Latest / The Biorevolution Podcast / Into the dark – finding meaning within the depth of our proteome

Transcript

Into the dark – finding meaning within the depth of our proteome · The Biorevolution Podcast

• 0:04
  Speaker 0: The Biorevolution podcast.
• 0:06
  Speaker 2: Your hosts.
• 0:07
  Speaker 0: Luise von Stechhoch.
• 0:08
  Speaker 2: And Andreas Reuchler.
• 0:13
  Speaker 2: The Biorevolution podcast, this time into the dark, finding meaning within the depth of our podium.
• 0:20
  Speaker 2: This time we have a very, very interesting guest.
• 0:24
  Speaker 2: He comes from the US, slash India.
• 0:26
  Speaker 2: He comes from India originally, but has been in the US for a long, long, long time right now as an academic, as a scientist, as a researcher.
• 0:36
  Speaker 2: And as always easy, we start with a quote this time from our guest
• 0:42
  Speaker 0: from
• 0:43
  Speaker 2: a book yet to be published.
• 0:50
  Speaker 0: Yes,
• 0:50
  Speaker 2: the book
• 0:51
  Speaker 0: is called Eclipse Horizon by Sotakaran Prabhakaran.
• 0:55
  Speaker 0: And I think it will be out in February.
• 0:58
  Speaker 0: And in this book, I think he really captures the essence of what our podcast is about pretty well.
• 1:04
  Speaker 0: which is this really revolutionary potential of biotechnologies that span from potential to really save our species from extinction towards really changing humanity in a very profound way and also leading to the understanding of what it actually means to be a human in a biological sense.
• 1:25
  Speaker 0: In this book we start in the year two thousand one hundred and eighty four.
• 1:33
  Speaker 0: Humanity stands at the precipice of an evolutionary divergence.
• 1:36
  Speaker 0: The old earthbound lineage has reached its limits, trapped by the constraints of biology, physics and an increasingly inhospitable planet.
• 1:46
  Speaker 0: What began as a threat, a combination of climate collapse, resource depletion and the looming specter of planetary extinction has birthed a radical solution.
• 1:56
  Speaker 0: the conscious compression of our genome, the shift from Homo sapiens to a newly optimized species.
• 2:03
  Speaker 0: Homo minimus is underway.
• 2:05
  Speaker 0: I think this is a great start to a book, makes me want to read more and I was lucky enough to actually do read more and it continues being a very very good read.
• 2:15
  Speaker 0: We will of course link this book in the show notes.
• 2:18
  Speaker 0: And now let me quickly introduce our guest before we dive right into this really, really interesting topic.
• 2:25
  Speaker 0: Dr.
• 2:25
  Speaker 0: Sudhakaran Prabhakaran is an associate teaching professor at Northeastern University, and he's also the CEO of a biotech non-exomics that works at the intersection of computational biology, AI-driven drug discovery, and the dark genome.
• 2:41
  Speaker 0: And there he really wants to explore the potential of groundbreaking genomics technologies and proteomics technologies for finding novel therapeutic hypothesis.
• 2:54
  Speaker 0: And as I introduced, he is also the author of the upcoming book, Eclipse Horizon, which takes this journey through the dark genome, but goes into the questions of evolution of the future of our species, of the future of our planet.
• 3:10
  Speaker 0: And might I say even the meaning of life a little bit.
• 3:15
  Speaker 0: Let's dive into this discussion and maybe start a little bit small because now I really laid it on pretty heavy in the beginning and maybe we can take smaller steps towards approaching all these exciting topics.
• 3:28
  Speaker 0: So we talked about it before, right?
• 3:30
  Speaker 0: There are a lot of parts of our genome that don't make sense to us as researchers and there has a term been coined for it in the nineteen seventies, which is junk.
• 3:41
  Speaker 0: which I think was debated already in the scientific community as maybe not being the most scientific term for parts of the genome that we don't understand.
• 3:50
  Speaker 0: And I think it was also meant by the guy who phrased it more in a controversial way just to spark interest, to spark debate probably.
• 3:59
  Speaker 0: But it was picked up, I think.
• 4:00
  Speaker 0: So for me, that was a common term when I studied biology that we have junk DNA.
• 4:06
  Speaker 0: this junk DNA, maybe we could classify as the parts of the genome we just couldn't make sense of, right?
• 4:12
  Speaker 0: Just the parts that do something, maybe they don't do anything, and maybe they don't have any meaning whatsoever.
• 4:19
  Speaker 0: And this really sparked the debate already of functionality.
• 4:23
  Speaker 0: So why do we have so much stuff in our genome that doesn't make sense?
• 4:28
  Speaker 0: And there are a number of cues of why maybe this large part consider it maybe ninety-eight percent of our genome that don't make sense.
• 4:40
  Speaker 0: The question of why would we actually carry along such a heavy load of junk?
• 4:47
  Speaker 0: That really doesn't seem to make too much sense, right?
• 4:50
  Speaker 0: So the question is, is it really all junk or is there some hidden meaning in it?
• 4:55
  Speaker 0: And I think this is something that we want to dive in today.
• 4:59
  Speaker 0: And maybe I can hand over Sudhakaran to you.
• 5:02
  Speaker 0: So where would you say are the most, I mean, in this trajectory of classifying, we have DNA, it does something, we have a hypothesis of how much of it is meaningful.
