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Archive for the ‘Biochemistry’ Category


I have written the following to my Brexit Party Representatives in the European Parliament. At the heart of parliamentary democracy is the idea that our representatives do indeed represent the interests of their constituents, regardless of Party politics. Of course interests have to be balanced but when these are win-win, there can be no reason for not representing a particular interest. As the matter is not a personal one, then I have also put it on my blog, since there is no reason for secrecy.

I will, of course, post any further correspondence, unless it is confidential for some reason.

“Dear Ms Fox (& cc’ed to Mr Nielsen and Mr Bull)

I am writing to you as one of your constituents regarding an issue which affects me personally and the region. As a University Professor I have over the years been awarded research funds from various Framework Programmes. Most recently, I am part of the €4M FET-OPEN programme “ArrestAD”. This aims to test a new paradigm for Alzheimer’s Disease screening and lay the foundation for a new class of drugs that would arrest the disease.

FET-OPEN projects are very much blue skies and in our case we appear to have hit the jackpot. The trials of the diagnostic in Paris and Warsaw  are quite spectacular and our own work has shown that the targets which ArrestAD has proposed are eminently druggable.

ArrestAD is a 4 year programme. As in any blue skies research, towards the end of the penultimate year a decision is made by the research team whether we should apply for a new, larger project, under one of the translational programmes available under H2020, or to can the idea, in the event it isn’t going to deliver.

Since ArrestAD is delivering its promise, the team will be going forward and applying for a translational programme. This will involve further clinical centres and greater industry participation, since we need more patients and, for drug development, far greater resource.

Alzheimer’s being what it is, ArrestAD obviously impacts widely and not just on myself: there are substantial social and economic ramifications for our region, the UK, and beyond.

The problem we face is that with a so-called No Deal Brexit, the UK loses access to funding from H2020 and the future framework programme. There is no  legislation in the UK Parliament that would guarantee funding as a 3rdcountry. The upshot is that Brexit will prevent my continued contribution to this likely life-changing research programme. Importantly, it will prevent the UK from reaping economic benefit (clinical trials, pharmaceutical industry).

As my representative in the European Parliament, it is imperative that you work to find a solution, which ensures that the drug development arm of this project remains based in the UK, and that the UK is able to participate fully in the wider clinical trials of the diagnostic. I think you would agree that given the impact of this dreadful disease, this is in everyone’s interests.”

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For those who follow the news, though helium is rather common in the solar system, it is rare on earth. The shortages were predicted some years ago, and were put off only by the Pentagon agreeing to put some of its strategic reserve into the market.

We now face the first self-inflicted shortage: helium is now rationed in the UK. Self-inflicted, because we waste it, e.g., balloons and no recovery of the gas at point of use. This of course is all down to cost, and testimony, in a small way, to the failure of applying market principles across the board without any strategic consideration.

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Universities are always cash strapped, and over the last few decades there has been a drop  in the number of PhDs funded by the UK government. In essence stipends have been increased (absolutely necessary and credit to The Wellcome Trust for pushing this), but funding has not increased commensurately. So numbers have dropped.

The response of institutions has been to push for more overseas students and to develop, from internal monies various funding  schemes. However, generally this has only served to replace losses in numbers funded by government. Gone are the days when every PI expected a new PhD student every year. This has a detrimental effect on research culture, as it leads to centralisation, a reduction in diversity (in the broadest sense of the word) and fewer trained scientists. The UK relies extensively on scientists trained elsewhere for its R&D and we need to do more in relation to training. Granted science is a mobile and international profession, but without contributing proportionally to the global talent pool, our R&D may wither in the long run.

The problem is money: institutions have limited funds they can use for PhD studentships. Our European model, where PhD students are fully funded for a set number of years (usually 3-4, sometimes a few more) is in my view preferable to the US one, where students work to support themselves. This is for the simple reason that the latter model can lead to feudalism and abuse of power, which is well documented.

There is money available for institutions willing to take leadership on the Open Access Agenda.

