Ottoline Leyser: the story of my life | 91TV
Transcript
- Thank you so much, Linda, for the very kind introduction, and thank you everybody for coming,
- both really in the room and online. It's a huge honour to be here giving this lecture, which has
- been around for hundreds of years. It's rather a daunting task to be speaking in this series Such
- an extraordinary list of previous recipients. If I were standing on the shoulders of giants,
- it would be a very, very tall stack of giants on whose shoulders I'm standing by now. So, daunting
- for that reason, but also daunting because of the extraordinary calibre of the audience and
- the breadth of the audience. So because of that, I was thinking quite hard about what I should talk
- about, what would be the most kind of engaging story to tell about the various things I've been
- engaged with over my career. Thinking about it, I came to the conclusion that the best story to tell
- would be a story about stories. So that's what I'm going to try to do, because stories are incredibly
- important to all of us as people. Stories are deep in the way that we think about things.
- They are incredibly important tools for thought and for understanding and for communication,
- and that's equally true in science, where your ability to think through a complex situation,
- to communicate that, to marshal your thoughts, is hugely helped by the story that you tell.
- So why is that? I think there are a couple of reasons for that. The first is that stories are
- linear. They have a beginning, a middle and an end, and that linearity helps you to layer up
- your thoughts and your thinking about things as you move through your understanding of them, and
- to bring people with you if you're communicating some complex topic. So that linearity is critical,
- and then it follows a very familiar structure. Normally, you set a scene, there's a defined
- set of characters who face some kind of challenge or problem, and then there are a series of events
- with a very causative narrative that, in the end, resolve. That familiar structure allows you,
- again, to think through a complex issue, to anchor the complexity in familiarity, and to
- bring people with you if you're communicating and building understanding between you.
- Indeed, here I am setting the scene for my story today, introducing you to the main protagonist,
- which is the story, and the problem, the problem that I have with the story,
- is that whilst on the one hand it is a fantastic tool for thought, on the other hand,
- rather like Jane Austen's Emma, in trying to be so helpful, occasionally it gets things
- horribly wrong. It's the power of the story to help you that simultaneously creates risks
- of constraining the way you think through its familiar structure and its linear narrative,
- and that is something that we in science, but actually more broadly, then need to guard very
- heavily against. So I'm going to try to illustrate this with several stories from my life in science,
- but also in science policy, and I'm going to start with a story about auxin.
- So this is a molecule that I've spent very much of my life working on. It's a molecule that if
- you work in plant biology, you more or less can't avoid, because it is central to so many
- critical processes in plants, and like many problems in biology, the story of
- auxin starts with Darwins. It starts with this book by Charles Darwin and his son Francis, The
- Power of Movement in Plants, where they describe an iconic experiment investigating the ability of
- plants to bend their growth towards light. What they establish is that the site of perception in
- the shoot for the light, which is the very tip of the plant of shoot, is not the same as the site of
- bending, which is further back down the shoot, and therefore there must be a mobile signal that moves
- from the site of perception to the site of bending to transmit the information that bending should
- happen in that particular direction. That signal turned out to be auxin, and indeed, subsequent
- work has demonstrated that auxin does everything. It's absolutely involved in that tropic growth,
- bending towards light, towards gravity, but it does a huge range of things in plant biology, and
- that huge diversity is itself intriguing and also perplexing, particularly when it seems to do the
- opposite things in roots and shoots quite often. In shoots, auxin typically promotes elongation,
- but in roots, it inhibits it. In roots, it typically promotes branching, but in shoots
- it inhibits it. Then there are a whole range of patterning processes, like where the leaves form
- in the growing tip of the shoot, or how the vascular strands in the leaves are arranged,
- for example, and other things like the formation of root hairs. A huge list of things that it does.
- So what then, what is the story? What is the story of auxin? You can view it in the classic
- structure. The main protagonist, it's auxin. At the time that I started thinking about this, I had
- no idea who else was involved in the story, what the other characters were. I found both
- the scene-setting and the problem articulation for this story incredibly unsatisfying. Auxin
- does everything. Oh really? It does things opposite things in different parts of the plant.
- What does that mean? Absolutely no causative narrative at all, and no, then, resolution.
- I encountered this molecule at various points in my education in school, in high school, and
- then later in university, and I found it deeply unsatisfying. That unsatisfying-ness is actually
- something I'm very grateful for, so I would like to thank Mrs Duffell, my A-level biology teacher,
- and David Hanke, absolutely brilliant lecturer in plant science at Cambridge, who piqued my
- curiosity, but left it totally unsatisfied. As a result, I have spent a lot of time trying to
- understand how auxin works, and that you can break into a couple of different questions. How does it
- work? How do cells know how much auxin there is? How does it even work as a molecule in regulating
- anything in plants? But then, also, how does it control plant development? As Linda mentioned,
- I've actually spent most of the time worrying about how it controls plant development,
- and using shoot-branching control as an example, but I'm not going to talk about that today. I'm
- going to talk instead about the story behind how the plant knows how much auxin there is.
- I'm going to talk about that, despite the fact it's rather ancient history, because the story
- of our progress to elucidating that mechanism, it exemplifies brilliantly both the power of the
- story in helping you to make progress, but also the pitfalls into which you can fall if you dig
- yourself too deeply into the narrative that you've set up. So, once upon a time, in some laboratories
- long ago, we were thinking about how auxin might be recognised by cells, and at that time there
- was quite a well-established story about how cells recognise signals altogether - here's
- a cell with its nucleus, here's a signal - and the entire kind of framework about how
- signalling worked involved proteins at the cell surface, receptor proteins, that were
- able to bind to the signal in a perception process, and that triggered a whole range of
- downstream activities that move the information that the signal had arrived into the cell.
