Research

Universities ‘must read applicants’ work

by reestheskin on 08/11/2018

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Leading universities should pledge to actually read the work of applicants for research positions rather than use controversial metrics during the selection process, a Nobel prizewinner has argued.

No, not a spoof, but words from Harold Varmus. Sydney Brenner, a good while back, observed that people tended not to read papers anymore, they just xeroxed them.

Modesty

by reestheskin on 05/11/2018

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Modesty seems to be under negative selection — among modern scientists, at least. So I warmed to this comment on a report of some recent work on the genetics of Africa and hunter-gatherers.

Rare genetic sequences illuminate early humans’ history in Africa

Deepti Gurdasani, a genetic epidemiologist at the Wellcome Sanger Institute in Hinxton, UK. But it’s plausible, she adds. “There is literally nothing in Africa that is not possible since we have no idea what humans were doing on the continent 5,000 years ago.”

On observing those not so ‘minute particulars’

by reestheskin on 01/11/2018

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This is from an article in Nature.

Under pressure to turn out productive lab members quickly, many PhD programmes in the biomedical sciences have shortened their courses, squeezing out opportunities for putting research into its wider context. Consequently, most PhD curricula are unlikely to nurture the big thinkers and creative problem-solvers that society needs.

That means students are taught every detail of a microbe’s life cycle but little about the life scientific. They need to be taught to recognize how errors can occur. Trainees should evaluate case studies derived from flawed real research, or use interdisciplinary detective games to find logical fallacies in the literature. Above all, students must be shown the scientific process as it is — with its limitations and potential pitfalls as well as its fun side, such as serendipitous discoveries and hilarious blunders.

And from a letter in response

My father designed stellar-inertial guidance systems for reconnaissance aircraft and, after he retired, would often present his work to physics and engineering students. When they asked him what they should study to prepare for such a career, he would reply: “Read the classics,” by which he meant Aristotle, Ralph Waldo Emerson, Jean-Jacques Rousseau and Blaise Pascal.

The best scientific and technical progress does not come out of a box. It is more likely to emerge from trying to fit wild, woolly and tangential ideas into useful societal and economic contexts.

As the historian Norman Davies once said:

“Since no one is judged competent to offer an opinion beyond their own particular mineshaft, beasts of prey have been left to prowl across the prairie unchecked.”

Or as the Economist once put it”

“…professors fixated on crawling alone the frontiers of knowledge with a magnifying glass.”

This is the tragedy of our age: 90% right and 100% wrong. And that is even before we get to  medicine.

Predictive analytics in medicine: its all over now baby blue

by reestheskin on 19/10/2018

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Big Data and Predictive Analytics: Recalibrating Expectations | Clinical Decision Support | JAMA | JAMA Network

Yet despite these innovations and those to come, quantitative risk prediction in medicine has been available for several decades, based on more classical statistical learning from more structured data sources. Despite reports that risk models outperform physicians in prognostic accuracy, application in actual clinical practice remains limited.

It seems unlikely that incremental improvements in discriminative performance of the kind typically demonstrated in machine learning research will ultimately drive a major shift in clinical care. In this Viewpoint, we describe 4 major barriers to useful risk prediction that may not be easily overcome by new methods in machine learning and, in some instances, may be more difficult to overcome in the era of big data.

The hype cycle marches on.

The business of academic publishing: “a catastrophe”

by reestheskin on 11/10/2018

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The business of academic publishing: “a catastrophe” – The Lancet

How is it that publishers can continue to make profits of 30–40%? How can Elsevier get away with charging, as described in the film, $10,702 for an annual subscription to Biomaterials? It’s partly that if you are a major research university you need access to all journals not just some of them, says Richard Price of Academia.edu, a platform for academics to share research papers. It’s a question of moral hazard, explains Stuart Shieber, a Harvard professor of computer science: the consumers of the research, the academics, are not the people who have to pay. It’s the libraries who pay, and the academics remain insensitive to price…..

