term the stem cell transplants develop Lewy bodies.

Turnip via the forum: How do you stop cells turning cancerous?

Rosemary: The short answer is that we don't yet know. Cells become cancerous when they start to divide and cannot stop. For stem cells, these cells are naturally programmed to divide, as their main job is to provide a large number of primitive cells that can then be converted to specialised cells such as nerve cells.

So stem cells switch on genes and cell processes that help them to continue to divide. We don't yet know a way to switch off stem cell division, without manipulating the genes in the cells, which itself may cause a risk. This is called genetic modification, similar to what is done in GM crops.

Scientists are working on ways to stop stem cells dividing, or to convert 100% of stem cells into non-dividing cells, so that when the cells are transplanted there will be no risk of tumours forming in the transplant.

Susan via our website: If stem cells eventually are used in the cure for Parkinson's and are found to be a success, will the treatment be permanent with no more treatment needed or will it only last for so long and have to be given again?

Rosemary:  Here, we can look again at the clinical trials that have already been carried out in patients with Parkinson's, using nerve cells. The evidence is that if scientists and doctors get the procedure correct, then patients can have transplants that function well and the new cells remain alive for 10 or more years.

Some patients still need to take drugs alongside their transplant, though in many cases the dose can be lowered.

The key will be preventing the stem cell transplants from succumbing to the underlying disease process. We also know that we need good survival of the transplanted cells, and very precise placement in the brain to make sure they can wire up with the host nerve cells and function at their best.

If we get the process right, then the hope is that the treatment will be permanent.

Turnip via the forum: How does the stem cell get told to be a particular type of cell?

Rosemary: A stem cell develops to become a mature cell in 2 ways.

One way is internal to the cell. It is thought that specific genes can be switched on and off during the cells maturation, and that these genes act like a predetermined code - a pattern that tells the cell exactly which type of mature cell to become.

The other way is for stem cells to receive signals from their surrounding environment. These signals are only present for defined periods, so that when a stem cell is exposed to the signal it will begin to develop into a particular type.

For instance there are different molecules (signals) expressed in the brain to those expressed in the spinal cord, and these different signals help to tell the stem cells whether to be a nerve cell in the brain, or a spinal cord nerve cell.

It is likely that for all cells a combination of both the internal and external signals are important. This is a very hot topic in science as we try to determine precisely what the signals are for making any particular cell type.

Wilco via the forum:  How does one overcome the ethical bias against the use of embryonic stem cells in research? I should point out from the outset that I have no bias either way.

Rosemary: I feel that the decision people make on whether it is ethical to use embryos to produce stem cells for potential therapies is an individual one.

There are many factors to weigh up: on the argument for using embryonic stem cells, one can consider that these are taken from a 5-6 day old embryo, that is very immature, and most of the human embryonic stem cell lines are taken from unwanted embryos that are generated during IVF treatments.

Also, a single embryo could provide millions of stem cells to treat hundreds of patients, so one embryo would be destroyed but would potentially cure many patients.

On the other side of the argument, what right do we have to take a human life, and use their cells to implant into other humans?

Interestingly, although many different types of stem cells are being investigated to treat Parkinson's disease, the embryonic stem cells seem at present to have the most potential to work.

An alternative for the future may be to re-programme patients' own cells to make stem cells that are called induced pluripotent stem cells (iPS cells). These experiments are currently underway in laboratories, and are supported by Parkinson's UK.

Not only would these iPS cells get around the issue of needing embryos, but they would be derived from the patient, so there would be no rejection of a transplant.

Turnip via the forum:  How would stem cell treatment be administered?

Rosemary: Stem cells would have to be implanted directly to the brain. This procedure would require surgery where a needle is lowered into precise locations within the brain tissue and the cells delivered where they are required.

The procedure is fairly challenging, but there are a number of hospitals around the world who are now expert at delivering cells to the brain. The surgeons use co-ordinates and imaging to make sure they target precise areas and avoid damaging any other parts of the brain.

Turnip via the forum:  If only foetal cells were usable would research stop or slow down?

Rosemary: If only human embryonic or foetal cells could be useful for Parkinson's treatments, then the development of their use may be restricted, as many countries ban the use of these cells, or restrict use to cell lines that have already been generated. Restricting research to only a few cell lines may give a skewed understanding of how stem cells work, and could slow progress towards the clinic.