- For example, a very common activation, very common thing that happens after that perception,
- is the triggering of the addition of phosphates to downstream proteins by kinase enzymes,
- and this is part of a kind of transduction process that quite often follows an implicative cascade.
- So the phosphates are passed along a chain, amplifying at every stage, until you wind up
- phosphorylating some molecule or some protein, which actually regulates the downstream processes
- involved. So maybe it's a transcription factor that, as a result of being phosphorylated,
- moves into the nucleus, can bind the regulatory sequences associated with particular genes,
- and turn them on. So this is the kind of archetypal signal transduction pathway that was
- kind of in the literature and circulating at the time we began to think about how auxin might work.
- It involved perception, transduction and response through this clear linear chain.
- So everybody around was then asking, auxin signal transduction, how does that fit into this
- story? This is the familiar story. How does that relate to auxin? People started to look for those
- components in the context of auxin, and a very early success from that point of view, was to look
- for genes, the transcription of which very rapidly changed in response to auxin. So what could we
- find out about this end of this linear pathway? There were a number of labs involved in that.
- Prominent amongst them was the laboratory of Sakis Theologis, who wrote this review in 1986, which
- was just as I was graduating from my undergraduate degree at the University of Cambridge. It was
- subsequently shown, primarily, by Tom Guilfoyle's lab, that those auxin up-regulated genes had a
- very characteristic sequence in their regulatory regions, in their promoters,
- that were termed auxin response elements, and genes with that DNA sequence in their promoters
- were able then to bind to particular transcription factors called auxin response factors, and those
- transcription factors were able to switch those genes on in an auxin-dependent way.
- So that gave us then these two kinds of anchors at the end of the signal transduction pathway that
- we were thinking about for auxin, the auxin at one end, and these rapid changes in gene expression at
- the other end, and so people then started looking for all the bits in between. I've got to say that
- people found proteins that bind auxin, and they found proteins that were rapidly phosphorylated
- in response to auxin, but many, many years later, the precise role of those proteins is
- still very poorly resolved, and they don't seem to be part of this rapid gene transcription story in
- any significant way. Indeed, the extent to which they're really a core part of the auxin signalling
- machinery is still a matter of some debate. So, despite all of that work, we were still at a
- loss for the other players in the story, at which point along comes the awesome power of genetics,
- which in many ways I think of as the phone-a-friend of biology.
- So the joy of genetics is that you don't have to make assumptions about the function of the
- proteins that are involved about the other people in the story. You don't have to know what those
- characters are. You don't have to guess that their kinases or whatever. You ask the organism to tell
- you what genes it has, that if you mutate them, if you take those genes away by mutation, take away
- simultaneously the ability of that organism to do the thing in which you're interested. I was very
- powerfully moved by this power, through a whole series of lectures I had as an undergraduate,
- on the extraordinary ability of people to figure out what's going on in the development
- of Drosophila through this mutational approach. Fortunately for me, at exactly that moment,
- the laboratories of Elliot Meyerowitz, Chris Somerville, Maarten Koornneef and others were
- driving up the adoption of Arabidopsis as the equivalent to the fruit fly equivalent for plants.
- Before that, there was lots of lovely genetics in plants, but it was primarily in crop plants,
- which took a very long time and big fields to grow, and therefore not very powerful - well,
- I mean super-powerful, but super-slow - and in the development of Arabidopsis as a model,
- it's completely transformed all kinds of understanding across plant biology.
- I was very fortunate to be able to join the lab of [?Ian Ferner 0:12:39.6] for my PhD,
- and then Mark Estelle for my postdoc, who were very early adopters of Arabidopsis, which,
- as I say, has been just transformational for plant biology. My work on auxin started in Mark's lab,
- and Mark had pioneered a screen for auxin-resistant mutants. So as I say,
- you randomly mutagenize the organism, you make a huge collection of mutants that lack individual
- genes because they've been mutated, and then you ask which ones of these thousands and thousands
- of plants are no longer able to respond to auxin. The approach Mark took was a very powerful one,
- by looking for plants that were able to maintain a long root even when you added auxin.
- So typically, if you add auxin, these little seedlings have a very short root,
- but you can find mutants in this collection that have a long root even on auxin, and those are the
- ones you take forward and analyse. The first one we looked at was a mutant called AXR1,
- which had a long root on auxin, but also all kinds of other problems that are auxin-related,
- which is exactly what you would expect if you've taken away the plant's ability to respond normally
- to auxin. So this plant was relatively short and very bushy, has all kinds of problems.
- We were able to identify the gene that had been randomly mutagenized in this plant. You have to
- bear in mind that this plant and this plant differ by only that one gene - you can show
- that by classical genetic approaches - and we could find out what that gene was, which at the
- time took a horrible amount of time and pain, but these days is trivial, and that's another story.
- What it turned out to be was kind of a shock. So it turns out to be, to encode part of an
- enzyme that adds a small peptide called RUB1 onto another enzyme complex, and that enzyme
- complex is a core part of the targeted protein degradation machinery in plants. What does that
- do? It targets proteins for degradation, and it does that by conjugating onto them, through this
- enzyme system, another small peptide called ubiquitin and a ubiquitinated protein is then
- chopped up into tiny bits by the 26S proteasome. Particular proteins are selected for degradation
- in a regulated way through the action of this thing here, this multiprotein complex, which
- is called an SCF type ubiquitin protein ligase. We found that the AXR1 gene, the AXR1 protein,
- is required to modify part of this complex that makes it work well, and that suggested that auxin
- signalling involves targeted protein degradation. That suggestion was massively emphasised, or our
- confidence in it grew massively, when a second gene in Mark's lab was identified by Max Reugger,
- and it came out of a slightly different screen. It's a protein called TIR1, and
- that protein turned out to be the F-box protein part of this SCF-type ubiquitin protein ligase,
- and that protein is the protein that has the specificity that chooses which proteins are
- supposed to be degraded. The other ones are just involved in helping ubiquitin be stuck on it.
