It’s the Magnesium!

How times change!

In an episode of the making of molecular biology, Sydney Brenner was lying on a beach in California thinking about why the experiments he had been doing were not working. He had gone to California with F. Jacob to try to isolate messenger RNA, an elusive entity at the time which genetics and theory had predicted should be there. The days were passing by and mRNA kept on escaping their clutches. In the recollection of Jacob in his autobiography (The Statue Within):

“That is why, thanks to the solicitude of the biochemist Hildegaard, we found ourselves lying limply on a beach, vacantly gazing at the huge waves of the Pacific crashing onto the sand. Only a few days were left before the inevitable end. But should we keep on? What was the use? Better to cut our losses and return home. Curled in on himself, Sydney exhibited the closed mask of a bulldog. From time to time, one of us repeated the litany of the failed manipulations, trying to spot the flaw. A good woman, Hildegaard tried to tell us stories to lighten the atmosphere. But we were not listening. Suddenly, Sydney gives a shout. He leaps up, yelling, “The magnesium! It’s the magnesium!” Immediately we get back in Hildegaard’s car and race to the lab to run the experiment one last time. We then add a lot of magnesium. In my haste, I miss a tube with my pipette which then spills a huge quantity of radiophosphorus into Weiglf’s bain-marie. A short time later we tiptoe down to the basement to conceal the contaminated bain-marie behind a Coca-Cola vending machine. Sydney had been right. It was indeed the magnesium that gave the ribosomes their cohesion”.

…and thus the mRNA was caught and seen. Can you imagine this scene today? A middle-aged biosciences researcher on a beach, obsessing about their (failed) bench work and springing into action on the spur of a brainwave? If not, is it because there are no big questions in Biology? Is it because when you go to the beach you don’t like to think about experiments? Or perhaps it is because the fabric of science has changed? The spirit maybe has not changed, after all the one thing that keeps many of us going is the pursuit of the unknown, the search for logic in what seems unfathomable. But something has changed in the execution of this interest and the context in which it happens. Where once there was a scientist, there is now (particularly in the biomedical sciences) a “PI”. We do know, or think we know, what is to be a scientist but, what is it to be a PI? This is not an easy question to answer. Where Brenner and Jacob were thinking about experiments and concepts in a beach and how to implement them in the lab, today the figure tinker, tailor, soldier, spy comes to mind in the form of administrator, mentor, writer, speaker, politician…many tasks but not those one associates with an old fashioned scientist. A postdoc thinks more about positions and papers than about discovery, a young PI’s main concern is with grants, meetings and journal editors; science only comes into the picture in these contexts. Surely, you and I know exceptions, individuals that are true to the time-honoured tradition of bygone times. However, the truth of the matter is that for the most part, the PI is, as I have suggested before, more a manager of a small business or the CEO of a large cooperative than someone tinkering in a lab or in their heads. Nowadays, success seems to be measured by how many conferences and lectures one is invited to, papers in HIF journals and international collaborations than by what one finds (and too often I see people bragging about this). This leads to scientists spending more time in airports than talking to postdocs and students (doing experiments is out of the question); we all know the phenotype. I hasten to add that there is nothing wrong with this. A bit like evolution: if it works, it will stay for a while. And this is the case with this phenotype. There are two problems, though, with this development – at least from my perspective-. The first one is that this is not widely known yet and that this ignorance creates an aspirational image for young researchers which is different from that which brings them into science in the first place. To avoid frustrations, it is important that this is made clear. The second one is that in the transformation from a craft to business/industry we might miss ‘the magnesium’.

Nowadays, grants are start ups, labs are small companies, students and postdocs employees trying to move up a corporate ladder and Science just a means to an end which amidst a lot of publications (the main currency of the business) sometimes makes something useful or what we used to think of as a discovery (though I would argue that everything is useful in Biology, after all it is information). Peter Lawrence has written eloquently about unintended consequences of this situation e.g the bureaucratization of the enterprise and how it affects the development of young people and the progress of science. It is difficult not to agree with him but, unfortunately, there is a point missing in his arguments and it is that the situation has not been designed by some mean group of administrators intent in benefitting themselves on the back of scientists. The situation is an inevitable consequence of the increased numbers of scientists (or I should say of practitioners of science), the devaluation of the scientific enterprise as techniques and data gathering substitute (sometimes justifiably) thinking, the exchange of content (ideas and real discoveries) for publications and the need to find a way to control all this. Lawrence’s solution is to get back to the good old days when one would tinker away in a corner, as he did in a well funded and stimulating institute. This, today, is not possible. Doing science then was a privilege and today, when such privilege is placed at the fingertips of large numbers of people, we see its cost and the need to manage it. I also like letters and pens and old photographs and one month long holidays in the small fishing villages in Spain, sometimes, think with some nostalgia about all that. But those days are gone and the post office is changing delivery schedules not because it doesn’t like letters but because the way we communicate has changed, and one month long holidays are not workable (and lazy fishing villages do not exist anymore in Spain). Solutions to the problems that we have created have to come from looking, creatively, at the future not to a past which is not fit for current purpose.