• 5:16
  Speaker 0: Where would you say are the maybe the most surprising events, the most surprising findings over the last decades where you felt like the field went through a shift?
• 5:26
  Speaker 1: First of all, thank you, Luis, for inviting me to your podcast.
• 5:29
  Speaker 1: And thank you, Andreas.
• 5:31
  Speaker 1: as well.
• 5:31
  Speaker 1: It's great and it's a honor to be here and I've been following your podcast covering biotech research findings and excitement in the field.
• 5:38
  Speaker 1: It's an honor to be here.
• 5:39
  Speaker 1: So to answer your question, a lot has to happen and you probably know as well as I do because you've been in the field working as a PhD student in postdoc as well, right?
• 5:48
  Speaker 1: So it started with a human genome project which culminated in two thousands.
• 5:53
  Speaker 1: When we finished the first draft of the human genome, as humanity, we realized that there are around twenty thousand to forty thousand genes.
• 6:01
  Speaker 1: But initially prior to the sequencing, it was estimated that we should have at least hundred to two hundred thousand genes.
• 6:08
  Speaker 1: A bit more complex than other organisms that we have sequenced like Drosophila and Ease, which are like smaller organisms.
• 6:14
  Speaker 1: But the puzzle was like, you know... Why do we still have the same number of genes as those organisms, right?
• 6:20
  Speaker 1: And then from two thousand to two thousand twenty up until now, a lot of people started looking at to, you know, what is this doing?
• 6:29
  Speaker 1: Are these other regions that were, as you rightly said, Stephen Ono, I believe, in nineteen seventies coined the term junk DNA.
• 6:35
  Speaker 1: Are these really junk?
• 6:37
  Speaker 1: Are they doing anything at all?
• 6:38
  Speaker 1: Then there was this big consortium of academic labs and Organizations that came together under an umbrella called the ENCODE project, and they systematically curated, like, what are these other regions doing?
• 6:51
  Speaker 1: And they noticed that, and they kind it with an interesting term, they called it biochemically active.
• 6:56
  Speaker 1: They said the rest of the genome is also biochemically active.
• 6:59
  Speaker 1: And it means a lot of things to a lot of people.
• 7:02
  Speaker 1: For example, there are mutations that affect other proteins, other genes, the known genes rather.
• 7:08
  Speaker 1: There could be regions that are opening up and closing.
• 7:11
  Speaker 1: enabling and disabling gene expressions and there could be regions which are basically repeat regions like multiple repeat regions and there could be.
• 7:20
  Speaker 1: there are regions which are actually making RNAs but not proteins so they were called as non-coding RNAs and non-coding RNAs blah blah blah.
• 7:29
  Speaker 1: and then there was this other fear which emerged from that effort where they noticed viruses being embedded in those regions, and that itself is a different, complete fail.
• 7:40
  Speaker 1: So around twenty fourteen, like when we started observing that these other regions, the rest of the ninety eight percent, can also make proteins.
• 7:48
  Speaker 1: That was the thing that we personally got excited in.
• 7:51
  Speaker 1: That was during the end of my post-rotler days, and we kind of, few other labs were also reporting that the human genome has this capability pervasively to make proteins, and that's kind of started off.
• 8:04
  Speaker 1: whatever I did in the last ten, fifteen years.
• 8:06
  Speaker 1: So proteins, RNAs, viruses, repetitive treatments, everything is biochemically active.
• 8:12
  Speaker 0: And I think one thing that also struck me as really exciting is that parts of the genome can just jump around.
• 8:18
  Speaker 0: That is interesting.
• 8:20
  Speaker 0: That we thought is something that only happens in bacteria and then maybe in plants and then it turned on.
• 8:25
  Speaker 0: happens in humans as well, and more than we thought.
• 8:28
  Speaker 0: And this, of course, also has some profound implications, right, that our genome is not as stable as we thought.
• 8:35
  Speaker 0: So it's not this, we think of the genome as this like, you know, like ancient text in a library that can only be touched by like the special librarian with the white gloves and no one can do anything about it.
• 8:47
  Speaker 0: And it seems more like a Word document where stuff can be like kind of shifted around and This is actually kind of interesting.
• 8:55
  Speaker 1: Very well said, yeah, exactly.
• 8:58
  Speaker 1: So from the seventies when we kind of addressed, when I say V, I'm kind of referring to humanity as such, kind of referred to these regions as junk, then there were these ideas, as you mentioned, some of these repetitive regions were actually moving around.
• 9:12
  Speaker 1: And that sparked a big debate.
• 9:14
  Speaker 1: There was somebody called Richard Dawkins who wrote this book called Selfish DNA, where he kind of put in this thought that they're probably existing just to copy themselves.
• 9:24
  Speaker 1: They're not doing any favor to host genome.
• 9:28
  Speaker 1: And that's primarily the primordial reasons why we are all here, because our need to copy, whether it's a small repetitive genome or a big genome, that's probably what happened after that.
• 9:50
  Speaker 2: May.
• 9:51
  Speaker 2: I quickly jump in first off must confess.
• 9:53
  Speaker 2: I'm really happy.
• 9:54
  Speaker 2: It's not two thousand one hundred and something yet because I have no interest whatsoever to become all more minimalist.
• 10:02
  Speaker 2: So
• 10:03
  Speaker 0: maybe you will be much optimized.
• 10:05
  Speaker 2: Probably.
• 10:06
  Speaker 2: Yes.
• 10:06
  Speaker 2: But I'm not so looking forward to that.