- So these two proteins are clearly involved in targeted protein degradation. This work
- demonstrated quite conclusively that targeted protein degradation is a critical part of the
- auxin signalling pathway. This caused, at the time, quite a lot of shock and horror,
- because none of these things were the sorts of things anybody was expecting.
- I had people in conferences complaining to me that my work didn't make any sense,
- because I hadn't found a receptor or a kinase, or any of those things. What was I talking about?
- So we had to take our knowledge that this was something to do with targeted protein degradation,
- and then build from that a new version of the linear narrative that incorporated targeted
- protein degradation as an approach. So we've got our auxin-regulated genes here, we've got
- auxin coming along, and we now have to include the fact that somewhere in there is a protein that, as
- a result of the auxin arriving, is degraded, for example. That, we could ask we could hypothesise,
- then, allowed the genes to be activated. So what those proteins might be, fortunately for us,
- emerged rather miraculously from the second gene that we identified through this mutant
- approach. So that was identified through the analysis of this mutant, which is called AXR3,
- another mutant that managed to grow a long root on auxin, and also has all kinds of phenotypes or
- other characteristics associated with inability to respond to auxin, so you can see its root
- has absolutely no idea which way down is, and really no response to gravity whatsoever. Another
- characteristic phenomenon that auxin does. So we identified which gene underpins this,
- and it turned out that AXR3 was a member of a transcriptional repressor family called the
- Aux/IAA family, and fortunately for us, it was just emerging at that time that these Aux/IAA
- proteins could physically interact with those ARF transcription factors that are involved in
- auxin response that I told you about. So we could hypothesise, then, that this protein
- was blocking the ability of the ARF protein to activate transcription, and that was very
- consistent with some excellent work going on in Tom Guilfoyle's lab at the time. He had done a
- lot more analysis on these auxin response factors and demonstrated that they had this multi-domain
- structure. There was a DNA binding domain, as you would expect, for a transcription factor. This
- middle region, which is responsible for driving the activation of transcription, and this region,
- which at the time people thought were two domains that they called three and four, but have since
- been reclassified as one domain, called the PB1 domain, and this works kind of like a LEGO brick.
- Proteins with those domains can kind of stick together in the way that LEGO bricks can, and
- those Aux/IAA proteins I told you about, of which AXR3 is one, has that PB1 domain. So this allows
- these Aux/IAA proteins to multimerize them, stack onto these Aux/IAA proteins, the ARF proteins, at
- the promoter of auxin-regulated genes, that brings this EAR1 transcriptional repression domain to the
- promoter and blocks the activation of those genes. What we were then very struck by was this domain,
- domain II, which at the time we didn't know what it did, and we were very fascinated by domain II,
- because domain II is where the mutations were in the AXR3 mutants that I showed you before. Now,
- I've explained to you about mutation as a great way to tell which genes are important,
- because effectively, you've got one plant that has a gene that works, and one plant that doesn't
- have the gene that doesn't work. These mutations were not that sort of mutation. They were dominant
- mutations. So they were able to do something extra or different to the normal function of the gene,
- and they had these very specific changes in domain II of particular amino acids, which somehow or
- other conferred these auxin resistant phenotypes. So to cut a long story short,
- we had to find out what domain II did, to try and address why it is that these
- mutations in domain II result in impressive auxin resistance. The answer transpired,
- largely collaborations with Judy Kellis and Mark Estelle and my lab, is that domain II is
- a so-called degron and it's an auxin-regulated degron. What we found was that any protein where
- we stuck that domain II sequence became unstable in an auxin-regulated way. So if you added auxin,
- the protein was degraded, and all you needed was domain II to make that happen, and we were able to
- show that that process was dependent on AXR1 and TIR1, which we had previously shown were necessary
- for the auxin response. Then, impressively, that TIR1 directly interacts with domain II,
- which is exactly what we would imagine if those domain II-containing proteins are
- the target for the SCF ubiquitination process with TIR1, that it picks for degradation, and
- that interaction was auxin-inducible. The domain II mutations that I told you about abolish the
- ability of the domain II to interact with TIR1. So all fitted together absolutely beautifully,
- and I've got to say, within those experiments were some of the few occasions in my career where you
- make a straightforward hypothesis - maybe this domain II is an auxin-regulating degron - and
- you design an experiment to test it, and it turns out that your hypothesis is fully validated. That
- almost never happens in science. This part of the story ran smooth, very smooth. So we have
- a situation now where it's these Aux/IAA proteins that are interacting in an auxin-driven way with
- TIR1, and as a result, they're being degraded, and those proteins are inhibiting transcription
- from ARF-containing promoters. So it all just works wonderfully, and then we have to find out,
- how is it, then, that auxin promotes this interaction? What is it that allows auxin
- to interact with TIR1? Aux/IAA proteins do interact with TIR1 only when auxin is present.
- Then, we were able to return to our nice, comfortable story that we had set ourselves
- at the beginning. Maybe it was going to be something like this. Auxin would arrive,
- it would bind to its receptor, there would be some kind of phosphorylation cascade, or similar, that
- would result in the modification of the Aux/IAA protein with something like phosphorylation, and
- that modification would be the thing that allowed it to interact with TIR1. There was, again,
- existing literature that allowed us to make that as a kind of plausible hypothesis. There
- were various other targeted protein degradation systems that worked in essentially that way.
