It’s the Magnesium!

Slide1How 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”( http://www.pnas.org/content/112/7/1912.full and see also http://www.pnas.org/content/111/16/5773).

NIGMS-Age-DataNB: the data in the Figure on the left is from http://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.

Science is Global

following the Science is Global campaign we have had a chance to look back at our history and have realized that the mantra of  the campaign is true and that, indeed, our science has always been international, something we have enjoyed and valued. These are the nationalities that through the bonds that link generations of students and postdocs, are the fabric of our group.

Flags

Of codes and machines in Biology I; elements for a discussion

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NB. As I was writing this post, a couple of comments came up on Twitter on whether the machine metaphor was a useful one for biological systems. The discussion did not change the view that is expressed here: a machine is a good metaphor and one that, to a large extent, remains untested.

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I am no fan of science fiction but there is a novel which I have always liked –for the philosophical background more than the plot- and that has come to my mind when recently thinking about genes and cells: Carl Sagan’s ‘Contact’. The key element of the story is the reception of an extraterrestrial message by scientists which, after some toiling, is revealed to contain instructions for building a machine. The instructions do not contain any hint of what the machine is for and only vague ideas of how its detailed shape will look like; both emerge as it is built. The story has many twists and turns, deals with some of the preoccupations of Sagan and, in some ways, the recent ‘Interstellar’ touches in a more saccharine manner, with some of the same issues. But the bit that has grabbed my attention over the last few weeks has been the notion of having a set of instructions without a clear picture of what they are for (self assemble furniture instructions feel like this sometimes) that, when followed, generate a machine and only when the machine emerges, one can think of what it is for.

The reason I was thinking about ‘Contact’ has to do with a preoccupation to figure out what it is that we want to know. I am well aware of things that we need to know, but given that there is always limited time, one needs to decide what it is that one would like to know; understanding is ambitious and, probably, out of reach. Modern cell and molecular biology have placed in front of us a formidable technical arsenal which, in principle, allows us to explore any question we may have. As I have hinted at before, it is unfortunate that a collusion of editorial and career interest are giving precedence to classifications and listings, sometimes one at a time, over real questions but…….. it is also true that questions are difficult to find and, more importantly, to answer. And it is in trying to understand what are important tractable questions, that something caught my eye, something which I am sure some of you either know or have thought about in a different manner. The problem of Developmental Biology is how the information in the DNA is decoded and transformed into the tissues and organs that configure an organism. Most seminars and reviews on the subject start like this only to then proceed with genetic or molecular screens. Nonetheless, as a consequence of this work, classical and popular genetics have created the mirage that there are genes for this and that i.e. that the DNA harbours instructions for digits, eyes, hair colour or height and, in the worst twist often promoted by newspapers, that there are genes for diseases. This is the basis of our current understanding of how the information in the DNA is interpreted and turn into an organism but……. if one thinks about it and thinks from first principles, genes are ONLY instructions to build machines (M in the figure below): ribosomes, transcription and replication enabling machines, membranes, cytoskeletal devices, etc….their remit does not go beyond this. These machines, once built (through the central dogma), become assembled, much like a 747 or a transatlantic liner, into a larger product, a device with the capability to process information, react to it, do work, sense the environment. This device is what we call A CELL. In multicellular animals, subtle variations in the composition and performance of the component machines, lead to different cells that can be further assembled into tissues and organs and these into an organism. Thus, don’t forget that the instruction in the DNA do not code for much that is 3D, and certainly lack any information about the function of the machines or the devices they code for. Like the extraterrestrial message in Sagan’s novel, the instructions are for a machine whose purpose only becomes clear once it is built.

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Fig1. Top, A general principle whereby functional interactions between machines built by instructions from a blueprint, configure a device that works according to the laws of Physics and Chemistry. Bottom, a translation of the principle to a biological system.

Something interesting happens once the machines and their suprastructures, the cells, are assembled: space arises (the information in the DNA does not contain, convey or encode space, maybe time, but not space). As a consequence of the generation of space (surfaces and volumes), mechanics makes an appearance and it does so at two levels: the molecular one (the machines) and the cellular one (the device).  Thus, the emergence of space leads to the emergence of mechanics which feeds-back on the processes of decoding and assembly and, in more than one way, tissues and organs and ultimately organisms, are the outcome of these feedbacks and the interactions they create. The decider of what the output of these interactions should be is function, as dictated in a blind manner by Natural Selection.

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Fig 2. Tissues and organs do  not arise from instructions but result from the feedbacks that the emergent properties of the performance of the machines assembled in cells. More explicitly from the feedbacks that generate new activities and behaviours in those machines and cells.