In addition, publishers sell bundles of journals. It’s like cable television, you get a few things you do want along with a lot you don’t, explains one librarian. But unlike cable television you don’t know what others are paying—because publishers do secret deals with libraries.

Yes. But it speaks volumes about universities, too.

Theory follows practice

by reestheskin on 04/10/2018

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When working in Africa in the 1980s with my good friend Victor Pretorius, I heard a legend about an important tribe in Central Africa, the Masai. The legend claimed that a genius member of the tribe in the nineteenth century or earlier had the idea that cow’s urine was the safest fluid for washing cooking utensils. Compared with the previous practice of using far from clean river water, it avoided the dangers of dysentery and probably saved many lives. This simple and effective public heath practice was cast out by medical missionaries who had quite different ideas, more religious than medical, about what was clean and what was dirty. Neither the original genius, nor the missionaries, knew anything about the epidemiology of water-borne disease. Whether or not there is any substance to this legend, it has stayed in my mind as a metaphor appropriate for many of our problems today. Inventions such as Newcomen’s steam engine, Faraday’s electrical machines, and the idea that fresh urine is a sterile fluid, all came long before their scientific understanding.

James Lovelock, A Rough Ride to the Future. This is like so much of real discovery in clinical medicine, although the academy gets to write the history of how it is supposed to work.

Food for thought

by reestheskin on 27/08/2018

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For a baseline life expectancy of 80 years:

  • Eating 12 hazelnuts daily (1 oz) would prolong life by 12 years (ie, 1 year per hazelnut)
  • Drinking 3 cups of coffee daily would achieve a similar gain of 12 extra years
  • Eating a single mandarin orange daily (80 g) would add 5 years of life.

Conversely:

  • consuming 1 egg daily would reduce life expectancy by 6 years
  • eating 2 slices of bacon (30 g) daily would shorten life by a decade (an effect worse than smoking).

Well these are all taken from John Ioannadis’ article in JAMA. He asks : “Could these results possibly be true?”

The great financial crash led to some (but not enough) soul-searching about the state of academic economics and, in turn, the academy. Whole swathes of the modern research university are geared to the production of unreliable knowledge.  There is money in it. Without wishing to understate in any way Ioannadis’ major contributions, we have known that there are fundamental methodological flaws in much of observational epidemiology for a long time (for instance see the late Alvan Feinstein’s article in Science). A must read. 

(The Challenge of Reforming Nutritional Epidemiologic Research John P. A. Ioannidis, AMA. Published online August 23, 2018. doi:10.1001/jama.2018.11025)

“The song remains the same”

by reestheskin on 17/08/2018

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From an obituary of Paul Boyer.

“Paul Boyer was approaching the finish line of his career when he risked everything with a jaw-dropping proposal. He addressed one of the most important, as-then-unanswered questions in biochemistry”

“We were attending a UCLA seminar in 1972 when I noticed that he wasn’t paying attention to the speaker. Afterwards, Paul approached us in a very excited state. This was surprising because he was known for his calm demeanour. He confessed that he had spent the hour thinking about old unexplained data. He asked: “What would you say if I told you that it doesn’t take energy to make ATP at the catalytic site of ATP synthase,” (as was universally held at the time) “but rather that it takes energy to get ATP off the catalytic site?” This was a eureka moment.

As is often the case with transformational ideas, early reactions were negative. When the Journal of Biological Chemistry rejected our manuscript containing data supporting this concept, Boyer told me without animosity that he could see why they would do that — “It was a very striking claim.”

Well, I have never had an idea to compare with this. But sitting through talks that do not light my fire, I have always found conducive to thinking creatively about something else. Its similar to the way that some writers practice their craft better in a coffee shop than in a silent office. Intellectual white noise.

Remember: the best ideas are not in the literature. If they were…..

