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Life_s Left Turn_ The Strange Science Behind Molecular Asymmetry · Luke's English Podcast

• 0:06
  Speaker 1: Folks, so welcome to another episode of Science of the Times.
• 0:09
  Speaker 1: I'm Simon Khalid.
• 0:10
  Speaker 2: And I'm Tim Coulson.
• 0:12
  Speaker 3: So, Tim, how's the week been?
• 0:14
  Speaker 2: Oh, it's the end of term, so holidays are in sight,
• 0:19
  Speaker 2: heading off to South Africa in less than two weeks.
• 0:22
  Speaker 2: How about you?
• 0:23
  Speaker 1: I mean, I thought every day was a holiday for you,
• 0:25
  Speaker 1: but we won't go into that now.
• 0:27
  Speaker 3: Okay, thanks.
• 0:28
  Speaker 1: I'm really excited about today's guest because it's, you know,
• 0:31
  Speaker 1: I'm a bit biased.
• 0:31
  Speaker 3: It's quite close to my own research.
• 0:34
  Speaker 2: No, and he's in my department. So, you know, we
• 0:36
  Speaker 2: both know Tom. And it's all about the sort of
• 0:41
  Speaker 2: chemistry of the way that life works and the way
• 0:44
  Speaker 2: that cells operate.
• 0:44
  Speaker 3: Yeah, absolutely.
• 0:46
  Speaker 1: It's all about sort of possibly understanding why biology chooses
• 0:52
  Speaker 1: molecules to be arranged in a certain way over others.
• 0:56
  Speaker 1: you know, when there's a 50-50 choice, ostensibly anyway, a choice.
• 1:00
  Speaker 2: Life is selective of the types of the shapes of molecules.
• 1:02
  Speaker 3: Yeah, yeah.
• 1:03
  Speaker 1: The way shapes are arranged in space. So it turns
• 1:06
  Speaker 1: out that he might well have cracked this problem that's
• 1:09
  Speaker 1: been plaguing people for a long time.
• 1:11
  Speaker 2: No, that's super exciting. Well, before we invite Tom Richards on,
• 1:16
  Speaker 2: just to say, please, if you enjoy the podcast, please subscribe.
• 1:20
  Speaker 2: We'll put a link to Tom's paper that we're going
• 1:22
  Speaker 2: to be talking about beneath the podcast Also, please like
• 1:26
  Speaker 2: it and please share it online.
• 1:29
  Speaker 3: Yeah, tell all your friends all about it.
• 1:30
  Speaker 2: Tom, would you like to introduce yourself?
• 1:33
  Speaker 4: Okay, so my name's Tom Richards.
• 1:35
  Speaker 5: I work in the Department of Biology at the University
• 1:38
  Speaker 5: of Oxford and my research team is really interested in
• 1:41
  Speaker 5: understanding the diversity of microbial life. And what we realised
• 1:46
  Speaker 5: quite early on, along with many other people, is that
• 1:49
  Speaker 5: actually most of the tree of life is composed of
• 1:51
  Speaker 5: microbial organisms.
• 1:53
  Speaker 2: And that's not just bacteria and And an archaea, is it?
• 1:57
  Speaker 2: There's all sorts of things.
• 1:58
  Speaker 4: Indeed.
• 1:59
  Speaker 5: A lot of our close relatives are actually single-cell microbes.
• 2:02
  Speaker 5: But like us, they also have a nucleus where they
• 2:05
  Speaker 5: store most of their DNA. And that's the group we're
• 2:07
  Speaker 5: really interested in.
• 2:08
  Speaker 2: So those are eukaryotes, is that right?
• 2:10
  Speaker 4: They are eukaryotes, yeah.
• 2:11
  Speaker 5: And so there's a specific type of eukaryote that's sometimes
• 2:16
  Speaker 5: called protists. But we also study microbial fungi and we're
• 2:19
  Speaker 5: trying to fit them on the tree of life and
• 2:21
  Speaker 5: then understand how the tree of life was shaped by
• 2:24
  Speaker 5: various evolutionary processes.
• 2:26
  Speaker 1: Well, our listeners know all about the tree of life now, don't.
• 2:28
  Speaker 3: They, Tim?
• 2:28
  Speaker 2: I was going to say exactly that because Simon and
• 2:31
  Speaker 2: I chatted to Max Telford about more the animal part
• 2:34
  Speaker 2: of the tree of life. So it's fantastic to actually
• 2:36
  Speaker 2: get you on, Tom, and hear about what most people
• 2:39
  Speaker 2: is kind of the overlooked bit. But before, I mean,
• 2:41
  Speaker 2: you've kind of possibly got a solution to one of
• 2:45
  Speaker 2: something that's been been puzzling biologists for a very long time.
• 2:49
  Speaker 2: We'll come on to that in a sec. And that's
• 2:51
  Speaker 2: really good. Simon's the expert questioner on this, the expert
• 2:55
  Speaker 2: questioner on this compared to me. But before we get on,
• 2:58
  Speaker 2: you told me something amazing just before we came on air,
• 3:01
  Speaker 2: that you've discovered a single-celled fungus that's got an eye.
• 3:05
  Speaker 4: Yes, yeah.
• 3:06
  Speaker 5: Actually, the year before I was born, a great hero
• 3:11
  Speaker 5: in the world of fungal microbial research called Martha Powell
• 3:15
  Speaker 5: did some electron microscopy. So that's microscopy where you can
• 3:18
  Speaker 5: see really fine details of cells. And she saw a
• 3:21
  Speaker 5: structure on the side of these fungal cells that looks
• 3:25
  Speaker 5: just like the eye of insects, the compound eye of insects.
• 3:30
  Speaker 5: And a couple of years ago, we discovered that the
• 3:32
  Speaker 5: proteins that make up that eye structure are similar proteins
• 3:37
  Speaker 5: to what we use to detect light in our eyes.
• 3:40
  Speaker 5: And then we've gone on to show that this structure
• 3:43
  Speaker 5: functions like an eye and enables the fungi to move
• 3:46
  Speaker 5: towards light.
• 3:47
  Speaker 2: That is amazing.
• 3:48
  Speaker 3: Like rhodopsin or something.