However, it is likely that foetal cells will not be the only stem cells usable for Parkinson's therapies. There are a number of adult stem cells that show promise, so may be useful for stem cell therapies.

These include iPS cells, that scientists have already managed to convert to nerve cells that produce the chemical dopamine, although in fairly low numbers at present.

We also have some stem cells in our adult brains, and one idea is to stimulate them to switch back on and be converted into specific nerve cells. This is proving more of a challenge at present.

At the moment there is no one stem cell type that shows more promise over the others. Therefore it is important to maintain research into all types of stem cells and to learn key information to help drive the research forward.

Turnip via the forum:  Would stem cell treatment be reversible if something went wrong?

Rosemary: This would be more of a challenge, and would really depend on what scientists and doctors predict might go wrong. So, for instance, if they were worried about stem cells dividing in the transplant and forming tumours, then stem cells could be engineered so that if they started to divide, a death signal would be switched on.

However, it is difficult to engineer cells perfectly, to get 100% of your cells to do the same thing. Also to engineer cells you may have to introduce new genes, a form of genetic modification (GM), which might cause problems in itself.

Another issue that makes stem cells tricky to manipulate following transplantation is that they often will move away from the site where they are transplanted and integrate with brain cells. This would be helpful for rewiring the brain, but problematic if you wanted to target all of the transplant to remove it.

Anonymous via the website: I saw an article recently which said that it is possible to get stem cells from teeth. Is this true?

This is a very interesting and topical news report looking at the potential of deriving stem cells from tooth pulp. Companies are currently being set up to harvest stem cells from teeth, so that these can be stored for potential use for an individual in the future.

This ides is not entirely new. Currently many new parents choose to store the umbilical blood after their child is born, as this can be used to generate stem cells. The fact is that many parts of our bodies contain stem cells, and the hope is that these can be transformed to specific cell types such as insulin-producing cells for diabetes, or dopamine nerve cells for Parkinson's.

What is not known yet is the potential for any one type of stem cell to make a specific mature cell. For instance there was some research in the late 1990s that suggested that stem cells in the blood could turn into nerve cells, a very different cell type. However, more recent research has questioned whether this can really happen.

One current theory is that stem cells may be fairly restricted in the type of mature cells they can turn into, for instance blood stem cells only turn into mature blood cells, and skin stem cells only turn in to mature cells in the skin.

Scientists don’t yet know how far they can manipulate stem cells from one region of the body (eg tooth pulp), to make mature cells from a different part (eg nerve cells). We don’t know if such a leap is possible, but many laboratories are trying to do just that!

Turnip via the forum:  Is it just dopamine cells in the brain that are being looked at or are there other cells?

Rosemary: The main focus for stem cell therapy in Parkinson's has been to use them to generate the dopamine cells similar to the ones in the substantia nigra whose death causes the main movement symptoms.

However, stem cells can be manipulated to form many other types of neurons, so there is potential to replace other neurons that might be dying as part of the Parkinson's disease process.

There is currently less research in this area, partly as we still don't know the general pattern of nerve cell death in other regions of the brain, and how feasible it would be to replace nerve cells in these regions.

About Dr Rosemary Fricker

Dr Fricker began working on developing methods of transplanting nerve cells to the brain while undertaking her PhD with Professor Stephen Dunnett.

She found her interest in stem cells while spending 3 years in Lund, Sweden developing this work with Anders Björklund. She later began her own research group at Cardiff University. Rosemary moved to Keele University in 2005.

The research group's current interest is finding ways to improve the conversion of embryonic stem cells to dopamine nerve cells.

In particular, they have looked in the developing brain to try to find proteins that might signal to developing nerve cells to tell them to mature and become this specific type of dopamine nerve cell. This research project - Which proteins help dopamine-producing nerve cells develop from stem cells? - is currently funded by Parkinson's UK.

The group is working with a small number of novel proteins they have discovered, which we think might be able to influence the fate of embryonic stem cells. The ultimate aim is to generate dopamine nerve cells more efficiently from embryonic stem cells, which can then be tested in models of Parkinson's.

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