Sausages, and ‘unprofitable activities’ (aka students).

by reestheskin on 08/06/2018

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Besides, “university league tables are like sausages: the more you know about how they are made, the less you want to [do with] them”.

“Research was structurally unprofitable even if you scored really well in the research excellence framework,” he claims. “It’s being financed by surpluses on taught master’s. I think that’s fine because part of the reason people came on the taught programmes was because the place was very highly ranked in research, and they thought they were going to be sitting at the feet of the best economists around. Academics had to understand the dynamic and deliver the teaching because that was what was paying for the research. Yet because of the history of underfunding [undergraduate] students [before the introduction of £9,000 tuition fees in 2012], a kind of mood gained ground in British universities that [all] students were an unprofitable activity.

Paris to London: Howard Davies on the finance sector and universities’ common interests | Times Higher Education (THE)

Diagnosing money.

by reestheskin on 14/05/2018

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Science 21 June 2013: 1394-1399.

For most alumni, university fundraising may seem to be uncoordinated and lacking in focus—an assortment of phone calls, solicitous letters, and invitations to a class reunion. But for Steven Rum, it’s a science. And the goal is to carry out more research.

Rum is senior vice president for development and chief fundraiser for Johns Hopkins Medicine in Baltimore, Maryland. Last year, his team had a banner year, raising $318 million. Their approach places the physician scientists at Hopkins on the donor front lines. The goal is to turn the positive feelings of “grateful patients” into support for new research, faculty chairs, academic scholarships, bricks and mortar, or simply defraying the cost of running a multibillion-dollar medical center.

Rum has 65 full-time fundraisers on a staff of 165. Each one is responsible for meeting weekly with physicians—their “caseloads” range from a dozen to more than 30 docs—to discuss which of their patients might be potential donors. The conversation is designed to help them identify what Rum calls a donor’s “qualifying interest” and connect it to their “capacity,” that is, the ability to make a donation.

More often than not, Rum’s team finds that sweet spot…..

”Ideally, I’d like to have one gift officer manage no more than six doctors,” he says.

Link

The breakthrough is just a filing away.

by reestheskin on 01/05/2018

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Article in Nature. I largely agree, although my views are as much based on the hype-upon-hype that characterises so much of medical research, especially cancer. I do not have a reference, but whatever one’s views about the late David Horrobin, his Lancet article about cancer trials — written when he was dying from lymphoma — is worth a read. What a mess!

Key quotes from this article:

In 2017, my colleagues and I completed a study of all 48 cancer drugs approved by the European Medicines Agency between 2009 and 2013 (C. Davis et al. Br. Med. J. 359, j4530; 2017). Of the 68 clinical indications for these drugs (reasons to use a particular drug on a patient), only 24 (35%) demonstrated evidence of a survival benefit at the time of approval. Even fewer provided evidence of an improved quality of life for symptoms such as pain, tiredness and loss of appetite (7 trials; 10%). Most indications (36 of 68) still lacked such evidence three or more years after approval. Other groups in other regions have observed similar trends. For example, a 2015 study demonstrated that only a small proportion of cancer drugs approved by the FDA improved survival or quality of life (C. Kim and V. Prasad JAMA Intern. Med. 175, 1992–1994; 2015).

But the key point he makes is:

I believe that the low bar also undermines innovation and wastes money.

When assessments — whether in medicine or education — are flawed the loss in value is not in short term financial costs, but in what might have happened 10 years down the road.

Five years (left to cry in)

by reestheskin on 29/03/2018

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There are periodic evaluations, but a poor result means losing only a fraction of your funding, says Schuman, who previously held one of the plum positions in U.S. science: as an investigator funded by the Howard Hughes Medical Institute on a 5-year contract. “I did not realize how the renewal clock of 5 years dissuaded me from going for risky ideas until I became a Max Planck director,” she says.

Cue, David Bowie:

 

Book review on sun, skin and physics

by reestheskin on 12/03/2018

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The following is an excerpt from a review in press with Acta. You can see the full article with DOI 10.2340/00015555-2916 here

 

From the solar constant to thong bikinis and all stops in between. 