• 10:09
  Speaker 2: I rather stick to who I am.
• 10:10
  Speaker 2: I like it.
• 10:11
  Speaker 1: But if you want to go to Mars or beyond Mars,
• 10:14
  Speaker 2: I don't.
• 10:15
  Speaker 2: Yeah,
• 10:16
  Speaker 0: we will.
• 10:16
  Speaker 0: We will a little bit.
• 10:17
  Speaker 0: I think this is this is a really Really, really interesting thought experiment that I think we have to dive into a little bit at the end of this podcast.
• 10:27
  Speaker 0: Once we discussed like the hard science, I think we'll get there.
• 10:30
  Speaker 2: But as a non-scientist on the table, this was my initial point.
• 10:34
  Speaker 2: Listening to you, I must say that I would be very interested to know a little bit more about where do we stand right now.
• 10:42
  Speaker 2: So if I look at the timeline around the year two thousand, we thought we figured it out finally.
• 10:50
  Speaker 2: Then a little bit later, we find out junk is not that junkie after all.
• 10:56
  Speaker 2: So we're in a process.
• 10:58
  Speaker 2: where would you say with these mighty plus percent, where do we stand right now?
• 11:03
  Speaker 2: And what is your thinking?
• 11:05
  Speaker 2: What is your take about?
• 11:06
  Speaker 2: What is about to come?
• 11:07
  Speaker 1: That's a very interesting question, Andreas.
• 11:09
  Speaker 1: In fact, it's quite scary.
• 11:11
  Speaker 1: I'm living in the Boston area.
• 11:13
  Speaker 1: As you probably know, every week there's a new company with a new technology that's emerging.
• 11:18
  Speaker 1: A lot has happened since two thousand.
• 11:20
  Speaker 1: You know, it used to cost us around two billion dollars to sequence a single genome.
• 11:24
  Speaker 1: Now we are talking about a hundred, two hundred dollars, right?
• 11:27
  Speaker 1: Yes.
• 11:27
  Speaker 1: And then we are also talking about computational power.
• 11:30
  Speaker 1: We are no more doing it in our systems at our home.
• 11:33
  Speaker 1: We are doing it in cloud.
• 11:34
  Speaker 1: We are talking about we are in gendered AI space now.
• 11:37
  Speaker 1: A lot of genomics is now almost in gendered AI space.
• 11:41
  Speaker 1: We figured out the structures of proteins of almost all the proteins that is ever known using Alpha Fold and ESM Fold and a lot of other machine learning slash gendered AI tools.
• 11:52
  Speaker 1: It's quite scary to even predict what's going to happen in the next six months.
• 11:56
  Speaker 1: to be really honest and I don't know where it's going.
• 11:58
  Speaker 1: And a lot of my colleagues whom I kind of talk to I invite them to present in my even sessions.
• 12:05
  Speaker 1: They are also kind of in the same boat.
• 12:07
  Speaker 1: They don't know where it's going.
• 12:08
  Speaker 1: But I think the world will be a lot different from where we are right now.
• 12:11
  Speaker 1: I think that's for sure.
• 12:13
  Speaker 0: So what we're discovering are more and more regions that might have functional relevance also through just sequencing more of the genome and having more insights by AI.
• 12:27
  Speaker 0: which of these variants of the genome might be functionally relevant?
• 12:31
  Speaker 0: and I think one thing that I think we didn't discuss yet but that we'll get into is the question is when is it functional?
• 12:39
  Speaker 0: because not everything is functional in everything.
• 12:41
  Speaker 0: context, because it doesn't have to be.
• 12:43
  Speaker 0: But biology is like a super, super complex map of interactions of buffering of network of feedback loops or whatever.
• 12:53
  Speaker 0: So you will have functionality under a certain condition under a certain in the morning, but not in the evening.
• 13:00
  Speaker 0: If you're standing up, but not if you're sitting down, if you're a man, but not if you're a woman, if you are at but not if you're a twenty, if you had sugar, if you didn't have sugar.
• 13:09
  Speaker 0: And I mean, this is a very very, very simplified version of all the other things that can go on.
• 13:15
  Speaker 0: And this means functionality is not a yes-no status.
• 13:19
  Speaker 0: It's a status of under which conditions does it have a function.
• 13:23
  Speaker 0: And I think here this makes it so complicated to say something is functional or non-functional because there are conservative people who say like only eight percent are or ten percent of the genome are functional because there if you take them out, everything would collapse kind of.
• 13:42
  Speaker 0: But again, then the question is under which conditions would it collapse, which brings us to our thought experiment in a second.
• 13:48
  Speaker 0: But what I think we are discovering is that we have a number of different regulatory elements.
• 13:53
  Speaker 0: We have these viral remnants, these herbs and herbs, these elements that used to be viruses somehow integrated into.
• 14:02
  Speaker 0: our DNA and with our, I mean, also the evolution that came before humans.
• 14:07
  Speaker 0: So it's not human specific.
• 14:08
  Speaker 0: There are a lot of remnants of viruses such as retroviruses that actually infected our ancestors at some point and then just became part of our genome.
• 14:18
  Speaker 0: For example, the placental gene for the mammal origin actually seems to be at least influenced or part of a retrovirus.
• 14:27
  Speaker 0: So here, I mean, there is a really these viruses interact with us, not all of them, but some of them can actually also be reactivated.
