Thinking About Science in Trump’s USA: A Warning from History

The old Chinese curse, “may you live in interesting times”, has been thrust upon us; interesting times, indeed. Well, more than interesting, surreal. Brexit and Trump are just what is closest to us but let us not forget the puzzling situation in Syria and the mystery that Russia always is (the famous adage of Churchill about the Soviet Union always comes to mind: “a riddle wrapped in a mystery inside an enigma”). One of the most surprising features of these times is the disregard for logic and sense, the creeping influence of “the falsehood” and a plump disregard for objective, fact based scientific reasoning. There is so much going on that it is easy to be desensitized, to not give importance to things that matter and to forget that actions have consequences. At this, there is one area where the discussion has been going on for so long that we can easily overlook its importance. The news that Trump is revoking the Obama legacy on climate change, reactivating drills and the coal industry in ways that put in peril the environment have been headlines news. People have complained and engaged into reasonable debate but, like so much these days, this has just fallen into the flow of news. Perhaps the most painful aspect of the New White House trend is the disregard for scientific evidence in favour of ideologies and false economic reasoning without thinking of the long term consequences.

We have seen this before. Hegel said that history repeats itself, first as tragedy then as a farce and it seems to me that this is happening today. Farces also have consequences though. The denial of climate change for ideological and social reasons has been going on for a while but the Trump administration, like in many other things, is taking it to another level. Not only there is an open denial of clear facts and evidence, there are also attempts to destroy evidence. Files are being deleted and scientists linked to the administration banned from raising their voices. The reasons behind this are the selfishness of certain elites that bargain the (our) future to feed (their) short term gains. We have seen this before, and perhaps it is worth remembering one such episodes which echoes in the climate change discussion.

A plot of Science at the service of Ideology developed in the Soviet Union during the 1930s and 40s and led to the destruction of Soviet Biology, in particular Genetics, and henceforth to the poor state of this field today in Russia and its satellites. The name associated with this achievement is Trofim Lysenko and a doctrine called Lysenkoism. The plot is simple (well, not that simple but will try to summarize) and characteristic of those times and place. Even in the complicated environment of Russia in the 1920s, Science was still (just) workable and Genetics, as it was on the rise, became a normal staple of soviet Science under the influence and organization of Nikolai Vavilov (Russian stamp at the top). The importance of agriculture in a country the size of the Soviet Union with its large peasant population was obvious, so perhaps it is not surprising that much effort was focused on plant genetics and agriculture (the main specialty and interest of Vavilov). Fruit flies also had a good representation and Hermann Muller (a declared socialist) spent time in Moscow teaching and consolidating the laws and practice of transmission Genetics. The great Nikolay Timoffef-Ressovsky, was a product of this period.

It is not surprising that in a deeply ideological society even Science has to bend to the prevalent social and political thoughts; see Galileo’s trial or the attitudes of the Nazis towards ‘Jewish’ science, but also in a more benign version the role that capitalism has played in the development of modern scientific culture. Thus in the Soviet Union, the collectivization of agriculture in the 1920s had led to great famines and deaths. This was the result of a mixture of poor agricultural practices and the weather, always harsh and unpredictable in most of the territory. With this in mind, it is not surprising that Genetics would be at the centre of any discussion to tackle this problem and that Vavilov, as the leading figure in the field, would take a leadership role and worked hard to address the problem. He travelled the world collecting seeds and trying to fit them to specific locations where they could grow and yield in the complex soviet geography. But Nature has its rules and if you want to change them you need to let Natural Selection work over long periods of times. The soviets did not have time.

Enter Lysenko (left), an agricultural biologist of peasant extraction who became interested in understanding why some crops needed to be planted in Winter and some in Spring. This was not a new question, not without scientific merit and for this reason Vavilov himself had been interested in it and supported this research. Building on experimental work of several years, Lysenko observed that exposure of Winter seeds to humidity and extreme temperatures in ‘laboratory conditions’ would allow them to germinate and to be planted in Spring when they would grow as the natural plants. In this manner the laboratory conditions could bypass difficult winters and ensure harvest. He called this process ‘vernalization’, a term that already existed but which has become synonymous with Lysenko. Furthermore, he suggested that this acquired resilience and ability would be transmitted to the offspring which then would not need to be treated. If this neolamarckism were true and properly done this would avoid the vagaries of the Soviet climate and increase the yields. And of course, if this were true, it would be possible to control at will the development of the plants and the yields of crops. In an increasing climate of Ideology over Reason, much of this fitted well with premises of the emerging soviet socialism in which even the laws of Nature had to be at the service of the people.

A complex web of Science, Politics and Social Engineering was woven around Moscow in the 1930s. This led, almost imperceptibly to a political interest in shaping Science. Surprisingly Mendelian genetics, slowly but surely, become a focus of these activities. The rules and vagaries of random assortment of characters, the notion of ‘the gene’ and the Darwinian principles that underpin much of Biology were put into doubt. Suddenly facts became servants to ideology and the gene was first questioned, then doubted and finally ridiculed, expunged from teaching and research. It is difficult to believe that scientific knowledge would be a dangerous asset in the early part of the XX century but as heliocentrism in the 1400s, Mendelian genetics could take you to the gallows. Muller had to leave Moscow in a hurry when it the notion that “biologists are fly lovers and people haters” (as quoted in Wikipedia Lysenkoism) started to spread. Over time, 3000 Soviet scientists were either killed or interned in camps during the 1930s and 40s, mainly for espousing or being seen to be associated with scientists linked to Mendelian genetics. Amidst this the biggest casualty was Vavilov who tried to make his clout count to help Genetics but who, in the end, succumbed to the conspiracies and power in fighting. In the ascendancy of Lysenko and the complex web that was being built between Science and Soviet ideology, Vavilov’s links with the West provided the catalyst that the State needed to build the case against him. He died in a camp in 1943. In 1948, Lysenko was appointed director of the Institute of Genetics within the USSR’s Academy of Sciences and Genetics was declared a pseudoscience. He reigned supreme over Soviet Biology until the death of Stalin.

It is not difficult to see traces of this piece of history in the recent official decision of Trump administration to undo Obama’s climate change policies. The attack of the evidence of man made climate change is decried as pseudoscience and the reason behind this consideration is none other than an ideological one: to favour a kind of backwards industrial development for the people, a pro-business, pro-money, anti-science attitude of the administration. Of course, unlike the closed Soviet Union, this is happening in a well connected world where we are aware of news and events and in a country with a free press and without the risks that were so prevalent in Stalin’s USSR. However, let us not be fooled by these differences. The point is not whether Trump is like Stalin, he is not. The point is to remember that when Ideology takes charge of Science there are likely to be long term consequences. The USA has had, and still has, its issues with ideologies and science, creationism and intelligent design come to mind, but never before has been an administration leading the ideological charge. For the attitude towards climate change is mirrored by other national institutions like the Department of Agriculture, and the Center for Disease Control and Prevention. Nowadays, the cuts to the NIH and the appointments at the higher level of individuals with little knowledge of, respect for and belief in Science do not bode well for a Society which has given and gives so much to Science.

The US academic and scientific community has enough power and foundation to resist but it will need help and this is where a reminder of history matters. Lysenkoism affected the USSR and never spread (though it tried) but the damage to the culture of that country was immense and long lasting. While Mathematics and Physics come to mind when thinking about Soviet of Russian Science, Genetics and Biology do not. In fact these are represented by what often is called the Lysenko affair. Such events unfold over long periods of time so lest we forget and make sure that we heed the warnings from History.

The image of Lysenko is from http://hplusmagazine.com/wp-content/uploads/2013/05/lysenko.jpg the picture of the stamp with Vavilov is from Wikipedia https://en.wikipedia.org/wiki/Nikolai_Vavilov

  1. This post emerged while reading Simon Ings’ “Stalin and the Scientists: A History of Triumph and Tragedy 1905-1953” which reminded me that those of us who are scientists have a responsibility to defend the proper use of scientific evidence. Further reading, if you are interested, on the recent events in the USA:

https://www.theguardian.com/commentisfree/2017/mar/28/arctic-researcher-donald-trump-deleting-my-citations

http://www.newyorker.com/tech/elements/donald-trumps-war-on-science

http://www.vox.com/science-and-health/2017/1/25/14370712/trump-science-gagging-explained

https://www.scientificamerican.com/article/trump-administration-orders-epa-to-remove-its-climate-change-web-page1/

and some good news….http://www.sciencemag.org/news/2017/01/trump-officials-suspend-plan-delete-epa-climate-web-page

A Short Tale about Brachyury

Once upon time….somebody said that Genetics is Ariadne’s thread of Biology, the only way to guide us out of the labyrinth that is a biological problem. Nowhere has this been more true than in the analysis of development, the processes underlying the emergence of an organism. In this spirit, it is the systematic application of genetic analysis to Drosophila melanogaster and Caenorhabditis elegans spearheaded a deluge of information that started modern ‘Developmental Biology’ (the study of the dynamics of pattern and form in embryos, as opposed to ‘Embryology’, the detailed description of the different stages associated with embryos). The success of these two invertebrates took its time to permeate the mammalian embryo. There are good reasons for this. Two possibly important ones come to mind: the challenge that is to study an embryo that develops inside the mother and, not unrelated, the difficulty of applying Genetics to such an object. In retrospect we can see that most of the mutations that have given us insights into developmental events are embryonic lethal and it has been the pathological, or if you don’t want to sound so dramatic say phenotypic, analysis of those mutations that has yielded a view of the process. Notwithstanding husbandry and breeding details, the mammalian embryo, small and hidden in the confines of the uterus, is not an ideal target of systematic screens (the mammalian genetics papers) but with patience and focus, Genetics was applied and the usual combination of serendipity and method have yielded their fruits.