A review of: “Sun Protection: A risk management approach.” Brian Diffey. IOP Publishing, Bristol, UK. ISBN 978-0-7503-1377-3 (ebook) ISBN 978-0-7503-1378-0 (print) ISBN 978-0-7503-1379-7 (mobi)

Leo Szilard was one of half a dozen or so physical scientists who, having attended the same Budapest gymnasium, revolutionised twentieth century physics. In 1934, whilst working in London, he realised that if one neutron hit an atom which then released two further neutrons, a chain reaction might ensue. Fearing of the consequences, he tried to keep the discovery secret by assigning the patent to the British Admiralty. In 1939, he authored the letter, that Einstein signed, warning the then US President of the coming impact of nuclear weapons.

After the war, in revulsion at the uses to which his physics had been applied, he swapped physics for biology. There was a drawback, however. Szilard liked to think in a hot bath, and he liked to think a lot. Once his interests had turned to biology he remarked that he could no longer enjoy a long uninterrupted bath — he was forever having to leave his bath, to check some factual detail (before returning to think some more). Biology seemed to lack the deep simplifying foundations of the Queen of Sciences.

Conferences

by reestheskin on 07/03/2018

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But all of that media can’t really replace the socializing, networking, and simply fun that happened as part of (or sometimes despite) the conference formula.

I don’t know how to fix conferences, but the first place I’d start on that whiteboard is by getting rid of all of the talks, then trying to find different ways to bring people together — and far more of them than before.

Marco Arment

I no longer go to many conferences, and that is a good thing. But fixing them is a problem, not least because many academic conferences are businesses that collect money that supports other activities. This is not always bad, but is often not good. ‘Getting rid of the talks’ is of course attractive. Leo Szilard once suggested that you should stand up, briefly report your conclusions, then sit down. Only if the audience were sceptical of your results would you have to speak for longer. As for size, there is no single right size. However the best conferences I have every attended were all small, with less than 40 people. But I wouldn’t t have got to these small ones, unless I had gone to the big ones.

Money doesn’t talk, it swears

by reestheskin on 02/02/2018

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The surge in open-access predatory journals is making it harder for contributors and readers to distinguish these from legitimate publications — a confusion that is fostered by the predatory-journal industry. One solution could be to deploy a variant of a well-established quality-control test. The scientific community could submit replicate test articles several times a year to a wide array of open-access journals, suspect and non-suspect.

From Steven N Goodman who, as ever, is worth reading. Of course, in one sense, it is a question of serial monogamy, or polygamy.

How long does it take to learn?

by reestheskin on 31/01/2018

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After earning his medical degree in 1951 he trained in hospitals in Montreal. “To my surprise I also found I enjoyed clinical medicine,” he wrote in his Nobel prize biography. Then he quipped, “It took three years of hospital training after graduation, a year of internship and two of residency in neurology, before that interest finally wore off.”

David Hubel

Asleep at work

by reestheskin on 26/01/2018

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This is from the obituary of Ben Barres [link]

An utterly committed researcher, Professor Barres would regularly work until 2am or 3am. He “slept on the floor of my small office”, recalled Professor Raff. “Every morning when I arrived and opened the door, it would whack him in the head – he eventually learned to sleep facing the opposite direction.”

Somewhere, I cannot remember where, after one of his seminars, his intellectual depth (Ben Barres) was judged more favourably to that of his ‘sister’. His sister was his his former ‘self’, Barbara Barres. Such a neat experimental design to tease apart causality.

I too worked somewhere where people slept overnight in the lab, although I think the deciding factor there was an inability to find or pay for a suitable flat, rather than enthusiasm

Carving Nature at the joints

by reestheskin on 04/01/2018

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David Hubel, on statistics: “We could hardly get excited about an effect so feeble as to require statistics for its demonstration.”

