Podcast: Designer cells, and a Breakthrough researcher

Host: Benjamin Thompson

Welcome back to the Nature Podcast. This week, we’re looking at building cells from the bottom up.

Host: Shamini Bundell

And we’ll be hearing from a Breakthrough Prize winner. I’m Shamini Bundell.

Host: Benjamin Thompson

And I’m Benjamin Thompson.

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Host: Benjamin Thompson

First up this week, reporter Geoff Marsh has been learning about creating synthetic cells.

Interviewer: Geoff Marsh

Biologists have been tweaking cells for decades – knocking out, adding, editing genes, adding compounds, removing compounds – essentially taking a top-down approach, starting with the living system in all its complexity and tinkering with it to figure out how it all works. Biology is complicated, so it makes sense that scientists have taken this top-down approach, and it’s served us well, helping us understand the inner workings of cells and create ground-breaking therapies. But more recently, research groups around the world have begun to take a bottom-up approach. Starting from scratch, their aim is to rebuild living systems with a precise knowledge of the individual components. I wanted to talk to a few scientists on the frontlines of this biology engineering and I started with Dan Fletcher, a professor at UC Berkeley in the US.

Interviewee: Dan Fletcher

The basic idea is that from bottom up we can work with components that we understand, so this is where the opportunity to design systems in predictable way comes.

Interviewer: Geoff Marsh

To put it crudely, you’re trying to make cells.

Interviewee: Dan Fletcher

We’re trying to make systems that behave like cells. I think the idea of a synthetic cell is we’re abstracting parts of the cell that we might want to use and seeing if we can build those in controlled ways.

Interviewer: Geoff Marsh

What are the technical challenges of this type of engineering biology because cells, I don’t know, I’ve seen them down the microscope and they just look quite simple and small like little beans, so what’s the challenge?

Interviewee: Dan Fletcher

It’s much easier to take things apart than to put them back together, and I think one of the biggest barriers is developing technologies that let us reassemble minimal parts of cells into synthetic cell-like structures. And another part of the challenge is to incorporate a genome that can continue to produce proteins and regulate the function of the synthetic system, so it’s almost a two-part process.

Interviewer: Geoff Marsh

We’ll come back to creating synthetic genomes in a moment, but as far as making the physical cell structure goes – the 3D membranes made of a lipid bilayer – it turns out that making this isn’t necessarily that difficult. Here’s the University of Minnesota’s Kate Adamala explaining how they make these so-called liposomes.

Interviewee: Kate Adamala

Essentially the same way you make soap bubbles. If you ever played that game where you have dish soap and you have a little loop, and you blow into that loop and you end up with a soap bubble, that’s how we make liposomes basically. They essentially are soap bubbles.

Interviewer: Geoff Marsh

I just got the most fantastic imagery in my head of how fun your lab must be.

Interviewee: Kate Adamala

Laughs. Yeah, our bubbles are smaller.

Interviewer: Geoff Marsh

What are the remaining technical challenges to how we create synthetic cell membranes and compartmentalise stuff?

Interviewee: Kate Adamala

Depending on how do you reconstitute the membrane – what kind of lipids you use, what kind of proteins do you use – you end up with a membrane with very different properties. But also, we need to not only figure out what kind of composition we need, but how to precisely control that composition using that cell’s own metabolism because when we’re building a cell we want that cell to be able to eventually self-replicate and self-sustain everything inside it, including the membrane. So, for example, if we decide that we need 14 different lipids at very specific ratios, then we need to find a way for the metabolism of the synthetic cell to make those lipids at those very specific ratios to maintain the composition of the membrane over the life cycle of that synthetic cell.

Interviewer: Geoff Marsh

Kate also told me that to get close to a real-life cell, these membranes would also need to be studded with a complicated array of proteins and sugars that perform a multitude of functions. Also, she said it’s surprisingly difficult to programme a cell to know how big to grow. In live cells of course, a lot of these instructions ultimately come from the DNA within the cell, and introducing a genome into a synthetic cell comes with its own challenges. Synthetic genomics could be argued to be more top-down that bottom-up because ultimately, they are using genes that exist in nature rather than creating them totally from scratch, but the truth seems to be that it’s somewhere in between. Scientists like John Glass at the Craig Venter Institute in the US recently created an organism with what they deemed to be the bare minimum set of genes required for life. Here’s John.