It could be said that there are many kinds of Ariadne’s threads. For example, mammals have an interesting aspect of their make up that is not a bad one into the labyrinth and that, in my view, has not been exploited as much as it might: haploinsufficiencies. Dominant phenotypes caused by the loss of one allele that are related to the function of a gene and it is with a haploinsufficiency that mammalian Developmental Biology started with the discovery of the mutation that lends its name to the gene Brachyury. In some ways the story (or the path if you want to stick to the mythology) of Brachyury is a story which highlights the highs and the lows of the connection between Genetics and Development, that reveals how easy it is to be distracted by the underlying complexity of biological processes, how molecular biology can simplify things but also how we should not be complacent and forget that genes are not causes but simply tools and elements to understand a process. It is also an example, as it unfolded, of the power of the blend of Genetics and Embryology that forms the core of XX century Developmental Biology. Also, perhaps surprisingly to some, Brachyury paved the way for the genetic analysis of development as it was the first mutation (genes are related to mutations but are not the same) associated with a developmental defect, many years before Poulson’s work with Drosophila Notch (1).

170213 T CrossWe do know today that Brachyury, also known as T or T/Bra, is a gene that encodes a transcription factor of a family called the T-family because of their structural relatedness, that play crucial roles in early development (2). We also know that it has a central role in the processes of gastrulation and axial extension in chordates and that its existence extends to invertebrates where it has a variety of roles in early patterning of embryos (3).

The origin of Brachyury lies in the 1920s Paris where Nadine Dobrovolskaia-Zavadskaia, a Russian emigrée from the revolution, was working at the Institute for Radium (an interaction between the Curie Laboratory and the Institut Pasteur) looking for the ability of X-rays to induce mutations in mammals (4). In the course of a screen involving 3000 crosses of mice across three or four generations she found two mutations that bred true, one of them she called T. The mutation had a dominant phenotype reflected in the length of the tail, hence the name T for taillessness (the capital for the dominant phenotype) but was, also, embryonic lethal (5).

An obsession with T starts and, in parallel with the discovery of recessive alleles, t, and interacting mutations (in laboratory and wild mice), descriptions of the phenotypes of different genetic combinations suggest an involvement of T, whatever it was, with the development of spinal cord and of the vertebral column (6-8 and then, if you want to follow on, read the more general accounts in refs 9 and 10). One thing is to describe a mutant phenotype –a forensic exercise- and a different one to wonder whether it tells something general about the connection between genes and developmental processes; I am, not sure that we have yet resolved this problem. It was, probably, Salome Gluecksohn-Schoenheimer who began to do the second through her analysis of T and t mutants (8, 10). There had been descriptions of the defects of the mutants (6-8) but she went further. Having worked in Spemann’s laboratory (11) the defects in the development of the notochord, neural tube and somites associated with T mutants, made her think of the effects of the organizer and of a possible relationship between T and its activity. These thoughts were no doubt encouraged by her discussions with, particularly C. Waddington, and the parallels she drew with mutations affecting the patterning of the Drosophila wing, suggested that T was saying something of how genes related to developmental processes (10, 11). But these were early days to see, let alone study, this relationship. Ariadne’s thread was in a badly tangled ball and the genetics of T did not help. Mutants with T like phenotype, some allelic, some not but which acted as modifiers were isolated in wild and laboratory strains, and their relationship to the original T mutant proved genetically complex (see brief discussion of these matters in refs 9, 10 and, more extensively, 12). The notion that these genetic interactions were linked to the function of T, led to a labyrinthine situation.

The problem was, and still is, that the genetic analysis of a biological process has its limitations; it is a bit like palm reading. It requires interpretation and, in the case of complex processes –like Development- it is not the way to unravel Mechanism. To quote a very prescient thought from Gluecksohn-Schoenheimer  “A mutation that causes a certain malformation as the result of a developmental disturbance carries out an “experiment” in the embryo by interfering with the normal development at a certain point. By studying the details of the disturbed development it may be possible to learn something about the results of the “experiment” carried out by the gene. However to discover anything about the nature of the action of the gene is a much harder task. It is necessary for this purpose to be able to trace back all the results of the action to certain original causes” (8). Furthermore, Genetics for its own sake (the analysis of the complexity of interactions, alleles, pseudoalleles, complex complementation associated with the breeding of a trait) can intervene, capture our imagination and lead us astray. A bit like maths without Physics; elegant and fun but lacking bite.  However, Genetics was what there was and the genetics of T proved a bit of a tangle (12), particularly when it came to the question of the link of the mutants (and at the bottom the wild type gene) to the generation of the embryo.

The question of what was the relationship between genes and development was an important issue in the 60s and the 70s. It would emerge from the molecular and cellular analysis of T, and in parallel of the bithorax complex (BX-C) in Drosophila by Ed Lewis. How genes controlled development did not look a simple affair at the time. Being interested in the topic as a graduate student in the late 70s and the early 80s I remember reading the seminal –but somewhat arcane- 1978 paper by Lewis on the BX-C (13) and a profoundly puzzling one on T (14). I must admit at having been simultaneously fascinated and befuddled by both but particularly by the mouse one. The complexity and the challenge to unravel them was part of the excitement to solve the puzzle. The Drosophila case seemed easier to unpack, perhaps; and it was. The reason probably lies in the rather Cartesian organization of the embryo –which was rather well laid out at the time- and the linear manner in which events unfold that allowed a rather rapid connection between genes and specific developmental events. It has interested me recently, how much hard work was going on to outline the battleground to apply Genetics to mammalian embryos when the buzz was about the genes of Drosophila. But T was not forgotten as it held a key to how mammalian embryos were built and therefore needed to be addressed.

170213 T ExpressionFrom here, the story gathers pace and the riddles find their solutions. And so it was that the era of molecular cloning clarified matters. In the 80s the systematic application of DNA cloning and analysis to the harvest of mutants screens from Drosophila and C. elegans, paved the way for similar work in other organisms, particularly mammals, and started to lift the fog that Genetics has laid on T. The BX-C turned out to encode three transcription factors and a complex regulatory region (15,16), while T/Bra encoded one transcription factor (17,18). The nature of the devilish genetics of T/t still lingered in the background but the brutal simplicity of molecular analysis delivered its verdict: T was, IS, a transcription factor expressed in the notochord as well as the progenitors of the spinal cord and the mesoderm (see Figure). The question then was, not how this related to the complex genetic analysis revealed by the multiple alleles and crosses –this is, apparently, still work in progress- but how this related to the activity of the protein, encoded by the gene and revealed by its loss of function. And this was just the beginning (in developmental biology, knowing what kind of protein is encoded by a gene –that we have come to know from a mutant phenotype- often opens more questions than it answers). The question was now the original one and again Gluecksohn-Schoenheimer, presciently posed it;  in 1938 thinking about how Spemann’s group approached the problems associated with embryonic development she mused about how in an ideal world to approach mammalian development: ‘The events that take place in the development of the mammalian embryo have not been subjected to an extensive causal analysis so far. The reasons for this are to be found mainly in the lack of suitable methods. It is not possible yet to use transplantation, isolation or vital staining techniques on mammalian embryos as they have been used on amphibian embryos. In the course of time it probably will be possible to analyze the mammalian embryo by transplantation and isolation just as thoroughly as has been done with the amphibian. For the present, however, the experimenter is not able “to take an active part in the course of events that take place during the embryogeny of the mammalian embryo,” nor “to alter the course of events at a chosen point in a chosen manner and draw conclusions on their relations from the resulting changes.” (Spemann 1936.)’ (8). An amazing paragraph for the time. She was more right than perhaps she thought and the molecular biology of T was going to pay high dividends that would make her musings true. The 80s gold rush of gene cloning revealed that T/Bra was conserved across phyla and its discovery in Xenopus led to a fruitful link with mesoderm induction that Jim Smith and his colleagues pursued in an enlightening manner for many years, establishing how T/Bra worked at the molecular level and established a connection between T/Bra and gastrulation (see e.g 19, 20). In parallel, Rosa Beddington began to apply the techniques that were being developed to study mouse development to the molecular insights and reagents thus unravelling the connections between T/Bra and mammalian development that lurked behind the genetics for so long (21-23). This work was soon picked up by one of her collaborators, Valerie Wilson, who has been pursuing the intricacies of the relationship between T/Bra and the mammalian body plan for the last many years answering many of the questions that had been posed by the early Genetics of the mutant. There is still much to do because, thought we have learnt much, the question of the relationship between gene and effect, mutant and phenotype, remains. But now we have the tools and the framework to try to answer it. We just need not be distracted by the ease to gather facts and remember the questions.

