Jon Palfreman is a reporter, writer, producer, director and educator best known for his documentary work on Frontline and Nova. He has won awards for his journalism, including the Peabody Award, Emmy Award, the Alfred I. duPont-Columbia University Silver Baton, Writers Guild of America Award, and the AAAS-Westinghouse Science in Journalisim Award. Palfreman has written, directed and produced documentaries on a wide range of topics, but specializes in topical and often controversial issues involving science and medicine. Palfreman is the author of Brain Storms: The Race to Unlock the Mysteries of Parkinson’s Disease, and was himself diagnosed with Parkinson’s disease while doing research for the book. He has also authored The Case of the Frozen Addicts: Working at the Edge of the Mysteries of the Human Brain (with J. William Langston), and The Dream Machine: Exploring the Computer Age (with Doron Swade). He is also president of the Palfreman Film Group. (from his Wikipedia page)
The following has been paraphrased from an interview with Dr. Jon Palfreman on March 22nd, 2018.
(Click here for the full audio version)
Your first book, The Dream Machine, about the rise of computers, was remarkably prescient given it was written in the early 90’s. How has your thinking around computers changed since?
I have to say, we put out that series in 1992, and some of the developments in computing we failed to predict. The big one we missed was the internet, back then it was a very clunky platform that scientists used to share data, nobody imagined the world wide web, which has probably been the single most important technological platform to emerge in our lifetimes.
But on the other hand our treatment of artificial intelligence holds up quite well. It was always something that promised more than it could deliver, though lately neural networks have made real progress and now our computing machines are fast enough and the data voluminous enough to enable computers to drive cars, do radiology, and other things that seemed pretty far fetched back then.
Do you have any hope that our machines might be able to help us solve problems like Parkinson’s disease?
Well, I think biology is a lot more complicated than physics. Biomedical technology has all sorts of new promising tools that have enabled us, as an example, to sequence the human genome. But success has proved elusive. People used to believe that once the human genome was sequenced it would lead to a revolution in medicine, we can sequence genomes pretty cheaply and quickly now but the breakthroughs that have resulted are few and far between and that is because biology is more complicated than we thought.
To date diseases like Alzheimer’s and Parkinson’s have proved intractable. There is this tortuous process that we have to go through where we test therapies with animal research and pre-clinical testing and then phase 1, phase 2, phase 3, clinical trials….this has lead to numerous disappointments. Each compelling new therapeutic concept goes through a process that takes about 20 years to prove safety and efficacy and in the worst case you find, as Pfizer’s neuroscience division recently learned, that nothing is really working for diseases like Alzheimer’s and Parkinson’s, so they’ve abandoned the brain all-together. Such news has made me a little pessimistic at the moment.
You wrote a piece in the Journal of Parkinson’s disease called ‘Hedgehogs Wanted’, in which you made the case for the need for more generalists in the field. Since you wrote that (5 years ago), have you seen more hedgehogs emerging?
Not really, Parkinson’s is a very heterogeneous disease, we do have common symptoms, but we each have our differences as well. It’s an easy disease to split into symptoms, so scientists tend to become either splitters or lumpers, which is similar to the idea from Isaiah Berlin that scientists come in two varieties: hedgehogs or foxes. The foxes are good at solving many small problems, but then there are hedgehogs, like Albert Einstein, who solve big problems. To solve Parkinson’s we are probably going to need people who think of it as a big integrated problem rather than a lot of little problems. What we see in the field is a lot of splitting that tries to deal with the symptoms of PD almost like a type of gerontology, you’ve got psychiatric problems, problems with your feet, your gut, your bladder, as well as your movement. There is a whole canopy of symptoms which you can try and compartmentalize in the clinic, but we don’t have many people looking at how it all connects. We do have one big idea, which is if we can prevent the spread of clumps of this rogue misfolded alpha-synuclein protein that might slow or prevent or possibly reverse the disease. That is our current big disease-modifying hypothesis, though it is not clear if that is going to work yet.
How much of the problem is modern science itself and the system that has built up around it that often shapes and determines the direction of basic science?