• 14:35
  Speaker 0: So we have these guys, we have a lot of RNAs that have many different functions.
• 14:40
  Speaker 0: And when I studied in two thousand two, I think the micro RNAs and as RNAs were pretty freshly discovered in the late nineties.
• 14:51
  Speaker 0: And I was so fascinated that there was a completely new molecule being discovered that no one had ever heard of.
• 14:58
  Speaker 0: So I'm wondering, Suthakaran, do you think there will actually be new molecules that we don't know about, that we are seeing emerging from, I mean, maybe not completely new species, but new species of RNAs or peptides or something that we haven't heard about or something completely different that will come out of the dark genome, maybe?
• 15:17
  Speaker 1: Thank you, Luis.
• 15:17
  Speaker 1: You're actually a good segue into what we've been working on all these years.
• 15:21
  Speaker 1: I can explain that in that context.
• 15:23
  Speaker 1: So as Luis mentioned, function means a lot of things to a lot of people.
• 15:27
  Speaker 1: For us, function means the ability to make proteins, right?
• 15:30
  Speaker 1: So what we have seen and a few other groups as well have noticed is that we have personally systematically curated and cataloged two hundred fifty thousand additional set of proteins on top of the twenty thousand that is known and seen and investigated by every other group.
• 15:46
  Speaker 1: This additional two hundred fifty thousand proteins we have in the last couple of years mapped their structure and inferred their function and inferred their dysfunction and different diseases and also investigated whether they can be modulated.
• 16:00
  Speaker 1: by different mechanisms and cure those diseases.
• 16:03
  Speaker 1: So that is all known and true information that I'm just giving you.
• 16:08
  Speaker 1: But in addition to that, computationally, we have predicted there are at least two million such proteins in the human genome.
• 16:15
  Speaker 1: And as Louise correctly mentioned, they're not all the time being made.
• 16:19
  Speaker 1: And they're being made under specific conditions or specific physiological state.
• 16:26
  Speaker 1: For example, different periods of growth, different disease conditions, different tissues, different statuses and situations.
• 16:33
  Speaker 1: The way I look at it is that the twenty thousand or so known proteins is something like housekeeping genes, like something that is necessary to make us all.
• 16:42
  Speaker 1: But then there's a difference between different individuals and different organs.
• 16:47
  Speaker 1: respond to different kinds of stress and for that they can't just rely on those twenty thousand genes.
• 16:51
  Speaker 1: so they have to make new things like think of genome as a as a Lego.
• 16:55
  Speaker 1: you just take bits and pieces of Lego and make a new protein and then the new protein does a new function.
• 17:02
  Speaker 1: now you can ask why are we not finding them all the time?
• 17:05
  Speaker 1: probably after the stress is gone this protein disappears.
• 17:09
  Speaker 1: you know doesn't need it.
• 17:10
  Speaker 1: for example What we have shown in the evolutionary analysis is that newly evolving regions of the human genome that are called accelerated regions that are not even present in primates, they make proteins and those proteins are very strongly associated with schizophrenia, bipolar, those kind of cognitive dysfunctions, which indicates that there are some new proteins that are being made and specific for human cognition and probably they are disrupted in cognitive diseases like... Schizophrenia bipolar, psychotic diseases.
• 17:42
  Speaker 1: So it kind of puts in all these things together and we have seen this in other organisms too, even fishes.
• 17:48
  Speaker 1: We have shown that speciation occurs not by changes to the existing known set of proteins but by making new proteins that is needed for that specific environment.
• 17:58
  Speaker 1: And I'll come into that example in a bit more specifically giving you what that example is.
• 18:03
  Speaker 1: So that's pretty much what I want to explain to you that functionally we are seeing proteins being made throughout the human genome.
• 18:10
  Speaker 1: In fact, a lot of these long non-coding RNAs that we have claimed that they are not making any proteins, we have shown that and other people have also shown that they're making proteins.
• 18:20
  Speaker 1: Yeah.
• 18:20
  Speaker 1: So some of them are not the full-length proteins that three hundred amino acid proteins that we are usually used to seeing.
• 18:26
  Speaker 1: There could be thirty amino acids, four hundred amino acids, you know.
• 18:30
  Speaker 0: Why is it that we're only now seeing these proteins?
• 18:34
  Speaker 0: Why didn't we capture them in the human genome project back then?
• 18:38
  Speaker 1: Thank you for asking.
• 18:39
  Speaker 1: I get this asked all the time.
• 18:40
  Speaker 1: It's not that we are just making it up.
• 18:42
  Speaker 1: It's just that.
• 18:43
  Speaker 1: let me let me give you another metaphor.
• 18:45
  Speaker 1: Let's say we are flying at forty thousand feet in a Boeing three seven three seven right over the Himalayas and we are able to see only the top eight peaks right.
• 18:55
  Speaker 1: and then as we come down to twenty thousand feet we are seeing other peaks which are less than eight thousand meters.
• 19:01
  Speaker 1: and then as you keep landing we are seeing smaller valleys and then small houses and small trees and small stones.
• 19:07
  Speaker 1: So the reason why we didn't see is primarily because we are not looking for it.
• 19:11
  Speaker 1: Our technology didn't allow us to look for what the entire genome is capable of doing.
• 19:15
  Speaker 1: What is it doing?
• 19:16
  Speaker 1: We were just seeing what we wanted to see.
• 19:18
  Speaker 1: For example, currently if you ask how proteomics experiment is done, people look at a set of whatever they're collecting mass spec data or ribosome data.