• 3:49
  Speaker 4: It is a rhodopsin.
• 3:51
  Speaker 5: And what's cool about this rhodopsin is it's fused to
• 3:54
  Speaker 5: an enzyme that generates the messenger that we use to
• 3:59
  Speaker 5: perceive light, to generate an action potential.
• 4:01
  Speaker 2: So can you break that down for me? Rhodopsin's a protein.
• 4:06
  Speaker 3: It's a membrane protein.
• 4:07
  Speaker 2: Okay, so it's on the edge of the cell.
• 4:09
  Speaker 1: Yes.
• 4:09
  Speaker 2: And it gets hit by a bit of light.
• 4:11
  Speaker 1: Yeah, and there's a conformational, there's a change in shape
• 4:15
  Speaker 1: that occurs.
• 4:16
  Speaker 3: That's the key.
• 4:17
  Speaker 1: Okay.
• 4:18
  Speaker 2: So they can see what's going on around them? Yes.
• 4:21
  Speaker 5: So what's really weird is one subgroup of this fungi
• 4:24
  Speaker 5: has three types of this rhodopsin, and it can see
• 4:27
  Speaker 5: from far red light frequencies right through to blue light frequencies.
• 4:31
  Speaker 5: So technically this fungus can see a wider span of
• 4:34
  Speaker 5: light wavelengths than we can and respond to it. And
• 4:38
  Speaker 5: a lot of people are interested in this system because
• 4:40
  Speaker 5: you can manipulate these proteins to generate action potentials directly
• 4:46
  Speaker 5: in cells. So you can stimulate nerves. So people are
• 4:49
  Speaker 5: using them to engineer optogenetic circuits to control nervous responses
• 4:56
  Speaker 5: by shining lights at cells, essentially.
• 4:58
  Speaker 1: So for our listeners, basically, we can send signals.
• 5:01
  Speaker 2: You can flash a light at one cell. And send
• 5:05
  Speaker 2: a signal down the nose.
• 5:06
  Speaker 5: And actually, this is how neurobiologists are mapping the brains
• 5:09
  Speaker 5: of rats, essentially, by shining lights on different neurons and
• 5:14
  Speaker 5: seeing how they respond.
• 5:17
  Speaker 2: My God, well, that's amazing. It sounds like this fungus
• 5:19
  Speaker 2: would go nuts in a disco. But actually, what we
• 5:24
  Speaker 2: really want to talk about, you've just published a, congratulations,
• 5:27
  Speaker 2: a paper in a journal called PLOS Biology, which is
• 5:30
  Speaker 2: one of the best journals to publish in if you're
• 5:32
  Speaker 2: a scientist, isn't it, or a biologist?
• 5:34
  Speaker 1: Yeah, for sure.
• 5:35
  Speaker 2: And it potentially cracks something that scientists have been bewildered
• 5:41
  Speaker 2: by for a long time, which is life is either
• 5:43
  Speaker 2: left or right handed, but not like I'm right handed.
• 5:48
  Speaker 1: Well, it's not that dissimilar in some ways. Well, it's
• 5:52
  Speaker 1: not so dissimilar to your hands, shall we say, right?
• 5:55
  Speaker 1: So the concept of chirality is, and this is what
• 5:59
  Speaker 1: we're talking about. We're going to be talking about chirality
• 6:02
  Speaker 1: is just for our listeners. It's a, take each one
• 6:04
  Speaker 1: of your hands and your little finger is always connected
• 6:08
  Speaker 1: to your ring finger.
• 6:10
  Speaker 2: Right, okay, down here, yeah.
• 6:11
  Speaker 1: And that's always connected to the longest finger.
• 6:13
  Speaker 2: So they join down.
• 6:14
  Speaker 3: Yeah, so both hands will have the same joints.
• 6:17
  Speaker 2: So if all that fat wasn't there, you'd see where
• 6:19
  Speaker 2: my bones would join.
• 6:20
  Speaker 1: But they're actually mirror images of each other. You cannot
• 6:22
  Speaker 1: pick up one and superimpose it on the other one
• 6:25
  Speaker 1: without flipping it.
• 6:26
  Speaker 2: Yeah, yeah.
• 6:27
  Speaker 1: And so molecules, certain molecules with certain properties.
• 6:30
  Speaker 3: Have this effect.
• 6:32
  Speaker 1: So they're connected to the same atoms, but in space
• 6:36
  Speaker 1: the way they're arranged is different.
• 6:38
  Speaker 2: And life only uses, so Tom, life only uses one hand.
• 6:44
  Speaker 5: All the DNA and RNA of life that we know
• 6:47
  Speaker 5: is right-handed and all the proteins, the amino acids of proteins,
• 6:52
  Speaker 5: apart from one, is left-handed. And that one is called
• 6:57
  Speaker 5: glycine and it doesn't have stereochemistry. And the important thing
• 7:02
  Speaker 5: about the origin, the reason it's so important for the
• 7:04
  Speaker 5: origin of life is that if you polymerize right, right, right, right,
• 7:10
  Speaker 5: the polymerization can carry on. But if you interrupt that
• 7:13
  Speaker 5: with right, right, right, left, then it stops polymerization.
• 7:17
  Speaker 2: A polymer is a long molecule that life uses.
• 7:20
  Speaker 5: So DNA, amino acids form a polymer to make proteins.
• 7:26
  Speaker 4: So whole of life requires polymerization.
• 7:28
  Speaker 2: So it has to choose one or the other.
• 7:29
  Speaker 1: Yeah.
• 7:30
  Speaker 2: And it could, they're kind of equally abundant, are they?
• 7:33
  Speaker 5: So if you have an abiotic chemical reaction... One of
• 7:37
  Speaker 5: the reasons you know it's not produced by life is
• 7:39
  Speaker 5: it's 50-50% production of right and left-handed. And actually many
• 7:45
  Speaker 5: of the drugs we use are abiotically produced and they
• 7:48
  Speaker 5: have a 50-50% combination of those two things.
• 7:51
  Speaker 3: Which is bad.
• 7:52
  Speaker 5: Which is bad because actually, for example, the thalidomide drug,
• 7:57
  Speaker 5: one stereochemical form stops nausea during pregnancy and the other
• 8:03
  Speaker 5: stereochemical form causes development abnormalities. So there's been this massive
• 8:07
  Speaker 5: challenge in pharmacology to try and separate the two stereoisomers.