The story of T/Bra is a good example of the way in which the blending of Genetics. Embryology and Molecular Biology have enlightened the relationship between genes and development. History can be anecdotal but it is also informative. The recent history of developmental biology is very focused on Drosophila and C. elegans and it may come as a surprise to many that T/Bra, as a question and as a reality, was there before Bicoid and Wnt and Notch, highlighting the questions that needed an answer. History, in this case, also highlights the perils of the purely Genetic analysis of a biological process and the need to remember that Genetics is a language, a formal language, to ask questions. In the analysis of Development, it leads us to the elements of the system but might not be the element of choice to see how they come together to make an organism. The position of Genetics to Biology is a bit like Mathematics to Physics: a language that allows one to formulate a question in formal terms which then provides a machinery to work towards the answer but the output of this operation needs to be interpreted.

The history of Brachyury also has an interesting element in that it highlights the important contribution of women to the field; most of the important breakthroughs and insights in the story come from women: Nadine Dobrovolskaia-Zavadskaia, Salome Gluecksohn-Schoenheimer, Virginia Papaioannou, Rosa Beddington, Val Wilson. An influence worth emphasizing as we celebrate Women in Science week.

In the end, the tale continues. Rather than the English and “they lived happily ever after’, we could quote the French “ils vécurent heureux et eurent beaucoup d’enfants” (they lived ever happily after and had a lot of kids), the kids being the myriad of questions that have been raised by the great discoveries about T over the last twenty years. Discoveries which open the door to answer to the questions that T/Bra leads us into: about Development, Genetics, Evolution, about Stem Cell biology and, in the near future, of the engineering of living systems.

 

NB One appreciates that this piece just skims through the surface of the story and its implications. Still, one hopes that this will inform at some level and, also, encourage thinking about the connections between Genetics and Developmental processes. I am grateful to Peter Baillie-Johnson for the suggestion of the title. The image on the genetics of T is from: http://www.biologydiscussion.com/gene/genes-types/genes-types-top-6-types-of-genes-genetics/67413

 

References

1. Poulson, D. 1940. The effects of certain X-chromosome deficiencies on the embryonic development of Drosophila melanogaster. J Exp Zool 83: 271–325.

2. Papaioannou VE. (2014) The T-box family: emerging roles in development, stem cells and cancer. Development 141, 3819-3833.

3. Technau, U. Brachyury, the blastopore and the evolution of the mesoderm. BioEssays 23, 788-794

4. Korzh, V. and Grunwald, D. (2001) Nadine Dobrovolskia-Zavadskaia and the dawn of developmental genetics.  Bioessays 23, 365-371.

5. Dobrovolskia-Zavadskaia, N., 1927 Sur la mortification spontane´e de la queue che la souris nouveau-ne´e et sur l’existence d’un caracte`re (facteur) he´re´ditaire “non viable.” C. R. Seances Soc. Biol. Fil. 97: 114–116.

6. Dobrovolskia-Zavadskaia, N, Kobozieff N, and Veretennikoff S. Etude morphologique et genetique de la brachyourie chez les descendants de souris a testicules irradies. Arch de Zool Exp 1934;76:249±358.

7. Chesley P. (1935) Development of the short-tailed mutant in the house mouse. J Exp Zool 1935;70:429±459.

8. Gluecksohn-Schoenheimer, S. (1938) The development of two tailless mutants in the house mouse. Genetics 23: 573–584.

9. Pappaioannou, V. (1999)The ascendency of developmental genetics, or how the T complex educated a generation of developmental biologists. Genetics.151. 421-425.

10. Gluecksohn-Schoenheimer S. (1989) In praise of complexity Genetics 122, 721-725.

11. Gluecksohn-Schoenheimer S. (1992) The causal analysis of development in the past half century: a personal. Development 1992 Supplement

12. Silver L.M. (1985) Mouse t haplotypes. Annu. Rev. Genet. 19, 179-208.

13. Lewis, EB (1978) A gene complex controlling segmentation in Drosophila. Nature 276, 565-570.

14. Artzt, K., McCormick, P. and Bennett, D. (1982) Gene mapping within the T/t complex of the mouse. I. t-lethal genes are nonallelic. Cell 28: 463–470.

15. Bender W, Akam M, Karch F, Beachy PA, Peifer M, Spierer P, Lewis EB, Hogness DS. (1983) Science 221, 23-29.

16. Gehring, WJ (1992) The homeobox in perspective Trends in Biochem. Sci. 17, 277-280.

17. Hermann, B. G., S. Labiet, A. Poustka, T. King and H. Lehrach,  1990 Cloning of the T gene required in mesoderm formation in the mouse. Nature 343: 617–622.

18. Kispert A, Koschorz B, Herrmann BG. (1995) The T- protein encoded by Brachyury is a tissue specific transcription factor. EMBO J. 14, 4763-4772.

19. Smith JC, Price BM, Green JB, Weigel D, Herrmann BG. (1991) Expression of a Xenopus homolog of Brachyury (T) is an immediate-early response to mesoderm induction. Cell 67, 79-87.

20. Saka Y, Tada M, Smith JC. (2000) A screen for targets of the Xenopus T-box gene X-bra. Mech Dev. 93, 27-39.

21. Beddington RS, Rashbass P, Wilson V. (1992) Brachyury, a gene affecting mouse gastrulation and early organogenesis. Dev Suppl. 1992:157-65.

22. Wilson V, Rashbass P, Beddington RS. (1993) Chimeric analysis of T (Brachyury) gene function. Development. 1993 Apr;117(4):1321-31.

23. Rashbass P, Cooke LA, Herrmann BG, Beddington RS. (1991) A cell autonomous function of Brachyury in T/T embryonic stem cell chimeras. Nature 353, 348-351.

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.

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!

The case of the Irish Elk, a parable for the weight of the glamour journals

The case of the Irish Elk, a parable for the weight of the glamour journals

Irish Elk 2In one of his wonderful and educational essays, SJ Gould discusses the story of the Irish Elk, a spectacular species of elk that became extinct because……well, it is unclear why but the late specimens did have a very visible trait: enormous –and I mean enormous- antlers; the elk was over 3 meters tall and had antlers 3.3 m across. There have been many theories to explain the mysterious extinction of this magnificent animal but the one Gould discusses and the one I like to think about in certain contexts is that the Irish Elk was brought down by the weight of its own pride. The speculation goes that selection was in action for bigger and bigger antlers which, in the end, brought down –literally- the elk. And for selection, read in many instances, sexual selection. I am aware of the controversies associated with deciding whether selection is involved in a process or not and, more so when sexual selection is involved but, have always been interested in the Irish Elk as a parable from that perspective.

As a practicing biologist these days it feels like groundhog day in certain issues, particularly that of publications/glamour journals/Impact Factors (IF)/evaluations and the like. By now we all agree, more or less explicitly, that the biological sciences (I can only speak about them) are in a crisis because of a change of emphasis: what matters is the publication and not necessarily the research. Of course, there is some correlation between the two and so called high IF publications tend to publish more appealing reports than others, but it is difficult to accept that ‘more appealing’ means ‘better science’. In fact how we measure good science is something that is rarely debated outside the arena of the IF/h-indexes and related metrics and perhaps we should reflect upon this and try to return to value science for its intrinsic value, for the question that the scientist asks. I see few debates about what is a good question, what are the important questions but, in the context of my comments about the “LMB hut” probably this –questions in the biological sciences- is another issue that should go down to the fossil record of the history of science. Be that as it may, in the midst of the latest storm about how to deal with journal glamour (the latest idea to remove journal titles from websites) it is difficult to feel optimistic about any change soon, though it is clear that change is needed and, as I say, not only in our appreciation of the just value of scientific outputs, but about the actual value of the science we do. But…sorry, perhaps inevitably, I digress….allow me a thought.

Maybe the NCS’s (Nature Cell Science for those who are not familiar with the acronym) and the likes, there are some crude imitators around –are like the antlers of the Irish Elk. They are useful in mindless combat, they have a selective value, but as they grow they become more important than other body parts and, above a certain size, they will bring the organism down. I suppose the only response to that would be to grow a body size that keeps up with the size of the antlers. This did not happen in the case of the elk -though their body mass did increase and they were formidable specimens- and certainly cannot happen in the case of the biological sciences. The impression of many is that the kind of pressure that exists to value publications is distortive, creates serious problems for the development of the biological sciences and is certainly affecting the development of careers (the antler v the body and the long term survival of the organism). The question is not as simple as some people would make it sound and this is why nowadays, at meetings, there are entire sessions devoted to discussions of the issues associated with this topic. The problem, I think I have said it before, is that we are running a XXI century enterprise with a mid XX century business model, one that catered for a smaller, more focused community, a content centred enterprise with a smaller constituency. Today there is too much, too much that is good –at least technically sound- and a very large constituency. We need to evolve. Unfortunately the way we are doing it now is by selecting for bigger antlers without thinking about the consequences. There is too much talk about the form (publications) and very little about the content (science) and, slowly we are forgetting what this is about. Look at the indexes of most journals and have a think. The mantra that the science has become the publication is true and, because of its nature, the biological sciences will lend themselves to this gimmick because you can always find a new gene, a new function for a known gene, a new cell, a new drug, a new technique, any of which will be hyped by the impact department of any of ‘those journals’. No wonder some of us often ask if there are any Questions left.