• 19:28
  Speaker 1: they're only looking at a known set of proteins that they have already identified and then seeing the signatures.
• 19:34
  Speaker 1: okay is this protein being expressed in the cell line?
• 19:36
  Speaker 1: is this protein being expressed and they take off those boxes but they discard around sixty seventy percent of information that they don't know what to do with it.
• 19:44
  Speaker 1: either the too noisy because the technology was not that sensitive or they don't know what to do with it.
• 19:49
  Speaker 1: it's it's been always there in fact a lot of information that we collect.
• 19:53
  Speaker 1: It's been already collected by other groups.
• 19:55
  Speaker 1: We just take that information and re-analyze it.
• 19:58
  Speaker 1: Ten years ago, we couldn't do those algorithmic crunching.
• 20:01
  Speaker 1: that we are able to do right now.
• 20:04
  Speaker 1: And more data is becoming available because the sequence it costs is, as I said, come down from two billion dollars to a few hundred dollars.
• 20:11
  Speaker 1: So all of this has enabled us to dig deeper.
• 20:20
  Speaker 0: Could you explain briefly what the role of ribosome sequencing is and how that works like in a way that also maybe our non-scientist listeners might glimpse why this is actually important?
• 20:32
  Speaker 1: So thank you.
• 20:33
  Speaker 1: So the ribosome is a machinery where the RNAs bind to the ribosomes and they make proteins, right?
• 20:40
  Speaker 1: So ribosome sequencing is nothing but a methodology where as the RNA is binding to the ribosome, it's fixed.
• 20:48
  Speaker 1: in some using some chemical induction and then we pull out those ribosomes and sequence whatever that is bound to the ribosome the RNA that is bound to the ribosome.
• 20:57
  Speaker 1: Here we are kind of taking a big leap faith assuming that whatever that is bound.
• 21:01
  Speaker 1: RNA that is bound is getting translated into proteins.
• 21:04
  Speaker 1: So the actual term for that is translate home not proteome because we're just inferring whatever is bound to RNA.
• 21:10
  Speaker 1: ribosome is getting converted into proteins.
• 21:13
  Speaker 1: But then there's another technology which I'll come to, it's called mass spectrometry, where we are actually directly sequencing the proteins and not relying on whether they are binding to ribosome or not.
• 21:23
  Speaker 1: So there's a kind of two complementary methodology that we always use to identify these so-called dark proteins.
• 21:29
  Speaker 0: What does a dark protein mean to you?
• 21:32
  Speaker 0: How would you classify what a dark protein is?
• 21:36
  Speaker 1: It's a very interesting question.
• 21:37
  Speaker 1: So that protein for us means simply proteins that have not currently annotated.
• 21:42
  Speaker 1: So what I mean by annotation is at the moment there are around twenty thousand or proteins that are coming from what the so-called known genes.
• 21:49
  Speaker 1: So the problem with this known gene concept is that it has been set in stone, meaning thirty to forty years ago.
• 21:57
  Speaker 1: they said a gene should look like this.
• 21:59
  Speaker 1: A gene should have a certain length and it should have a certain structure like a start site, stop site, multiple exons, exon boundaries, intron boundaries, stop site, poly A tail, and all of this has made us to look for these genes and proteins that are coming from these genes.
• 22:16
  Speaker 1: It's like saying, okay, a car, when I say a car, we think of like a sedan car, right?
• 22:21
  Speaker 1: Like with four doors, four wheels and a steering wheel.
• 22:25
  Speaker 1: But if I say a car can be like a Cybertruck, like Tesla's Cybertruck or...
• 22:29
  Speaker 0: This is not a car.
• 22:30
  Speaker 0: Yeah,
• 22:30
  Speaker 1: it's not a car.
• 22:32
  Speaker 1: Not a truck, right?
• 22:33
  Speaker 1: So we're kind of forced to rethink what it is.
• 22:37
  Speaker 1: So for us, these proteins, proteins that are coming from these unconventional regions is what we call as dark protein.
• 22:43
  Speaker 1: It could be shot in land.
• 22:44
  Speaker 1: It could be coming from... alternate regions.
• 22:47
  Speaker 1: so just to get in depth of this protein is actually encoded in what is called as one frame of the genome meaning every three nucleotide quotes for a codon and twenty codons make a protein right.
• 22:58
  Speaker 1: but then if you shift one codon you get a completely new sequence what we call as alternate frames or frame two and likewise if you move one more codon you get another sequence of proteins.
• 23:10
  Speaker 1: so it turns out that you can actually encode three different kinds of proteins in the same genome sequence.
• 23:16
  Speaker 1: The interesting part is viruses and bacteria have been clever and they've been using this forever to make, you know, encode as much pack information as much as they can.
• 23:25
  Speaker 1: But in humans, we have known that this happens but we even investigated.
• 23:30
  Speaker 1: So we did that and few other, you know, recently people have also done that.
• 23:33
  Speaker 1: It turns out that almost every gene that we have encodes proteins in all frames and that expands the protein numbers that we know of.
• 23:41
  Speaker 1: and that is actually the premise of this book.
• 23:43
  Speaker 1: like coming back to this concept of how do we encode that information.
• 23:48
  Speaker 0: Would you say we need to update our based on what you find the idea of what a gene is?
• 23:54
  Speaker 1: Yes, we have been calling for a redefinition of a gene since twenty sixteen time.