Much has been made of the selfish gene hypothesis (and I hasten to add that I am not an evolutionary biologist and know little about evolution) which suggests that the machines and the devices have the aim of reproducing the genes which encode them. I find this naïve, deterministic and anthropocentric. There might me no purpose in the assembly of those machines, maybe all is a game of molecular flaunting and selection is not simply looking at the replication of the genes but at the performance of the machines (I realize that I shall need to expand this here but, like Fermat, for that I need more space than the one I can afford here). Perhaps it is a widespread unconscious focus on the genes that for a long time has placed our emphasis on the decoding, which misses many of the important points and problems the need to be addressed. In this regard, it is interesting that while cell biologists have focused on the machines and, sometimes, how they are connected, developmental biologist have focused on the decoding in a kind of naïve manner: a gene for each season. I would surmise that the important problems in developmental biology require, at least for now, thinking about the machines, the devices they configure and their functioning rather than in their component parts. Only in this manner we shall be able to go beyond genes/instructions and start to look at tissues and organs from the same perspective as Nature does: the ability of the cell to integrate and process information. Work on the decoding of gradients in developmental systems (James Briscoe, Marcos Gonzalez Gaitan, Thomas Gregor, Johannes Jaegger, and Arthur Lander) or of oscillators during somitogenesis (Alexander Auhlehla and Andrew Oates) do just that and, to my mind, are some good examples of the way forward, of how to integrate quantitative cell biology, hypothesis testing and modelling. These efforts gauge the information processing ability of cells rather than in the micromanaged organization that most molecular biologist do. Perhaps phage and E. coli supervise closely every step of their biology but, while not impossible, this is not probably the way multicellular developmental systems operate. They are likely to use coarse graining, space and time averaging of molecular events, system level strategies that we can easily miss by focusing on the details of the molecular events.

Much of what we have done so far to understand higher order organization of biological systems (and there is work to do) deals with temporal aspects of the system: simple gene regulatory networks that try to capture sequences of gene expression linking them to specific cellular events. The challenge comes when we face the nature and details of the feedback that space creates on the decoding, the assembly and performance of the machines and their coming together into the devices that we call cells. It is the feedbacks involved in these processes that we need to understand and represent. Turing when thinking about the problem of development in his 1952 paper, was well aware of the challenge when he wrote:

“……one proceeds as with a physical theory and defines an entity called ‘the state of the system’. One then describes how that state is to be determined from the state at a moment very shortly before. With either model the description of the state consists of two parts, the mechanical and the chemical. The mechanical part of the state describes the positions, masses, velocities and elastic properties of the cells, and the forces between them.(….) The chemical part of the state is given (in the cell form of theory) as the chemical composition of each separate cell; the diffusibility of each substance between each two adjacent cells rnust also be given….(…). The interdependence of the chemical and mechanical data adds enormously to the difficulty (of understanting the state of the system) and attention will therefore be confined, so far as is possible, to cases where these can be separated”

This is a pre-molecular way of looking at the problem but remember that Turing was trying to think about Development and doing this in a very prescient manner. The interdepence he refers to is the essence of the feedbacks mentioned above which turn cells into tissues and organs. Along similar lines, a few years ago F. Julicher pointed out something to me which highlights the essence of the problem and, at the same time, the difference between Physics and Biology. It can be stated simply: whereas in a physical system, Chemistry generates mechanics and the reverse is not true, in biological systems both work (Physics generates Chemistry and Chemistry generates Physics) and it is in this feedback and interactions that, probably, lies the essence of biological systems.

The current focus and craze on screens and single cell transcriptomics (proteomics is coming) should not make us forget that these endeavours only address the parts. Moreover, as I have discussed before (http://amapress.gen.cam.ac.uk/?p=1094) the system we are trying to understand has evolved to respond to selection (and remember that this is what screens are about, a highly selective selection of the ability of cells to respond to a stimulus) and the response is based on dynamic heterogeneities that we still do not understand but which, one suspects, have something to do with the feedbacks I have outlined. The exciting thing (to me) in ‘Contact’ is the machine, what it does and how both its structure and purpose unfold as the system is built. The parts that configure the system could have been used to build anything but the instructions turn them into a space-time machine. In Biology, right now there is too much emphasis on the parts. This would not be a bad thing were it not because we endow parts with functions that correspond to the wholes they are part of. How do we avoid this? The real aim of Systems Biology is to avoid falling into this trap. It is therefore unfortunate that in most realms, Systems Biology has become a proxy for data analysis. Cell and Developmental biologists should embrace a proper version of Systems Biology because right now it is the only way to get out of the describe-the-parts loop and move towards understanding on the way to re-engineer cells and tissues.

Acknowledgement: I want to thank F. Julicher and S. Grill for very enlightening and inspiring discussions on the subject of this post. Also, note that there is a I in the title. There will be a II which aims to deal with ‘questions in Biology’.

Epilogue: The Twitter feed I mentioned above led to many interesting suggestions. They all described different kinds of machines. Even the notion of City, much liked in the thread, can be construed as a machine. What this reflects is that machines are ways to describe (and then engineer) assemblies of parts with some functional aim. It is difficult not to see this in the fabric of a cell and, in many ways, it is a useful, working notion. If properly used it could be helpful as in its day was the vision of the central dogma, as information transfer and decoding.