The main problem with, let us call it, the IF question, is that it is breaking up the biomedical sciences into two: those who can afford to publish in certain journals and those who can’t. It is not only about science and ideas, it is about whether you have the stamina and the resources to deal with the whims of editors and reviewers. As it has been pointed out before, the editors have lost the plot and they will ask for bigger antlers (experimental responses to reviewers’ comments) that add very little to the content of the paper, propagate the myth of the specific journal as a tough place to publish and conflate the antlers with the rest of the body. Of course, not everybody will be in a position to respond in kind to the reviewers’ comments, to grow bigger antlers. The consequences of this are dire in the short term though I am convinced that in the large canvas of history the system, like the Irish Elk, will be extinct (don’t forget that this is an evolving system) and in the future we shall look foolish from the perspective of a more sensible science adapted to the times and to the people.

The good news is that slowly, and certainly in Great Britain, I begin to see some sense emerging and while there are still some old fashioned colleagues looking at the publication, more and more are realizing that in this manner you select, mostly, for antler size. If that is what you want, go ahead, grow your antlers and, on the side of the panels and the editors, pick your elks. Content, Science is something else.

NB SJ Gould essay follows an article he published: Gould SJ (1974) The origin and function of the bizarre structures: antler size and skull size in the Irish Elk. Evolution 28, 191-220.  The picture is a modified version of a picture first published by JG Millais in 1897, often reproduced in the web and shown in Gould’s essay: Natural History. 82 (March): 10-19 which you can read in Gould, S.J. 1977. The misnamed, mistreated, and misunderstood Irish Elk. Pp. 79–90 in Ever Since Darwin. W.W. Norton, New York. The person at the bottom of the picture could be construed as a panel member looking for some substance that can keep the elk up.

 

Good bye to a hut and to all that

“On a summer day in the late fifties a delegation from the Soviet Union appeared in Cambridge demanding to see the “Institute of Molecular Biology”. When I took them to our shabby prefabricated hut in front of the University Physics Department, called Cavendish Laboratory after its nineteenth century benefactor, they went into a huddle until finally one of them asked me: “And where do you work in winter?” They wanted to know how I had planned our successful Research Unit, imagining that I had recruited an interdisciplinary team as Noah had chosen the animals for his ark: two mathematicians, two physicists, two chemists, two biochemists and two biologists, and told them to solve the atomic structure of living matter. They were disappointed that the Unit had grown haphazardly and that I left people to do what happened to interest them” Max Perutz Nobel lecture http://www.nobelprize.org/nobel_prizes/themes/medicine/perutz/

"The Hut"The other day getting into work through my favourite route, the New Museum site next to the old Cavendish laboratory in the Center of Cambridge –nothing scenic, by the way-, I noticed a dramatic change, a hole in a familiar landscape. A small one floor building in the form of a large bungalow or hut occupied by Rolls Royce for the last few years, was gone. Instead, one of those modern multi story bicycle parking lots had been erected. But the loss was, is, historic as this was the old ‘hut’, home to the toilings of Max Perutz, Sydney Brenner and Francis Crick amidst others in the 1960s when they were laying down the basis of Molecular Biology (picture from http://www2.mrc-lmb.cam.ac.uk/?attachment_id=2631). It was in that hut that myoglobin was crystallized, that phage mutations leading to the genetic code were isolated and interpreted. That was the place of interesting discussions to which we owe much of what we do in Biology today. Surely one could take a moment to reflect. Change is necessary and, after all, the hut was a relic without much use or future, hardly noticed by passers by and in any case hardly known by many of the people who work around the site on a daily basis. Its demise led me to reflect on a number of issues that are associated with the hut and made me think that a way of doing Science so attached to the spirit of the hut, has also gone. The reflection that followed, and that follows here, is not intended as a nostalgic yarn but as a statement of fact, as a wake up call to a reality that we need to accept and work around. Science, Biology, as we have known them, is gone and is not coming back.

If you have read some of the classics of the history of molecular biology: “The eighth day of creation”, “Phage and the origins of molecular biology” to cite but two of the greatest, you will not find there stories of discussions with editors, rejected papers or grants or glossy statements in High Impact Factor magazines/journals. Instead you will find a riveting story of pursuit of some of the deepest secrets of Nature. The heroes that we so often praise did not spend their time arguing with editors, or doing experiments to satisfy reviewers and editors comments. They spent their time doing experiments, writing and publishing progress reports –which did not go through two rounds of review and excess comments by editors- and, within a competitive environment, moving on and along. There was a collective sense of what was important, people competed but also respected each other and the experiments and Science, rather than the publication, was what mattered; as it ought to be. They did not ask ‘where did you publish’ but rather ‘what did you publish?” “what did you find?”. Those were different times. I cannot imagine M. Nierenberg in the famous Moscow meeting at which F. Crick saw the tip of the genetic code, trying to catch the interest of an editor of Cell, Nature or Science. It is difficult to imagine Brenner having anything but contempt for journals telling him how to shape his legendary paper on phage mutations and the genetic code and I really can’t imagine J. Watson –whatever I or you think of him- in front of a career development award panel. The focus of Science then was research and important questions not careers or publications. When I came to Cambridge in the early 1980s there was still some of that spirit. The question at the time was not the molecular basis of heredity or the genetic code but, equally enthralling, the molecular underpinning of embryonic development. And we pursued this with a spirit not dissimilar to that of the 60s: toiling with questions and techniques, trying to get answers to questions we felt would be important. Journals were, still –but just-, vehicles to report progress, subservient to our needs. Change, however, had started and in some ways the emergence of Cell –run by an ex-lecturer from the University of Sussex and aiming to shape the content and form of contemporary Biology- was starting to take hold of the field. Then imperceptibly and in parallel with an explosion in terms of the number of researchers, fields of studies and journals, all changed.

Today it is unclear what is the relationship of what we do to Science as understood in the past. Nothing wrong with this but I do feel uncomfortable when at some meetings, panels of over 50s scientists gather with students and postdocs to advice them on their future. Often they tell them how they –the old guard- became great and that all the young generation has to do is follow the same steps. This is, at the very least misleading if not disingenuous. To survive today in Science, particularly in Biology, requires more than a good question or an original idea, much more than focused hard work, good judgement and luck. I say survival with intent and don’t mention “success” because this, more than ever, is relative. Today you need a combination of ingredients of which good Science (in the old fashioned way) is just one. If you try the old recipe, unless you are very lucky, you will fail. Times change and the advice need to go with the times. My advice is that if you are starting a lab today you should not model it on the attic at the Institut Pasteur where Lwoff, Jacob and Monod peered into the secrets of gene regulation, but on a small business. What you will face is the need to get funds to maintain an enterprise which, if you are lucky (which these days often mean to end up in a well endowed institute for a few years), will be close to your interests but which, in general, will have to adapt to fashions and funding needs. Your currency will not be your ideas or your results but your publications and while we wean ourselves off the pernicious influence of the HIF journals, you will have to keep an eye on them and live under their shadow because them (and the scientists that form their core) determine the agenda -my heart sinks every time I hear the pernicious and mistaken mantra that you need a HIF publication (warholian fifteen minutes of fame) to get a job, that the perception of the value of those papers, when published, will determine your value in some virtual and ethereal stock market of labs which, in turn, will determine how much funding you have and thereby the performance of your business. Things are changing and we have to push for change but, for now and while change comes, we need to be aware of the reality. In this climate you have to be careful and strategic.

And as part of this advice let me tell you that the best time to do Real Science today is your PhD because, if your supervisor allows you, it is the only time in your career when you are going to have some time to explore freely what you want to do. Afterwards, your work will be marked in a more or less open manner by a business model in which the name of the game is to survive, you will have to think carefully about what you do because your future will depend on it and this will become more apparent if you are not in one of those large Institutes which have the potential of doing a lot of good (and many do) but which for the most part suck resources from the environment and contribute to an increasing gap between different tiers of research. There is a lot of technical quality around and most people can do a competent job which increases competitiveness. Furthermore, Biology will never fail to produce a ‘new’ situation, either a new job for a well known gene or a new gene for a well known function and there are endless way of looking at DNA and RNA. This means that competition for resources is fierce and how you ‘sell’ what you do is more important (or at last as important) as what you sell (do). And the problem is that (maybe just my opinion) a question, let alone a good question, is not easy to find (see Coda on Einstein and Valery) and gets buried in a sea of data and techniques. While we are good at finding flaws in papers, we are not good at defining their context and, for the most part, we get lost in a forest of three letter acronyms and data. Unfortunately, in an age of shrinking budgets, translational pressures, data collection and technology driven projects, good old fashioned real questions and problems is not what shines (though I should say that come committees and institutions can sometimes throw a surprise or two of judgement).

It is difficult to gauge what is fundable and target it. It is not easy to tread the thin line between real science and a business model. If you want to survive and have the small amount of shallow success that will allow you to get funding, you need to go to meetings, be some part of the small circus that journals have created, talk to editors, to PIs who like to feel important and are influential. More importantly, be aware that the short term future of Biology lies in collaborations, formal collaborations. Brenner, Perutz, Crick, Sanger, the inhabitants of ‘the hut’ were collaborative, intellectually, they fed on their discussions and each other’s ideas but now it is different. One has to show coherence, added value, joint up projects. This is the reality and there is no point in looking away.