• 24:00
  Speaker 1: There are academic concessions.
• 24:02
  Speaker 1: Also, thinking on those lines, standardization of what a gene should be.
• 24:05
  Speaker 1: And a lot of people are now aware of that, and we are continuously, you know, big organizations like Sanger and other organizations in the US, Brood Institute, are all involved in such efforts right now.
• 24:17
  Speaker 1: It took us a long time to show that these so-called dark proteins are true, and they are stable, and they are functional, they are involved in diseases.
• 24:25
  Speaker 1: They're not just biological
• 24:26
  Speaker 0: noise.
• 24:26
  Speaker 0: They're not an artifact, or noise.
• 24:28
  Speaker 0: Yeah.
• 24:37
  Speaker 2: But then again, if you have a new definition, then I look at computational power that is doubled in maybe one year's time or so, you have new findings.
• 24:49
  Speaker 2: have to
• 24:50
  Speaker 0: redo, redo
• 24:51
  Speaker 2: again probably.
• 24:52
  Speaker 0: But there is a lot of unknown stuff.
• 24:55
  Speaker 0: So I mean, it took us ages to get to the two percent.
• 24:59
  Speaker 0: And now we have ninety eight percent left that still need to be deciphered.
• 25:03
  Speaker 0: So I think the computational power can increase a little bit more to make sense out of the genome.
• 25:08
  Speaker 0: I mean, the thing is that the genome is not as we thought like something that only as Sudhakaran just introduced.
• 25:16
  Speaker 0: I mean, it doesn't only read one way, but we have I mean, we have multiple frames to read it.
• 25:21
  Speaker 0: So basically, it's like a book that's written in, it's not written in multiple languages, but it has hidden messages within the sentences that it has.
• 25:31
  Speaker 0: And then there are regulatory elements that have influences over long stretches of DNA that do something because, I mean, DNA is coiled around and very nonlinear in a sense, despite the fact that we have been made to believe that it's a very linear flow of information because we have this strong double helix image and this, okay, now we have the meaning.
• 25:56
  Speaker 0: And then it became very messy.
• 25:58
  Speaker 0: Which actually brings me to a question, Sudhakar, and if I may, do you think there is the way that we think about genes, that we think about the genome, the dark genome, is influenced by the belief system of researchers at the time to an extent?
• 26:12
  Speaker 1: It's an interesting question.
• 26:13
  Speaker 1: There are evidences, right?
• 26:14
  Speaker 1: People are going by what they're observing and experimenting.
• 26:18
  Speaker 1: The thing that you mentioned, this whole field of three-dimensional architecture of the genome itself, how it is regulating the expression of genes and giving rise to the complexity that we know of, right?
• 26:29
  Speaker 1: So I didn't even touch upon that.
• 26:31
  Speaker 1: That is another huge goldmine.
• 26:33
  Speaker 1: So for different people, it's a different thing that they're passionate about.
• 26:36
  Speaker 1: And I think for us, for us investigating these proteins that we are definitely seeing because we have tagged them, we have knocked them out, we are seeing a phenotypic observation if we knock them out.
• 26:46
  Speaker 1: So we are excited to know what are these twins doing.
• 26:49
  Speaker 1: So that is kind of the world that we live in.
• 26:51
  Speaker 1: Yes, we are aware that there are other developments and exciting areas, but for us, this is the part that...
• 26:58
  Speaker 0: Probably, I mean, the thing is there is so much going on, you cannot focus on all of it.
• 27:11
  Speaker 0: Maybe we can dive a little bit into the more, how you say, I mean, not philosophical, but into these parts of what does this all actually mean?
• 27:20
  Speaker 0: Because I think this is what I find really fascinating about your book.
• 27:24
  Speaker 0: I have to say sometimes when there are multiple pages with the calculations, I'm not following one hundred percent, but I know what the outcome is.
• 27:35
  Speaker 0: But I think this idea of... evolution as information theory that you introduce, which I find really fascinating.
• 27:45
  Speaker 0: Maybe you could introduce a little bit what your view is and also maybe what other researchers are exploring in terms of, we started right with this question, why are we carrying all this evolutionary baggage with us?
• 28:00
  Speaker 0: Because other organisms that are less complex arguably than humans have partly more condensed genomes maybe don't have as much repetitive messy things going on and I mean it takes a lot of energy right to replicate that in each of our many many cells every time that a cell divides and during the formation of the embryo.
• 28:25
  Speaker 0: And what one also has to take into account, we have very elaborate systems to constantly scan and repair our DNA in order not to cause mutations that we don't want to avoid cancer or other issues.
• 28:38
  Speaker 0: So we're really investing a lot in keeping a lot of DNA going that we might not really need.
• 28:45
  Speaker 0: So what's going on there?
• 28:47
  Speaker 1: Thank you.
• 28:48
  Speaker 1: You're asking me to give away my secret of the book, but I'm happy to do it.
• 28:52
  Speaker 1: You can
• 28:52
  Speaker 0: hint towards it.
• 28:53
  Speaker 0: Maybe you can do the calculations for us.
• 28:56
  Speaker 1: There's no hidden message or it's not a mystery book.
• 28:58
  Speaker 1: The premise that is set in the book is that the genome has this adaptive potential.
• 29:03
  Speaker 1: What is adaptive potential?
• 29:05
  Speaker 1: The ability for it to make a new gene and new protein whenever and as and whenever it needs.