Expensive or Insightful Biology?: Single Cell Analysis as a Symptom

160727_800px-Musei_Wormiani_HistoriaLists, catalogues and classifications have always been the business of the biological sciences. The nature cabinets of the XVII and XVIII centuries, the collections that occupied much of the XIX century and which fuelled the work of Darwin are good examples of this. Beetles, butterflies, fish, pigeons, plants occupied (and occupy) the time of individuals, often amateurs, interested in Nature. The nature of this enterprise is captured in Umberto Eco’s book “The Infinity of Lists”

When we don’t know the boundaries of what we want to portray, when we don’t know how many things we are talking about (….) when we cannot provide a definition by essence of something and so, to be able to talk about it, to make it comprehensible or in some way perceivable, we list its properties (…………….). We call this representative mode the list, or the catalogue

Indeed: to make something whose limits or meaning we ignore, we make lists, if they are organized according to some criterion (and since Linnaeus but even before, they are) they have the potential to reveal something of the essence of that which is being classified. Physicists and chemists know well how this works: stars, spectra and the elements come to mind. But the level and intricacy of what the biological world offers to the catalogue aficionado is different, probably, boundless. To go back to Eco, it is unclear where the limits of the biological world lie. No wonder E. Rutherford said that one could reduce the sciences to Physics and stamp collecting; he may have had the biological (then natural) sciences in mind and this perhaps is why S. Brenner famously retorted that what Rutherford did not know is that there are some stamps that are worth collecting.

In the History of Science lists have the potential to highlight generalities which allow precise questions to be asked and answered. Physics and Chemistry have been good at reaping the benefits of this activity. In Biology a most famous outcome of this cataloguing is, of course, Darwin’s great work which revealed a principle running through the continuum of transformations that stares from large collections, ordered collections (the word ordered and in what manner the order comes about being important here), of plants and animals. In a different way, the work of Mendel is a culmination of less structured but no less significant collection of lists of the output of many lists; after all, it is seeing patterns in the outcome of crosses of plants that leads to genetics. In all cases the assumption is that if the lists are arranged according to the right criterion, they will reveal an order and, behind that order, some mechanism -in the sense of a causal explanation for a set of observations and not as the usual Figure 7 characteristic of modern biology papers- that will provide an insight into a system. In the end, sometimes, the insight can lead to the manipulation of the system for the benefit of the observer: lists lead to science that leads to engineering which leads to progress.

There is a danger in these lists and it is that they might become an end of themselves. That the scientist becomes a collectionist, forgets Brenner and gives credence to Rutherford. Surely the lists are valuable resources for those that want to ask questions, but the truth is that as we turn into list makers, we can forget that there are questions behind the observations and habit turns us lazy and content in our collecting. Sometimes one feels that this is happening in the biological sciences, that biologists are becoming professional collectionists. There might be a reason for this:  the essence of biological systems is the generation, selection and competitive propagation of novelty and variation. As a result, every species, every genome, every cell in every genome, every organelles in the cell, every protein in the organelle, is subject to this continuous generation of variation, to the exploration of a large space of form and functions. If one assumes that every cell type in an organism is different and that these differences are species specific, one can do a simple calculation: the range of different cell types varies between 3 in a plachozoan to about 1014 in a human and if, as it is currently assumed, there are on the order of 8.5 x 106 organisms on the earth, one could say that there might be on the order of 1020 different cell types to explain (NB this is assuming that all individuals within a species are similar and forfeiting the development of an organism during which large numbers of transient cell types are generated that differ from their final types). This number, 1020 , is already a large number relative to the approximate number of stars, 1012 . It may be small relative to number of atoms, 1080 in the Universe –and one has to remember that atoms need to be proportionately distributed into 117 elements which is where the differences appear i.e all atoms of an element are essentially the same and thus, the 1080 number needs to be tempered by its being bundled up in the abundance of each element. It is here, in this notion of similarity of all the atoms of an element, that the main difference between the biological and physical systems appear. The stars are very similar to each other in composition, and this is why we can study them from a distance by using the spectra. On the other hand, every organism, every cell type in every organism is different, unique. In fact you and I are very similar but our cells in similar places in similar organs are likely to be different. Enter DNA, which is the way to explain uniqueness in Biology: if we accept, as we must, that every cell type responds to a ‘transcriptional code’ of sorts, and we focus just in humans with our approximate 20,000 genes (I am not interested in philosophical discussions of what is a gene and hope that you and I will agree that this is a lower bound), simple calculations allow for 220000 combinations, to account for those 1014 different cells (and don’t forget those developmental intermediates). If you throw this number into your calculator, it will be confused as it will approach infinity. Of course, the toilings of Natural Selection ensure that only part of that repertoire is used but still, the number is large and dwarfs anything the inorganic world can produce. Surely we are stardust, like the moons of Jupiter, but DNA and RNA have found a way to turn that dust into a creative material device.