• 8:15
  Speaker 5: And so lots of people think about this. And our
• 8:19
  Speaker 5: discovery that certain membranes act as is not necessarily new.
• 8:23
  Speaker 5: We've known that there's certain types of compounds will separate stereoisomers.
• 8:29
  Speaker 5: But the demonstration that a membrane that's biologically relevant we'll
• 8:35
  Speaker 5: do it at very high rates, was one of the
• 8:37
  Speaker 5: key discoveries we found.
• 8:39
  Speaker 1: We should probably just let our listeners know that stereoisomers
• 8:42
  Speaker 1: mean the two different types of molecules.
• 8:45
  Speaker 2: The left and the right.
• 8:46
  Speaker 3: The left and the right are called stereoisomers.
• 8:48
  Speaker 2: Yes.
• 8:49
  Speaker 1: And so, okay, so if we go back, I guess,
• 8:53
  Speaker 1: in time and in the development of life, at some point,
• 8:59
  Speaker 1: biologically active or actually biologically important molecules became encased In
• 9:05
  Speaker 1: a membrane.
• 9:06
  Speaker 4: That's right.
• 9:07
  Speaker 5: So we know that's for sure because all life on
• 9:10
  Speaker 5: this planet has a membrane of some type. And what's
• 9:13
  Speaker 5: interesting is that it's not always been the same chemistry.
• 9:17
  Speaker 5: In fact, we have a different membrane chemistry than bacteria do.
• 9:22
  Speaker 4: It's only slightly different. And then archaea have one that's
• 9:27
  Speaker 4: much more different.
• 9:28
  Speaker 2: And archaea, they're an early microbe that's separated from the bacteria.
• 9:33
  Speaker 5: Like So in 1977, Carl Wust discovered a third type
• 9:38
  Speaker 5: of life forms, which are microbial, called archaea. They originally
• 9:42
  Speaker 5: thought they were just a different type of bacteria. But
• 9:45
  Speaker 5: then it was argued that they have so many fundamental
• 9:47
  Speaker 5: differences to bacteria that they were made a separate type
• 9:52
  Speaker 5: of life. And one of those fundamental differences is the
• 9:55
  Speaker 5: membrane chemistry. The phospholipids that make up the membrane are
• 9:59
  Speaker 5: very different. to that of bacteria and eukaryotes.
• 10:01
  Speaker 1: So the eukaryotes and bacteria, in one sense, have similar...
• 10:06
  Speaker 1: They're very similar, yes. And then the archaea ones are different.
• 10:09
  Speaker 1: We can argue on whether they're similar or different, but
• 10:12
  Speaker 1: in one aspect that's key for your work, they're similar, right?
• 10:15
  Speaker 4: Sorry, which one's similar?
• 10:17
  Speaker 3: Sorry, that's my fault.
• 10:19
  Speaker 1: The bacteria and the eukaryotic ones are similar.
• 10:20
  Speaker 4: Generally the same, there's one slight difference.
• 10:24
  Speaker 5: And often, you know, all these membranes have additional chemistries
• 10:29
  Speaker 5: added to them, as you well know better than I do.
• 10:32
  Speaker 5: but the archaea ones are very different. Do you want
• 10:35
  Speaker 5: me to explain how?
• 10:36
  Speaker 2: Yes, please.
• 10:36
  Speaker 5: So the archaea ones are the chain that forms the lipid.
• 10:41
  Speaker 5: The tail is an isoprenoid chain, whereas in bacteria and eukaryotes,
• 10:46
  Speaker 5: it's fatty acids.
• 10:47
  Speaker 2: So they're made from different molecules.
• 10:49
  Speaker 4: Yes, yeah.
• 10:50
  Speaker 5: And then they have a different, they both have this
• 10:53
  Speaker 5: glycerol phosphate head group, which is where the phosphate joins
• 11:00
  Speaker 5: to the lipid. And that is, in archaea, it's bonded
• 11:05
  Speaker 5: at a different point in that sugar molecule. And that
• 11:08
  Speaker 5: bonding reverses the stereochemistry.
• 11:11
  Speaker 1: So just for our listeners who aren't familiar with phospholipids
• 11:16
  Speaker 1: and such, I guess the easiest way to explain it
• 11:18
  Speaker 1: is to say that these molecules have an oil-like fatty
• 11:22
  Speaker 1: acid in bacteria and eukaryotics, chain that doesn't like water
• 11:26
  Speaker 1: and excludes it but of course they're surface facing so
• 11:29
  Speaker 1: then they also have a component the phosphate head group
• 11:32
  Speaker 1: and the rest of the bit that goes on top
• 11:34
  Speaker 1: that faces the water and likes to be in water
• 11:37
  Speaker 1: so they're special molecules they have a little bit that
• 11:39
  Speaker 1: doesn't like to be in water and then they also
• 11:41
  Speaker 1: have a bit that likes to be in water that's
• 11:43
  Speaker 1: why they make such good barriers.
• 11:44
  Speaker 5: Exactly and it's the combination of those two characters you
• 11:47
  Speaker 5: just described that means that they can self-assemble into these compartments.
• 11:52
  Speaker 1: So if you take them and chuck them in a
• 11:54
  Speaker 1: load of water, shake them around, they will form a nice.
• 11:57
  Speaker 4: Generally, yes.
• 11:58
  Speaker 2: A bit like water and oil.
• 11:59
  Speaker 4: Yes, absolutely.
• 12:00
  Speaker 3: For sure.
• 12:01
  Speaker 4: I mean, the classic example is a soap bubble.
• 12:05
  Speaker 5: And actually, some great experiments show that you could extract
• 12:09
  Speaker 5: material from meteorites and essentially form these kind of compartments.
• 12:14
  Speaker 4: But they were.
• 12:16
  Speaker 5: More simplified versions of that. They were made of fatty acids.
• 12:19
  Speaker 5: And they, so they lack the phosphate bit, which is
• 12:22
  Speaker 5: the bit that attracts water.
• 12:23
  Speaker 2: Yeah.
