Podcast: Atherosclerosis and disruptive science

Host: Benjamin Thompson

Welcome back to the Nature Podcast. This week, we’ll be hearing how team size might affect research innovation.

Host: Nick Howe

And learning about the links between poor quality sleep and atherosclerosis. I’m Nick Howe.

Host: Benjamin Thompson

And I’m Benjamin Thompson.

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Host: Benjamin Thompson

Now Nick, you’ve just joined the team as we discussed last week, and I’m sure you’ll have noticed that there’s not that many of us.

Host: Nick Howe

Agreed, we’re a small group.

Host: Benjamin Thompson

Nimble, I’d say, and talented.

Host: Nick Howe

Modest too.

Host: Benjamin Thompson

Well, quite, and team size albeit in a research context is something you’ve been looking into this week.

Host: Nick Howe

That’s right, Ben. Scientific research today seems more complicated than ever. There’s simply too much out there for one person to be an expert on everything. This may be one of the reasons why research teams are getting bigger and bigger. And big teams can bring benefits. For example, there’s a strong positive correlation between the numbers of authors on a paper and the number of citations it receives. But are there any advantages of working in a smaller research group? Are we losing something by focusing on bigger teams? A paper coming out in Nature this week has been looking at how the size of teams, in all areas of science and technology, affects their outputs. I spoke to the corresponding author of this paper, James Evans from the University of Chicago, who’s been crunching the numbers.

Interviewee: James Evans

So, we looked at 65 million teams – scientific teams, inventive teams, teams that develop software – and we identified the degree to which the products from each of those teams either developed things or disrupted the frontier of ideas and technologies. And we found that with each additional member on those teams, there was a dramatic drop in the likelihood that their products would disrupt the frontier of science.

Interviewer: Nick Howe

For every additional person on a team, the less likely a research paper is to be ‘disruptive’, but what does that mean? James and his colleagues were trying to distinguish between papers that either upset the scientific status quo, making a potentially big sudden change, and papers that consolidate and develop existing knowledge. So, what is the value of disruption?

Interviewee: James Evans

For the vast majority of science and technology, our purpose is not just to get a few more eyeballs, in the same way that a big production studio is more likely to pick Transformers 9 and fund that over an independent script, in the context of developing new films. If our purpose is to develop and feel new ideas which have the potential to really change science and technology, our findings show that it’s much, much more likely that those are going to be sourced from small teams.

Interviewer: Nick Howe

But how do you measure how disruptive a paper is? In this research, disruption is all about the kinds of citations a paper gets. Disruptive papers are often the beginning of something new, so authors tend not to cite research that has come before it, whereas consolidating papers form part of an ongoing body of work, so when they get cited, it will be alongside older and newer research. So, James uses the way in which a paper has been cited as a metric for disruptiveness. Pierre Azoulay from the Massachusetts Institute of Technology, who’s written a News and Views article on this research, thinks that there’s a convincing argument to suggest that citations and disruptiveness are linked.

Interviewee: Pierre Azoulay

And so, they’ve done sort of a number of checks that really establish the plausibility of this sort of disruptiveness interpretation. So, for example, they’ve looked at Nobel-winning contributions and conversely, they’ve looked at review articles, right, so articles are in some sense written without necessarily introducing new ideas. So, for example, they’ve been able to check that the Nobel-worthy contributions are very disruptive according to this index, whereas the review contributions are very consolidative according to this index.

Interviewer: Nick Howe

So, having checked the metric by assuming that Nobel prizes are ‘disruptive’ and review articles are not, the team are able to back up their claim that small teams are more disruptive. But does this new finding hold up cross the board? In some fields, large teams are often the norm – think of the huge collaborations in physics projects like the Large Hadron Collider – whereas in mathematics papers, typically there’s only a few authors. How universal is this newfound correlation?

Interviewee: Pierre Azoulay

They’ve established that that’s a pretty robust finding, so it holds across disciplines – it holds for publications, for patents and for code repositories. And then they do something that to me really sort of nails it, which is that in the case of papers, they show that the result holds even for a given author, meaning, let’s imagine that you observe that individual in a small team and in a large team, you will see that the articles that were written with a large team tends to be more consolidative than the articles that were written when that same individual was part of a small team.

Interviewer: Nick Howe

So, this paper suggests that larger teams are less disruptive, and this holds across different fields of study and when looking at the same authors. But this does beg the question – why? Why do small and large teams behave differently and what could be driving this? James has some ideas.