• 29:11
  Speaker 1: So this is not in a theological sense, but it's in a systems biological sense.
• 29:15
  Speaker 1: It's better to be adaptive.
• 29:17
  Speaker 1: When I used the word purpose, not in a theological sense, but systems biological.
• 29:21
  Speaker 1: how much information that you can actually put in such a way that if I transmit a piece of DNA, I've explained why DNA is used as a method to transmit information, but then if we go beyond that, if you accept that, if you go to Mars, if you go to Neptune, if you go to Andromeda, if you go to the center of Milky Way Galaxy, it's all going to be different environment, right?
• 29:40
  Speaker 1: But you have only one stretch of DNA, and how do you make that such a way that this particular set of DNA is going to thrive in every place?
• 29:48
  Speaker 1: It's going to make a set of proteins that is going to make an organism in that place.
• 29:52
  Speaker 1: It's going to make an organism in Andromeda.
• 29:55
  Speaker 1: All of these organisms should flourish and multiply, create diversity, and all of that.
• 29:59
  Speaker 1: So that's where this book starts with.
• 30:01
  Speaker 1: The ability to, why do we have, you know, if you really look at it, there are twenty thousand genes that we know of, comes from forty to sixty million base pairs.
• 30:10
  Speaker 1: But we have three point two billion base pairs.
• 30:13
  Speaker 1: So what are the rest of the things doing?
• 30:15
  Speaker 1: not only for us, but for all other organisms, it's just that it has this adaptive capacity to encode environmental information such that when it encounters new environment, it makes new proteins that enable it to survive.
• 30:29
  Speaker 1: The simplest information, that's about it.
• 30:32
  Speaker 1: And how minimum that should be is what we have, you know, I wouldn't say the equations and calculations in the book are perfect and final, but it's a sitting process link, you know.
• 30:42
  Speaker 1: Okay, given these constraints, this is what with that equations, what I calculated was we can reduce three point two billion base pairs to one point two billion base pairs.
• 30:50
  Speaker 1: So it's like thirty seven percent reduction.
• 30:52
  Speaker 1: And that is just to escape solar system, just our solar system.
• 30:56
  Speaker 1: Now, if you want to go beyond that, there are some equations.
• 30:59
  Speaker 1: that tells you what needs to be changed.
• 31:01
  Speaker 1: So that's the kind of thing.
• 31:02
  Speaker 1: How much you can reduce and how much you can use, you need to have the adaptive potential still retained.
• 31:08
  Speaker 1: So that is the whole point.
• 31:10
  Speaker 0: I find this really fascinating because this sounds very science fiction, but in a simpler system, like in bacteria, microplasmum, genitalium, I think it was, and also then later in E. coli, researchers at the Craig Vanter Institute.
• 31:25
  Speaker 0: Vanter is one of the genome project guys who was in the race to sequence the first genome, and I think was also the first, but I mean, it didn't matter in the end.
• 31:33
  Speaker 0: I
• 31:34
  Speaker 1: mean, it does matter because they have contributed to the sequencing.
• 31:38
  Speaker 0: Yeah, they did.
• 31:38
  Speaker 0: They did a lot.
• 31:39
  Speaker 0: And they actually went into this idea of compressing the genomes of microbes.
• 31:45
  Speaker 0: And these are the first synthetic microbes that have this very limited, this minimum set of genes that they need to survive.
• 31:53
  Speaker 0: So this idea of moving that from the smallest possible organism to us as humans is, of course, from a thought experiment really, really, really fascinating.
• 32:05
  Speaker 0: How would you say along?
• 32:07
  Speaker 0: I mean, you mentioned also speciation and the role in other species.
• 32:11
  Speaker 0: Would you say the dark genome is what evolves more than the light genome?
• 32:18
  Speaker 0: Let's put it like that.
• 32:19
  Speaker 0: Would that be a statement to make or is that pure speculation that I'm throwing out here?
• 32:25
  Speaker 1: You're spot on.
• 32:26
  Speaker 1: I need three or four more podcasts.
• 32:28
  Speaker 1: Podcast series to talk about this because this is an exciting area of research and I'm passionate about it.
• 32:33
  Speaker 1: That's what we say and that's what.
• 32:34
  Speaker 1: because the problem is, let's say, you know, if you've been noticing the recent press releases by NASA and other organizations, which brought back samples from Benoy and few other asteroids, they have been seeing tryptophan and few other amino acids, right?
• 32:49
  Speaker 1: Like pretty much fifteen out of twenty, I believe.
• 32:51
  Speaker 1: Amino acids have been already found.
• 32:53
  Speaker 1: in asteroids which are more than four billion years old, like beyond Earth's time, right?
• 32:58
  Speaker 1: So all this is just showing that, you know, the primary constructs have been there.
• 33:02
  Speaker 1: So what we are saying is that the random set of DNA, we don't call it genome, the random set of DNA is constantly exploring the environment and making proteins as they need.
• 33:13
  Speaker 1: And that's where when they see a new protein is very important for its function.
• 33:18
  Speaker 1: And it's fixed, meaning across multiple eras of evolution, it keeps those proteins.
• 33:24
  Speaker 1: Whereas those that are not needed as much, they're just kind of throwing it out or making a new product out of it.
• 33:30
  Speaker 1: So this constant process is going on like testing what is needed, testing what's not needed.
• 33:35
  Speaker 1: And that's why we have come to this twenty thousand.