I came across this (below), in my end of year clear out. And even if this was 2016, rather than 2017, it is as good a thought to open 2018 with, as any other. It is from a review of “Life’s Greatest Secret: The Race to Crack the Genetic Code”, by Matthew Cobb. The review is by H Allen Orr. NYRB

Finally, and perhaps most important, Life’s Greatest Secret highlights the power of the beautiful experiment in science. Though Cobb pays less attention to this subject than he might have, the period of scientific history that he surveys was the golden age of the beautiful experiment in biology. Biologists of the time—including Nirenberg with his UUU, Crick and Brenner with their triplet code work, and others including Matthew Meselson, Franklin Stahl, and Joshua Lederberg—were masters of the sort of experiment that, through some breathtakingly simple manipulation, allowed a decisive or nearly decisive solution to what previously seemed a hopelessly complex problem. Such experiments represent a species of intellectual art that is little appreciated outside a narrow circle of scientists……..

But the larger lesson of Life’s Greatest Secret is one that may be worth remembering. When scientists require definitive answers, not merely suggestive patterns, they require experiments that are decisive and, if all goes well, beautiful.

Teaching led research, anybody?

by reestheskin on 03/01/2018

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There is something about teaching that makes you a better researcher. I know this is very countercultural wisdom, but I believed it all along. Luria, Magasanik, and Levinthal all believed it. Levinthal and Luria both had a very strong influence on me in this regard.

An (old) interview with David Botstein, in PloS genetics. Link

At least we are spared the ‘research led teaching’ mission statements.

The fatal success of obfuscation

by reestheskin on 01/01/2018

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“For example, I studied Physics, so I learned about how physicists think… and it is not how most people think. They have these tricks which turn difficult problems into far easier problems. The main lesson I took away from Physics is that you can often take an impossibly hard problem and simply represent it differently. By doing so, you turn something that would take forever to solve into something that is accessible to smart teenagers.”

Daniel Lemire’s blog

But the opposite is now much more common. I think there are whole swathes of modern institutional and corporate life, that are designed to make the simple, complicated. At best, simple may sometimes be wrong, but complicated is usually useless — or much worse. I seem to remember Paul Jannsen, when asked why we do not seem to be able to discover revolutionary new drugs like we once did, respond: ‘in those days the idea of obviousness still existed’.

First, the practice, then the theory

by reestheskin on 28/12/2017

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Yan Lecun of Facebook wrote:

In the history of science and technology, the engineering artefacts have almost always preceded the theoretical understanding: the lens and the telescope preceded optics theory, the steam engine preceded thermodynamics, the airplane preceded flight aerodynamics, radio and data communication preceded information theory, the computer preceded computer science.

Science and Technology links (December 8th, 2017) – Daniel Lemire’s blog

This is so true for (much) medicine, too. The journal comes after the discovery.

Compound interest, USS and all that

by reestheskin on 29/11/2017

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Take salary: as Mrs. Neal told us during her crash course, you’ll carry your whole life the compound price of an un-negotiated first salary.

From Frederic Filloux in the Monday Note. A great article which, whilst focussed on the topic of journalism schools, has bags of relevance to future and therefore present day medical schools. The professional schools have a lot in common.

 

Most lawyers don’t make anything except hours.

by reestheskin on 17/10/2017

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This was a quote from an article by an ex-lawyer who got into tech and writing about tech. Now some of by best friends are lawyers, but this chimed with something I came across by Benedict Evans on ‘why you must pay sales people commissions’. The article is here (the video no longer plays for me).

The opening quote poses a question:

I felt a little odd writing that title [ why you must pay sales people commissions]. It’s a little like asking “Why should you give engineers big monitors?” If you have to ask the question, then you probably won’t understand the answer. The short answer is: don’t, if you don’t want good engineers to work for you; and if they still do, they’ll be less productive. The same is true for sales people and commissions.