Interviewee: James Evans

So, for example, small teams are much more likely to search much more deeply into the distant past, they’re much more likely to pick up and cultivate ideas that were unpopular that they built on, and small teams are more likely to be flat, so a higher proportion of team members are likely to perform multiple roles on the team, they’re less likely to be well funded. And it turns out that all of these features end up contributing to the fact that their work – if and when it becomes important – becomes disruptively important.

Interviewer: Nick Howe

James has some thoughts on other potential mechanisms. Perhaps large teams with big budgets are less able to change their approach – if you’ve spent billions building infrastructure to look for, say, gravitational waves, it’s not easy to then change direction and look at particle physics. A small team’s flexibility might allow them to follow new, riskier avenues. At the moment, it’s unclear what the mechanisms are, so what happens next? Here’s Pierre.

Interviewee: Pierre Azoulay

We need to proceed with caution here. It’s not a policy paper. It doesn’t establish sort of a causal mechanism. What we need now is to have a few important funders who take those results as sort of a hypothesis to be tested and actually run experiments to think about what happens when you sort of vary the extent to which you push scientists to form large teams versus small teams.

Interviewer: Nick Howe

A better understanding of what the mechanisms behind this potential causation are is needed. This could benefit policymakers and science funders, helping us drive scientific discovery effectively. One thing that isn’t clear is how much are the findings of this research to do with the changing nature of science? Fifty years ago, when smaller teams were the norm, was research more disruptive? There is also a potential problem with the metric of disruptiveness. It can only be applied to papers after they have been out for years and have accrued citations – it can’t be used to assess recent papers. While small may be splendid, big isn’t necessarily bad. Pierre and James think we need both little and large teams for the advancement of science.

Interviewee: Pierre Azoulay

Science needs both kinds of contributions. It’s not like incremental innovation and elaborating initial ideas, it’s not like this is not an important activity. It’s a super important activity and we need a balance.

Host: Nick Howe

That was Pierre Azoulay. You can read his News and Views article and James’ paper over at nature.com/nature.

Host: Benjamin Thompson

Coming up in the show, we’ll be hearing how diet drugs could stem mosquitoes thirst for blood – that’s coming up in the News Chat. Now though, it’s time for the Research Highlights read this week by Shamini Bundell.

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Shamini Bundell

Many insects on Earth are in danger of extinction and the results could be catastrophic. A new review paper has collected evidence of huge drops in insect numbers all over the world, and concludes that 40% of insect species could go extinct in the next few decades. They’re disappearing eight times faster than mammals, birds and reptiles, and a lack of insects would have dramatic effects on ecosystems and human food chains. The main cause of insect declines seems to be habitat loss, but climate change and the use of pesticides also play a role. You can read more in the journal Biological Conservation.

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Shamini Bundell

What will your hometown look like in 60 years’ time? Researchers in the US have created an interactive web app to show how the climate of North America might have changed by the year 2080. It compares the predicted climate for a particular area with places that have a similar climate today. For example, in 60 years, Dallas in Texas will have a warmer and wetter climate more similar to that of today’s Estelle, Louisiana, if emissions continue to rise. The authors hope that this model could help people in North America understand just how climate change could affect their lives. You can read that study in Nature Communications and interact with the results yourself at tinyurl.com/urbanclimate.

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Host: Nick Howe

We’ve known for a long time about the importance of getting a good night’s sleep. Not having enough or just getting poor quality sleep is linked to increased risk of several diseases, although not much is known about how these health problems arise. Now, a paper in this week’s Nature has found a potential mechanism in mice that links disruptive sleep and a disease of the blood vessels known as atherosclerosis. Reporter Anand Jagatia spoke to author Filip Swirski about the study, and started by asking him how atherosclerosis develops.

Interviewee: Filip Swirksi

Atherosclerosis is a chronic inflammatory disease where cholesterol as well as white blood cells accumulate in the vessel wall and cause these plaques or lesions that, if they rupture, can lead to heart attack or stroke.

Interviewer: Anand Jagatia

In your paper, you were looking at mice. So, first of all, how did you keep the mice awake? How did you disrupt their sleep?

Interviewee: Filip Swirksi

We placed these mice in these sleep fragmentation chambers. There is a sweep bar along the bottom of the cage that gently sweeps across the bottom of the cage, waking these mice up. It interrupts their sleep – one could think of it as akin to constantly waking up due to noise. It really is a curtailment of sleep quality rather than quantity.

Interviewer: Anand Jagatia

So, what did you find in the mice that had disrupted sleep?

Interviewee: Filip Swirksi

What we found was that over time, these mice developed progressively larger lesions and so we then turned our attention to the production of immune inflammatory cells and specifically to the production of monocytes and neutrophils.