- So we had to ask ourselves, then, what does auxin do to domain II? Is it phosphorylation? Is it some
- other kind of modification? Stefan Kepinski in my lab, who may or may not be in the audience - there
- he is, he's at the back - hi, Stefan - spent a long time looking for what that modification
- might be, and we did so many different things to find out what that modification might be.
- In the end, we concluded that, what does auction do to domain II? Nothing. That was kind of
- unfortunate, but it's okay. We picked ourselves up off the floor and we revisited our lovely linear
- pathway and said, 'Okay, maybe auxin doesn't trigger the modification of the Aux-IAA proteins
- to allow them to interact with TIR1. Maybe it triggers the modification of TIR1.' So we devised
- all kinds of assays for looking at the interaction between the Aux/IAA protein, and in fact just the
- peptide, but you could make a synthetic version of the peptide, which made our lives very much
- easier, and ask, what needed to happen to TIR1? What kind of modification might need to happen to
- TIR1 in order for it to be able to interact with that peptide? That resulted in us developing a
- whole bunch of ways to purify TIR1 and treat it in various different ways, and all of this kind
- of stuff. In developing those assays, the more we worked on it, the fewer and fewer things it
- seemed to be necessary for the Aux/IAA protein to interact with TIR1 in an auxin-independent way.
- Eventually, we came to the conclusion that maybe nothing else was necessary at all,
- except the auxin and the TIR1 and the Aux/IAA protein or domain II. So, unfortunately, down the
- corridor from us there was the laboratory of Harv Isaacs and Betsy Pownell, and they were working
- with Xenopus. So we were able to do an experiment where we expressed TIR1 in Xenopus eggs,
- and then we asked, is that TIR1 that's spent its whole life in a Xenopus egg able to interact with
- the domain II peptide in a way that's regulated by auxin? The answer was yes, and this is almost
- the only real result I'm going to show you. This is adding increasing amounts of auxin, and the
- intensity of this black line is, essentially, how much TIR1 we were able to recover as interacting
- with that domain II peptide, and the more auxin you add, the more interaction you get.
- So all you need, apparently, is the TIR1 and the domain II peptide, and in fact,
- it transpired that, if you used radiolabeled auxin in this experiment, it was part of that complex,
- so evidence for absolute direct binding involving TIR1, the Aux/IAA,
- and auxin itself. So that co-purification of auxin with that Aux/IAA/TIR1complex led to this model,
- which has since been validated in a whole variety of ways, whereby here we have some off genes and
- some Aux/IAAs inhibiting transcription via their interaction with ARFs. The auxin comes along,
- and it can bind to TIR1 and create a surface that is sticky for the Aux/IAA proteins. In fact,
- we now think about this as a molecular glue, where it's almost a kind of co-receptor process,
- where the auxin kind of sticks the Aux/IAA protein onto the TIR1, and that allows it to be degraded
- via ubiquitination, and that, of course, frees up the ARF protein to switch on genes.
- So this entire pathway that we had stared at lovingly for however many years,
- turns out to be a load of nonsense. The entire thing collapses into these two
- proteins hanging out in the nucleus. None of this other stuff. The auxin
- just gets into the cell, goes into the nucleus and sticks together these two
- proteins. That leads to the degradation of the Aux/IAA and the activation of those genes through
- the ARFs. So this is a story which goes, 'Once upon a time they all lived happily ever after.'
- Or did they? So I've, in all good storytellers, kept back from you some secret bit of information
- that we actually knew a little bit earlier in the story than I've told you. That is that amongst
- these families of rapidly-induced genes that are very rapidly switched on in response to auxin,
- is the Aux/IAA family of genes. So what that means is that,
- when auxin comes along, amongst the genes that are switched on are those Aux/IAA genes, and that
- means those Aux/IAA proteins are synthesised, and that means the genes are switched back off again.
- Now, that negative feedback loop is not - I mean, it's quite common in biology - but the incredible
- shortness of that loop, and the very small number of proteins involved, I think create in that
- system a very different dynamic than the kind of thing we're used to. There isn't really in this
- story a beginning, a middle and an end. It isn't really a story about a cell that met some auxin,
- and some things happened, and some genes came on, and after a while the genes went off again. The
- situation is much more like this. Auxin modulates flux through a cycle. That's mostly what it does.
- You've got this dynamically-occurring cycle all the time, and what auxin is doing is
- driving part of that cycle faster, which then has knock-on effects on the rate at which - the way
- in which the rest of the cycle is balanced. So it's constantly changing in its levels,
- and modulating the flux through that cycle, and that's a very different way of thinking about
- the signalling pathway, and addresses another thing that people complained about bitterly when
- we started to elucidate this pathway, which was it's terribly wasteful. 'Why would you make this
- protein all the time that was being degraded all the time? What an incredible waste.' The answer
- is, if you think about this as a dynamic process, where the question that the cell is asking is not
- how much auxin is there, it's how much, how quickly and in what direction are auxin levels
- changing, then this kind of dynamic cycle is what you need to answer that question. It's not no
- auxin, some auxin, do something. It's continuous monitoring of what the change is, what's going on
- around you in your auxin landscape. That's what the cell really cares about, and that's why this
- story that we told ourselves at the beginning, whilst being incredibly helpful for allowing
- us to design some experiments, is actually incredibly wrong in a whole variety of ways.
- There is no doubt that there are parts of the cycle of the experiments we took,
- which we might have got through much more quickly if we had thrown away this story, or
- at least zoomed out from this story sufficiently, to allow ourselves to think differently about it.