Where am I going with this? Over the last few years technical developments have allowed us to peer into single cells at the level of their transcriptional complement and, with increasing accuracy, at the level of their genomes. The observation is that even within what histologically is a (one) cell type, there is a great deal of heterogeneity. It is difficult to silence the genome, and we are learning that cells –particularly in development- are exploring their transcriptional space in a dynamic manner. The result is that within an organism much of that space of 220000 combinations is likely to be explored and much of it represented. The technical developments are allowing increasing volume and accuracy in the observation of this process (gene expression at the level of single cells) and of the delivery of these results. In consequence this creates interesting challenges for classifying, for making lists, which are taken on by groups of computational biologists whose interests lie in dealing with complexity rather than in understanding its meaning. Meetings are held on the subject of gene expression at the level of single cells and while at the moment the possibilities lie in honing our ability to describe the expression patterns of single cells and of characterizing the genomes of cells in tumours, the holy grail on the horizon is the analysis of epigenetic marks at the level of single cells and the ambition of getting the genome, epigenome, transcriptome and proteome in single cells. Our infatuation with these techniques, what it reveals and the possibilities associated with it are powerful and thus reviewers and editors lurk in the background to ask you for a single cell analysis of your favourite system, if everything else has failed to hamper the publication of your work. But, at the moment, it is also expensive and begs the question of where does it lead to? What is the meaning of this work? Are we paying lip service to Rutherford?

160727_Untitled.001The analysis of single cell gene expression can have -and sometimes had- an impact in three areas of Biological research: Cancer Biology, Immunology and my area of interest, Developmental Biology, which aims to understand how an organism builds itself. In all cases, single cell analysis allows the identification of ‘rare cells’ which sometimes have a function and sometimes, they don’t. The issue is that more often than not and in the best tradition of Biology, these studies reveal the temptation of collecting data under the banner of its ‘importance’ without realizing that we have fallen to a fad, that cataloguing has taken precedence over understanding. The description of a biological process demands a link between a cellular and a genetic description of the process and there is little doubt that the arrival of single cell transcriptomics and associated techniques, particularly single cell lineage tracing, has revolutionized the field. However we should be careful not to be swayed by the collectionist syndrome and remember that behind the data there are questions and that if we cannot see them, we should acknowledge that. We should not confuse cataloguing and collecting with Science. In some ways there is no great difference between beetles and genes, and we might be developing a XXI cabinet of genes and cells. It might require more challenging techniques than those collections of the past but there is no difference between collecting one or the other. Already papers in journals tend to be divided into two: either analysis of gene X in tissue Y in organism Z, or increasingly, single cell analysis of process W in organism Z. And in the best tradition of classical Systems Biology, one hopes that in the analysis of the data, the question and the answer will emerge at the same time as one stares in hope at the data.

Single cell analysis of expression is the epitome of this strange hypothesis-free science that is often hailed in reviews and social media. We are in the midst of it. Slowly we fool ourselves that large data and cataloguing will lead us to the essence of a process, that it will allow us to talk about something that we cannot define. And while it is true that Biology has a habit of revealing principles from lists I cannot help but thinking that with this trend of hoarding data, we are losing perspective of the processes that still need addressing. It would be good if, as R. Feynman said, we don’t confuse naming something with understanding something. Developmental Biology in particular, is losing itself in this naming game and single cell analysis will –unless checked- provide the ultimate distraction from questions that are there but we are too…..may I say ‘lazy’? to ask. We should not forget that there are things to explain, that cataloguing is a way to answer, and sometimes to unlock, those ‘things’ but also that we need to make an effort to search for them.

The allure of the information that can be gathered in one of those experiments is enormous but one needs to remember that in addition to being expensive and data rich, it needs to be insightful. The difference between a collectionist and a scientist should lie not in the ability to make observations but in the ability of the second to use the observations to answer specific questions about Nature. Biological systems have a boundless ability to generate (constrained) variability and it seems to me that the challenge is to understand the nature of the machine –for it is a machine- that generates, processes and uses that variability, written in that tape that is the DNA, interpreted by the transcriptional machinery and supervised by Natural Selection. It is the process, not its output, that needs to be explained. Questions are cheaper than data gathering but good questions are hard to come by.

Epilogue

One of the most disturbing aspects of the current trend in the single cell field is the lack of cross reference or discussion of the data. Often the same system is surveyed in more than one paper without any reference to the other, related, pieces of work or even, on occasion, to the general problem. While this is in keeping with the current trend in the biological sciences in which the publication rather than the finding is what matters, it is no less disturbing. If we do not get hold of the boundless nature of that data by using questions to clean it up and thus reveal what is good and bad data, we shall do a disservice to the system that puts up the money for that research and, more importantly, to Science itself. Surely, there is meta-analysis, Darwin’s great work can be construed as a meta-analysis- but nowadays, often this is done not so much with a question in mind but with the idea of multiplying the data-analytical power. The boast tends to be not in what has been learnt but in how large the data set is. And in the end, the danger is that, increasingly, what we do is expensive collecting; XXI century cabinets of genomic data, without a good reason, without a good question –which exists. We seem to have relinquished our ability to interpret what we observe and lost our interest in asking questions because, I agree, it is easier to order and catalogue this diversity that we call Biology. Still, the issue buzzes in the back of my mind: there are questions, important questions, to be asked and….all that data!