Interviewer: Anand Jagatia

So, these are white blood cells, right?

Interviewee: Filip Swirksi

Exactly, these are white blood cells that are constantly produced in the bone marrow and they also have very important roles in atherosclerosis, and so in mice subjected to sleep fragmentation, we noticed there were more of these cells circulating in the blood, and what we found was a higher rate of production of these immune cells in the bone marrow.

Interviewer: Anand Jagatia

Okay, and so then I suppose your next question was what is causing this increased production of white blood cells in the bone marrow, and then what did you find next?

Interviewee: Filip Swirksi

We decided to investigate the production of neuropeptides, so these are proteins that are produced in a region of the brain called the hypothalamus. One protein that caught our attention is a protein called hypocretin. It is a neuropeptide that promotes wakefulness and what we found was that over time as these mice were developing more atherosclerosis, as they were producing more immune cells, we found lower levels of hypocretin in the hypothalamus, less hypocretin in the blood. And on the other hand, we had hypocretin-deficient animals that were not subjected to sleep fragmentation which developed larger lesions, had higher numbers of circulating immune cells in the blood and had a higher rate of production of these cells in the bone marrow.

Interviewer: Anand Jagatia

Okay, so hypocretin could be important then. So, mice that had their sleep disrupted produced less of this protein and also their atherosclerosis was worse. And also, you’re saying that mice that were genetically unable to produce hypocretin produce more white blood cells and their atherosclerosis was worse even though they had normal sleep.

Interviewee: Filip Swirksi

That’s right, and that really raised the question, are these processes linked causally? They key that really helped us to directly link hypocretin production in the hypothalamus and production of immune cells in the bone marrow was the identification of a small subset of cells that reside in the bone marrow that can directly respond to hypocretin. And so, when you’re awake these high levels of hypocretin communicate to this cell to supress production of immune cells and when you’re asleep, hypocretin levels are low, immune cell production is high. The problem with sleep fragmentation is that production of hypocretin diminishes. We don’t know exactly why. We think that it’s a form of exhaustion and what that does is, in essence, it takes of the brakes and so now when we are awake, the hypocretin levels are diminished and really increase the number of inflammatory cells that circulate in your blood and can give rise to atherosclerosis.

Interviewer: Anand Jagatia

So, this experiment was obviously in mice – are there any immediate implications for this pathway and for sleep in humans?

Interviewer: Anand Jagatia

We already have some clues that it might be. So, we know that heightened numbers of immune cells is a risk factor and predicts for cardiovascular disease. We also have a handful of studies in humans that have connected diminished hypocretin production with risk for cardiovascular disease. There is actually a drug on the market called suvorexant for insomnia. So hypocretin Is a wakefulness promoting protein and the idea is that if you can interrupt its action on wakefulness, it will help you sleep better. Our studies throw some caution because our studies suggest that hypocretin has anti-inflammatory properties and so is a blocking of the hypocretin receptor, is this a potentially problematic approach that might heighten inflammation, and this is something to test for in the future.

Host: Nick Howe

That was Filip Swirski from Harvard Medical School talking to Anand Jagatia. To read the full paper, plus a News and Views article on the study, head over to nature.com/nature.

Interviewer: Benjamin Thompson

Lastly this week, it’s time for the News Chat, and I’m joined in the studio by Nature’s European Bureau Chief, Nisha Gaind. Nisha, thanks for joining me.

Interviewee: Nisha Gaind

Thank you for having me. Hi Ben.

Interviewer: Benjamin Thompson

For our first story today, we’re going to talk about funding, we’re going to talk about Europe and we’re going to talk about a short list of giant projects.

Interviewee: Nisha Gaind

Yeah, that’s right. We’re looking forward to 2021 when the European Commission is supposed to be launching its next round of these massive science projects that are funded to the tune of about €1 billion.

Interviewer: Benjamin Thompson

Wow, so these really are a big deal then. What sort of areas are we talking about?

Interviewee: Nisha Gaind

So, what they’ve done now is they have whittled down some proposals into a short list of six projects, and they will fund up to about three of these to become the fully-fledged initiatives in 2021. The ones that they have shortlisted, there’s a huge range actually. There is a project on AI enhancement, one on cell and gene therapies, one on personalised medicine, a couple of projects on solar energy and perhaps most excitingly, something called the Time Machine, which is a digital humanities project.

Interviewer: Benjamin Thompson

Tell me about that one.

Interviewee: Nisha Gaind

So, quite unusually, this is a cultural heritage project. The previous flagship projects that the European Union has funded have all been quite hard science, shall we say, on the brain, on graphene, on quantum technologies, so the fact that we’ve got this heritage project in the mix competing for this funding is really exciting.