The argument is as follows:

Imagine that you are a great sales person who knows you can sell $10M worth of product in a year. Company A pays commissions and, if you do what you know you can do, you will earn $1M/year. Company B refuses to pay commissions for “cultural reasons” and offers $200K/year. Which job would you take? Now imagine that you are a horrible sales person who would be lucky to sell anything and will get fired in a performance-based commission culture, but may survive in a low-pressure, non-commission culture. Which job would you take?

But the key message for me is:

Speaking of culture, why should the sales culture be different from the engineering culture? To understand that, ask yourself the following: Do your engineers like programming? Might they even do a little programming on the side sometimes for fun? Great. I guarantee your sales people never sell enterprise software for fun. [emphasis mine].

Now why does all this matter? Well personally, it still matters a bit, but it matters less and less. I am towards the end of my career, and for the most part I have loved what I have done. Sure, the NHS is increasingly a nightmare place to work, but it has been in decline most of my life:  I would not recommend it unreservedly to anybody. But I have loved my work in a university. Research was so much fun for so long, and the ability to think about how we teach and how we should teach still gives me enormous pleasure: it is, to use the cliche, still what I think about in the shower. The very idea of work-life balance was — when I was young and middle-aged at least — anathema. I viewed my job as a creative one, and building things and making things brought great pleasure. This did not mean that you had to work all the hours God made, although I often did. But it did mean that work brought so much pleasure that the boundary between my inner life and what I got paid to do was more apparent to others than to me. And in large part that is still true.

Now in one sense, this whole question matters less and less to me personally. In the clinical area, many if not most clinicians I know now feel that they resemble those on commission more than the engineers. Only they don’t get commission. Most of my med school year who became GPs will have bailed out. And I do not envy the working lives of those who follow me in many other medical specialties in hospital. Similarly, universities were once full of academics who you almost didn’t need to pay, such was their love for the job. But modern universities have become more closed and centrally managed, and less tolerant of independence of mind.

In one sense, this might go with the turf — I was 60 last week. Some introspection, perhaps. But I think there really is more going on. I think we will see more and more people bailing out as early as possible (no personal plans, here), and we will need to think and plan for the fact that many of our students will bail out of the front line of medical practice earlier than we are used to. I think you see the early stirrings of this all over: people want to work less than full-time; people limit their NHS work vis a vis private work; some seek administrative roles in order to minimise their face-to-face practice; and even young medics soon after graduation are looking for portfolio careers. And we need to think about how to educate our graduates for this: our obligations are to our students first and foremost.

I do not think any of these responses are necessarily bad. But working primarily in higher education, has one advantage: there are lost of different institutions, and whilst in the UK there is a large degree of groupthink, there is still some diversity of approach. And if you are smart and you fall outwith the clinical guilds / extortion rackets, there is no reason to stay in the UK. For medics, recent graduates, need to think more strategically. The central dilemma is that depending on your specialty, your only choice might appear to be to work for a monopolist, one which seeks to control not so much the patients cradle-to-grave, but those staff who fall under its spell, cradle-to-grave. But there are those making other choices — just not enough, so far.

An aside. Of course, even those who have achieved the most in research do not alway want to work for nothing, post retirement. I heard the following account first hand from one of Fred Sanger’s previous post-docs. The onetime post-doc was now a senior Professor, charged with opening and celebrating a new research institution. Sanger — a double Laureate — would be a great catch as a speaker. All seemed will until the man who personally created much of modern biology realised the date chosen was a couple of days after he was due to retire from the LMB. He could not oblige: the [garden] roses need me more!

More Big data, rather than Big ideas

by reestheskin on 29/09/2017

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No, I could not run, lead or guide a pharma company. Tough business. But I just hope their executives do not really believe most of what they say. So, in a FT article about the new CE of Novartis, Vas Narasimhan, has vowed to slash drug development costs; there will be a productivity revolution; 10-25 per cent could be cut from the cost of trials if digital technology were used to carry them out more efficiently.