- I think that's a really invaluable lesson, that stories are incredibly important, and to tell
- a comprehensible story, to get the value out of them that you need, it has to be linear. It has
- to have a beginning, a middle and an end, and it really helps if you follow the familiar structure
- and the familiar narrative, but most of the things anyone's interested in are not really like that,
- and so you have to be really careful that the story you tell doesn't constrain your thinking and
- create a situation where it's actively misleading. I want to just spend the last ten, fifteen
- minutes, maybe a bit longer, illustrating that point in the context of the science
- policy landscape where I now live. I got into the science policy landscape, largely, as Linda said,
- through my interest in how you create high-quality research cultures. I was increasingly concerned
- that the way we construct our research cultures and our research environments actually undermines
- our ability to do high-quality research, and a particular focus from that point of view,
- is the area of research careers in academia, which are absolutely perceived and conceptualised as an
- incredibly linear, unidirectional process where you go to university as an undergraduate and
- you never leave. So you do your PhD, and then you do some postdocs and then you become a lecturer,
- although these days it's called an assistant professor or something - I'm old - and then you
- become a professor, and that's a research career. There are, obviously, far more people doing
- undergraduate degrees and PhDs than there are professors, so it's a pyramid, and your ability
- to move along that line in that lovely linear way are gates kept by very competitive, very
- narrowly-focussed criteria. I watched this ramp up through my life, and get worse, in my opinion,
- and worse in the narrowness and the focus of the criteria, in a loop almost, that was concerned
- about fairness - we need to have the right people moving along this pathway - but the result of
- that was an increased narrowing of the criteria, which became less and less relevant or properly
- Th concordant with the values people had in coming into these careers in the first
- place. So research careers got less and less fun for people, particularly at that junior stage,
- and a disaster, in my opinion, and we've got to do something about this.
- Along with that crushing of the fun and the creativity out of it emerged this very strong
- narrative of the leaky pipeline. This is the story that you see told over and over again.
- It's a linear pathway with people progressing along it and it leaks. People leave at various
- points and go and do other things. They are lost. The attrition is quite regularly talked about,
- and what you find is that by the time you get to this end, the type of person, the diversity
- of all kinds, in the broadest sense, of people at this end is much less than the diversity of people
- at this end. Everybody then throws their hands up in horror and says, 'This is terrible.' Clearly,
- the gates we have kept along here are not fair - they're biased - and so we need to find ways
- to stick people more firmly to this line so that everybody can move along it, whoever they are,
- using these narrower and narrower criteria, squashing these people through thinner and thinner
- doorways. It's not a good approach, because, if you want more and different people at this end,
- you have to think not only about this end of the line and where people go after they've
- started at that end of the line, but how you can bring people back onto the line.
- In fact, I think we should get rid of the line altogether, and we should ask ourselves,
- what are the full range of things you can do in the widest sense of the research system, and how
- can we support the idea that different people will want to move through this landscape in different
- ways? So maybe you leave school and you go into a practice-based role, like in the care sector,
- and you're working in the care sector for a bit and you realise you want a bit more training,
- so then you go and do an undergraduate degree, and then you go back to the care sector and you get
- increasingly frustrated that some element in that sector is not working properly. You can see how
- you could add value by conducting some research to see how you could do something better. So then
- maybe you choose to do a PhD, and on your PhD you come up with a really valuable intervention
- that maybe leads you to develop an app that's incredibly helpful for supporting people to
- maintain independence in their own home. So then, you start a company that markets
- this app, and it does very well and is acquired by a bigger company, but you
- don't really like working in a bigger company. You want to go back into the research system,
- so you go to do some kind of postdoctoral research, and then you realise that actually
- if you really want to influence this system, you need to take all of that knowledge you have from
- working in practice, from working in academia, from starting a company and go into policy.
- This kind of career, we should be absolutely supporting and valuing, and if we want to increase
- the diversity at this point, at this node in this system, we need to think about all the people who
- might be able to do a very good job in that role, however they've progressed through that pathway,
- and that means we need to, among many other things, radically fix the assessment
- criteria we use, so that we support that full range of careers that people need to take.
- So that's one example where our desire to tell a story, a linear story,
- particularly sitting in our perspective in academia, I think leads us to a conclusion
- where the solutions we put in place - it's not that there's anything inherently wrong with
- the solution. We should definitely continue to do all of the things that we're doing to support the
- full range of people who want to work in academia, but we will never fix the problems if we think
- of it as that linear, narrow pathway. We need to zoom-out, look at the full range of possibilities,
- and change fundamentally the way the systems work. Change the story to include a much wider
- range of career paths as valuable things for the research and innovation system. That brings me to
- the second example that I want to talk about briefly. This is a very familiar example to
- a lot of people, because it's well known to be a problem, but somehow or other we can't shift
- that linear narrative again sufficiently. That's the question of innovation, where
- we still conceptualise innovation as a linear process that starts with a brilliant discovery
- in some laboratory, that is then translated or commercialised into a product. Although, people
- have done quite a good job of thinking about it in the other direction, thinking about pull,
- some brilliant idea you have to add value in the economy, which is kind of a good definition of
- an innovation to add value either economically or socially. So you've got that brilliant idea,
- and you want to reach back into the research base to pull through the stuff you need to do
- to deliver your innovation, but that's still linear, and it still results in,
- essentially, quite strong balkanisation of people thinking of themselves as operating at one end
- or other of this spectrum. Again, our reward systems, the way we invest money tend to think
- in a very polar way about the opposite ends of this spectrum - we build up two communities that
- are not sufficiently integrated - and that results in both the solutions we think of, in terms of
- improving the connectivity between discovery and product development, as being about things...
