Sunday, July 06, 2008

A Parkinson's Disease Week.

When I was a young man, middle distance running was a hugely popular sport. I used to train for hours on end. At schoolboy level the reward was the pick of admiring school girls. Anyone winning the Olympic men's one mile or 1,500 metres title was admired across the world. Just think of the pick he had. Women's sport didn't have quite the same following in those days. In 1976, the Olympic Champion was New Zealander, John Walker. I can still see his flowing locks in my mind's eye, as he beat all comers for years.

In all, he ran 135 sub 4 minute miles. 16 years ago he was diagnosed as suffering from Parkinson's. The Mail on Sunday has a great piece on him today. As is common with Parkinson's sufferers, he's incredibly positive. Unfortunately I can't find the story online. Its on pages 92/93.

The MoS has another Parkinson's Disease story today - about the link between Dopamine and compulsive behaviour, in this case gambling. Dopamine is produced naturally in the brain, but not after Parkinson's strikes. Medication is based on stimulating the production of Dopomine. Today's story was about how gambling had destroyed the marriage of a sufferer. A sad story.

Over the last few days I've attended two Parkinson's Disease events. The first was in Cardiff when Edwina Hart, the health Minister spoke. John and Sue Day from Montgtomeryshire were there, and joined me for the above photograph. Both of them are sufferers, as is John's brother and father. And yesterday, I joined Karen Emberton on their stall at the big fair in Montgomery - that's the other photograph. Reason I take such an interest is that I'm president of the Montgomershire Branch.

13 comments:

Anonymous said...

Glyn> I completed my PhD in '95, and went, sadly, onto other things, but in '95 I was probably, for a limited time, one of the world's most knowledgeable experts on the likely structure of the dopamine receptors - if only because I had read just about every published research paper and was using computational techniques of the most advanced kind (including maybe a hundred or so pages of supercomputer code that I wrote, compiled and run to perform Fourier analysis of multiple sequence alignments between D1 through D5 (the dopamine family of transmembrane receptors found in the human brain ... and in other high functioning organisms too). In fact I used the sequence of a cloned dopamine receptor solved by a scientist who died in the Pan Am Flight 103 Lockerbie terrorist incident.

For a while (still do really), I knew down to atomic detail the structure and chemical features of the dopamine binding pocket in the D1 through D5 receptors. I was asked to write by a scientific publisher to write a review of the field based on my knowledge of learned publications in the field. My research was secret to the extent that it was, in major part, funded by big pharma.

What was sad was that I was dirt poor and couldn't afford to spend the time to write the review, I had to be on a post-doc in a flash if not quicker because I was stone cold broke - though my PhD was covered and I did pretty much the maximum amount of teaching to top up my pathetic PhD stipend, but the money we earned was so pathetic I was forced to live on porridge for breakfast and tea, and tins of gamma irradiated stewing beef for main meal), I was paying out on a mortgage on a house in Cardiff, and living in digs in Glasgow, so money was supertight, I couldn’t afford to go home to Cardiff one Christmas money was that tight so I hung out with foreign students who couldn’t afford the flights home and/or did not recognize Christmas.

So a week after completing my PhD I had to move to a job immediately, which turned out to be a job at Bath Uni. I just wish there was some financial way I could have carried on with the intricate research, and tried to get financing from Parkinson's charities but they had "their favourites" and so I stood no chance. Very sad as I was attached to a transmembrane protein structural group that was then world famous for solving the structure of LH1, the light harvesting complex (also a transmembrane protein) that plays a critical role in photosynthesis. The set up in Glasgow was ideal to carry on with my research on the dopamine binding pockets, but it was never to be.