• 12:24
  Speaker 5: And that mean, and they were less stable, right? So, so, so, but, but,
• 12:28
  Speaker 5: but at some point in the evolution of life, we
• 12:30
  Speaker 5: moved to this kind of, this, this fatty substance, this
• 12:34
  Speaker 5: oil that, that was bound to phosphate. And that gave
• 12:39
  Speaker 5: it this kind of increased integrity, which means that you
• 12:41
  Speaker 5: can form much more stable kind of compartments.
• 12:45
  Speaker 2: So basically you're, The types of membranes that you get
• 12:49
  Speaker 2: around bacteria, eukaryotes and archaea, even though they kind of
• 12:54
  Speaker 2: do differ in their structures a little bit, they quite
• 12:57
  Speaker 2: easily form in water as long as you've got the
• 13:00
  Speaker 2: right chemicals there to get them going.
• 13:04
  Speaker 4: That's the key. Yes, they do form quite easily.
• 13:08
  Speaker 5: There's this idea that it was a phase before phospholipids,
• 13:13
  Speaker 5: which was just fatty acids, so it didn't have the phosphate.
• 13:15
  Speaker 5: And they will form readily, but they will also disperse
• 13:19
  Speaker 5: much more easily, especially when there's ions around. And actually,
• 13:25
  Speaker 5: the ions are quite important because they drive some of
• 13:28
  Speaker 5: the chemistry that enables polymerization. So you need a step
• 13:33
  Speaker 5: beyond that where the lipid becomes a phospholipid and becomes
• 13:38
  Speaker 5: more stable.
• 13:39
  Speaker 3: Cool.
• 13:40
  Speaker 1: And so at some point, these molecules surrounded... and formed
• 13:45
  Speaker 1: a barrier and encased and protected other biologically important molecules.
• 13:51
  Speaker 5: Yes, so there was a theory for that called the
• 13:54
  Speaker 5: odd cell hypothesis, which essentially that kind of bag kind
• 13:58
  Speaker 5: of encapsulated some biochemistry that was occurring. and therefore enable
• 14:06
  Speaker 5: it to become subdivided from the environment around it.
• 14:09
  Speaker 2: So like a protocell?
• 14:11
  Speaker 4: Yes, yeah.
• 14:12
  Speaker 1: And so your latest findings suggest that it might be,
• 14:16
  Speaker 1: I mean, you describe it to us, but something about
• 14:20
  Speaker 1: the properties of the membrane itself had something to do
• 14:24
  Speaker 1: with what was encased inside.
• 14:25
  Speaker 2: I was wondering why. where the left-handed, right-handedness was going
• 14:28
  Speaker 2: to come in.
• 14:29
  Speaker 5: So there's been lots of study on the bacterial type
• 14:31
  Speaker 5: and the eukaryote type membrane chemistries we talked about earlier,
• 14:35
  Speaker 5: but really the archaeal type ones have been ignored. And
• 14:38
  Speaker 5: so our study was to focus on what is the
• 14:41
  Speaker 5: permeability characteristics of archaeal membranes. And that's when we found
• 14:45
  Speaker 5: out that actually, in many cases, they're much more permeable
• 14:50
  Speaker 5: And actually some of that permeability characteristic is selects for
• 14:54
  Speaker 5: certain types of stereochemical isomer. So the key initial finding
• 15:00
  Speaker 5: was that the archaeal membrane would exclude right-handed, sorry, left,
• 15:06
  Speaker 5: must get it the right way, exclude the left-handed ribose
• 15:10
  Speaker 5: and deoxyribose, and therefore allow much higher rate of uptake
• 15:16
  Speaker 5: of the right-handed deoxyribose and ribose. And they're the pentose
• 15:21
  Speaker 5: sugars which are so critical for forming DNA and RNA.
• 15:25
  Speaker 2: Please, if you're enjoying this, do subscribe, do like, and
• 15:28
  Speaker 2: please share it. We'll be back in a minute.
• 15:32
  Speaker 4: Hi, Tim.
• 15:32
  Speaker 3: You're looking particularly snazzy today. What are you wearing?
• 15:35
  Speaker 2: I'm wearing a piece from a company called Grace and Garbo.
• 15:40
  Speaker 2: And actually, you know a little bit more about them
• 15:42
  Speaker 2: than I do, to be honest.
• 15:43
  Speaker 3: Yeah, you're right, I do.
• 15:44
  Speaker 2: You're the fashion queen.
• 15:46
  Speaker 1: I'm also wearing a piece from Grayson Garbo. So this
• 15:49
  Speaker 1: is a delightful knitwear outfit set up in Birmingham. What
• 15:54
  Speaker 1: they do is they source knitwear, quality knitwear from all
• 15:58
  Speaker 1: around the world. It's vintage, one-off pieces, many of which
• 16:02
  Speaker 1: they then hand embellish, like the one you're wearing today
• 16:05
  Speaker 1: with its beautiful purple flowers. And so they're big on sustainability.
• 16:10
  Speaker 1: You know, nothing goes to waste. Everything is sort of
• 16:13
  Speaker 1: recycled and reused. And if you want to know more
• 16:16
  Speaker 1: about them, then have a look at the link beneath
• 16:19
  Speaker 1: this episode.
• 16:20
  Speaker 2: And thank you very much to them for supporting our podcast.
• 16:23
  Speaker 2: I hope their sales soar.
• 16:26
  Speaker 3: Thanks a lot, Grace and Garvo.
• 16:28
  Speaker 2: Welcome back, everyone. And we're talking to Tom Richards about
• 16:34
  Speaker 2: why life favours one-handed business. right-handed or left-handed, depending on
• 16:41
  Speaker 2: whether you're talking about the RNA and DNA or the protein,
• 16:44
  Speaker 2: the amino acids and the proteins. And so there's obviously
• 16:49
  Speaker 2: quite a lot to talk about because in the break,
• 16:52
  Speaker 2: which we may put a little discussion on, the two chemists,
• 16:57
  Speaker 2: the two people who know more about chemistry than me.
• 16:59
  Speaker 4: I'm definitely not a chemist.
• 17:02
  Speaker 2: We're going at it.
• 17:04
  Speaker 3: In a friendly way.
• 17:05
  Speaker 2: In a friendly way, yeah.