Brexit: The Pyrenees, the Channel and the Ocean

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I few months ago I was asked to speak at the Society of Spanish Researchers in the UK (SRUK) annual Symposium in London. SRUK is a grass roots organization which has evolved over the last few years to act as a reference for Spanish researchers in the UK and as a vehicle between the UK and Spain in scientific matters. With this in mind and having been asked for a perspective on Science in the UK and Spain from my experience as a researcher and teacher here, I gave a title (The Pyrenees, the Channel and the Ocean) based on three geographical barriers which acted as cultural barriers for Spanish people of my generation. I wanted to emphasize the value of breaking those barriers, how good this feels, how important this has been for Spain and how the UK as a cultural melting point with strong and (in my experience) welcoming institutions is a working example of this. Then, June 23rd, Brexit, happened.

The UK is my home and has been my home for the last 33 years. I realize that my view of the UK is a biased one (from Cambridge and London) but having lived here so long I have had a chance to experience a broader Britain and I can say that have never felt a foreigner here. Have never felt glass ceilings in Cambridge and have always found the UK an exciting and forward thinking multicultural place anchored in worthwhile traditions. It is here that I have learnt much of what I know about how to do and run Science, where I have come to appreciate the structure and value of a scientific culture that would be good to export to Spain. I have also come to appreciate the value of a society which, at the grassroots level, I find kind and integrative with much that can serve as a model for others. It is here where my wife and I have developed our lives and our careers, where our children have grown up, where I have learnt to look at and to see Spain and, importantly where over the years I have received young people in search of a future -which many times could be and has been here- and have help them to graft into this interesting place which is Britain. These people come from many places, mostly continental Europe, and have always taught me something and I have seen them change their views of their countries through their experience in the UK: it is in this cultural tradeoff that one becomes richer at so many levels. It is from here that I have seen, and have had the opportunity to contribute –in a small manner- to the enormous transformation of the biomedical sciences in Spain, particularly, over the last 15 years and my what I have learnt by being here has been crucial for this. And it is for all these reasons, but significantly because through my personal experience I am well aware of the effects that isolationism, that I am sad for what has happened and what it has revealed to me about a UK which, I guess, I did not know or I had missed. Or perhaps I had ignored.

 

Like many people I had a strange sense of anger and disbelief on the morning of the 24th and felt like saying much –which I did- just to vent the frustration. At the time (I guess) there were two things that fuelled my feelings. The first one was the way the debate had been conducted and what it revealed to me about an isolationist craze hidden outside London-Oxford-Cambridge-Scotland; how this debate revealed a fear of foreigners – which I had taken as part of a humorous past- and its consequences. The second one was the fact that I -and some millions like me who have lived and paid taxes for a long time, could not vote on something that mattered to us and our families- had not been allowed to vote (for those that complained about lack of democracy in the EU, what kind of democracy is that?). I felt like venting my frustration with a few lines but realized that this would be more emotional than reasoned and decided to wait. The SRUK event gave me more ammunition and some distance to reflect from. In that event I wanted to reflect on what breaking barriers meant to a country like mine from the perspective of an open one, the UK. Brexit cast a shadow on those thoughts. The SRUK symposium, where I had a chance to meet many Spanish researchers spread through the UK, was proof of the value of the open society that Britain has been up to now. At the meeting there were postdocs but also fellows, lecturers, readers, professors and all with a positive experience of their time in the UK, sharing that they have learnt here and, judging by their work, contributing to the growth of this society.

 

There is much that is uncertain at the moment, and not just about Science. There is also a lot of fear about what might happen and some short term consequences of this uncertainty. For example, we are all pragmatic and perhaps it is not surprising, that EU wide projects will look with some suspicion at the potential participation of UK groups. After all, Science is (increasingly) very dependent on collaboration and money that attracts money; if the UK is not going to be part of the game and wants to take more than it gives, it should be looked at with suspicion. I appreciate this and also that the result of the referendum has come as a surprise to many, that there is no plan for the situation in which we (because I and others like me are part of this society) find ourselves, but it would be good to hear soon from the government that Science, which is such a central element of this society, will continue to play the leading role that it has up to now. The repeated emails from the vice-chancellor of my University are reassuring, strengthen the concerns and single voice view of the academic community, but also highlight the extraordinary circumstances we have been thrown in.

