Real-time sulfotransferase assay

More sulfation

Earlier this year Simon Wheeler (who now has a well deserved substantive position, congratulations!) and Steve Butler published the first output from the BBSRC TDRI awarded to Steve, with myself and Ed Yates in supporting roles. It is always nice to collaborate with real chemists, as it reminds me I am very much a pseudo chemist, and I learn a lot. After what I would consider a quite heroic effort on the synthesis front, Simon and Steve pulled out a very useful sensor, based on a europium complex. The Eu sensor has good selectivity for PAP over PAPS, the universal sulfate donor. The assay works well and is very amenable to high throughput 384 well format assays (= more papers on the way). So we can now measure sulfotransferase activity in realt-ime independently of the acceptor for pretty much any enzyme-substrate combination. This represents an important tool for the wider sulfotransferase community. 

The paper also demonstrates the importance of social media in science, as a means to access in a non-direct manner new information that sets off an innovative project. I saw tweet from @Fieldlab highlighting a paper from Steve’s lab on lanthanide sensors able to discriminate nucleotide phosphates and read the paper. Naively I thought PAP/PAPS sensing using such compounds should be easy, so I contacted Steve. After some preliminary tests with PAP and PAPS on his side, we wrote the grant – another lesson here, as the application neared final from I went over to Loughborough for a meeting, which allowed us to iron out a few problems far more effectively than by electronic communication. The work was, as hinted above, far from straightforward, but like everything that is new, very rewarding and continues to be so.

I have just moved from the bird site to the proboscidean one and things look like there will be even more of such ‘random access’ of information there, so let’s see what turns up!

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Over? It hasn’t even started!

Where are we in the pandemic?

The bottom line here is that anyone making the statement ‘coming out of the Covid environment’ has not kept up with the data, which demonstrate the following:

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Clots and vaccines

Blood clots, for example, deep vein thromboses or pulmonary embolisms, are serious and we should rightly be concerned about these. With ~ 17 M doses of the AZ vaccine delivered into people, we have reports of 15 cases of deep vein thrombosis and 22 cases of pulmonary embolism. Deep vein thrombosis occurs at rate of 0.1% (so 1 in 1000) across all age groups, increasing with age. So every day that means around 47 cases in a population of 17 million – in fact it will be more, because those vaccinated are not representative of the population, but an older segment.

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We’re back & rocking

Our building complex of Biosciences and the research parts of the connected Life Sciences and MerseyBio buildings opened this week – a two week pilot and the first research building complex on campus to re-open after the lockdown. In reality, like a number of buildings in the Faculty, these had never closed. A small number of covid-related projects were running during lockdown, including our glyco one. These required skeletal support services. Moreover, key maintenance, from plants, to fly strains and flushing the water system to prevent a Legionella outbreak had to continue during lockdown.

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Heparin inhibits SARS-cov-2 cell infectivity

With new data in hand, our first preprint on SARS-cov-2 receptor binding domain (RBD) interacting with heparin now has a sibling, which demonstrates that heparin inhibits the infection of Vero cells by SARS-cov-2

Some of the key points of the team’s new work are:

1. Inhibition of viral infectivity in a Vero cell model by heparin, which is a better inhibitor for SARS-cov-2 than SARS-cov.
2. Analysis of the interactions of a more extended library of model heparins with the SARS-cov-2 receptor binding domain. As with many other heparin-binding proteins, these data show that while sulfation is critical for RBD binding, the amount of sulfate is not, but instead it is the spatial arrangement of sulfate groups that is most important.

Together the data point to heparin being a potentially useful therapeutic to reduce infectivity.

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Work on Week March 16

E-mail I sent out to the research group today.

Dear All,

From now on we really do need to reduce lab work and enforce strictly social distancing, something we stated last week.

The first transmissions from Scousers who picked up the virus on match night (bars, clubs, hotels) from Athletico fans will occur this coming week and next week; we will then get F2, F3 (F number related to contact: primary = F1, a contact’s contact = F2 etc.) transmission.

