Interview with Stem Cell Pioneer Prof. Roger Barker

 

 

The following has been paraphrased from an interview with Prof. Roger Barker on March 23rd, 2018.

(Click here for the full audio version)

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What impact might Brexit have on research in the UK?

The simple answer is we don’t quite know because nobody knows exactly what the outcome of Brexit is going to be. But, there are three big anxieties when it comes to Brexit with respect to science and medicine in the UK. One is funding, a lot of research here has benefited from being part of European funding streams, if we were to sit outside of that it would put us in a difficult position. For example, our work here on stem cells has relied on collaborations with other parts of Europe.

The second anxiety is that the scientists that we get here in the UK are often of extremely high caliber, but if there is a change in the visa system that might make it more difficult for them to work in the UK and they might seek employment elsewhere.

The third is that it may detract investors from medical research in the UK because they may only have access to the UK market rather than the European market.

I suspect that the government is starting to listen to the scientists and now believes that being part of Europe scientifically and medically makes much more sense than being isolated. I’m more optimistic than I was a year ago that ultimately we will still be integrated into the European network of research and medicine.

Has any progress been made in determining which sub-types of Parkinson’s disease might be best suited for cell replacement therapy?

The idea that Parkinson’s is one disorder and that one therapy might be able to help everybody is true on a superficial level, as everyone with PD, by definition, has to have some dopamine deficiency. But, I think we can say that there are two extremes of this disease. There is clearly a group of younger people who progress more slowly, and who have a disease primarily just around dopamine related motor problems. Then there is a more senior group, typically over the age of 70, who have motor problems, but who also have a lot of other non-motor symptoms. I think it is important to distinguish those two because in cell replacement therapy, at least in the beginning, you want participants that have the best chance of benefiting from the therapy. So, since cell replacement therapy is designed to alleviate motor problems associated with dopamine deficiencies, we should start with the younger cohort of people.

One of the most worrisome aspects of cell replacement therapy for many patients is the run-away dyskinesia (abnormal, uncontrolled, involuntary movement) that some patients experienced in the earlier trials. What methods have been developed that might enable us to control the release of dopamine after the transplantation?

First, I think the prominence of what are referred to as graft-induced dyskinesia is not quite as great as the original papers led us to believe, but they clearly are an issue. There are two theories as to how they happened, one was that the grafts produced hot spots of dopamine cells, where we had large amounts of dopamine released in one area. The other theory, which I think is more likely, is that the earlier trials used dissected bits of the fetal brains that included more than just dopamine cells, making the grafts unable to properly regulate the release of dopamine. This is believed to have caused some of the dyskinesia patients experienced. We now overcome this problem by much more carefully selecting the cells we use in transplantation, to date we haven’t seen any graft-induced dyskinesia in the patients we have treated over the last few years. Going forward this is going to be even less of an issue because now we use cells produced from stem cells, that allows us to better control the kind of cells we use.

Ultimately, what we would like to do is make dopamine cells that we can regulate. One way is by engineering the cells to have light sensitive channels. This technique, called optogenetics, allows us to turn the cells production of dopamine on or off by shining special kinds of light on it. The other way is by putting into the cell a certain type of receptor that responds to a specific drug, allowing us to switch off the activity of those cells if needed. These new techniques will likely be incorporated into the next generation of cell replacement therapies in 5-10 years.

How much of a concern is figuring out where exactly in the brain to transplant the cell into?

It’s not much of a concern for me. There is a belief in PD that it’s not the cell body that dies first but the synapses (the ends of the cell where they deliver dopamine and other neurotransmitters to the next cell). I don’t think that the environment where you put the stem cells would have a major impact on their survival or where their synapses develop.

There is also the issue of the pathology spreading into the transplants, which was shown to happen after 10 years in the previous fetal tissue transplants. But the rate at which that happens indicates that it will only become a problem for the patient after about 40-50 years.

What role do you see patients playing in helping push this therapy forward?

One of the issues that we face is ethics as embryonic stem cells bring with them some ethical concerns. I think having educated debates about the issue is important and that patients should be able to provide unique input into those discussions, particularly in America where people tend to be very polarized on this issue.

Patients should also take a more active stance against some of the more cowboy stem cell clinics out there. If patients were more active against these clinics that feed off vulnerable people, we could relieve some of the fraud going on.

Patients can also offer fantastic insight into what risks they are willing to accept. Generally, regulatory bodies are very conservative with what trials they allow to go forward. I think having patients say they are prepared to take the risk, after having heard all the evidence, would help.

Another area patients should have a voice in is how we design the clinical trials around these therapies. This is particularly true in cell therapy as the current double-blind, placebo controlled trial model forces us to do sham surgeries. This is pretty controversial, especially with cell replacement therapy because it generally takes 2-3 years to receive benefit, meaning some patients will spend three years in such a trial and receive nothing. Patients should have a say in whether or not they are willing to go through that.

What role do you think iPS cells, autologous (using patient’s own cells) or otherwise, will have in cell replacement therapy in the future?

People have been interested in induced pluripotent stem cells over embryonic stem cells for some time because it gets around the ethical issues, so it might be more palatable to the general population, particularly in America. I think ultimately there isn’t much difference between them, but autologous iPS cell therapy would have some distinct advantages. They come from the patient so there’s no issues about where to get them or immune rejection. But they are considerably more expensive, though the costs associated could be significantly decreased if regulation becomes a little more lax. The other concern is that patient’s cells already have a predisposition to developing PD and could, more quickly, succumb to the disease process. Though that is more theory than reality, a paper came out last year showing that iPS cells transplanted from people with PD into monkeys were no different from those of healthy people after two years. But, that was in a normal monkey brain, not a person with Parkinson’s.

What do you think can be done to improve the system of science to ensure young researchers are motivated more by advancing science than publishing and securing funding? 

I think there are a lot of people in science that are in it for the right reasons, people that are just fascinated by biological questions. However, they still have to be cognizant of publishing because if you don’t publish you don’t get grants.

I think something that has been transformative in Europe, which has been less explored in America, is the formation of research consortia. They allow groups of people with different skill sets to come together to solve a common problem. The success of the work is the success of the consortia, not the individual. The beauty of that is you can bring in people who have no interest in Parkinson’s disease, but who are fascinated by how, for example, brains make dopamine cells. This allows them to work on the problems they are interested and lets us build a pipeline of people pursuing their own interests, but in mutually beneficial ways.

We also need more long term funding for junior researchers. What tends to happen is people go into PD looking for a cure, but their fellowships only last three years, your not going to develop a cure in three years so they end up doing things that are not as exciting but which have a better chance at producing an outcome. It also pushes them to show success by whatever means necessary, this is part of the reason why we have so much fraud and findings that can’t be replicated. Longer funding terms would allow people to tackle bigger questions and offer less of a need for them to publish in high-impact journals, as well as less incentive for them to doctor their findings.

Bringing patients into the basic research process could also help. Doing so does often result in new questions being raised that force researchers to look at things in ways they otherwise would not have. However, patients are generally interested in quick fixes, they want solutions that can materialize in 10 months, not 10 years. Also, the difficulty of the science itself makes it hard for many of them to contribute.

Finally, there is at times an over-emphasis on translational research. When Fred Sanger worked out how to sequence DNA in 1977, he wasn’t thinking about how this was going to be helpful for people with genetic disorders, he just wanted to find out how to do it. You do then need other people to build off that kind of work and see how it can be translated, but that should not be the explicit goal of everything we do.

 

Click here for more information on the work going on at Prof. Roger Barker’s lab in Cambridge or watch this video to learn more about cell replacement therapy.