An aggressive pursuit of an Open Access agenda, as has been done in Germany, The Netherlands and Sweden, and most recently UC, means cancelling subscriptions to the journals of the Big Four. This frees up a substantial budget, with no ill effect on research and scholarship. A portion of the funds would, of course, need to be used to hire librarians supporting document sourcing by UG and researchers and the balance to fund PhD students. I note that teaching UGs these skills is important, since most STEM workplaces (industry, where many STEM graduates and postgraduates work) do not have large libraries. One advantage of using internal funds is that one can select and so only take the very best candidates, rather than restricting enrolment to those with access to funding. While such proposals will likely be met with horror by a good many academic staff, once in place it appears that no one notices much change and continues to work productively. This is the experience of countries and institutions that have cancelled subscriptions to one or more of the Big Four.

Sadly, with my University running workshops on “How to get published in Nature”, it appears that we are 20 years behind the times and this simple and effective means to improve teaching and research (PhD students being an engine room for research) is unlikely to see the light of day here.

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Today was the culmination of Zaid’s PhD journey, when he successfully defended his thesis on the use of gold nanoparticles to probe the mechanism of action of a peptide that inhibits ‘flu virus infectivity. Though he approached his viva with trepidation, his beaming face afterwards told a different story. The usual smattering of corrections, a paper already up on Bioarxiv ready to submit for peer review and another to put up on Bioarxiv, and in a few weeks he will be truly done, with a CV to match.

 

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Friday Pat Eyers pushed our two papers on new screens we have developed for sulfotransferases up onto Biorxiv. More about the history of this work later. For now the briefest of summaries.

The heparan sulfate 2-O sulfotransferase paper is here

and the tyrosine sulfotransferase paper is here.

The key messages are:

(1) Mimetics of PAPS, the universal sulfate donor, that inhibit sulfotransferases are present in kinase inhibitor libraries.

(2) We demonstrate selectivity, in that some compounds inhibitor one sulfotransferase better than they do the other.

(3) PAPS mimetics look like providing a rich vein of sulfotransferase inhibitors of varying selectivity, rather like ATP mimetics have done for kinases.

(4) We have two very effective high throughput screens, which means no sulfotransferase is now beyond our reach.

Sulfation has been frustrating due to the lack of chemical tools to selectively inhibit a particular sulfotransferase. With these two papers we can foresee such tools in the not too distant future and with these, we can unpick the role of sulfation in biology, from development, through homeostasis to disease.

Exciting times!

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While reading and correcting a PhD thesis on ‘flu virus I thought I would check what strains I have encountered.

In February 1978 after playing a match for what was then RC Hermance (now HRRC) on a Sunday. I fell ill on the Tuesday, called home and was picked up by my mother.  Unfortunately, though a very smart person, critical thinking was not part of her education, which stopped at 16, and she dabbled in homeopathy. So I got sicker, spent 4 days at 41°C or above, but happily was then under our local GP (my mum was not daft) and was receiving anti-pyrogenic injections.  That time is a bit hazy, though my mother did say she thought she would lose me, so I must have been pretty ill.  This turns out to be an H1N1 virus, which only affected those under 26 years old. As this article  argues this particular ‘flu virus seems likely to have emerged from a lab (bio warfare) accident in the USSR or from vaccination (infection?) tests with live virus in China or the USSR, since the strain was almost identical to that from 26 years earlier and had not been seen in the wild in the intervening quarter century.

Fast forward to 1999 and I get a call from Tristan Bernard, past teammate at RC Hermance (now Life President, well deserved, a true evangelist for the sport) asking for a bed for him and a mate who were watching the World Cup; Liverpool was on a commute between games. A great evening, stated off in the Vines, and finished with a meal sometime after 2 am. A few days later ‘flu – this was I think brought to the UK by an Australian supporter and was an H3N2 strain virus. Not a major health incident for me though, a few days in bed and I was fine.

So the worst that rugby has done for me is ‘flu, twice, though I do have a wobbly ankle joint too.

As a side issue the murky past of the 1978 H1N1 ‘flu virus highlights the stupidity of allowing the gain of function engineering of pathogens. Regardless of whether the 1977 ‘flu virus did re-emerge from a lab, accidents, by definition, happen and viruses such as ‘flu remain an obvious war tool. I would be far more worried by N. Korean efforts in the molecular biology of viruses than by a few missiles with nuclear warheads. The latter can be stopped in flight, whereas viruses cannot.

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Congratulations to Aiseta!

On Monday 4 December Aiseta Baradji successfully defended her thesis. A long journey and a hard one as ever with its ups and downs, surprises and a certain amount of head scratching over data that push us in new directions. In the end a great thesis that will be consulted in the labs of her supervisors for a long time. Now onto the next phase.

 

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