I was pretty certain I could work out the final details of the chemical requirements of agonist, partial agonist, antagonist and partial antagonist molecules/drugs and during the final months of my PhD research I became aware of a research group in CT (Connecticut) that claimed to have software for determining the ability (or lack thereof) of molecules to penetrate membranes. A professor in charge of that group with the software found out about my work using supercomputers to solve transmembrane proteins and wanted to see me on a trip to the UK - at another big pharma set up - at the marketing department in a town west of London (can't remember it's name, even though I remember some guy going nuts there with an automatic weapon (not Hungerford).

I was so broke that I had to go cap in hand to the head of department for money to attend the interview, he actually offered to pay for the trip there and back, but as it happened I managed to get money off a welfare organization (yes, I was that desperate), but not enough money to stay in overnight in a hotel, so I got a ticket that took me to the town via Bristol (I think), but I got off at "Bristol" to buy a return ticket to Cardiff and in Cardiff had a shower in my own house and immediately got back to Cardiff Central and then got on a train to Bristol and picked up the next train to the town, I effectively broke my overnight train journey to be fresh for the interview).

Anyway, this prof had software that could work out with some precision what molecules (i.e., prospective drug candidates) would pass through a membrane (such as the brain/blood barrier). I realized that this prof's CT software and computer kit could be incredibly useful tool/adjunct to my dopamine rational drug design project (the big pharma sponsor of the dopamine receptor research wanted to go for a rational drug design approach, hence their interest in my dopamine structure/binding pocket research).

All very convoluted - yes? But I worked out the CT software combined with my research would likely mean a HUGE break-through for new drug treatments (agonists for Parkinson's disease and antagonists for patients suffering schizophrenia and other dopamine related conditions; Parkinson’s is lack of dopamine, someone hearing voices is getting too much dopamine binding to their dopamine brain receptors). But guess what, all my careful planning/’scheming' didn't work out - I just could not wait on the decision by the CT professor to hire me to set up a supercomputer to speed up the running of his code (my PhD and especially my masters degree involved the user of supercomputers, in fact one of the guys now in charge of the supercomputer at Cardiff Uni was also a senior staff member at the lab where I did my masters research - TCS (Theory and Computational Science at the then SERC Daresbury Laboratory near the village of Daresbury (so called "Alice in Wonderland" country), I was so totally broke that I needed to be earning real money to pay the mortgage and get back on my financial feet, I had no savings, and no where to go – I just couldn’t manage a few weeks without money.

Funny thing is, I still have the idea of connecting the dots to come up with rational design of drugs to treat Parkinson's disease (and ‘opposite’ brain disorders) - but can't do anything about it, because I still don't have the money to do anything about it.

The “moral of this story”: it is sad that PhD qualified scientists who for a time are world experts in their field are not permitted to apply directly for grants to continue their research and charities that should listen to them play favourites.

Great opportunities have been missed, and will continue to be missed all for the lack of a few thousand pounds of funding. What could have happened if I could have waited for the CT's prof's decision, and I could have combined my PhD research on the dopamine binding pockets with state-of-the art software/supercomputing to work out which drug candidates should be investigated further. My work naturally allowed me to work out the differences in function/structure of the dopamine receptors verses other brain transmembrane receptors, thus the goal was rational design of drugs that could pass through the blood/brain barrier and bind to a particular dopamine receptor instead of other receptors in the brain thus decreasing side effects in the patient requiring treatment.

It's like this in the UK: we invent/discover but just can't carry through to commercial development - we invented MABs (monoclonal antibody technology), but failed to commercial it properly – leaving it to foreign companies who have made hundreds of millions out of MABs, a quintessential British technology. The list is pretty endless ... and meanwhile we give away our future indigenous high-tech jobs/wealth creation/tax base to fund our public services such as the NHS and we end up reliant on hand-outs via, e.g., Objective One funding and the rest. Quite pathetic.

Anonymous said...

John Walker was the finest and most consistnt middle distance runner that ever graced the running tracks of the world. Its a tragedy that such an athlete should be afflicted with this disease.

Savonarola said...

Anon

A strange tale to a layman.