As I said above and repeat here, I do not yearn for bygone times, the spirit of the hut or the way science was done. I like to read and think about all this and feel proud to be part of that tradition. I am not nostalgic for history but, it is important that we know and accept that today those times and places are not a model for us more than Newton is a model for modern physicists at CERN. It is not right to tell people today that because they do good science they will succeed (whatever this means). The definition of good science has changed. Today people will not recognize a good idea if they see one; what matters is how you sell what you do. Ah, and as an average PI you will find yourself chasing money, going to meetings, dealing with editors and reviewers and, if you are in a high profile institute you will have to deal with periodic reviews. Nothing like the ‘spirit of the hut’. It is important to acknowledge where we are and look for ways to evolve it and to make the most of it.

IMG_6049For me the disappearance of ‘the hut’ has been a statement of the times and a reminder that a way of doing Biology is gone and that, like the hut, is not coming back. Perhaps there is something metaphorical in that the space of the hut has been occupied by a bicycle parking because this, in some ways, what has happened to Biology. What you will get with your PhD is a bicycle which you should use to move around and sell your skills which are not the same that they would have been if you had been working in Biology 40 years ago. I insist, nothing wrong with this, just be aware of it and don’t try to follow the paths of those days; they don’t work. In this regard I shall finish by saying that I do not expect The Crick, one of the examples of corporate science in the UK, to produce anything like what the hut did. The reasons for this is the changes I have been discussing. Science today is different……

CODA on ideas: It is said that Paul Valery, french poet and philosopher with an interest in the nature of creativity and the process of creation once met Albert Einstein. In the course of the conversation Valery asked Einstein how he worked to which Einstein explained that often he took walks and that during the walks he ran thoughts through his mind. Valery quickly retorted that surely he would have a pencil and a paper with him. Einstein was puzzled: a pencil and a paper? What for? Valery sighed; but ‘bien sure’ when you have an idea you write it down. Ah, now I understand; you see, Einstein said, I do not need those items, an idea is so rare that if I had one, I would remember it.

Boltzmann, Darwin and THE current challenge of the life sciences

Boltzmann2

Ludwig Boltzmann 1844-1906 (http://en.wikipedia.org/wiki/Ludwig_Boltzmann)

The XIX century will be called the century of Darwin (L. Boltzmann)

While most people have heard of Einstein and Newton and Feynman, Boltzmann is not a household name when thinking about famous physicists. Ludwig Boltzmann was a theoretical physicist extraordinaire who at the end of the XIX century, in that Vienna that was going to give so much to the world in the ensuing years, taught us a most interesting way of thinking in material terms about the structure of matter and abstract concepts like heat and energy. Spurred by his philosophical inclinations, in his latter years he wanted to transcend what he had done and thought, by looking at Evolution from the physical perspective. In this process he clearly absorbed much of Darwin at a time that darwinism was not as popular as it would become later: “… If you would ask me about my heartfelt conviction, whether the nineteenth century will be called one day the iron century or the century of the steam engine or the century of the electricity, I answered without any doubt it will be called the century of the mechanistic conception of nature, the century of Darwin…”. There is little doubt from this statement that Boltzmann understood Darwin but there is also an inkling, if you know something about the work of each of these individuals, that he might have had a deeper insight than he let us know in his writings.

Physics and Biology share one challenge: the mechanistic understanding of the relationship between events that happen at the limit of our visual detection –the microscopic world- and what we can observe and sense i.e. measure (any act of perception is a more or less conscious measurement) at the macroscopic level. The way we do this is nicely put in a statement attributed to the physicist Jean Perrin, which suggests that one of the cornerstones of Science is the craft of revealing the invisible through the visible. In some respects this is what we do in Biology when we draw those diagrams that are meant to represent events supposed to happen inside cells. While some of them are probably accurate (and for accuracy on the basis of our current understanding of our molecular structural knowledge, see D. Goodsell visions of the cell: http://mgl.scripps.edu/people/goodsell/) others do not capture, yet, what they want to represent. And so, there is a two way road from the macroscopic to the microscopic. A topic of many talks in Biology is, we are told, that what we want to know is the relationship between the genotype and the phenotype, between the genes and the cell. However, behind this statement there is the dream of some sort of a linear relationship between both which has not and will not be found because 1) it does not exist and 2) this might not be the right question to ask. If you are an evolutionary biologist you spend a great deal of time relating genes to the structure of populations and therefore you know about the problems of simple linear models and of the slippery nature of quantifiable variables which are sometimes needed to deal with biological systems. However, it is precisely in the challenge of relating genes to, for the sake of argument let us say phenotypes, that the connection between Boltzmann and Darwin emerges and might provide some inspiration for today’s challenges.

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Figure 1. One of the big challenges in Biology is how to relate the events that are described by molecular networks with the organs and tissues that characterize the make up of an organism.  It is obvious that cells and their lineages are the vehicles for this transformation.

The breakthrough of Boltzmann stemmed from his belief in the reality of atoms and their fundamental role in the understanding of physical systems. A belief it had to be since at that time it was impossible to penetrate the structure of a cell, let alone that of a molecule or an atom. Taking this view as a starting point, he developed a theory which provided a mechanistic explanation (watch it, not in the sense of the modern biologists i.e. figure 7 of your NSC paper, but rather, to quote my colleague Ben Simons, as a causal explanation for an observation) for observables like Pressure, Temperature or Energy. He showed how if one accepted the existence of atoms, one could derive these properties from the spatially constrained interactions between them. Since the number of molecules in a macroscopic observable is enormous (remember Avogradro’s number is 6.02 X10 23 molecules in a mole), even those who were interested in the subject, found it very difficult to comprehend how could one devise a mechanistic and mechanical way to connect these large numbers to the observables. If you were a committed newtonian you would have to calculate the trajectories and energies of every atom and its interactions with all the other atoms and then find a way to compute the total sum (or product) of the resulting numbers! The way forward, as Boltzmann saw, was assuming the reality of the atomic structure of matter, to perform a proper statistical analysis of the behaviour of ensembles of molecules in different conditions. He reckoned that with such large numbers, the connection between the elements and the properties of the system was through statistics –in its infancy at the time- and that under the simple conditions of an ideal gas, a statistical treatment of the kinetic relationships between individuals in populations of molecules (microscopic) would yield the macroscopic measurable (Pressure, Temperature, Kinetic Energy…); a proper treatment of the problem shows how the observables result from the constrained averaging of the individual variables. It was a deep insight that what mattered were the statistical properties of the population rather than the details of the individual behaviours which became averaged at the higher level. This work provided a solid foundation for the work of the Scottish physicist JC Maxwell who had calculated the distributions of velocities of an ideal gas on similar terms, thus laying a significant foundation for the kinetic theory of gases -this is why today we talk about the distributions of velocities and energies in physical systems as the Maxwell-Boltzmann distribution. But Boltzmann took the basic ideas of a statistical analysis of the structure of matter further and provided a material basis for that most elusive notion: Entropy (which in thermodynamic terms can be defined as the amount of energy, thermal energy, which is not available to do mechanical work). With apologies to the physicists (if any reads this) for the simplification, he envisioned matter as a problem in combinatorials of its constituents: a particular structure being one, and only one, of a huge number of configurations of its constituent elements. If that structure disappears, or changes, it means the system has acquired a new configuration and will search for the original one in the large space of all the other configurations. Not surprisingly it will find many ‘disorderered’ ones before finding the original one. Entropy, Boltzmann saw, is a measure of that number of non-structured configurations. He extrapolates this to the Universe and suggests Life as the chance result of a fluctuation in a small space of a large heat bath. It is these thoughts about the Evolution of physical systems that probably led him to consider darwininan concepts: “… The struggle for existence of the living beings is not a fight for basic materials—these materials are available in air, water and soil in sufficient quantities for all organisms—it is also not a fight for energy that is available in the form of inconvertible heat in every body but it is a fight for [negative] entropy, which becomes available by the transition of energy from the hot Sun to the cold Earth. In order to exploit this transition as much as possible, the plants spread out the incredibly large surface of the leaves and force the energy of the Sun before it falls down to the temperature of the Earth in a not yet understood way to perform synthetic chemical reactions that are still completely unknown in our laboratories. ..”. Much food for thought here and I shall leave it for another time. Suffice to say that the deep gauntlet that lies in here was taken later by E Schrodinger who in his famous book “What is Life” discussed at length some of these notions and introduced the eye catching but misleading notion of negative entropy, free energy really (Gibbs or Helmholtz); he might have been influenced by his youth in Vienna studying Physics under the aura or the great Boltzmann.

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Figure 2. Boltzmann’s insights that allowed him to use statistics of the mechanical properties of the particles under several constrains to deduce the macroscopic properties of the system. In the process he provided a physical description of Entropy (S) in terms of the configurations of the system (W).