- We talk a lot about the valley of death between these things. It tends
- to be conceptualised as not enough money, and it's not that that isn't a problem,
- it's just that it doesn't actually encapsulate the breadth of the problem, and therefore the
- full range of the solution space. To my mind, it's the segregation of people to either end of
- this spectrum that inhibits information flow in the form of skills, knowledge and knowhow, and
- slows down the rate at which the new ideas bump into each other in a way that sparks
- innovation. We have to stop thinking about that linear pathway, and start thinking
- instead about the full range of people who support all of the aspects of that pathway,
- and how we incentivise that fully-connected system, which goes completely back onto that
- career map. I told you, if we've got people moving through those much more dynamic career paths that
- cover different parts of this system, going in and out of the investor community, going in and
- out of the policy community, going in and out of the research base and the innovation community,
- in that joining-up way, you inherently bring together, draw together and make much closer,
- all of the things you need to make the research and innovation system work, so that discovery
- and delivery of value are so intimately connected through all the parts of the system
- that it all works in that much more rapid way. That's something that we as a nation, a relatively
- small nation, with relatively small amounts of money to invest, it's our only solution for making
- this work. That's the third and final example I want to cover, and that's how we use that to build
- national prosperity, in the broadest sense of the word. Here, I would say, it's a bigger problem.
- We need to zoom-out further. The difficulty is in constructing the linear narratives that help
- people see the connectivity that there is in the system, that we need to think about more broadly
- than just an intervention with an input and an output. The way I think you can conceptualise it,
- which is not that linear narrative, is something like this. I like to think of it, essentially,
- as a triangle around three things. There are high-productivity, innovative, high-growth
- businesses that have really high-quality jobs. There are public services. So high-quality,
- high-productivity, innovative and therefore affordable public services.
- I would include, obviously, things like the NHS, but also our education system,
- including our university system. We need those services absolutely critically, and they need to
- be high-productivity and innovative, and unless we can embed that innovative spirit, they will
- not be affordable. They will get stuck down in old ways of working, and they will be expensive.
- So these are two points of the triangle, and the third point of the triangle is the people.
- It's fundamentally what we're about, is a society that has highly-skilled, prospering
- people who are really thriving. You have to have those people, or you simply can't have
- the high-productivity, innovative businesses, and you can't have the high-quality public services.
- Of course, the public services support the people in their agency, in building their
- ability to thrive, and so you have this fully joined-up loop of those three things, which,
- if we get our public policy right, can drive themselves around in a virtuous cycle, driving
- up all three of them at once in a connected way. There are a few key points for that connectivity
- in the middle, and obviously, the tax revenues to the government are part of that fuel. They
- need to be invested and they need to be invested wisely, but that investment I think, critically,
- can't just go straight into the things that need to be paid for, which would be the public
- services. There has to be some of that, but if you want to drive the cycle around that loop
- to drive everything up, then you need to invest taxes also in high-quality public procurement,
- which not only supports your high-quality services, because you've got high-quality,
- innovative products going into it, but simultaneously supports the high-productivity
- businesses that are innovating to develop those products. So public procurement is one critical
- element, and it is not surprising that I also think that public sector investment in research
- and innovation, and research and development, is another critical component of that.
- That public sector investment, not only supports the innovative businesses and supports innovation
- in the public services, but it is a key part of providing and supporting those highly-skilled
- people, because the money we invest in R&D not only discovers new things, but simultaneously
- trains that full range of people that you need to do high-quality R&D. Those people discover things,
- and those discoveries support both the innovative businesses and the innovative public services. All
- of that needs to sit in an enabling environment that includes things like high-quality regulation,
- prioritisation, deep engagement with relevant overseas partners, and so on and so forth.
- Now this is a networked set of critically interdependent activities. It's not a linear
- story, and it is difficult sometimes to tell that - it's taken me a while to
- talk through this slide - but the point is, you can tell it as a linear story.
- You can tell it as a linear story in multiple different ways, starting at multiple different
- points, in a way that therefore speaks differently to the different audiences with whom you might
- want to engage. So, for example, you might start with the terrible problem of the NHS.
- You might say, 'The NHS, we love it, but it is really struggling. How can we support the
- NHS better? How can we drive up innovation, make sure people are getting really the latest things,
- make sure it can cope with the full range of services that it needs to deliver?' You might
- say that the solution to that is just put more tax in. Well, we know we haven't actually got
- enough tax to do that, and so one solution would be to put your taxes up. Take more tax money out
- of the innovative businesses and their employees through the jobs that they have. Well that doesn't
- work very well if you're trying to support innovation in a way that you need actually
- to drive up innovation in the public services. An important additional thing to do with your tax
- money is to balance how much you invest indirectly with your investment in public procurement,
- and make sure that your investment in public procurement, which of course,
- allows you to buy the latest everything's in your hospitals, is supporting also the
- high-productivity, innovative businesses that are developing those new products. Therefore,
- allowing those businesses to build their markets through guaranteed growth in public procurement
- and get them then over their valley of death into a situation where they can market much more widely
- and continue to grow. So investing tax money in public procurement is a way to support public
- services in a way that also supports business, rather than in a way that is in tension with
- business. Simultaneously, if you invest public money in R&D, you are fuelling the productivity
- and the innovation in both the public services and in higher education, for example, in the same way
- that you are in in those innovative businesses. As I say, if you invest in public R&D, you will
- also invest in the skills of the people who are conducting that R&D, and of course, if there
- are high quality jobs from high-productivity businesses and from high-productivity public
- services, those people will have wonderful jobs to do, and that will help them. If there are
- wonderful public services, including education and so on, that will support those people in thriving.