Presumably you are now in gainful employment, have a cv and contacts and should be in a position to continue where you left off.

Anonymous said...

Savonarola> "doesn't work like that" ... e.g., need grant funding to get 'bench space', need to pay the university money - they pay the researchers out of designated grants. No grant, no bench space, no research. Grant -> bench space -> research. The opportunity for using another group's years of experience/kit/software in CT has long gone. But with money I could get the kit/software running and get my 3D models up and running again on a nice Silicon Graphics work station or similar and access to supercomputer kit and display the resulting 3D models on the graphic workstations - but where's the money for the kit/supercomputer time/bench space/to pay the university so that I get paid out of a designated research grant? Long time researchers and profs can write the grants up because they are designated as 'university research lecturers', i.e., permanent members of staff whereas PhDs are essentially temporary workers being paid out of a designated grant managed by the university, once the grant money runs out 'you' had better be on your bike to another temp post-doc position paid out of another designated grant probably at another university hundreds if not thousands of miles away from where you did your PhD. There's a good reason why the USA gives UK PhDs instant access to the US research scene via J1 visa program - when I got my PhD the turn around time for getting a J1 from the US Embassy was just two weeks - freshly minted Britisth PhDs got the royal treatment and what's more we could work in the USA for up to two years without paying US taxes or British taxes. That's one of the biggest dumb-ass reasons why the UK loses so many PhDs to the USA, once in the USA many British PhDs decide to marry and start families and often only come back to the UK to visit family and friends.

Like 'what she wrote', freshly minted PhDs can't apply for grant money, and at the end of a PhD I was broke and then some. I was desperate and in some sense quite vulnerable. Scientists coming off a PhD need money - we are often stretched to breaking point - there's a period after the research is finalized in which we write up the thesis and pass the oral/viva. During this time there's often very little money for the PhD candidate to live on. In fact this is the biggest reason why there are so many PhD level scientists who don't write up because they move into a job and find it very hard to find the motivation to work like the clappers writing up the thesis while holding down a new research job that often is not friendly to the idea of giving their new employee time off to write it up.
We loose some VERY good PhD level scientists that way. It's a hard business writing up. Some students are OK, they have savings and parents able to help out.

I actually wrote up three chapters before completing my research - so I was ahead of the game, but it still took me a couple of months to finish the write up and get through the oral/viva. My mistake was not having savings. I applied before the end of my PhD for post-doc positions and had to accept the first one offered - Profs only wait so long for a reply and don't like being told to wait for a response, I couldn't wait for the CT prof to get back to me - he rang me a couple of times to make sure I was still interested, but just took too long to make me an offer - I think he was hoping for a CT or someone in America to apply - but there were not that many people around who understood membranes and the issues involved in drug candidates passing through, e.g., blood/brain barriers - e.g., L-Dopa (a carboxylated version of dopamine) can cross the blood/brain barrier but the natural agonist dopamine can't. The CT group had the software I needed - and the money to buy a new supercomputer. It would have been a natural adjunct to my research - but for the sake of a couple of thousand pounds I could not wait on the CT prof - and took a post-doc position working on a different transmembrane protein molecule and I felt terrible. I wish I could have had just a little bit of money to tied me over, but nope. I contact some Parkinson's disease charities whereupon I discovered they spend their collections on favoured profs. I could not waite, I was in financial straits. I do feel a huge opportunity was missed, but I'm sure this kind of thing often happens to newly minted PhD qualified scientists and after that experience I started to realize why so many PhDs go abroad, the UK loses most of its PhDs to foreign universities and foreign competition - so while the UK trains us, it fails to pay us enough to stay here. If I had gone to CT I would have come back or at least still be in a position to join up the dots. When I got my PhD you could count on one hand the number of groups using supercomputers to solve the dopamine binding issues. There were two groups, one was in France and the other in the USA. There was some scattered work in the field in the UK, but they were recent PhDs like me and not able to apply for their own grants. It's pretty crazy, its a war of attrition - PhDs have to stick out maybe 10 years before they can apply for grants - but they are world experts in their fields - it is hard to be so on top of your field again - three years of doing nothing but research and keeping up with every publication in your field - I was a bit lucky, I could read up on different fields that looked like it could help solve the dopamine binding issues - the CT group had some critical know-how/software on determining which molecules would pass the blood/brain barrier and there was me with critical detailed knowledge of the dopamine binding pocket in D1 through D5, and with a masters in biotechnology with a research project completed at the Daresbury TCS facilities.