With the biosciences becoming so expensive, interdisciplinary, and therefore collaborative, with the demands to justify tax-payers’ money, and large numbers of people to manage, it is not possible to go back to a system that catered for a few working on a small number of defined problems. Where in the 70s and 80s a postdoc had a more than 70% chance of getting a job and more than 50% of getting a first grant as a new investigator, today because of sheer numbers trying to enter the trade at the highest level, the chances of both are low. What we need to do is to face the situation, which is what begets the problem in the first place, and find solutions that fit the status quo because as has been said and I agree wholeheartedly “the root cause of the problem is the fact that the current ecosystem was designed at a time when the biomedical sciences were consistently expanding, and it now must adjust to a condition closer to steady state”( https://www.pnas.org/content/112/7/1912.full and see also https://www.pnas.org/content/111/16/5773).

NB: the data in the Figure on the left is from https://drugmonkey.scientopia.org/2012/02/14/nigms-data-on-the-timeline-from-ba-to-phd-to-asst-prof-to-r01/ and is US based, though it would be interesting to see the same for Europeans.

It does bother me how, at some meetings, sessions are staged on how to develop a successful career. In these sessions, older scientists tell the tale of how they became ‘successful’ twenty -thirty, forty- years ago, of how ALL THAT MATTERS is to do good science and that if you do that, the rest will follow. Really? Sometimes it works, and I have seen cases, but this is luck. The overwhelming reality today is very different from the one many of us experienced as postdocs: success –which today is to get a job and a grant- does not follow from just doing good science. The recipe is fuzzy and involves strategy and luck. What worked for us (over 50s) will not work for young people today because the environment, the goals and, importantly, the form and content of the biological sciences have changed. One example of this change is in the structures that are emerging in the UK with a number of intermediate positions between a postdoc and a tenured position: career development awards (of various kinds) and senior fellowships being two stages which most postdocs look at with hunger.  The most important thing to do right now is not to pine for older times but to face the situation and see how we can change it in a useful manner (NB. I am aware that many organizations are trying).

Do I have any practical thoughts on how to go about this? Difficult question but there is one thing that comes to my mind: a need for radical thoughts on the nature of our enterprise and the career structure. This at two levels, the first one is to face the realization that there are no PI jobs for everybody and that not everybody that has a paper in Nature, Science or Cell can have a job (many discover this to their surprise). Importantly, although many people involved in a lab like doing science, not everybody wants to be a PI. The fact that nowadays so many people get their first job in their mid late 30s (and increasingly nearing 40) should be a sign of alarm. Maybe we should face the reality of labs as small business and promote groups with established scientists, beyond PIs, as a solution (the much berated French system has something like this but it would need some tinkering). The second all important fact refers to education, to a revolution that is upon us and impinges on the first one. Biology is becoming analytical and quantitative and people need to be trained in the computational arts. The future in Biology belongs to those who can deal with large data working together with those who generate the data and, importantly, the questions. A significant impact from this development will be the increase in employability of graduates. If a physicist does not want to do Physics, they have many doors open. Biologists these days linger in labs late into their 30s doing technicians jobs (for this is what screens are), with low pay and morale and few opportunities. If they had a proper quantitative training not only they would increase their market value in the biological sciences, they could look beyond.

Science the way we have known it, is gone and we should not fool ourselves, and less our students and postdocs. Today, rather than ‘it’s the Magnesium’ and back to the lab, the thought that crosses the mind of a PI is “It’s Thurdsday, it must be Heidelberg or…is it Boston?’ and then, rather than the lab, goes to the airport.

CODA: I am sure that, even if one is so far removed from the bench as modern PIs are, that one could think about important issues while travelling but, one is too concerned about grants, paper revisions and visibility to worry about such things.