Interviewer: Benjamin Thompson

And what’s it going to do?

Interviewee: Nisha Gaind

So, it’s a project that is trying to develop methods so that historical records in European cities, which as you can imagine are written on pieces of paper going back hundreds of years – all sorts of different types of records – it’s trying to develop methods to enable the digital search of these records. And it’s already worked on historical documents from the city of Venice, and they are proposing to try and roll this project out and the researchers are absolutely thrilled. They said it was a big surprise to be chosen in this shortlist because as a cultural heritage project, they thought they were a bit of an outsider to be competing for this traditionally very scientific funding.

Interviewer: Benjamin Thompson

So that’s one of the six then, and you’ve listed the other five there too – when does the shortlist get whittled down to the winners and when do these projects begin?

Interviewee: Nisha Gaind

That’s something we’re not quite sure about at the moment. The European Union does science funding in these seven-year blocks, and the next one is going to start in 2021, so we think they will launch in 2021 when this next funding framework kicks in, but the European Commission says it is still trying to figure out how these mega-projects, as they’re called, are going to fit in with this funding programme.

Interviewer: Benjamin Thompson

Let’s move on to story number two, and it’s about mosquitos. Nisha, I must say I’m quite lucky – I seem to be quite repugnant to mosquitos and they don’t often come near me and bite me, but of course, they are super important in the world of public health and I don’t think it’s churlish to say that potentially they’re the deadliest animal of all time – think about all the diseases that they carry. Now, researchers are trying to maybe stymie their hunger a little bit – what can you tell me about this one?

Interviewee: Nisha Gaind

Yeah, absolutely, mosquitos are the insect that everybody loves to hate, and a lot of research projects are focusing on how to decrease the amount of diseases that they spread like malaria, and dengue and Zika. So, in this new research, which was published in Cell, researchers have taken a pretty novel approach to how they can supress mosquitos’ hunger for blood, which ultimately stops them from biting people, and they have used diet drugs.

Interviewer: Benjamin Thompson

Which I guess kind of makes sense, and these are human diet drugs, I suppose, so by giving these drugs to the mosquitos, they suppress their appetites?

Interviewee: Nisha Gaind

Yeah, that’s right. So, the researches knew from previous research that a mosquito’s desire to feed is controlled by molecules called neuropeptides, and they suspected that one particular neuropeptide receptor might be particularly important, so they tweaked some human diet drugs which also target these same receptors, and decided essentially to feed these drugs to mosquitos and see what happens, and it worked. The mosquitos that ate these drugs were much less likely to try and approach what they call a lure, which basically has a human scent, and the drugs suppressed their appetites for two days.

Interviewer: Benjamin Thompson

So, happy days then, I guess just give these drugs to mosquitos and off we go, right?

Interviewee: Nisha Gaind

It if were only that easy – of course, there are a few catches here. One of them is that because they’re using human drugs, if this compound were to be fed into an environment in some way, it could of course have an effect on people, which isn’t what we would want. So, what the researchers then tried to do was to find a version of this drug that works on mosquitos and didn’t work in humans, and eventually they found six promising compounds. Now, the other problem is that they found they would have to administer these drugs in really, really high concentrations, which would probably make it prohibitively expensive to deploy in the field.

Interviewer: Benjamin Thompson

Well, finally then Nisha, and maybe this is a daft question, I don’t know, but how on Earth do you get a mosquito to imbibe an appetite-suppressing drug in the first place?

Interviewee: Nisha Gaind

No, that’s a really good question. So, in the research, they fed the mosquitos these drugs in a kind of solution, but that’s a bit more complicated to do in the wild because you would have to work out how to lure the mosquitos to something to feed on these drugs. Now, one way of doing this is to use basically something that has the profile of a human – it smells the right way – but using those, you might risk attracting other insects as well which you don’t want to damage.

Interviewer: Benjamin Thompson

So, still a way to go on this one then maybe.

Interviewee: Nisha Gaind

Yeah, it looks at the moment like it’s still a pretty complicated and expensive way of doing things.

Interviewer: Benjamin Thompson

Well Nisha, thank you so much for joining us as always, and listeners, to read more about these stories head over to nature.com/news.

Host: Nick Howe

That’s it for this week. Don’t forget to listen to our sister show Science Talk from Scientific American. You can find that wherever you get your podcasts. I’m Nick Howe.

Interviewer: Benjamin Thompson

And I’m Benjamin Thompson. Thanks for listening.