And of course:

(he) plans to partner with, or acquire, artificial intelligence and data analytics companies, to supplement Novartis’s strong but “scattered” data science capability.

I really think of our future as a medicines and data science company, centred on innovation and access (read that again, parenthesis mine)

And to add insult to injury:

Dr Narasimhan cites one inspiration as a visit to Disney World with his young children where he saw how efficiently people were moved around the park, constantly monitored by “an army of Massachusetts Institute of Technology-trained data scientists”.

And not that I am a lover of Excel…

No longer rely on Excel spreadsheets and PowerPoint slides, but instead “bring up a screen that has a predictive algorithm that in real time is recalculating what is the likelihood our trials enrol, what is the quality of our clinical trials”

Just recall that in  2000 it would have been genes / genetics / genomics rather than data / analytics / AI / ML etc

So, looks to me like lots of cost cutting and optimisation. No place for a James Black, then.

Minute particulars

by reestheskin on 30/08/2017

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This is from an article in Nature. And the problem is resolving differences in experimental results between labs.

But subtle disparities were endless. In one particularly painful teleconference, we spent an hour debating the proper procedure for picking up worms and placing them on new agar plates. Some batches of worms lived a full day longer with gentler technicians. Because a worm’s lifespan is only about 20 days, this is a big deal. Hundreds of e-mails and many teleconferences later, we converged on a technique but still had a stupendous three-day difference in lifespan between labs. The problem, it turned out, was notation — one lab determined age on the basis of when an egg hatched, others on when it was laid.

Now my title is from Blake:

He who would do good to another must do it in Minute Particulars: general Good is the plea of the scoundrel, hypocrite, and flatterer, for Art and Science cannot exist but in minutely organized Particulars.

And yet, I think I am using the quote in a way he would have strongly disagreed with. Some of the time ‘Minute particulars’ are not the place to be if you want to change the world. Especially in biology.

Its science Jim, but not as we (now) know it.

by reestheskin on 28/08/2017

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If you are interested in the history of science. Or put another way, how science can work when it is allowed to, check out this wonderful site: ‘Molecular Tinkering: How Edinburgh changed the face of molecular biology’.

I first became aware of ‘Edinburgh’ and its role in molecular biology by accident. In the late 1970’s I spent three months here doing a psychiatry elective, on the unit of Prof Bob Kendell. I stayed in self-catering University accommodation through the summer, knowing nobody, spending most of my free time tramping around the city on foot. Not always bored. There was a motley crew of people staying in the small hall, and one was a biologist from China. I had never met anybody from this far away and mysterious place. Of course, mostly I asked about barefoot doctors and the like, and questions that you would not now use your mobile phone to ask. No Alexa then. But I wondered why he was here. Molecular biology, he explained. Now, I could recite the story Jim Watson told about Watson and Crick, and even mention a few names who followed. But no more than a handful. ‘Recombinant DNA’ might have passed my lips, but please do not ask me to explain it. But from him, I learned something special has awoken. And for me it was literally a couple more years before the waves of this second revolution broke on the shores of MRC Clinical Training Fellowship applications.

A sample:

Throughout the 20th century film editors worked by identifying key scenes in their film reels, snipping precise frames and re-joining them to create a new narrative. This is exactly how the Murrays wanted to work with the long molecules of DNA. Restriction enzymes would be the editor’s scissors, making the cuts. As well as doing the cutting, the enzymes would be the editor’s eyes: recognising the precise frame at which to snip.

Or if you ever doubt that the space for discovery is infinite, listen to this from Noreen Murray:

“Looking back, it is amazing that Ken and I were the only people in the UK in the late 60s and early 70s to notice the potential of restriction enzymes.”

Or this, for a definition of what research leadership is all about:

Waddington had a real knack for selecting and recruiting interesting but often unproven biologists.