• 17:07
  Speaker 5: Yeah, so it's important to recognize that all the model
• 17:09
  Speaker 5: systems we're working on are one specific type of phospholipid
• 17:14
  Speaker 5: and highly pure. I mean, which is not very biologically realistic,
• 17:19
  Speaker 5: but that was chosen on purpose because we really wanted
• 17:22
  Speaker 5: to understand the characteristics of certain types of phospholipids.
• 17:26
  Speaker 2: Yeah.
• 17:27
  Speaker 1: And you have the most, I mean, PC is the
• 17:29
  Speaker 1: most abundant one in eukaryotes, so that makes sense.
• 17:31
  Speaker 4: Yeah, yeah, yeah.
• 17:32
  Speaker 2: So what did you do? What was the experiment?
• 17:35
  Speaker 5: So I have to say, you know, this is all
• 17:37
  Speaker 5: a collaboration with my great friend Stefano Pagliara, who's at
• 17:41
  Speaker 5: the University of Exeter. He's a physicist, and he spent
• 17:45
  Speaker 5: a lot of time studying how chemicals cross membranes, much
• 17:49
  Speaker 5: like yourself, Simon. And what we were trying to do
• 17:53
  Speaker 5: is recreate kind of membrane chemicals that which might have
• 17:59
  Speaker 5: been used at alternative phases of the tree of life.
• 18:02
  Speaker 5: And so what you do is you take this mixture
• 18:05
  Speaker 5: of phospholipids and you electroporate it, and they'll form these
• 18:09
  Speaker 5: big vesicles, so these big spheres. So they're forming a compartment,
• 18:14
  Speaker 5: and these are 10 microns in size, so roughly equivalent
• 18:19
  Speaker 5: to many cells.
• 18:20
  Speaker 2: Is that like bacteria? Oh, sorry, eukaryotes?
• 18:23
  Speaker 4: Yeah, that's a most.
• 18:26
  Speaker 4: Small eukaryotes about five microns.
• 18:28
  Speaker 1: Okay.
• 18:29
  Speaker 4: Yeah.
• 18:29
  Speaker 1: So you take electrodes, right? You take electrodes, you put
• 18:33
  Speaker 1: them on the membranes. That's the electroporation part, right? Yeah.
• 18:36
  Speaker 5: And it forms it. And then, and then we, then
• 18:39
  Speaker 5: we run these spheres, these tiny spheres. We, we, we
• 18:43
  Speaker 5: have this kind of, we've built these, these, these not,
• 18:47
  Speaker 5: we've built these unique types of plumbing devices called microfluidics.
• 18:52
  Speaker 5: And we, we put those spheres and we capture thousands
• 18:55
  Speaker 5: of those spheres in little compartments so we can look
• 18:59
  Speaker 5: at them down a microscope, right? And because they're in
• 19:01
  Speaker 5: this plumbing device, you can control the liquid that's moving
• 19:04
  Speaker 5: through that microfluidic device. And then you can, you can
• 19:09
  Speaker 5: change what chemicals are outside the membrane. And before we
• 19:15
  Speaker 5: put those membrane physicals in the microfluidic device, in this
• 19:18
  Speaker 5: plumbing device, we fill them with a fluorescent reporter and
• 19:23
  Speaker 5: that fluorescent reporter gets more fluorescent if it's, contact with
• 19:29
  Speaker 5: compounds which have crossed the membrane into the spherical vesicle.
• 19:37
  Speaker 3: That's really cool.
• 19:37
  Speaker 1: So basically you've got these round balls, you fill them
• 19:41
  Speaker 1: with some fluorescent dye which fluoresces even more once the
• 19:44
  Speaker 1: molecules go in and that gives you your signal.
• 19:46
  Speaker 2: Yes.
• 19:47
  Speaker 3: That's pretty neat.
• 19:47
  Speaker 5: And then you turn the tap on the plumbing device
• 19:50
  Speaker 5: and you run through a different compound, a buffer, a
• 19:55
  Speaker 5: fluid that's got a different compound in it. And you
• 19:57
  Speaker 5: can see how much of the compound crosses the membrane
• 20:00
  Speaker 5: by monitoring how the fluorescence changes.
• 20:03
  Speaker 1: Is the colour always the same for the different molecules?
• 20:06
  Speaker 4: Yes, it is. So you have to do them separately
• 20:08
  Speaker 4: one at a time.
• 20:09
  Speaker 2: Okay, so you're doing one at a time and you
• 20:11
  Speaker 2: can see that the left-handed ones are being taken.
• 20:14
  Speaker 4: Up more quickly than the right-handed ones.
• 20:16
  Speaker 5: Yes, so that's something we're interested in, right, is if
• 20:19
  Speaker 5: you had a 50-50 mix, would it change the rate
• 20:22
  Speaker 5: of uptake? And we've been doing some very preliminary molecular
• 20:26
  Speaker 5: dynamic simulations, which I'm always happy to get advice on,
• 20:33
  Speaker 5: And one of the things we look like is that
• 20:36
  Speaker 5: certain types of the stereochemical form seems like they stick
• 20:39
  Speaker 5: to the top of the glycerol phosphate, the top of
• 20:42
  Speaker 5: the phospholipid, and that might be affecting how permeability progresses.
• 20:49
  Speaker 5: So that's something we're interested in doing long term. So
• 20:51
  Speaker 5: that's me trying to elicit a collaboration now.
• 20:54
  Speaker 2: No, no.
• 20:55
  Speaker 3: That would be great.
• 20:57
  Speaker 2: And so... Has it cracked the problem of why life
• 21:00
  Speaker 2: is kind of right-handed for the DNA and RNA and
• 21:03
  Speaker 2: left-handed for the amino acids?
• 21:04
  Speaker 5: So it provides an explanation for why it's adopted. But
• 21:07
  Speaker 5: as scientists, we have to criticize our own work. And
• 21:11
  Speaker 5: the main criticism of this work is that the type
• 21:13
  Speaker 5: of phospholipid we're using, there's very little fossil record for
• 21:19
  Speaker 5: that type of phospholipid deep in.
• 21:21
  Speaker 4: Is that right?
• 21:22
  Speaker 1: Yeah.