 

It is very difficult to say anything new, original or inspired about the situation we live in. We are all waiting and whoever reads this is, anyways, a convert that much of what was in place with the EU is good and that what is wrong can only be repaired from being in. However, I shall say that I know what barriers do, how taking advantage of geographical and economic barriers leads to a cultural isolationism that is harmful and how when inward looking attitudes prevail, when a nation closes upon itself, Science and culture suffer and a social decay follows quickly. When I grew up in Spain, the Pyrenees were much more than a mountaneous ridge, they were a symbol of a cultural barrier that set us aside and apart from the rest of Europe. We, Spain, had the Pyrenees on one side and the Ocean on the other and although we did not have much at the time, we did not get much from the outside either. I remember the first time I crossed the into what we then called Europe (at the time we were only part of it geographically), my bewilderment at the world that I found, its wealth and its allure. Later when I crossed the Channel (the British Pyrenees) and the Ocean, this impression got magnified and I discovered a world that changed my life and one of the elements of that world that I have come to appreciate as the most important one, was its multicultural nature, what the US called “the melting pot”. Who I am has been shaped by my interactions with people from other cultures, nationalities and beliefs.

 

I left Spain in 1978 and have followed the transformation that it ensued from abroad, have witnessed how, as barriers fall, a country is enriched, becomes known abroad and, in contributing to the rest of the world, the rest of the world contributes to it. From the US and the UK I have seen how, over the years, Spain has turned from a culturally isolated country, to one exporting academics, to one which, using the lessons from other countries, welcomes foreigners and integrates them into its society. The benefits of being culturally open need time to emerge but it is easy to see in places like the UK and, of course, the US. Can one imagine US science without immigration?  Openness and integration are essential elements of social and academic progress because they promote tolerance and also, in the blending of views and attitudes, cultural development. In contrast with the slow development of cultural interactions, the losses created from isolation can be fast and become engrained before one realizes they exist.  Above all, what I learnt when I looked at Spain from abroad is how poor a country becomes when it isolates itself.

 

As I have said, it is difficult to say much that has not been said but I want to emphasize the dangers that will ensue from severing the structure of interactions that have emerged over 40 years with continental Europe. Science is a central part of those interactions and I am well aware of how much the British point of view is valued in those interactions. Brexit, if implemented in the way the Brexiteers want, will deprive Europe from the British input but, worst and importantly, slowly and inexorably it will make the UK a culturally poorer place and one in which, at a time in which science and technology are global endeavours, it will not be able to share and participate in those enterprises. As a biologist I know well the value of exchanges of genes and memes as well, and as much, as the damage that isolation can do to a group. I can hear some people thinking about the power base of British science and technology but these people will be living at the beginning of the XX century rather than in the global and interactive society of the XXI century. It is true that the UK has much that is good and solid, but by sharing it with the rest of the EU in an open manner it does much to promote its valuable institutions and influence. At the SRUK meeting I was asked what would I take to Spain from my experience in the UK. I did not hesitate: from the point of view of Science and technology, many of its institutions and their organization.

 

I am optimistic by nature and want to believe that in the end, sense will prevail, that whoever will do the necessary negotiations (and as of today it looks as if these are going to be hardcore Brexiteers) will see that much of what is in place in Europe is good, that freedom of movement within the EU has more positives than negatives and that this, and the structural benefits it brings along, are something worth preserving. It is possible (though I think unlikely) that the government will find a way to provide the funds that will be lost if the negotiation is not done with the UK’s real interests at heart. It is, as I say, possible, however, what the government can’t do is to buy what people coming to the UK, like I and many do, with open minds and eyes, to learn and, in the process, contributing, positively to the growth of a global society in which individual countries adapt to their idiosyncrasies the valuable aspects of other societies. You don’t lose your individuality in an open society, you enrich it. Brexit is a step backwards, the expression of a yearning for an order and a society which do not exist any more, that is encapsulated in that apocryphal headline “Fog in the channel, the continent isolated’; yes, a small island looks at a continent.

 

Let’s hope that sense will prevail and in the end, as the Prince says in Il Gatopardo: ‘everything has to change for everything to remain the same’.

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ASAPbio: The Dusk of Peer-Reviewed Glamour (a report from a virtual attendance)

The issue of publications of science manuscripts is reaching breaking point. Breaking in the sense of tearing down the enthusiasm of young investigators, the patience of seasoned ones and generating a lot of debate at institutional level. A few days ago, a survey by Nature News showed that more than 35% report taking 1-2 years to publish a manuscript and 20% 2-5 years (http://www.nature.com/news/does-it-take-too-long-to-publish-research-1.19320). What the bottom line of the article hid is that the time does not mean time sitting in the same journal –though some times it does- but time from submission to the first journal. For a more informed case study of the topic you should look at several posts in the always excellent S. Royle’s blog (https://quantixed.wordpress.com/); in the context of this post, I particularly like this one https://quantixed.wordpress.com/2014/04/15/some-things-last-a-long-time/. The point is that in science, but particularly in the biological sciences, something very fundamental has changed. Scientific publishing is an evolving enterprise but over the last twenty years it has moved, imperceptibly, from a medium scientists use to report their findings to a consumer good that uses scientists to develop its business model. It could be argued that this should not be a blanket statement but, actually it is pretty much that, particularly in the non-academic tier. Compound this with a sociological trend of too many scientists, disenchantment with career prospects and the emergent importance of media and this explains why scientific publishing has become a source of employment and a business that, as has been repeated many a time, uses scientists at all ends –from the bench to the editorial desk- of its fabric.