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The 2019 coronavirus (SARS-CoV-2) surface protein (Spike) S1 Receptor Binding Domain undergoes conformational change upon heparin binding

Thursday last week (Feb 27) Mark was up from Keele and popped his head around my office door – not a surprise, as he is often here to do circular dichroism on various heparin-binding proteins – to announce that Marcelo had managed to make some SARS-CoV-2 S1 receptor binding domain. Mark had asked Hao,  my postdoc, to do some SPR measurements to see if it bound heparin.

Later in the day I went over to the SPR/CD lab to find Courtney, Mark’s PhD student and Mark beavering away on the CD. A quick discussion. Hao had finished some work on our first grade A heparin functionalised SPR surface, so we set about injecting the SARS-CoV-2 surface protein (Spike) S1 Receptor Binding Domain – a one shot experiment, as amounts of protein were limited, so we injected 1 mL at 500 µL/min (I like high flow rates as mixing is way better, though still far from perfect).

Bingo.

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Easy and lazy

An article in the New Statesman this summer argues that the British degree has lost its value. The evidence is largely restricted to:

1. A complaint by students at the University of Sheffield (course not mentioned) which resulted in an uplift of the marks, particularly at the bottom end.

Without context this is a non-argument. Was the course new and there was a mismatch between what was delivered and examined? Was the marking rogue (not everyone does their job with due diligence…)?  And so on.

There follow a few paragraphs that provide no evidence, but plenty of hand waving.

The last paragraphs consider the increase in the number of students going to university and asks the question, sure, if access if wider, there should be more at the bottom, more failures. A corollary is that schools are doing no better now than they used to.

I agree there has been some grade inflation, which has two sources. The first is using the full range of marks available, rather than deciding in advance that there will be no more than one first class degree each year. Current practice is the right thing to do and past practice was wrong. The second source of grade inflation is due to the law of unintended consequences. Legal challenge, now possible because students can access their marks (transparency can only be a good thing) means there are issues at degree borderlines. Common responses have been to avoid all marks at borders (of course this fails singularly to solve the problem, since the final mark is an average of many, so student still end up under the border) and to push students up a % or two if their final marks are below a border. These and other responses to the problem have had an inflationary effect, but I would estimate it to be more more than a few %.

Counter arguments to very substantial and continual grade inflation are:

GCSEs and A-levels are harder than they were, and students are better prepared for university (just as primary students are much better prepared for the jump to secondary). While every year ministers and sections of the press whinge that the all time high level of passes represent a failure, the teaching profession (who have forgotten more about teaching than ministers or members of the 4^th estate ever knew) argue the opposite. I always take the expert over others and my limited personal experience of the matter supports the views of the teaching profession.

University courses have changed. At least for STEM courses, they are much harder and demand a lot more effort on the part of the students (my personal opinion is we have gone too far) than 40 years ago, when I was an undergraduate. There is far greater challenge and courses develop skills that in STEM subjects were not even touched on, such as critical thinking and critical analysis of data. Back in the day you either figured this out or you didn’t, so this was learned by the time-honoured system of osmosis. Importantly, a student’s abilities in these areas had no impact on the degree awarded. There is perhaps a generational difference between the young (18-35 and the middle aged and older graduates >35), with the former better at critical thinking  and analysis than their elders.

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An Open Letter to my Representatives – update

My e-mail of July 6 has yet to elicit a response. That is over 3 weeks ago, and our representatives should at the least acknowledge receipt of correspondence from their constituents within two weeks. Of course, it is quite possible that, as my representatives grapple with the complexities of their new hi-tech offices and systems, things are slipping through the net. So today I have resent the e-mail. With summer holidays on (though an MEP should maintain a skeleton staff at all times, since they have the taxpayer-funded budget for this), I would expect to receive a reply by the Bank Holiday.

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An Open Letter to my Representatives

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 3^rdcountry. 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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