What does this have to do with where we are at the moment? What is the point of all this to modern Biology? The current challenge, as some of us perceive it, is not to see how genes generate a phenotype but to link the molecular and the cellular realms. To explain cellular activities (motility, change of fate, higher order structure and dynamics of cell populations, etc) in terms of their molecular underpinning. In all this and what has become a game changer is our ability to measure or, if you will, to see and then to measure, and to be able to do this at the level of individual cells. What we are getting out of this process is large amounts of data, information, that we are accumulating in databases that are more or less centralized and organized. What we are lacking is not just methods to process this information, but questions, conceptual frameworks to interpret what the analysis of the data (which is more data) yields. The question then can be reduced to how the myriads of genes, proteins and their interactions at one level, generate behaviours at a different scale. How do the macromolecular complexes that underpin cell movement  and shape, the structure of a tissue or the dynamics of a tissue in homeostasis, generate those observables?. In this work, there are two connected relations: from the molecules to the cell and then from the cell(s) to the tissue. This statement contains the implicit statement that THE CELL is a vehicle to link molecules to tissues and organs. The numbers of the game are very large (genes, transcripts, cells) and become larger if we consider single cells, which is becoming routine. It is here that the work of Boltzmann becomes an inspiration. The secret will be the averaging and the way biological systems do what physicists call coarse graining, will provide the understanding; but first we need to define the variables that need to be averaged and the calculations that need to be made. Progress is being made but it is slow because, unfortunately, the emphasis is still in mindless data collection and on the naïve belief that describing it is understanding.

It was probably this deep insight into the population averaging of the properties of very large number of components of a system that led Boltzmann to have an intuitive understanding of Darwin. After all, the importance of large numbers and their dynamics is implicit in Darwin’s theory of natural selection and becomes explicit in the postdarwininan interpretation as in the work is R. Fisher, S. Wright and others, genes play the role of the atoms, and statistics is not just central, but develops around these ideas. Qualities, phenotypes, arise from the multivariate statistics of the effects of multiple genes. It is interesting, as has been discussed by J Gunawardena that much Genetics was developed without an understanding of the molecular structure of the gene and that for many years, the gene was a mathematical entity  (Biology is more theoretical than Physics, Mol Biol Cell. 2013 Jun;24(12):1827-9).

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Figure 3. Outline for a statistical mechanics inspired solution to the problem (for further thoughts see references at the end). At the more microscopic level there are Gene Regulatory Networks (GRN) which generate dynamic (revolving arrows) patterns of activity at the level of single cells (intrinsic component). An interaction between these patterns and external signals (extrinsic components) generate patterns of fates at the cellular level that result in distributions of cell populations which are the result of distributions of gene expression in those populations. In turn these interactions across scales result in macroscopic structures. At the moment we do not know what these significant variables are nor what are their relationships but there are glimpses of this in the literature (see references at the end).

We need to look at Physics for inspiration and the current impasse needs, quickly, some new paradigms to move from description to understanding. The single cell analysis of developmental processes and, in particular stem cell populations has raised the possibility that statistical mechanics can offer a useful paradigm. What you have read for the last few minutes is a statement in support of such programme. But what we shall need is to define the macroscopic and the microscopic variables in a precise and meaningful manner. Then, progress will follow. Perhaps Boltzmann was right and the XIX century belongs to Darwin, as much as the XX belongs, at least in Biology, to the gene. In this series, the XXI should be the century of the cell and I hope that it does not take us 100 years to realize that to name and count genes and proteins is as futile a task as that which Boltzmann circumvented: to calculate the position and momentum of every particle of a gas. In many ways Biology is the unwritten chapter of statistical mechanics, the chapter that beckons at the end of any text book in the matter.

Darwin gave Biology a way to use the information that has been collated by naturalists in their collecting frenzy (which Darwin practiced in his early days). Today, instead of beetles and plants, we collect sequences and genomic landscapes and this is important and useful. However, the wonder of these objects and the useful information they contain should not deter our attention from the real task in hand which is to formulate the questions that will allow us to link genes (and epigenes) to cells and cell populations and through these to tissues and organs.

A brief list of related references (to build a field: the statistical mechanics of biological processes)

Karsenti E. Self-organization in cell biology: a brief history. Nat Rev Mol Cell Biol. 2008 Mar;9(3):255-62. doi: 10.1038/nrm2357 (E. Karsenti is a pioneer of the attempts to understand biological systems bridging the microscopic and macroscopic realms. He has done most of his work trying to understand how molecular ensembles generate cells which is a first step towards higher levels of understanding. His work is very influenced by I Prigogine).

Lander AD. Making sense in biology: an appreciation of Julian Lewis. BMC Biol. 2014 Aug 2;12(1):57. With Julian Lewis in mind, an insightful meditation of models in Biology.

Gunawardena J. Beware the tail that wags the dog: informal and formal models in biology. Mol Biol Cell. 2014 Nov 5;25(22):3441-4. doi: 10.1091/mbc.E14-02-0717. Models? What kind of models?

The next three references deal with the all important issue of time which is not dealt with here but is very important in linking molecular, cell and developmental biology:

Kicheva A, Cohen M, Briscoe J. Developmental pattern formation: insights from physics and biology. Science. 2012 Oct 12;338(6104):210-2. doi: 10.1126/science.1225182.

Kutejova E, Briscoe J, Kicheva A. Temporal dynamics of patterning by morphogen gradients. Curr Opin Genet Dev. 2009 Aug;19(4):315-22. doi: 10.1016/j.gde.2009.05.004.

Nahmad M, Lander AD. Spatiotemporal mechanisms of morphogen gradient interpretation. Curr Opin Genet Dev. 2011 Dec;21(6):726-31. doi: 10.1016/j.gde.2011.10.002.

The next four references discuss in an explicit manner the need for an approach based in statistical mechanics to understand the dynamics of cell populations in development.

Chalancon G, Ravarani CN, Balaji S, Martinez-Arias A, Aravind L, Jothi R, Babu MM. Interplay between gene expression noise and regulatory network architecture. Trends Genet. 2012 May;28(5):221-32. doi: 10.1016/j.tig.2012.01.006.

Garcia-Ojalvo J, Martinez Arias A. Towards a statistical mechanics of cell fate decisions. Curr Opin Genet Dev. 2012 Dec;22(6):619-26. doi: 10.1016/j.gde.2012.10.004

MacArthur BD, Lemischka IR. Statistical mechanics of pluripotency. Cell. 2013 Aug 1;154(3):484-9. doi: 10.1016/j.cell.2013.07.024.

Trott J, Hayashi K, Surani A, Babu MM, Martinez-Arias A. Dissecting ensemble networks in ES cell populations reveals micro-heterogeneity underlying pluripotency. Mol Biosyst. 2012 Mar;8(3):744-52. doi: 10.1039/c1mb05398a.

On the dynamics of cell populations:

Klein AM, Simons BD. Universal patterns of stem cell fate in cycling adult tissues. Development. 2011 Aug;138(15):3103-11. doi: 10.1242/dev.060103. This is an important insight from physics on the dynamics of cell populations.

A new sort of engineering: I. Of inner forces, programmes and duality in living systems

Biology is a young science and this is easy to forget. For all the hype and glamour of modern conferences and publications, we still are in the midst of empirical data gathering. A bit what astronomers and tinkerers were doing in the XVII century. We have changed collecting and classifying beetles and butterflies for genes and regulatory regions, but the method has not changed that much: systematics.

This aside, there are, let us say, three issue in Biology: how a system builds itself, how it works and how it evolves, We know a lot about the second, have a good hypothesis about the last one and think we know, though really we do not understand much, about the first one. Our knowledge about the functioning of biological systems is reflected in the way we use this knowledge in immunology, cancer biology and neurobiology. However, this praxis is a bit like the building of devices by engineers in the XVIII and XIX centuries, empirical, and it will improve once we understand the underpinning of the systems. In Biology this means to understand the connection between genotype and phenotype, how genes build organisms, which we don’t. If we agree (and you don’t really have to) that this is THE problem, you will see that something is changing though, and the roots of this change can be found in history. When something repeats itself in history it is that it has some deep roots and we should not ignore it. The seeds of the story I want to tell lie with C.F. Wolff , follow with H Driesch and reveal how for a while, perhaps necessarily, we had to forget the important questions, though we don’t have to any more. Wolff and Driesch saw the questions and those questions are, today, at the forefront of the agenda of biological research.

On forces: CF. Wolff and H. Driesch

Slide4

In the midst of the XVIII century, guided by a curiosity about the development of embryos, C. F. Wolff carried out a number of dissections and reported findings that challenged the well established theory about the emergence of a living system; preformationism. The leader of this view was A. von Haller and Wolff entered into a lengthy and hard, though always polite, diatribe with him (for details see S Roe). In contrast with the at the time prevalent view that the embryo was preformed but not visible, Wolff favoured the notion that the organism emerged progressively from an informed mass which acquired shape and form progressively. The preformationist view may seem silly from the perspective of today but, it is not in the historical context, and I suspect that we also harbour many ideas that will look silly from the perspective of the future; the ‘power of the gene’ being a most interesting one. Wolff’s view was called epigenesis and its contrast with preformationism, took years to develop –such things always do-. Nonetheless, Wolff made his point and described how organs appear progressively from amorphous masses of tissue (cells were not yet the units of development), in two treatises (“Theoria Generationis” and “De Formatione Intestinorum”) and most clearly in the second. One question that Wolff was interested in was, naturally, what propelled this epigenesis.