- Then, all around that you wrap your wider enabling environment. So you can tell this as a story
- that starts with the public services. You could tell it as a story that started at any point on
- this diagram, and indeed, you could weave these other points into the diagram if you wanted to,
- and again, tell it as a story, but you need to build up through that this
- deep understanding of interconnection. One of the very exciting things that I think has happened
- in government recently, driven through very much by Patrick Vallance, but actually a wider
- realisation across government that you need to think about things in this joined-up way,
- is the science and technology framework. This is a list of ten things that you need to
- think about to support this cycle, to join things up in a way that really allow us to function as
- a country and drive-up prosperity. Indeed, this diagram is effectively a diagram of the science
- and technology framework. The framework was kind of put together in the context of the science
- superpower narrative. I like to think about that science superpower narrative as this quote,
- 'A society that is both powered and empowered by science,' and that's why this part of the
- triangle is so important, because in the end, this is all about people, and their empowerment
- to work together to solve the many challenges that we're facing as a society, as a planet. Obviously,
- all of these points of the triangle are also able to contribute directly to those solutions to
- transition to a net-zero economy, public services, public transport, all the rest of it, the many
- health care challenges that we face. So this joined-up system,
- operating in a cross-societal way in which everybody feels engaged, everybody feels
- part of the story, I think is our ticket to living happily ever after. In order to do that, we have
- to embrace the power of narrative, embrace the power of the story. We need to tell those stories,
- but we need to maintain the open mindedness to tell new stories when the old ones are
- not working. We need to be able to tell the old stories in new and different ways, and critically,
- we need to be able to tell some of the more complex stories in multiple different ways to
- communicate with the multiple different audiences who need to be able to engage. I will stop there,
- and would like to thank everybody. I started at various points in preparing this lecture to
- make a list of people I needed to thank, and it rapidly got far, far too long. I was at the very
- wonderful event last week, which was the launch of my sister's debut novel. She is a storyteller
- par excellence, and she, in thanking people at the launch of this novel, took this approach
- of saying she wasn't going to mention anybody because there were too many people, and so I
- feel kind of validated in my ability to do that. I've mentioned a few people as we've gone through,
- but I've had so much help and support and everything in making this journey,
- and I continue to depend on that, because collectively we can all do so much more
- than we can individually, and our collective endeavour is powered by shared stories. Thank you.
- Thank you so much. Ottoline,
- for an absolutely fabulous lecture. Wonderful science, wonderful vision of science policy. Truly
- inspiring. Thank you so much. So we have time for some questions. There'll be roving microphones,
- so please have a microphone to ask your question. The floor is yours.
- Oh, and we may have some online ones as well.
- So yes, there's one from Paul [?Kline 0:52:29.9] at Darwin College, Cambridge. What kind of story
- might the quantum biology concept as presented by Professor Jim Al-Khalili be telling us?
- Then I would need to know more about the quantum biology concept of Professor Jim Al-Khalili.
- A little off stage left. I
- don't think Jim's here. I mean, there are there are a lot of very cool quantum
- phenomena in biology. Julian can talk about quantum tunnelling in photosynthesis. No?
- I could do indeed, but I think that's an indirect answer to the question.
- As I say, I don't quite - does anybody know what Jim Al-Khalili's...?
- I have no clue.
- I'm sorry. Hopefully, will be able to get back to that one.
- Angela?
- Hello. Angela McLean, Government Office for Science. I'm also a huge fan of the
- ten big things that we now have to call the science and technology framework,
- and I wondered, Ottoline, if I could ask you to riff just a little bit on what you
- see UKRI's most important role is in actually making it happen now?
- Absolutely. So I am very excited about the framework. It is a list of ten things which are,
- effectively, covered on that slide. UKRI has a very direct involvement in really quite a lot of
- them, although, definitely not all of them, and it's more in some than in others. Some of them,
- like skills for example, we clearly have a major role in part of the skills system, but not another
- part of the skills system. The framework is part of a broader narrative about embedding research
- and innovation right across government, in the way government works and in the way policy is
- developed and delivered, and in how we use all of that to address the various challenges that
- we are facing. I liked drawing this triangle - no, diamond shape - which has the National
- Science and Technology Council and the OSTS at the top, thinking about those ten big things,
- and UKRI at the bottom, and all the government departments in the middle. It used to be all the
- government departments in a line in the middle. We now have DSIT sitting firmly in the middle of
- that, with that broad cross-government role too. So we have a full axis of organisations, or parts
- of the system, with pan-system responsibility. UKRI has that pan-system responsibility across
- all disciplines and across all sectors, and it has multiple levers to engineer, to tune the
- system to work better, to drive that connectivity I talked about, to support the full diversity of
- activities that we need, to ensure resilience across the system and of course, to promote and
- encourage that broad societal engagement that we need to make this truly a shared endeavour.
- Those four things that I just talked about are the principles for change that underpin our strategy,
- because those are the parts of the system that need re-engineering, and those are the things
- that actually also underpin how we manage to embed the ten big things across the way that we think.
- So I think it is an extraordinary opportunity, and I'm very excited that
- you will be there to help deliver that, because now is a time when I think there
- is a realisation that research and innovation are absolutely crucial for the future of the UK,
- and getting us out of what could easily turn into an irreversible debt trap,
- into something that is much more collective, generative solution-focussed outcome. It's
- hardly any of those ten things are not important in the way that we deliver in that fully joined-up
- system that I'm talking about, and we can talk about it a lot over the next year or two I think.
- Maybe I could ask one? You presented a very attractive picture of extremely
- flexible careers with people moving between contexts. What practical steps
- can UKRI and other organisations take to actually making that happen in practice?