• 21:22
  Speaker 3: For PC?
• 21:23
  Speaker 1: Yeah.
• 21:24
  Speaker 4: No, for the isoprenoid type, yeah.
• 21:28
  Speaker 2: But would it fossilize?
• 21:29
  Speaker 4: You're right.
• 21:31
  Speaker 5: You can get chemical traces from a fossil. But you're right,
• 21:35
  Speaker 5: there is for PC, but not for the... So geochemists
• 21:40
  Speaker 5: are skeptical from that perspective, right? Now, there's lots of
• 21:46
  Speaker 5: ways you could imagine that if there's a bit that
• 21:48
  Speaker 5: the process of physical growth... which we can talk about
• 21:52
  Speaker 5: a bit more if you're interested in, would actually lead
• 21:54
  Speaker 5: to purified vesicles, which could do this. And therefore you
• 21:58
  Speaker 5: get a system which is selecting its own growth. So
• 22:01
  Speaker 5: it becomes like a Darwinian. It's under selection system. But,
• 22:07
  Speaker 5: you know, still there's not much evidence that this type
• 22:10
  Speaker 5: of phospholipid chemistry was present early in abiotic conditions, which
• 22:15
  Speaker 5: means that it had to have probably come about through
• 22:18
  Speaker 5: metabolism or which means you would have had to have
• 22:21
  Speaker 5: some kind of proto-life form before this type of membrane
• 22:25
  Speaker 5: was utilised. So it's possible that this is, you know,
• 22:29
  Speaker 5: like the second act in evolution of life.
• 22:31
  Speaker 2: Yeah, rather than the very first. Yeah.
• 22:33
  Speaker 1: It's quite interesting, actually, because one of the very first
• 22:35
  Speaker 1: podcasts we did was we talked to Adi Pross.
• 22:38
  Speaker 2: That's right.
• 22:39
  Speaker 1: And we were talking about some of these issues and,
• 22:41
  Speaker 1: you know, the origin of life. And we also, you know,
• 22:44
  Speaker 1: we were talking, just talking about sort of The self-propagating,
• 22:48
  Speaker 1: like you.
• 22:48
  Speaker 3: Said, the selection rules and such.
• 22:50
  Speaker 2: Yeah.
• 22:51
  Speaker 3: And it's interesting how it all fits together.
• 22:54
  Speaker 5: So the reason we're so excited about this is because
• 22:56
  Speaker 5: actually if you get polymerization, like I was talking about,
• 23:00
  Speaker 5: with right on right on right for DNA and RNA
• 23:03
  Speaker 5: and left on left on left for amino acids, inside
• 23:06
  Speaker 5: a vesicle, a protocell, that vesicle, if there's enough phospholipid
• 23:12
  Speaker 5: hanging around, will grow.
• 23:13
  Speaker 2: Right.
• 23:14
  Speaker 4: Okay. And as it grows, the surface area increases.
• 23:17
  Speaker 5: Right. As the surface area increases, more permeability function occurs.
• 23:21
  Speaker 2: Okay, so you get more into the cell.
• 23:22
  Speaker 5: And you get what you'll understand, Tim, as like a
• 23:24
  Speaker 5: Darwinian demon. It's much more competitive than the things around
• 23:28
  Speaker 5: it because you have a circular economy. And that's why
• 23:35
  Speaker 5: we were so excited about this.
• 23:37
  Speaker 2: No, and it's very cool. I mean, there's very few
• 23:40
  Speaker 2: rocks that are 4 billion years old when this would
• 23:43
  Speaker 2: have got going. So is the lack of kind of
• 23:47
  Speaker 2: fossil evidence really that damning?
• 23:50
  Speaker 5: I don't think so, but I would say that. So
• 23:53
  Speaker 5: it comes back to these meteorites. So most of the evidence,
• 23:55
  Speaker 5: because most of the rocks on Earth are full of contamination, essentially.
• 23:59
  Speaker 5: But when you study meteorites and you look at the
• 24:02
  Speaker 5: chemical composition of meteorites, you can see like fatty acids
• 24:06
  Speaker 5: come out of it, which is the main components of
• 24:08
  Speaker 5: bacterial membranes, not archaeal membranes. And we were studying mainly
• 24:13
  Speaker 5: archaeal membranes. Now there's a Japanese group that said you
• 24:16
  Speaker 5: can get some selection for stereochemical compounds over bacterial type membranes,
• 24:23
  Speaker 5: but they showed it over a process of 15 hours.
• 24:25
  Speaker 4: This was very slow.
• 24:27
  Speaker 2: Very, very slow.
• 24:28
  Speaker 5: And our process was over three minutes. So it's much
• 24:31
  Speaker 5: more significant.
• 24:31
  Speaker 2: So, and we... Actually, we also spoke to Sarah Russell.
• 24:34
  Speaker 3: We did, yeah.
• 24:35
  Speaker 2: Didn't we, who was in charge of the OSIRIS-REx? Well,
• 24:38
  Speaker 2: was involved in the OSIRIS-REx mission that went to Bennu
• 24:42
  Speaker 2: and did this touch and go and grabbed some asteroid material,
• 24:46
  Speaker 2: brought it back to Earth, and they analysed that and found,
• 24:48
  Speaker 2: you know, 50-50.
• 24:50
  Speaker 3: She was looking at the sort of more inorganic.
• 24:52
  Speaker 2: Yeah, she was looking at the bright.
• 24:54
  Speaker 5: Yeah, but I spent a lot of time going through
• 24:56
  Speaker 5: their supplementary material, looking at what amino acids.
• 24:59
  Speaker 4: Are in there and what.
• 25:02
  Speaker 5: Where do we see selection across membranes for those amino acids?
• 25:06
  Speaker 5: And what was really cool about that study is it
• 25:08
  Speaker 5: was one of the first pieces of evidence I certainly
• 25:12
  Speaker 5: saw where there was an amino acid called arginine being produced,
• 25:16
  Speaker 5: which I didn't think would form abiotically because it's such
• 25:19
  Speaker 5: a big amino acid. And it was there, not huge amounts,
• 25:24
  Speaker 5: but it was there. And arginine was one of the
• 25:27
  Speaker 5: ones that showed the biggest selection for left-handed permeability. along
• 25:32
  Speaker 5: with alanine. So you've got one of the biggest ones, arginine,
• 25:35
  Speaker 5: and one of the smallest ones, alanine.