Interviewee: John Glass

In 2016, we produced an organism that its genome encoded only 473 genes. Now, to our astonishment, one third of those genes, we didn’t know what they did, and most of those genes are conserved not only in other bacteria but even in you and me and plants and life all across the planet. So, the essential operating system genes, this kernel of life, the functions that cells have to do, there is a whole lot of it that we don’t still understand.

Interviewer: Geoff Marsh

What you’re basically saying is bottom-up biology I suppose is going to have to work hand in hand with an element of top-down biology for synthetic genomics?

Interviewee: John Glass

Sure. Imagine that I have a gene that is absolutely essential and I don’t have any idea what it does. And so, if I can take an existing organism and remove that gene and see how it affects that existing organism, now I can incorporate that knowledge into my bottom-up construction of a new genome.

Interviewer: Geoff Marsh

So the synthetic genomicists are essentially kind of the mixologists of the synthetic biology world?

Interviewee: John Glass

Yeah, I guess you could say that. We’re the computer programmers, the guys who write the code.

Interviewer: Geoff Marsh

So with tools starting to come online for creating synthetic cells and manipulating them to have desired functions, Dan Fletcher, who you heard at the beginning of this piece, thinks it’s time the community came together to draw up some shared achievable goals. Here’s Dan.

Interviewee: Dan Fletcher

I think it makes sense to start the grand challenge of rebuilding a cell with a cell or a synthetic cell that could help us in some way. And so, I like the idea of focusing on red blood cells or platelets, things even without a nucleus that, if we could produce them synthetically, would have real health implications. We’d be able to provide synthetic blood to people who need it without bleeding people to get it. Having that as a target means that we can both figure out if our skills and our capabilities and our tools and our understanding are sufficient to rebuild a cell, while at the same time trying to reach a goal that could help people.

Interviewer: Geoff Marsh

And looking further afield, I mean it’s perfectly possible that we’ll visit Mars in the not-too-distant future. Do you reckon that synthetic cells will be coming along with us for the ride?

Interviewee: Dan Fletcher

Yes, I’ll go out on a limb and say we’re going to need them. We’re going to need engineered biological systems to help us overcome the challenges of new environments. We’re not going to be able to wait for evolution to build the biological systems needed to better exist on Mars, so let’s design them.

Interviewer: Geoff Marsh

I’m going to hold you to that. I should be alive in 10-15 years, I’m only 32.

Interviewee: Dan Fletcher

I won’t return your call if I’m wrong.

Host: Benjamin Thompson

That was Dan Fletcher speaking to Geoff Marsh. You also heard from Kata Adamala and John Glass. This week, Nature has a special issue on bottom-up biology that includes an Editorial, a Comment piece, a Feature article, and loads more on the subject. Find all of that at go.nature.com/bottomupbiology.

Host: Shamini Bundell

Later in the show, we’ll be finding out about another announcement in the world of open access publishing – that’s coming up in the News Chat. Before then though, we’re joined in the studio by Ali Jennings and he’s bought this week’s Research Highlights with him.

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Interviewer: Ali Jennings

At the earliest stages of star formation, unattached atoms of hydrogen float through space in giant, dark clouds. To make a star, pairs of hydrogen atoms must bond to form hydrogen molecules. However, it’s been hard for researchers to actually see this happen. But now a group have managed it. When they peered into the gloom of three dark clouds, they saw halos of hydrogen atoms hovering around the clouds’ cores slowly being converted to hydrogen molecules. The researchers suggest their findings may help us understand the speed at which stars, planets and galaxies form. To find out more, take a peek at the Astrophysical Journal, and you’ll be in the dark no more.

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Now, this next story is not for the squeamish. That is unless you like the idea of a swarm of tiny corkscrews burrowing into your eyeballs. Thought not. However, right now, if you want to treat the retina, you have to drop drugs onto the front of the eye and wait from them to diffuse through the eyeball, which can diminish their efficacy. Enter the eyeball screws. A team in Germany have created microscopic glass corkscrews coated in iron and covered in a slippery liquid. This structure allows them to twist their way to targeted areas of the retina. When the team injected the glass gizmos into a pig’s eyeball, the wriggling robots reached the back of the eye in a tenth of the time it would have taken a drug to diffuse there – a result the authors say could lead to faster drug delivery with fewer side-effects. Worm your way over to Science Advances to read more.