Now, Physics had a good grip of human reasoning at the time. Since the time of Leibniz, natural philosophers (aka scientists) were aware of the existence of vis or forces and, in particular of a vis viva, which drove the motion of bodies and later became known as kinetic energy. What Wolff had described led him to speculate on the existence of a vis (force) of sorts driving the emergence of shape and form; he called this force ‘vis essentialis’, a formative force or energy. The notion has often been hijacked by vitalists but, if you thought about it, ‘vis essentialis’ is not, like potential energy was, some spooky spiritual notion but something which tried to account for some observations. Reams of philosophy have been written on vitalist interpretations of the vis essentialis but let us not digress from the simple point that Wolff had identified some internal inertia of a biological system that was precise and reproducible and which he claimed had a physical basis. History and some historians have a habit  of making a meal of what someone may or may not have said or thought but the fact is that Wolff only tried to encompass with words what his intuition told him lied behind what his eyes saw. The thought was laid to rest while the dust settled in the epigenesist/preformationism debate which would be won, as we now know, by force of observation on the side of epigenesis.

Slide1 

The XVIII and in particular the XIX century are rich in the description of the development of all sorts of organism and this descriptive phase takes over until towards the end W Roux in his very programmatic statements opening the journal that bears his name (“W Roux Archives of developmental biology”, nowadays “Development, genes and evolution“) ushers developmental biology as an experimental science, away from the mire of descriptive embryology.  It is in this context that H Driesch makes his formidable entrance into the story with a series of experiments which, unknowingly, set up the agenda of developmental biology for the XX century. In the first and most famous of experiments he separates the first two blastomeres of a sea urchin embryo which, under normal conditions each would have given rise to a half of the organism, and watches what happens. As he puts it in his famous paper: (Driesch, H. 1892 Zeitshrift für wissenshaftliche Zoologie 53, 160-178 Translated to English in Foundations of Experimental Embryology 1964 B. Willier and JM Oppenheimer eds Hafner Press)

“I awaited in excitement the picture which was to present itself in my dishes the next day. I must confess that the idea of a free swimming hemisphere or a half gastrula with its archenteron open lengthwise seemed rather extraordinary. I thought the formation would probably die. Instead the next morning I found in their respective dishes typical, actively swimming larvae of half the size”

Leaving aside the style (what a wonderful time when you were allowed to muse over your results with freedom!), there is nowhere to hide the result which contradicted a view, descended from preformationism and prevalent at the time, that embryos are mosaic…. But the result is surprising, the cells regulate, each gives rise to a whole organism. He repeats the experiment at the four cell stage and later in a series of variations, and finds very similar results. He ponders how can this be.

 Slide2

In 1911 he gave the Gifford lectures in Aberdeen where he looks back at his work. The book that comes from the lectures is, for the most part, an apology of vitalism. After all, Driesch did become an unrepentant vitalist in the second phase of his career, but the first part of the book is an excellent summary of his toilings with the experimental observations that led him to ‘despair’; in a mild manner. The section concerning his reasoning through his experiments in an attempt to find a rational explanation for what he was seeing, is remarkable reading and I suggest you look at it (see here some of it). An important point in this text is where he tries to reason what kind of a machine could behave like this and he reasons.

Much as Wolff earlier, he lived in a physics led intellectual environment in which engineering and machines were part of the daily life. More than Wolff, he lived in the hayday of engineering and machines. One guesses that both Physics and Engineering provide a guide to think rationally about the seemingly irrational principles that guide living systems. So, what he wondered in a mechanical analogy is whether one could describe a living system as a machine and if so and in the light of his experiments, what kind of a machine should this be. In his own words:

We shall understand the word ” machine ‘ in a most general sense. A machine is a typical configuration of physical and of chemical constituents, by the acting of which a typical effect is attained. We, in fact, lay much stress upon embracing in our definition of a machine the existence of chemical constituents also; we therefore understand by the word ” machine ” a configuration of a much higher degree of complication than for instance a steam-engine is.  (….). And we know, further, that this truly whole development sets in irrespective of the amount and direction of the separation. Let us first consider the second of these points. There may be a whole development out of each portion of the system ” above certain limits ” which is, say, of the volume V. Good! Then there ought to exist a machine, like that which exists in the whole undisturbed system, in this portion V also, only of smaller dimensions; but it also ought to exist in the portion V^ which is equal to V in amount, and also in V2, in V3, V4 and so on.

Indeed, there do exist almost indefinitely many Vn, all of which can perform the whole morphogenesis, and all of which therefore ought to possess the machine.(…). A very strange sort of machine indeed, which is the same in all its parts (Fig. 14) ! But we have forgotten, I see, that in our operation the absolute amount of substance taken away from the system was also left to our choice.

 From this feature it follows that not only all the different Vn, all of the same size, must possess the hypothetic machine in its completeness, but that all amounts of the values  Vn – n, n being variable, must possess the totality of the machine also: and all values Vn – n, with their variable n, may again overlap each other. Here we are led to real absurdities !

He is absolutely right, what he is describing is, basically, a cell but, of course, at the time, cell biology is prehistoric, genetics does not exist and the functional structure of a cell is not even on the cards. So, he exclaims with despair “….no kind of causality based upon constellations of single physical and chemical acts can account for organic individual development; this development is not to be explained by any hypothesis of configuration of physical and chemical elements”. And,slowly, he turns towards vitalism for an answer. But before, just before, he leaves us a gem of his understanding of what needs to be explained. In trying to understand the development of an organism, he suggests that there must be a function of different variables that decides what we would call today the fate of a cell in development

pv (x) = f(x, l, E)

Where pv(x) is the prospective value of element x (which we could see as a cell), s is the absolute size of the system, l is the position of element x and E, the most interesting of all variables, is the prospective potency, what he called Entelechia. This notion had been used by Aristotle and Leibniz, but it is with Driesch that it lives up to its own etymology: Entelechia means ‘that which bears its end within itself’, and it is not difficult to see a connection between the vis essentialis of Wolff and the Entelechia of Driesch. Both are trying to grasp the observation (or intuition if you wished) of some internal material or measurable inertia that is reproducible and drives the generation of form in living systems. Unknowingly this is addressing the issue of the genetic programmes that drive development and that today we can see as the basis of both interchangeable notions. A. Garcia Bellido has been a modern bearer of these notions and the one who has placed Entelechia on a genetic footing, one where we can begin to try to think about the genetic programmes that drives the system (Wolff) and the system that drives its homeostasis (Driesch), developmental and adult.

More of this next time but before that, to wrap up this historical background a brief account of the last pre-genetics/cell biology ditch to search for a physical explanation of Biology.

On duality: N. Bohr and M. Delbruck in Copenhagen

Slide3

In 1932 Max Delbruck arrived to Copenhagen to meet the members of the famed School of Copenhagen of quantum mechanics. The day he arrived, Bohr was giving a lecture entitled “Life and light” in which he would tackle the problem of the physical nature of the phenomenon of Life. This was taking place at the height of the development of Quantum Mechanics and the wave-particle duality exhibited by matter and light had been accepted, understood and interpreted. In his lecture, Bohr speculated that maybe there was a similar duality for Life, and that in this case, understanding would emerge from probing this dual nature which, in his opinion, would have a material and a vital element. In this context Bohr wondered whether the study of Life might not reveal new Physical principles, much as the deep study of matter and light had revealed to Physics at the beginning of the century. Life was, after all a physical phenomenon. Delbruck was in the audience and was very taken with this lecture; with encouragement from Bohr and Heisenberg, he turned his attention to Biology. Intriguingly, although he founded the Phage School which led to molecular Biology, he never found the new laws of Physics in Biology, that Bohr had made him think about in Copenhagen, though he continued to search for them all his life.

Almost a century later, Life, Biology, has not produced many dramatic new physical principles, certainly not in the physical sciences. Crick provides a reason for this state of affairs when he contrasts Delbruck, searching new laws of Physics, with Pauling on the trail that Life is just chemistry. As he puts it “so far history has proven that Pauling was right”. For the moment the triumph of Chemistry is clear: life is just chemistry in nonequilibrium conditions and Biology has not needed of any new physical concept in its main body of knowledge. However, Crick made the proviso of ‘so far’ and we might be on the verge of some surprises which could explain what Wolff and Driesch sensed in embryos and Delbruck searched in vain: the inner forces that shape embryos and endow them with the ability to control space and time (next: A new sort of engineering II. Genes, time and space. Supervising self organization ).

A lesson from William Harvey in the XVII century on the value of model organisms

Screen Shot 2014-09-14 at 17.25.26It is well known that history repeats itself but, as we have limited memory and a tendency to think about ourselves and our times, we forget the lessons from the last time it came around. Let me tell you a story. Like many of you I associate William Harvey with the wondrous discovery of the circulation of the blood and the identification of the heart as the pump that keeps this movement going. I also was aware that he performed the first proper or recorded measurement in biology as the amount of blood going around the body in a given period of time. This was to show that for the number to be true the blood could not be supplied by some infinitely powerful source in the liver but most likely, circulated. As a developmental biologist I was also aware of his late book on the generation of animals (Exercitationes de Generatione Animalium, 1651) in which he describes the development of many organisms, with a particular emphasis on chickens and deers, and speculates on their embryological origin. In fact, this book was a summary of research conducted over many years which he would not have published had it not been for the intervention of George Ent, a friend who was aware of this work and encouraged, almost obliged him, to let it out . In many ways and despite its frontispiece (Omnia ex ovo), the book is a minor work compared to “de motu cordis” and, as has been acknowledged by historians, has more questions than proper answers, but does represent a major contribution to the development of embryology. These facts I knew, but a recent reading of the excellent book “Circulation’ by Thomas Wright, on the way Harvey worked out his theory about the heart, alerted me to facts I did not know, which made me realize HOW he worked out his remarkable conclusions. The process that led to “de motu cordis” made me see some features of his research which are interesting in the light of modern science. 