The problem is that the essence of the enterprise: finding-report-publication, has not evolved and what we have is a system that, basically, cannot cope with its essential fuel: science. Too much is being produced, all needs to be peer reviewed and peer review has evolved into an interesting sociological contraption that at some point should be the subject of some PhD thesis. The aim of peer review in its current incarnation is not to improve the work (this is the gimmick) but to ensure that a paper takes the longest possible time to be published and that its cost escalates to the point that what is considered good research is, basically, expensive research. And so it is against this backdrop (a much simplified version of it) that last week a meeting took place at HHMI headquarters with the cunning acronym of ASAPbio (Accelerating Science and Publication in biology: http://asapbio.org/). The meeting gathered an interesting mixture of senior scientists, administrators and editors with the aim of discussing preprints and preprint servers in Biology. For those of you who have not heard of preprints (and surprisingly there are many out there who haven’t and people at ASAPbio who acknowledged that they did not know they existed before the meeting!), a preprint -in the context of science communication- is a manuscript which has not been subject to external peer review and which is posted in a site for public viewing; it even has a Wikipedia page (https://en.wikipedia.org/wiki/Preprint), whose first words are “Publication of manuscripts in a peer-reviewed journal often takes weeks, months or even years from the time of initial submission,…..”, it says all.

ASAPbio was broadcast live on the internet and you could follow it on Twitter and social media; some of us did and you can see the videos now at the site (http://asapbio.org/). It was interesting. The gathering was representative of what we could call the establishment of science, principally the US establishment, and gave careful consideration to the culture of preprints and its future. Perhaps the most surprising thing to come out of it is that we have to fight a fear to preprints as forms of unvalidated science, preprint postings as a danger to “true research” and, surprisingly, some of these voices from qualified scientists (yes, the ones who have created and control the system we enjoy –or endure, as you choose-). There were exceptions amidst the old guard. The objection raised by those who worried was that preprints are not ‘controlled’, are not reviewed (forgetting really what lies at the heart of a manuscript at the time of submission), vetted. One had the impression that preprints are some kind of modern samizdats (in case you have not heard this word: https://en.wikipedia.org/wiki/Samizdat) forgetting that samizdats were a good thing in the cold war era. In fact, as a response to ASAPbio some went as far as posting tweets wondering whether what is in preprints is true or safe for consumption!. The answer to this question is simple: read the paper. Furthermore, physicists have been using preprint servers since 1991, particularly in the form of their very successful arXiv (http://arxiv.org/) home to over one million e-prints on all aspects of physical and mathematical sciences. Paul Ginsparg, founder of arXiv, participated at the meeting providing details of its history, value, mechanics and validation of and making clear that in many ways, preprints (e-prints at arXiv) are the bread and butter of the physics community. He also reminded (in some cases revealed) to the audience that arXiv introduced a section on quantitative biology which is proving popular. Along these lines a few years ago under the initiative of John Inglis, CSH started a parallel server, bioRxiv, which aimed at catering to do for Biology what arXiv does for Physics and Mathematics. There are other preprint servers of different flavours but bioRxiv aimed from the beginning to be arXiv like i.e. community oriented, user friendly, data rich. As it was reported at the meeting (and you can read here http://asapbio.org/biorxiv) bioRxiv is succeeding and that many of us –who have been using bioRxiv from the beginning- believe that it is a seed for and leads the way to the future of bioscience publishing.

The problem, for now, is that Biology lags culturally and practically behind Physics and this is reflected in many practical aspects, not only the publication ethos. Biology, as a science, hiding behind mindless collection of data has become more a culture of glamour than of content, of haves and have nots in which a good idea or a good point is likely to go amiss and where many bad ones get too much fleeting attention by virtue of where they are published. The question people most often ask you when you try to tell them about your work is not WHAT is it about, but WHERE have you sent the manuscript or, often, how big is your group. The science of the bioscience is a means to an end and so, it is not surprising that publishers have latched on to it and make the most of it. I don’t want to be misunderstood, there is a lot of good science around, it is just that not all that appears as good science is good science (though all data are useful). And thus it emerges the current tangled web of bioscience publishing. You, like me and many, have felt the dismay of starting the path of trying to publish something in what some people would call a ‘decent journal’. By now it is clear that the demands of peer review are not very different in most of those ‘decent journals’, that the difference between them is that in NCS you get rejections with arrogant and patronizing demands and messages from the editors, whereas in other journals you just get a directive to answer the often arrogant and patronising comments of the reviewers. I shall not bore you with details, we all have our stories. As has been said before, when people finally publish, there is a sigh of relief more than of elation. There are exceptions and I can only cite, within the realm of what I know, EMBO Press and The Company of Biologists. I wished I could cite eLife and PLoS but I am afraid that each in their own ways have failed to live up to their expectations (PLoS ONE has done a lot of good but has become slow and cumbersome as reviewers ask for more and more work, and PLoS Biology has become a place where people go when their papers have been rejected from NCS; in the case of eLife, with much that is good, it is unfortunate that so much power and resources are being channelled to beat NCS at their own game rather than in being really creative –for those who praise their excellent reviewing methods of eLife, you should know that EMBO journal had been using them for several years before eLife.