• 25:37
  Speaker 4: That's amazing.
• 25:37
  Speaker 5: So I was quite excited by that. So I was
• 25:40
  Speaker 5: really excited by those papers.
• 25:41
  Speaker 2: Well, what I'm really impressed at is, you know, every
• 25:44
  Speaker 2: time we write a paper, not all of our listeners
• 25:46
  Speaker 2: will know this, you put a lot of the detail
• 25:48
  Speaker 2: into supplementary information. And I don't think I've ever read
• 25:51
  Speaker 2: a supplementary information. So I'm very impressed.
• 25:55
  Speaker 5: Well, that is one of the few cases I did
• 25:57
  Speaker 5: because it was such an exciting result, you know, to
• 26:01
  Speaker 5: get that data so clean.
• 26:03
  Speaker 1: I'm going to ask what I think is probably likely
• 26:05
  Speaker 1: a very dumb question.
• 26:06
  Speaker 4: Okay.
• 26:07
  Speaker 1: And especially given I'm supposed to know something about this area.
• 26:10
  Speaker 2: Okay.
• 26:10
  Speaker 1: So do we know which way around things went?
• 26:14
  Speaker 3: So could it be that the permeability... You know what
• 26:17
  Speaker 3: I'm trying to say?
• 26:18
  Speaker 1: Could it be that the permeability came first and then
• 26:21
  Speaker 1: we had the encapsulation? Or could it be that those
• 26:25
  Speaker 1: were the molecules that needed to be encapsulated and so
• 26:28
  Speaker 1: the lipids were.
• 26:30
  Speaker 5: Yes, so it's a bit of a chicken and egg question, right?
• 26:33
  Speaker 5: And a lot of the origin of life research is
• 26:36
  Speaker 5: like that. So we don't know which way around it is.
• 26:41
  Speaker 5: In the paper there's a section where we say that
• 26:43
  Speaker 5: actually either way round, having this permeability selection would be favourable.
• 26:48
  Speaker 5: So if you're evolving life from scratch inside a membrane,
• 26:52
  Speaker 5: then you would be able to assemble the components which
• 26:55
  Speaker 5: would favour polymerisation. But then if you had a system
• 26:59
  Speaker 5: that's membrane-free, it would be constantly inhibited in terms of
• 27:07
  Speaker 5: function by contamination from the wrong stereochemistry.
• 27:12
  Speaker 2: Yes.
• 27:12
  Speaker 5: It may possibly have been able to have occurred, but
• 27:17
  Speaker 5: then moving to this memory would immediately give it an
• 27:19
  Speaker 5: advantage over stuff that's not. Now, there's some cool evidence
• 27:22
  Speaker 5: coming out that actually the steps in ribosynthesis, I'm going
• 27:29
  Speaker 5: to get this wrong, I might get this wrong, have
• 27:32
  Speaker 5: certain magnetic property. When they involve an iron, when they're
• 27:35
  Speaker 5: catalyzed by iron, in cell-free abiotic chemistry, you can get
• 27:43
  Speaker 5: different anatomers, sorry, stereoisomers are either attracted or repulsed. So
• 27:51
  Speaker 5: there is a way that in certain environment conditions you
• 27:53
  Speaker 5: can get like separated subunits. So you could have a
• 27:59
  Speaker 5: step where the compounds are forming abiotically that life would
• 28:04
  Speaker 5: require and then But to really get rate, to increase
• 28:09
  Speaker 5: its rate of production, it needs to move into an
• 28:11
  Speaker 5: environment where it excludes those other stereochemical isomers which interfere
• 28:19
  Speaker 5: with it. And that's why we think the membrane is important.
• 28:22
  Speaker 2: That's so cool. So I read a report. Actually, no,
• 28:25
  Speaker 2: I'm exaggerating massively. I read a news article about a
• 28:29
  Speaker 2: report that came out recently that said There is an
• 28:33
  Speaker 2: existential threat to life on Earth if chemists were to
• 28:38
  Speaker 2: create life that's the other handedness. So left handed DNA
• 28:44
  Speaker 2: and RNA and right handed and right handed amino acids.
• 28:48
  Speaker 2: And if they did that, apparently it would be a
• 28:51
  Speaker 2: massive bioweapon and we'd all be at risk of immediate death.
• 28:56
  Speaker 2: Did you hear about this report?
• 28:57
  Speaker 5: I did read about it.
• 28:58
  Speaker 4: So this is the kind of mirrored life report.
• 29:00
  Speaker 2: That's right, mirrored life, yeah. Is that nonsense or should
• 29:03
  Speaker 2: I be lying awake at night worrying?
• 29:05
  Speaker 5: It's one of those things that you could imagine in
• 29:07
  Speaker 5: ways it could be devastating, but whether they're actually realistic
• 29:12
  Speaker 5: or not is difficult to imagine. That's quite a circular statement.
• 29:19
  Speaker 2: I know what you mean, though. Yeah, yeah.
• 29:21
  Speaker 4: So let me think about this.
• 29:22
  Speaker 2: So.
• 29:24
  Speaker 5: I think the main fear is that essentially you would
• 29:28
  Speaker 5: produce agents that are kind of undetected by cellular process
• 29:33
  Speaker 5: that they interfere with physiology.
• 29:35
  Speaker 4: So a bit.
• 29:37
  Speaker 2: Like the developmental stuff you were talking about with the fluid. Yes.
• 29:41
  Speaker 5: Yeah, essentially, yeah. So there's lots of unintended consequences like that.
• 29:46
  Speaker 5: But in terms of the core function....
• 29:52
  Speaker 4: I can't quite imagine.
• 29:54
  Speaker 5: I mean, other than the, you know, because once, if
• 29:57
  Speaker 5: these things are being packaged up in polymers separately, then
• 30:00
  Speaker 5: they're not interfering with each other. It's when you mix
• 30:03
  Speaker 5: the compounds.
• 30:04
  Speaker 2: Together, that's when the trouble starts.