Glyn Davies said...

anon - you must be Christopher. There can't be another one!

anon 2 - I just thought he was such a relaxed and natural runner. One of the all time greats.


Savonarola - Well you asked for that!

Anonymous said...

Glyn> my lips are sealed absent a good shot of smooth Welsh whiskey. But seriously, there's a LOT of Welsh talent working for Uncle Sam. The 'brain drain' was helped along by the J1 galactic British PhD gold-rush to the USA. Loads of British PhDs got over here on J1s.

Open the Echo or Western Mail - see many jobs for PhD qualified scientists? If you look up stats on towns/counties over here in the USA they make a big thing about of how many PhDs they have to attract businesses - having lots of PhDs (often via the J1 visa program) gives a sense of pride to local communities in direct contrast to the UK.

Same goes for Germany where Directors in companies like to boast about how many PhDs are on their Board of Directors - PhDs in company board rooms are not a novelty in Germany in direct contrast to the UK. Probably goes a long way to explain Germany's huge export economy.

Savonarola said...

Anon

In summary then a wasted opportunity that cannot practicably be retrieved given your distance in time, current employment and geograppgy from the CT opportunity. Pity. But then your situation is symptomatic of the UK's long standing failure to capitalise on the intellectual capacity of its academics.

I suppose the emphasis in neurological research these days is in stem cell investigation.

Anonymous said...

Savonarola> u summed up the issues accurately and succinctly. Pity you are not in politics!

Simon Hatch - Parkinson's Disease Society said...

Glyn, just for your information at the event in the Assembly Mark Isherwood told me he and Alun Ffred Jones had started (or were starting- I wasn’t entirely clear) an All Party Assembly group on Neurology. I’m yet to find out any details but as and when I do I’ll let you know. As you know, I’ve been highlighting for years that Neurology is the most uncoordinated of Cinderella services in Wales and much could be done to improve the situation with some political will. Of course in rural mid Wales this becomes worse still – an All party group may be one way of shining some light on this issue. Best

Simon Hatch, Wales Manager, Parkinson's Disease Society

Glyn Davies said...

Thanks Simon. I'll contact Mark. I'd like to be involved if I can.

Savonarola said...

Anon

Good luck in your current endeavours. Somewhere, someday just maybe what you have done may be picked up.

We are all in politics albeit in various guises. I sit on the sidelines and try to encourage here and there. They also serve etc....

I saw John Walker in film and on TV. My favourite 880/miler was Peter Snell. Later just sorry Ovett and Coe did not compete against each other more frequently.

Helen said...

Glyn & Simon
I do sincerely hope that Mark Isherwood and Alun Ffred Jones form an All Party Assembly group on Neurology, and indeed if this happens, that patients from Montgomeryshire, suffering from Parkinson's Disease or any other Neurological Disease, will gain as much from it as the rest of the Country. It's a sad fact, but we are so often ignored here in Mid-Wales.

Glyn Davies said...

Savonarola - My favorites were a gritty Yorkshiremen named Derek Ibbotson who top man when I started running, and a Tanzanian named Filbert Bayi, who just ran away from every field in every race and was caught on the last lap - until the day came when he wasn't, and he won the Olympic Gold. I think he's done a lot of good work back in Tanzania. Neither had the stylish running technique of Walker or the power of Snell.