So, in terms of publication time and effort, things are getting worst all the time (see above). Enter preprints, that apparently dangerous and unsafe way of disseminating science. I must say that to label a preprint as dangerous or scientifically unsafe is to miss the point that publications in NCS can be worst because, as has been pointed out many times having been ‘peered reviewed’ they show the cracks of the system and the pitfalls of the glamour world those magazines promote: Arsenic life, the STAP problem or cold fusion come to mind and, in the case of STAP, don’t forget it led to the humiliation of a world renowned institute and the suicide of a much respected scientist with little consequence to the journal which published the manuscript in the first place. To say that preprints are dangerous is to overlook where the real danger lies and where the pursuit of glamour over science has led and leads. For those who say that preprints will be honey for garbage I shall say that having followed bioRxiv from the beginning, one thing has surprised me: there has been almost zero crank science. BioRxiv has had a steady increase in submissions and all of them -up to now it is possible to follow most of them- are sound science, no less controversial than what is published after peer review. If anything, one of the valuable aspects of preprints –if properly used- is that they represent raw science, before it is tampered with by editors and other scientists, who often have more competition in mind than the advancement of he science. It is clear that preprints in Biology are here to stay and that in the future will be the best way to present your science. I suggest that you go to the ASAPbio site and read through some of the views of the meeting and even if you have time, watch some of the discussions. More importantly, make sure that you use preprints to disseminate your science.

There were two other important issues discussed at the meeting. The first one was whether preprints should be allowed as an evaluation of scientific research. In theory, and in the light of DORA, this is a no-brainer but the discussion is important as the people gathered at ASAPbio represented a significant element of the establishment. Despite some concerns, it was also reassuring that, for the most part, people saw this in a positive light and many pledged not only to accept preprints (in preprint servers) as evidence of scientific quality, but to encourage their citation in job and fellowship applications. Many young scientists will appreciate this and I suspect that we shall see more of this in the future. The second issue was the mechanics and detail of such a cultural change. You cannot move this idea forward without attention to the organizational mechanics of the server, something arXiv and now bioRxiv know well. There were several references to this and it is important that in the enthusiasm of the move, we do not forget this important aspect of the enterprise.

ASAPbio was led by Ron Vale, whose excellent http://biorxiv.org/content/early/2015/07/11/022368.article-metrics served as a fuse for the meeting. There were well known people in the audience, like Michale Eisen, who have been doing a very open campaign for open science. However, while Eisen is good as a ramming bat against the establishment, we should not forget the many who in a quiet way have been adding to the momentum of preprints by convincing students and postdocs of the value for their careers and science of preprints servers. We need the chief scientists and administrators on board but, more than that we need the inertia created by people submitting their papers to preprint servers commenting on those servers (and don’t forget that you can comment in PubMed through PubMed Commons). It is clear when you come to think of it, that not only there is nothing to be lost by using e-print/preprint servers, but much –all- to be gained, particularly if you are a young Scientist. What is good for physicists cannot be bad for biologists.

ASAPbio was a formal recognition that something is changing and hopefully a formal start of a much needed move into new directions. I can see the worries of so called major publishers about the watershed that is coming, they might lose their stranglehold on the Science they own and shape, but a date comes to mind, 1789, and a voice that reportedly said “let’em eat brioche”. There will be no blood here but much needed change and a recovery of what is scientists’ privilege, the control over their work. I get the impression that something is moving. I sense not the dawn of a new era but the dusk of a short lived one based on much that is wrong and that we need to turn around. As it is being said these days, make sure that your next paper goes to a preprint server as it goes, or before it goes, to peer review. One senses that this is the way to solve, not only the emerging tyranny of journals but also peer review itself.

Season’s Greetings from the AMA Lab

With Christmas just around the corner, we have been adding a touch of festive cheer to the lab with a decorations competition. Novel uses were found for Falcon tubes, polystyrene packaging and Eppendorfs – in the end the prize went to the bay with the snowman!

We also gathered for our annual Christmas lunch, which was a great chance to get out of the lab and to share a meal together.

From all of us in the lab, have a very merry Christmas/happy Hanukkah and all the best for 2016!

Lab Decorations

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