• 33:37
  Speaker 1: And those twenty thousand are fixed and you know, we kind of are essential for us to function.
• 33:41
  Speaker 1: And then probably we can't tinker with them too much, right?
• 33:45
  Speaker 1: evolutionally they are fixed but whereas the other regions which are the most important ones because they're still exploring, they're still figuring out what is needed to take these guys to the next stage.
• 33:55
  Speaker 1: We need new.
• 33:58
  Speaker 1: oxygen levels are different, carbon dioxide levels are different, can we change something to make these guys more adaptable?
• 34:03
  Speaker 1: So there's this process going on but they can't touch the known.
• 34:07
  Speaker 1: So less evolution is going on there.
• 34:09
  Speaker 1: Although I wouldn't say there's no evolution going on there, but less evolution than in the so-called dark genome.
• 34:15
  Speaker 1: Because there's more flexibility to do things there.
• 34:18
  Speaker 2: Absolutely amazing.
• 34:20
  Speaker 2: And my mind is crossing right now.
• 34:22
  Speaker 2: First off, of course, we can continue this conversation in the second or third podcast because...
• 34:29
  Speaker 0: Yeah, I think there's more to explore.
• 34:31
  Speaker 0: Absolutely.
• 34:32
  Speaker 2: And it's so fascinating.
• 34:34
  Speaker 2: You know which image is crossing my mind right now?
• 34:37
  Speaker 2: A scientist two and a half, three thousand years ago, they looked at the stars and stuff and tried to figure out.
• 34:45
  Speaker 0: Yeah, and looked at the nature around and tried to figure out how the world works.
• 34:49
  Speaker 2: Exactly.
• 34:50
  Speaker 2: And they did.
• 34:51
  Speaker 2: science and theology and philosophy all at once.
• 34:55
  Speaker 2: Leaving me to the question, your findings and your... I have a sense of what it means to put together a book like this and how much stress on the one hand side, fulfillment on the other hand side, that means of course, but does this make you, in a sense, I might say humble?
• 35:15
  Speaker 1: I mentioned this to Louise last time when I met her.
• 35:17
  Speaker 1: When I started my PhD, microarrays and high throughput studies were becoming mainstream.
• 35:23
  Speaker 1: We did lots of genomics, proteomics, lipidomics, metallomics.
• 35:26
  Speaker 1: We got tons of data.
• 35:28
  Speaker 1: And then at that point, it was so exciting.
• 35:30
  Speaker 1: You know, we're going to figure out, fix schizophrenia, bipolar, we can cure diseases, right?
• 35:34
  Speaker 1: And that was twenty-two years ago.
• 35:37
  Speaker 1: And we're still here.
• 35:38
  Speaker 1: We still haven't understood anything.
• 35:40
  Speaker 1: And the more we scratch, the more we see.
• 35:43
  Speaker 1: And that's where we are.
• 35:44
  Speaker 0: Yeah, I couldn't agree more.
• 35:46
  Speaker 0: I think this is so interesting that we thought like, okay, now we read that like after the publication of the Human Genome Project was really like this belief.
• 35:55
  Speaker 0: Now we know it all.
• 35:56
  Speaker 0: And as you say, I mean, there is so much we still don't know and that we have to figure out.
• 36:02
  Speaker 0: And but this is also very cool.
• 36:04
  Speaker 0: And I mean, I also think it's humbling to know how much there is still to discover and how much excitement lies in there and how much understanding of what it means to be human and how our planet works and maybe how life outside our planet could work.
• 36:19
  Speaker 0: so I think.
• 36:20
  Speaker 2: You come too close for today but with understanding that there will be a follow-up I guess.
• 36:27
  Speaker 2: We'll make sure that we'll put a link to that book, of course, into the show notes, as well as some central findings, as always.
• 36:36
  Speaker 2: And thank you, thank you very, very much.
• 36:39
  Speaker 2: It was an amazing journey so far with you.
• 36:42
  Speaker 1: Thank you so much for inviting me here.
• 36:44
  Speaker 1: It's been fun.
• 36:45
  Speaker 1: And thanks for the thoughtful questions.
• 36:46
  Speaker 1: And thanks, Louise, for reading the book.
• 36:48
  Speaker 1: I don't know whether you got to finish it, but it's a lot of dense information in the middle.
• 36:51
  Speaker 1: And I heard that feedback from a few people who read that and gave me that feedback.
• 36:55
  Speaker 1: But thank you for doing that.
• 36:57
  Speaker 0: It's really a fun read.
• 36:58
  Speaker 0: I have to say, for me, it really hits this sweet spot between science philosophy and some like science fiction thought experiments.
• 37:05
  Speaker 0: So I think this for anyone who likes to think a little bit.
• 37:09
  Speaker 0: outside the box and about the bigger picture of science.
• 37:12
  Speaker 0: This is really a good book to read.
• 37:18
  Speaker 2: This was the Biorevolution podcast.
• 37:21
  Speaker 2: Many thanks for listening or following us on YouTube.
• 37:25
  Speaker 2: As always, feel free to comment to say something on Spotify, for instance, or YouTube.
• 37:33
  Speaker 2: We really appreciate that.
• 37:34
  Speaker 2: And further information, as always, you'll find on sciencetales.com.
• 37:39
  Speaker 2: Stay tuned.
• 37:40
  Speaker 2: We'll be up for... Many, many more episodes.
• 37:44
  Speaker 2: Thank you.