• 30:06
  Speaker 1: Yeah, I think I agree with that. Also, now, I mean, most,
• 30:11
  Speaker 1: I mean, fundamental reactions are so... The enzymes for those
• 30:15
  Speaker 1: are so optimized. They probably wouldn't, they recognize the wrong one,
• 30:20
  Speaker 1: probably just ignore it maybe.
• 30:21
  Speaker 4: I don't know.
• 30:22
  Speaker 5: I agree.
• 30:22
  Speaker 4: I think they would ignore it.
• 30:24
  Speaker 2: We're running out of time, but I've got one more question,
• 30:26
  Speaker 2: if I may. Do you think we're getting close to
• 30:28
  Speaker 2: being able to make artificial life in the laboratory? I mean,
• 30:32
  Speaker 2: you know, you've talked, as you say, about, you know,
• 30:35
  Speaker 2: why it uses kind of one-handedness over the other. This guy,
• 30:38
  Speaker 2: Adi Pross, was talking about dynamic kinetic states. You know,
• 30:44
  Speaker 2: so basically turnovers. We've talked about membranes here forming.
• 30:48
  Speaker 1: David Baker was also talking about designing enzymes.
• 30:53
  Speaker 2: Are we close or is it a long way off?
• 30:56
  Speaker 5: I think you could take, if you take not just
• 31:01
  Speaker 5: our work, lots of other work about this idea that
• 31:03
  Speaker 5: you can make self-sustaining polymerization inside vesicles, you could make
• 31:10
  Speaker 5: a system that looks like a living organism. as in
• 31:13
  Speaker 5: it's like growing and replicating, right? But it's not doing
• 31:19
  Speaker 5: metabolism to sustain itself. It's requiring an environment which provides.
• 31:26
  Speaker 4: All the metabolites in place.
• 31:28
  Speaker 5: Now, there's lots of life forms that are like that,
• 31:31
  Speaker 5: but so it has some characteristics of life.
• 31:35
  Speaker 4: So I think.
• 31:36
  Speaker 5: You could do that, but whether it would be so fragile.
• 31:40
  Speaker 4: That it's not really.
• 31:44
  Speaker 4: A stable organism.
• 31:46
  Speaker 1: So it wouldn't be able to make and use its
• 31:49
  Speaker 1: own energy. I mean, you can't make energy, but you
• 31:50
  Speaker 1: know what I mean.
• 31:51
  Speaker 4: Yeah, I know what you mean, yeah. No, it wouldn't
• 31:53
  Speaker 4: be able to do that.
• 31:55
  Speaker 2: Well, Tom, thank you very much for coming on. Congratulations
• 31:58
  Speaker 2: on the paper. It's a really great bit of work.
• 32:00
  Speaker 2: For sure. I love listening about that. And yeah, we'll
• 32:04
  Speaker 2: have to get you back on with the next breakthrough
• 32:06
  Speaker 2: at some point.
• 32:07
  Speaker 3: About the eyes. I want to know about the fungal eyes. Yeah,
• 32:10
  Speaker 3: the fungal with the eyes.
• 32:13
  Speaker 2: Fantastic.
• 32:14
  Speaker 4: Thank you for having me.
• 32:15
  Speaker 2: Well, that was absolutely fascinating, Simon. Honestly, I had no
• 32:17
  Speaker 2: idea that chemistry could be so interesting.
• 32:21
  Speaker 3: I don't know why I put up with you. Yeah, no, absolutely.
• 32:25
  Speaker 3: I think it's opened up.
• 32:27
  Speaker 1: It's answered lots of questions, perhaps, but it's also opened
• 32:29
  Speaker 1: up lots of questions. And so I think that's what's
• 32:31
  Speaker 1: also really nice about it is that Tom, you know,
• 32:34
  Speaker 1: he tells it like it is. And he's explained that,
• 32:37
  Speaker 1: you know, these membranes that they've worked with are, simplified
• 32:42
  Speaker 1: versions of the real membranes and it leaves a lot
• 32:46
  Speaker 1: of other questions. I think it's going to be an
• 32:49
  Speaker 1: interesting thing for us to keep an eye on for
• 32:50
  Speaker 1: a long time.
• 32:51
  Speaker 2: No, I think one of the things that, I mean,
• 32:53
  Speaker 2: this is what science so often does, right? You solve,
• 32:56
  Speaker 2: you make progress on one problem and then it throws
• 32:58
  Speaker 2: up a load more questions, right? Yeah, absolutely.
• 33:01
  Speaker 3: And it kind of, it has to, right?
• 33:03
  Speaker 1: None of the questions we address are ever, there's never
• 33:05
  Speaker 1: a full stop at the end.
• 33:06
  Speaker 3: There's always something else. And I think.
• 33:09
  Speaker 2: Which is just as well, otherwise we'd do ourselves out
• 33:11
  Speaker 2: of a job every time.
• 33:12
  Speaker 3: You'd be on holiday every day, Tim.
• 33:16
  Speaker 2: Something like that. Something like that. But no, I think
• 33:18
  Speaker 2: it's fascinating stuff and let's keep an eye on it.
• 33:20
  Speaker 2: And you might have got a new collaboration by the
• 33:21
  Speaker 2: sound of it.
• 33:22
  Speaker 3: Yeah, absolutely.
• 33:22
  Speaker 1: Well, I think Tom and I have been trying to
• 33:24
  Speaker 1: do this for a while. So yeah, we might get
• 33:25
  Speaker 1: around to it now.
• 33:26
  Speaker 2: Yeah.
• 33:26
  Speaker 3: Absolutely.
• 33:27
  Speaker 2: Well, if you want to know more, go and read
• 33:29
  Speaker 2: the paper, which is in the link below. And please
• 33:32
  Speaker 2: subscribe and please like and please share on social media.
• 33:36
  Speaker 2: And we'll see you Next week when dinosaurs, perhaps?
• 33:42
  Speaker 4: Possibly.
• 33:42
  Speaker 2: Yeah, who knows?
• 33:43
  Speaker 3: Could be dinosaurs, could be wasps. It could be anything.
• 33:46
  Speaker 3: You'll just have to watch out, folks.
• 33:48
  Speaker 2: We're more organised than that, listeners. Okay. Goodbye.
• 33:52
  Speaker 3: Bye.