A lot of work goes on in basic research between people who aren’t MDs, like molecular biologists and biochemists, who try to test in animal models theories that might lead to the identification of a target. The idea is to then attract a drug company to come in and take that target through clinical research. But this process is very laborious, it has to get through clinical trials, which are very difficult and take an enormous amount of time and money. Let’s say you’ve got an agent that you want to test to see if it will slow the course of the disease. First you’ve got to find a group of people that have early stage Parkinson’s disease, hope that they are reasonably similar, and then track their progress over 3-5 years using a test like the Unified Parkinson’s Disease Rating Scale (UPDRS). This scale itself is is pretty crude and varies quite a lot, and we use changes of two or three points in this scale as evidence that your treatment works. Even if you did have the cure, it’s very difficult to prove it works.
Do you still see people searching for a single cure or are they moving more towards compartmentalizing the disease into separate treatments that, as you’ve written about before, protect, revive and then replace neurons?
That idea was what was tried before, to use different strategies to protect the neurons using a drug like the MAO-B inhibitor rasagiline to in theory slow the course of the disease. Then alternatively, you could use a neurotrophic growth factor to revive ailing neurons, and then the most radical idea was to replace neurons using fetal tissue surgery. What we found by the early 2000’s is that all three of these approaches had failed to demonstrate efficacy. In the meantime Parkinson’s has been re-branded from being mainly a movement disorder to something more complicated so that even if you could replace the dopamine neurons with cell therapy there would be all sorts of other Parkinson’s symptoms that went untreated.
That is where we stood in the early 2000’s until we had this very exciting idea of alpha-synuclein, which people have been working on ever since. A lot of that has been basic research, targets have been identified and compounds have been synthesized and they are trying now to see if that works. What gives me pause is that Parkinson’s disease research is a few years behind Alzheimer’s disease. They’ve had compounds which they thought would work for nearly a decade now and they’ve had a pretty bad track record.
What role do you see patients playing in basic science?
I think patients have a big role to play, especially since there seems to be too much emphasis on disease prevention and not enough on symptom modifying interventions. I wrote an article, ‘Who dropped the ball with L-dopa?’, that describes this wonderful drug which was discovered about 50 years ago, yet it is still used the same way it was then and very little is understood about the mechanism behind how it really works. Since it was discovered we have been to the moon, invented the internet, sequenced the human genome, but we still take 3-4 Sinemet tablets a day and very little has been done to find better ways to deliver it to enable patients to live a decent life without fear of dyskinesia (abnormality or impairment of voluntary movement). There is a lack of what I call ‘applied clinical research’ to come up with ways to live with Parkinson’s better than we do. That has been neglected while the prospect of a cure has been somewhat exaggerated.
How much of a role do you think ego and bias play in slowing down our quest for better treatments?
They are a feature of science, it is a competitive area and people have big egos, it does somewhat slow down progress. The team in New Jersey that found the family whose genes lead to the discovery of alpha-synuclein, they wasted 6 or 7 years because they didn’t have a person with the molecular skills needed, I think you could argue that was partly driven by ego. However, it would be nice to think that these are the reasons we don’t have a cure, but the main reason is that the problem is immensely hard to solve. People with PD have lost a huge amount of dopamine and other cells, they are living in a condition with a depleted set of neurological assets and overcoming that deficit is a very difficult problem. Preventing it starting in the first place might be a better strategy but you’ve got to get in very early. I still hang on to hope, you’ve got to believe in hope and scientists are likely to work harder if there is a possibility of hope, even if they are slightly Panglossian when they talk of a “cure.”. There’s no real value in being too cynical, but one has to be realistic, if you spend time looking at the research you do tend to come away a bit sobered.
What would you tell your newly diagnosed self?
Live as positively as you can with the things that work, like levadopa and exercise. There are huge differences in the trajectories of people with this disease, some of it comes down to the biology, but a lot of it has to do with their attitudes, their exercise regime, and how they choose to live the rest of their life. So I’d tell myself to be as positive and as proactive as possible. The other things I’d tell myself is that the one benefit is that you get is access to a community of people that you never would have met, people like Pam Quinn and Sara Riggare, who you can gleam a lot of inspiration from.
For more from Dr. Jon Palfreman I highly recommend his excellent book Brain Storms.