Science works! Rewrite the textbooks

by reestheskin on 01/08/2017

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Little evidence is found for higher-order organization into 30- or 120-nm fibers, as would be expected from the classic textbook models based on in vitro visualization of non-native chromatin.

Well, chromatin structure might not be everybody’s cup of tea but I once shared an ‘office’ with a couple of French / Polish researchers in Strasbourg. It was all above my head, so I had to make do with the textbooks, and I stuck to my simple cloning of upstream regulatory regions of a retinoid receptor. Now, it appears from this article in Science, the textbooks will need rewriting. Science works.

RCTs and the kudos of stacking shelves

by reestheskin on 31/07/2017

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Many many years ago I wrote a few papers about — amongst other things — the statistical naivety of the EBM gang. I enjoyed writing them but I doubt they changed things very much. EBM as Bruce Charlton pointed out many years ago has many of the characteristic of a cult (or was it a Zombie? — you cannot kill it because it is already dead). Anyway one of the reasons I disliked a lot of EBM advocates was because I think they do not understand what RCTs are, and of course they are often indifferent to science. Now, in one sense, these two topics are not linked. Science is meant to be about producing broad ranging theories that both predict how the world works and explain what goes on. Sure, there may be lots of detail on the way, but that is why our understanding of DNA and genetics today is so different from that of 30 years ago.

By contrast RCTs are usually a form of A/B testing. Vital, in many instances, but an activity that is often a terminal side road rather than a crossroads on the path to understanding how the world works. That is not to say they are not important, nor worthy of serious intellectual endeavour. But the latter activity is for those who are capable of thinking hard about statistics and design. Instead the current academic space makes running or enrolling people in RCT some sort of intellectual activity : it isn’t, rather it is a part of professional practice, just as seeing patients is. Companies used to do it all themselves many decades ago, and they didn’t expect to get financial rewards from the RAE/REF for this sort of thing. There are optimal ways to stack shelves that maths geeks get excited about, but those who do the stacking do not share in the kudos — as in the cudos [1] — of discovery.

Anyway, this is by way of highlighting a post I came to by Frank Harrell, with title:

Randomized Clinical Trials Do Not Mimic Clinical Practice, Thank Goodness

Harrell is the author of one of those classic books…. . But I think the post speaks to something basic. RCT are not facsimiles of clinical practice, but some sort of bioassay to guide what might go on in the clinic. Metaphors if you will, but acts of persuasion not brittle mandates. This all leaves aside worthy debates on the corruption that has overtaken many areas of clinical measurement, but others can speak better to that than me.

[1] I really couldn’t resist.

A .. deep thinking, highly rigorous, no-BS [bullshit] research scientist..

by reestheskin on 26/07/2017

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Hours later, with Blackburn’s approval, the institute issued comments on the scientific records of the two women. It had “invested millions of dollars” in each scientist, Salk stated, but a “rigorous analysis” showed each “consistently ranking below her peers in producing high quality research and attracting” grants. Neither has published in Cell, Nature, or Science in the last 10 years, it said. Lundblad’s salary “is well above the median for Salk full professors ($250,000) … yet her performance has long remained within the bottom quartile of her peers.” The institute wrote that Jones’s salary, in the low $200,000 range, “aligns” with salaries at top universities, although she “has long remained within the bottom quartile of her peers.”

This is from an article in Science (Gender discrimination lawsuit at Salk ignites controversy). The context is a sex discrimination case, but the account is about an astonishing lack of vision. Short termism of stock markets is not the only way value is being destroyed by a cash-in-hand mentality. The best rugby coaches have rarely been the greatest players. Nobel laureates may not be the best leaders. No (bull) shit here…

All about shifting units

by reestheskin on 05/07/2017

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Of all the titles submitted to the 2014 research excellence framework, only “around a half in most subjects achieved at least one retail sale in the UK in the years 2008-14”. 

Worst sellers: warning of existential crisis for academic books | THE News