Harvey was a doctor who rose very quickly to a position of prominence in the London establishment. He had attended Cauis College in Cambridge (as my colleague David Summer never ceases to remind me!) and then, impelled by the flow of the time, went to Italy to follow his interests in Medicine and Anatomy; a  graduate study of sorts. It was there, in Padua, where where he became acquainted with the issues of the time in particular the details of the behemoth that was Galenic medicine.  Amidst his teachers there was Fabricio de Aquapendente, a doctor with an interest in anatomy and who was a pioneer comparative embryologist and who became a significant influence in Harvey’s studies. The organization and function of blood was a central issue of study at the time where the centuries old views of Galen prevailed. Essentially, blood mainly manufactured in the liver, ebbed and flowed through veins and arteries to end in the tissues within an open ended system. The heart was the source of heat and of the spirit, and acted as a sort of mixing blender; though an important organ it was not so important as the liver. There were alternative, speculative ideas around about the heart and Harvey took note of them. After his studies, he went back to England and quickly rose through the ranks in London medical society to become associated with the court, teaching anatomy and, eventually, becoming the Doctor of the King, most notably of Charles I. But all this is secondary to this story.  In the back of his mind, though, was the question of the workings and function of the heart. In a series of remarkable experiments conducted over a period of more than 10 years (a core of 1615-1625 can be identified by experts) in a laboratory set in his house, he developed and reasoned the theory that the heart was a plumbed pump that moves blood around the body. As a consequence of this study he assigned the correct function of veins and arteries and identified the direction of the circuit. Now, and here is my point. The knowledge came from a comparative study and without such a study he could not have reached the conclusions or, better, the detail supporting the conclusions. By comparative I mean, comparing different organism on the correct assumption that there is a conserved plan. You should read Wright’s book. It is a gem.

The studies began with corpses that he procured because of his association with hospitals but then, if you want to think of a pump, you need to see it at work. He did that, as it was customary at the time, with vivisected animals, principally dogs. A bit sensitive these days and as Wright points out, no less then but, on the other hand, necessary. One of the issues at stake was the function of the systole and diastole, the periodic movements of the heart which result in its physiological outputs. There was a debate as to which was the active phase and was a problem as all Harvey had to solve it was direct observation. The movements are too fast in mammals for him to discern the relationships between the actions and the consequences, with regard to the blood, and he puzzled and surely wrestled with his intuition and the facts. Notwithstanding this, as the animal died, the movements slowed down and he could get glimpses of how the system worked. But he needed to prove it in the living organism. Here is where it gets remarkable, at least in my eyes. In a series of studies, he looked at the circulation of the blood and the activity of the heart in a range of organisms from slugs to dogs, but paying special attention to cold blooded animals where the movement was slowed. In a particularly interesting study he watched the relationship between the pumping of the heart and the movement in some fish he got from the Thames. You cannot miss it in the glory of the zebra fish, as my colleague C Schroeter who worked with this organism remarked: it is a wonderful thing to SEE the blood leaving the heart through the aorta to the beat of the heart and this is published even if Harvey had seen this 400 years ago. These observations buttressed his views and made a seminal point for the circulation of the blood. Let me highlight the point: it was the model organisms that established in Harvey’s mind the universal principle that changed medicine and our notions of the heart forever. Of course, as you might have expected, when he put his views to the then public peer review, amidst many of the questions that came up, that of the actual value of the functioning of the heart was one of them but, another one was the value of the events in frogs and fish to humans. We would say that it was the XVII century but if you think about this you will find a parallel in today where the drive towards human biology often forgets and renegates of how much we have learnt from model organisms. 

Screen Shot 2014-09-14 at 17.08.21One very important point is that Harvey used the different organisms to answer an important question and this can be easily lost in the fog of today’s emphasis on publication and superficial ‘novelty’.  The major contributions of model organisms to current biology have been on important, general questions. The principles of genetics were worked out in plants and animals but this was not the place to look for the molecular nature of the gene. This required going to phages and bacteria on the assumption, which turned out to be correct beyond expectation, that it would be universal. This was the same as with Harvey (a fish heart is a heart as much as a human heart – much to mull over on such statement in the XVII century), and also guided us to unravel the genes that drive development -using flies and worms- the principles of early development -with frogs and chickens. In all cases, model organisms, as we have come to call them, have been instrumental. The current focus on mammalian and, in particular, human biology and the attempts to sidestep model organisms should take stock of the fact that model organisms have been a staple of medical and biological research since the times of Aristotle and that great discoveries, like that of Harvey, could not have been made without them. 

I want to end up with another, perhaps more subtle, analogy with the events 400 years ago. Harvey faced a problem, a serious one. The whole of the medical profession at the time was built around Galenic medicine. The open circulation model created an array of easy to implement cures for a variety of diseases through bleeding that were performed by the physicians at a costly price. If Harvey was right the whole system needed to change and many of his colleagues were, as it indeed happened, out of business. Sometimes the lessons from model organisms are hard to take and many people will resist them. 

There is an ongoing debate about the importance of supporting research in model organisms and as someone who has spent many years working with Drosophila I am in favour of this. However, it is important that we do not lose sight that the relevance of a model organism is related to the significance of the question that one asks in it. The technological advances and the cottage industry that has emerged around them leads some times to derivative science which has no other purpose of the publication. Let is use model systems but, like Harvey, to answer a good question; only then they will be vindicated and we shall put them in their rightful place.

A few references

Aird, WC. (2011) Discovery of the cardiovascular system: from Galen to William Harvey. J Thromb Haemost 2011; 9 (Suppl.1): 118–129.

Donaldson, IML. (2009) William Harvey’s other book: Exercitaciones de generatione animalism. J R Coll Physicians Edinb. 39:187–188.

Kilgour, F. (1961) William Harvey and his contributions. Circulation 23, 286-296. doi: 10.1161/01.CIR.23.2.286

Wright, T. Circulation: William Harvey’s revolutionary idea.

There is also an excellent movie about Harvey’s experiments: https://archive.org/details/WilliamHarveycirculationoftheblood4-wellcome

NB The image of the frog on the mouse is taken from http://letsbefriends.blogspot.co.uk/

Summer Musing

What is your favourite experiment? This is a question that is bound to come up in conversations of scientists, class rooms or retreats. It is sort of like: what’s your favourite novel or your favourite painter. It is always difficult to answer because one is bound to be wrong with what it is said on the spur of  the moment. Whatever one  says –and you will know if you have been here- you will change your mind later, because what you have said is what you remembered. Given time you are likely to come up with a list of experiments (or novels, or painters or pieces of music) which would be difficult to tease apart. In the end, logic and emotion will collude to choose a favourite. So, the other day I asked myself: what is my favourite experiment?

As a biologist there is no shortage to choose from. Some of the best and most popular ones come to mind. Avery, MacLeod and McCarty showing that DNA contains the hereditary material, Pasteur’s removing once and for all the notion of spontaneous generation. Of course, Meselson and Stahl’s beautiful proof of semiconservative replication. There is not much to match any of these in the last twenty years, largely because in Biology we have substituted Science for data collecting and gene (I mean bean) counting (something the big journals love). In the physical sciences there are many exceptionally beautiful experiments: the double prism experiment of Newton, the measurement of the bending of light by Eddington, the weighing of Oxygen by Lavoisier……. the list could be long; all tributes to the ingenuity and beauty of the human mind.

As a developmental biologist I have always been seduced by the experiments of Driesch in which he separated the two blastomeres of a sea urchin embryo only to find out that they would form two embryos, rather than two half embryos. And of course, the epic cloning experimentss of John Gurdon, which have an interesting history. These experiments are characterized by their conceptual simplicity but technical challenge to answer an important question.

But when I think about it, my favourite experiment is one that I rarely hear mentioned in this light. It is simple, even boring, but somehow ever since I heard about  it, has captured my imagination. It was performed by R Boyle in 1662 and, as I recently discovered, had the assistance of R Hooke in its design. Boyle had been interested in what he called “the spring in the air’ which led him to what we know as Boyle’s law, namely that Pressure is the inverse of Volume in a gas. While on this subject he had the idea that sound required the deformation of air i.e. that it was a form of pressure in the air. To prove this he prepared a remarkable contraption which allowed a bell to be placed inside a container from which the air could be removed –at the time methods to create vacuum efficiently had been discovered-. Now, he and his friend Hooke figured out a way to manipulate the bell inside the container as the air was being extracted .And herein the beauty of the art. The bell is moved before pumping out the air and it rings, then as the air is drawn out, the sound is dampened until, vacuum created, bell dangled, no sound! QED beautiful, simple, impactful. I can imagine the audience, dumbfounded.

No rational for this choice, many of the others (and many more that you can think of) will do just as well. I guess, all down to the fact that one of the beauties of Science is the sense of awe and wonder and this experiment has a good dose of both. It is also that thinking about experiments like Boyle’s and the others should serve as an inspiration and push us to think about good questions and good experiments to reveal the inner workings of Nature. This is the way it used to be and where we need to return.