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Host: Shamini Bundell

Okay listeners, in reporting, when you hear an event described as the ‘Oscars of X’, it’s usually a fairly lazy metaphor so obviously, you would never hear that said on the Nature Podcast.

Host: Benjamin Thompson

Why do I get the feeling, Shamini, that you’re about to describe something as the ‘Oscars of Science’?

Host: Shamini Bundell

Okay, listen. Last Sunday was the star-studded Breakthrough Prize award ceremony – it’s as close to the ‘Oscars of Science’ as we’re going to get. It was hosted by former James Bond actor, Pierce Brosnan, and featured a performance from Lionel Richie.

Host: Benjamin Thompson

Okay, so 007, Dancing on the Ceiling… okay just this once I’ll allow an event to be described as the ‘Oscars of Science’ on this podcast.

Host: Shamini Bundell

Thank you, Ben, that’s very gracious of you. The Breakthrough Prize recognises researchers making significant scientific advances, and are funded by a bunch of tech entrepreneurs. Once of the winners in the Life Sciences category was Angelika Amon, a biologist at the Massachusetts Institute of Technology in the US. She was recognised for her work investigating the causes of aneuploidy – that is having the incorrect number of chromosomes in a human cell – and how this can lead to serious health issues. Angelika chatted to reporter Zeeya Merali about her research and her excitement at finding out she’d won the prize.

Interviewee: Angelika Amon

I was driving in the car with my daughter and I got a phone call from a friend, who it turned out was on the committee and so forth, and he says sort of very secretly, can you talk and you cannot spill the beans, this is very secretive. So then he told me that I’d won and I had to be very, very careful to not start screaming and being all excited because of course, my daughter was sitting right next to me and her ears grew larger and larger and larger, the more mysterious the conversation went, right.

Interviewer: Zeeya Merali

So, as I understand it, you’re investigating the consequences of sort of abnormal numbers of chromosomes. Can you tell us why you were investigating this problem and what you discovered?

Interviewee: Angelika Amon

When the process goes wrong and cells end up with the wrong chromosome number it has profound implications for human health but we hadn’t really asked why. And so, we decided, you know, I think it’s time to really go deeper and try to understand why things go so badly wrong when chromosomes are mis-segregated. And basically, what we found in a nutshell, is that when you change the chromosome content of a cell, you change the gene content of the cell. And the processes that normally run on all the cellular pathways and run the things that cells do really go havoc, and that really explains how fetuses that have the wrong chromosome number start dying. They just don’t develop right anymore. And then finally, I think the big question is how these changes in copy number affect cancer, and here we’re still working on this. We’re still really facing a puzzle here because all our work on how the wrong chromosome number affects normal cells, it reduces their fitness, it reduces their proliferative capacity, and that’s really at odds with the disease of cancer which is sort of a disease that’s characterised by unrestricted growth and proliferation, right? And so how a condition that has such detrimental effects on normal cells is then exploited by the cancer cells to create a disease that kills you because these cells start proliferating when they shouldn’t, that’s really the big next challenge that we have to face.

Interviewer: Zeeya Merali

And do you think that winning the prize, has that sort of raised the profile of your research?

Interviewee: Angelika Amon

Have I gotten phone calls from pharmaceutical companies? Not so far. But it is my hope that people who are better equipped to translate these basic findings into clinical applications will find our work interesting and worth pursuing.

Interviewer: Zeeya Merali

This is an absolutely huge monetary prize – US$3 million. Have you had a chance yet to think about how you might spend it?

Interviewee: Angelika Amon

Obviously mundane things such as let’s pay off the mortgage come to mind, but I need to sit down and think a little bit more. I would like to do something useful. It’s been a little bit crazy lately.

Interviewer: Zeeya Merali

And right now, we’ve caught you just as you’re preparing to go to this wonderful Breakthrough Prize ceremony. I’ve been to one myself and they are hugely glitzy affairs. You’ve got sort of Hollywood actors and actresses there, it’s going to be hosted by Pierce Brosnan. How are you preparing for that, how is your family preparing for that? It must be tremendously exciting.