- So I think there are a lot of things we can do with selection criteria. So we are using the Royal
- Society resume for a researcher concept, to move away from an academic CV that consists of a list
- of your papers and a list of your glorious prizes, and instead asks people in four equal-sized boxes,
- what have they done to contribute to new knowledge, to discovery, to innovation? What have
- you done to support people around you? What have you done for the wider research and innovation
- system, and how have you engaged with people who think of themselves as outside the research
- and innovation system? Those are four things that we all agree everybody in research and innovation
- needs to do. You can do all of them in multiple different ways, and we need a way to be able
- to compare someone who's done them in a very conventional academic career, but also who's
- done them in that much more flexible career. So somebody who's followed the career that I
- kind of made up could easily fill out those boxes, and they could easily evidence the things that
- they've done to contribute in those four ways, but they would be very different from the things that
- I could put in those four boxes. It would still be possible for someone to compare those two things
- and decide who should get the job, who should get the grant otherwise. So allowing ourselves,
- in a transparent way, to compare people who have taken those very different careers,
- in an environment that is inevitably competitive, I think that's one critical element of it. The
- other one is just about culture. It's about who we are and what we say and what we value,
- and re-engaging with the values we had coming into research and innovation, which tend to get swamped
- and kind of sat on by the need to churn out the papers and bring in the grants. That is a critical
- part of the element, just to kind of bring joy back into the system, which is so important.
- You've got an interesting one online. Many of the decision-makers have successfully
- waded through the increasingly narrow gates of linearity, and so may be resistant to change,
- that I suffered, as will you. How can we overcome that?
- So this is a very interesting question, because I think part of the problem is that
- the environment we built in academic research is very anxious-making and insecure. Even if you've
- got the permanent job, you're still anxious and insecure, because you need continually to
- be winning the grant and all that. People tend to cling to, I'm okay, because I've ticked the boxes,
- to support their insecurity, but it's actually those boxes that are inherently undermining
- their security. So everybody would actually be happier if we were able to step out of that
- prison of needing to deliver against these very narrow criteria. So although it's difficult for
- people to let go of their security blanket, the Nature paper they published last week,
- I think it's achievable because it would be such a kind of positive win for all of
- those people in reality. When you talk to people - I've spent so much time in coffee,
- in grant meetings or whatever - where everybody sits there and complains about how terrible it is
- and how we're using these terrible criteria and we should change, and then when they go
- into the room, somehow it all comes out. So we need to give ourselves permission to
- do the right thing, and I'm actually going to point at Chris Friths over there, who wrote,
- or orchestrated, a brilliant paper on how to make good decisions in groups. That, to me,
- is exactly the sort of thing that gives those groups of people sitting around the
- table permission to do it well, rather than just to do what they think they've been told to do,
- which is count beans. We cannot do research and innovation on a bean-count basis. It won't do.
- One last question.
- So thank you for that wonderful lecture, and also for everything you've done to
- create a more liveable and supportive and creative research infrastructure within UK science, within
- different disciplines and also within different universities. I wanted to ask you if you could
- maybe say just a little bit more about the role of the university, which also has a very linear
- story attached - you go, you get your degree, you leave - if there's another version of a university
- where it might be a place you came back to. That you had a longer connection to as a place that you
- could come in and out of the way you come in and out of the other parts of your ecosystem,
- possibly for quite a short period of time even. Other countries have university systems
- that are much more lifelong learning, lifelong connections models of universities. I'm wondering,
- might that have a place, in your view, of changing the flux, as it were?
- Absolutely. I think the models for a lot of things are very up for grabs at the moment,
- for a whole variety of reasons. Technology, we've all just managed to operate universities through a
- pandemic and an extraordinary way, which opens all kinds of different ways of thinking about things.
- We know things are moving very quickly, and that whole lifelong learning concept is going to be the
- case for all of us. All of us are going to be able to, again, going to need to be able to kind of dip
- into additional learning opportunities throughout our lives. The breadth of stuff that we need,
- of people that we need, people with different skills, I think is critical. So I think that other
- element of that comes back again to this question of diversity. We have 140-something-or-other
- universities in this country. We need to support their diversity. They shouldn't all be aiming to
- be the same, to do exactly the same things. We need the full range of types of engagement
- that suit different people in different ways, at different points in their career.
- Again, we need to be positive and excited about that, not trying to rank people,
- rank universities into some narrow - again, we're just obsessed with ranking things by narrow
- criteria that don't actually reflect what we're interested in and what we care about. So how we,
- again, get back to a system that actually delivers on the values that we have that allows the full
- range of people to access the opportunities that they need in that much wider range of ways,
- I think is going to be critical. I do think there's a window to do that,
- for example, in the context of the skills pillar of the ten big things, and there is going to be,
- hopefully, as a result of that, proper integrated thinking about skills across all the domains and
- all stages in people's journeys. So there is a window of opportunity to change things,
- to tell the stories in different ways, and I'm really excited about our chance to take that.
- Ottoline, thank you
- very much for a truly inspiring Croonian Lecture. It's been great. Thank you.
- Thank you.
Croonian Prize Lecture 2023 given by Professor Dame Ottoline Leyser
Stories are an immensely powerful communication tool. People find linear narratives compelling and this shapes how we think. This is as true in science as in any other domain. Stories structure our thinking and aid understanding, but they can also constrain our thinking unhelpfully, and embed assumptions that are unwarranted. What’s more, however attractive a story may be, with a beginning, a middle and an end, life is not like that. Life does not work in linear narratives or we would not have to ask “What came first, the chicken or the egg?"
A key challenge in modern biology is to find ways to tell stories about these dynamic, non-linear processes that can aid our understanding, while supporting the open mindedness needed for progress. Leyser’s research in plant developmental biology has tried to address this issue, a challenge that is equally relevant for her current role in science policy. Her Croonian Lecture will include examples from both of these areas of her work.
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