Interviewee: Angelika Amon

Yeah, you know, not my favourite thing to be the centre of attention. It’s certainly going to be an exciting experience. My children are thrilled. They are very excited to meet Orlando Bloom. We had to spend a lot of money on clothing and makeup. That money better come afterwards.

Interviewer: Zeeya Merali

So, you told us about your kids wanting to meet Orlando Bloom but who are you excited to meet?

Interviewee: Angelika Amon

I’m excited to meet the founders of the Breakthrough Prize. I think they’ve done something very special and something very important. They’re really trying to put science into the public eye in times where sort of the truth and facts are continuously under attack. Everything is fake news. It’s a terribly important thing that they are doing.

Interviewer: Zeeya Merali

So, this prize is in recognition of your work so far, but what are the big questions that still need to be answered?

Interviewee: Angelika Amon

If you want to understand how life works, you need to understand how cells work. Without them, none of us would be here, right, so to a biologist they are sort of the unit of life, and to me, my greatest passion is to try and figure out how they work.

Host: Shamini Bundell

That was Angelika Amon speaking to Zeeya Merali.

Interviewer: Benjamin Thompson

Finally then this week, it’s time for the News Chat and I’m joined here in the studio by Richard Van Noorden, Features Editor here at Nature. Richard, thanks for dropping by.

Interviewee: Richard Van Noorden

It’s a pleasure, Ben.

Interviewer: Benjamin Thompson

For our first story today, we’ll be talking about an announcement from two large science funders, and they are the Wellcome Trust and The Bill and Melinda Gates Foundation. This announcement centres on the publishing of academic papers and Plan S. So, before we go any further, Richard, what is Plan S?

Interviewee: Richard Van Noorden

Plan S is a plan to get all science papers open access by 2020. Now, it’s only supported so far by about 13 funding agencies across Europe. So, that’s the plan – we haven’t actually seen how these funding agencies will implement the plan, but the Wellcome Trust has this week announced how it’s going to do it.

Interviewer: Benjamin Thompson

Hmm, and I worked at the Wellcome Trust many years ago and open access was very central to their kind of ethos. How has this changed what their plans are?

Interviewee: Richard Van Noorden

Well so far, their open-access policy allows a little delay before your paper has to be made open. Now, the Wellcome Trust says no, from 2020 everything has to be open and free to read immediately. The interesting thing about this is it’s the first time we’re seeing how someone who’s joined up with Plan S is actually saying how they will carry it out. Now, Plan S originally seemed to say that it would forbid its researchers from publishing in it might be as much as 85% of journals out there right now that don’t permit immediately open access publishing under a liberal publishing license in the way that Plan S wanted, so it looked like researchers could be prevented from publishing in all these journals. Now, the Wellcome interpretation is a little bit more flexible.

Interviewer: Benjamin Thompson

Flexible, how?

Interviewee: Richard Van Noorden

Many journals now are published in a hybrid method, which means they’re subscription. They collect money, they keep most things behind a paywall, but they will make some articles open if they receive payment. But Plan S said that it didn’t want scientists to publish in hybrid journals because these journals charge quite a lot for open access, and if lots of journals adopt this model, it’s not really impelling a global shift to open access. Now, the way that Wellcome has actually implemented Plan S is a little bit more flexible. It’s saying now we won’t provide funding for you to make your articles open in a hybrid journal, but if you really want to publish in a hybrid journal we’re not going to stop you, we’re not going to bar you if you can find the funds in another way. It’s also saying you can even publish in a subscription journal if the subscription journal will let you make an accepted manuscript available online under a liberal publishing license instantly. Now, it’s still really dissuading authors from publishing with hybrid journals or subscription journals, and there are a lot of subscription journals including Nature and Science that are still not currently compliant with what the Wellcome Trust wants.

Interviewer: Benjamin Thompson

Listeners, it’s important to say that Nature’s news team is editorially independent of its publisher. What are publishers of journals that could be affected by this saying about this decision?

Interviewee: Richard Van Noorden

Well, the publishers are anxious because many of them don’t see how to switch their business models, and when I asked them to respond to this latest announcement, most of them, frankly, said not very much. They said we support the Wellcome Trust and we are anxious to ensure that all kinds of open-access publishing models are considered which is, to some people, code for let’s keep hybrid journals going. And we’re still waiting to see at the end of this month what the other agencies that have adopted Plan S will say. Are they going to actually say we’re going to bar hybrid journals, you publish an open access or you don’t publish anywhere, or are they going to introduce some of those flexible loopholes that the Wellcome Trust has introduced.

Interviewer: Benjamin Thompson

I could imagine that when this comes in by 2020, this could quite drastically change the face of scientific publishing.

Interviewee: Richard Van Noorden

Yeah, it really, really could. Now, in another way, maybe it won’t because so far, the number of agencies that have signed up for this plan is 15. This week, the Gates Foundation, the American biomedical funder, also signed up. It already says it wants instant publication, but it hasn’t yet said anything about hybrid. So overall, those are some powerful funding agencies but they only represent a small percentage really of all of the papers that are published in the world, so if American and China don’t follow this then basically we’re left with if you are researcher funded by these agencies, you must publish open access but all the other researchers don’t have to. So, it really will have to see how other agencies will take this.

Interviewer: Benjamin Thompson

Certainly something to keep an eye on there, but Richard let’s move on to our second story today and perhaps some rather disappointing news from Antarctica.

Interviewee: Richard Van Noorden

Yeah, so this is about the ozone hole. It is of course shrinking which is great, although this year, rather disappointingly, slightly larger than what we’ve measured in the past couple of years. Now, the concern here is not about this particular year’s blip, but the wider concern is that there seem to be some rogue emissions of CFCs and other ozone-destroying chemicals, and we’re not sure where they’re coming from and they are slowing down the rate at which the ozone hole is shrinking.

Interviewer: Benjamin Thompson

Certainly, CFCs were the sort of poster chemical for terrible, ecological damage in the 80s and 90s. And I remember when I was a kid you know, they’d been banned from fridges and what have you. So, I mean, where maybe are these sort of rogue emission coming from?

Interviewee: Richard Van Noorden

Well, we know that one of the places they may be coming from still, now, is China. Separate investigations earlier this year by the New York Times and by an advocacy organisation called the Environmental Investigation Agency found that there are at least 18 Chinese factories still making or using a particular CFC called CFC-11, but they can’t be contributing to the rise of these mysterious CFCs in the atmosphere right now because it can take decades for these chemicals like CFCs to make it high enough into the atmosphere to start causing problems.

Interviewer: Benjamin Thompson

So, these ones that are being made now, then, aren’t necessarily the ones to blame for what’s going on up in the Antarctic atmosphere, but it’s ones from the past.

Interviewee: Richard Van Noorden

Exactly, so it’s a suggestion that either some of what’s being made now is getting up there more quickly or that something more was being made in the 2000s that we don’t know about, or perhaps researchers are wrong about how long these chemicals persist in the atmosphere. It’s all a bit of a mystery.

Interviewer: Benjamin Thompson

Yeah, I mean it does sound like a lot of a mystery. What happens next? How do we sort of zoom in on where these chemicals are coming from and do something about it?

Interviewee: Richard Van Noorden

Well, we are waiting for the Montreal Protocols panel that will reassess things like how much CFC is leaking from old refrigerators, and they issue a report every 4 years. And we talked to scientists who are involved in that and they are reviewing all of their measurements of CFCs taken in Japan and South Korea and China, to see if they can figure out where the extra emissions are coming from. And they’re also trying to get into near alleged sources in East Asia, also to get more measurements. And basically, if you can pinpoint where the emissions are coming from, that will help you narrow down that one bit of uncertainty in the whole puzzle.

Host: Benjamin Thompson

Well, thank you, Richard, and listeners, that’s it for this week’s show. As always you can find even more of the latest science news over at nature.com/news.

Host: Shamini Bundell

And if you like your science delivered in video form, check out our YouTube channel, that’s at youtube.com/NatureVideoChannel. Our latest video features a transforming problem-solving modular robot. I’m Shamini Bundell.

Host: Benjamin Thompson

And I’m Benjamin Thompson. Thanks for listening everyone, see you next time.

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