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0:07
MIKE: Good evening and welcome to Basic Science Lights the Way. I'm delighted to join you again for another evening of thought-provoking conversation. And tonight we have the pleasure of hearing from three biologists about the intricacies of our species' co-evolution with other beings. As humans have evolved over the last 300,000 years, we have shared the planet with many living things, interacting with and affecting one or another in many ways. At the heart of this discussion
0:40
lies the fascinating relationship between humans and Neanderthals, our ancient cousins who once roamed the Earth alongside us. The legacy of this union is etched into our DNA, shaping not only our physical characteristics but also our cultural and behavioral traits. Beyond our interactions with other hominins, our co-evolutionary journey extends to the plant kingdom where humans have played a pivotal role in the domestication and cultivation of crops.
1:14
Alongside our interactions with other organisms, humans have faced... have also faced the constant threat of pathogens and infectious diseases. As pathogens evolve to exploit new hosts and transmission roots, humans must adapt and develop strategies for survival, leading to a perpetual cycle of co-evolution. To help us explore this to topic further, I would like to introduce our moderator, Priya Moorjani, who's an assistant professor of genetics, genomics, evolution, and development.
1:50
Her lab focuses on questions of human evolutionary genetics. They use genomic data from living and ancient individuals like Neanderthals to understand our evolutionary history, adaption, and disease. To this end, her lab develops computational methods to reconstruct evolutionary events and identify genes and pathways related to human adaption and disease. And with that, I'm going to hand things over to Priya. Priya, the show is yours.
2:25
PRIYA: Thank you, Dean Botchan. I'm very happy to be moderating tonight's event, exploring the rich tapestry of human co-evolution and other organisms. From our ancient interactions with Neanderthals to the dance between humans and plants and even our ongoing battles with pathogens, our story is intertwined with that of the countless other organisms around us. This event serves as a platform to delve into the depths of the co-evolutionary saga, shedding light on the profound impact
2:57
it has had on our species and the world around us. So, thank you, all, for joining us today. Once we get underway, we encourage you all to post your questions in the chat box, and at the end of each talk, we'll try to take some of your questions and then ask... have another chance to talk to all the speakers at the end. Our first speaker is Elena Zavala, a Miller postdoctoral fellow in the Department of Molecular and Cell Biology. Elena's research focuses on the development
3:29
of new computational methods and laboratory techniques for working with degraded DNA in order to learn about our evolutionary history, as well as increase the success of historical human identifications. Elena is at the forefront of studying the co-evolution of homo sapiens with Neanderthals, co-authoring three recent papers on the topic. Elena, thank you for joining us this evening. Can you please tell us about your research?
3:59
ELENA: Thanks so much for having me. Let me just share my slides.
4:06
I'm very happy to talk to you all today about some of my research... recent work. And before I delve into it, I did want to give a little background to the field of ancient DNA, which really started here at the University of Berkeley -- California, Berkeley -- and with Allan Wilson, who published the first ancient sequences 40 years ago from a quagga, an extinct member of the horse family, as you see here. And unfortunately, Allan Wilson left us too early; however, his legacy goes on today
4:39
with many of his former group members, including Svante Paabo, who went on to sequence the first draft... sequence of the Neanderthal genome. He is now a Director at the Max Planck Institute in Leipzig. And his work was recently recognized with the Nobel Prize just two years ago. And you may notice when you look at the dates of these two different publications, one from 1984 and the other from 2010, there was quite a span of time between when the first ancient sequences were published
5:09
and the first sequence from Neanderthals. And this is really because of necessary advancements that needed to take place on the technical and methodological side. However, thanks to those methods, we do now have an established ancient DNA workflow going from DNA extraction to library preparation and sequencing that we can perform downstream analysis. And one of the important components of these advancements was the recognition that all of this work needs to be done in a clean room.
5:39
And so many of us who work in this field, you can often find us in labs dressed up in our suits, as you can see myself here with my whole suit, gloves, hairnet, mask, et cetera. Another great advancement that has happened recently and why you often see ancient studies now with large numbers of samples is we've also incorporated automated work with robots. And so this is a robot that I worked with for many hours during my PhD to generate some of the data that I worked on.
6:12
But today we'll be talking about human genetics with ancient DNA. And actually, if we go back in time, a hundred thousand years ago, not only were there early modern humans in Africa, but there was many other human groups throughout the world. We had Neanderthals. In Western Europe, we had Denisovans. They're our cousins in the East. And as you can see in the green circles, there were also other groups that unfortunately to this day, we just don't have DNA from.
6:39
And so while I'll be talking about Neanderthals and Denisovans and humans, I just want to acknowledge that there are actually many human groups back in time. And one of the reasons that we're interested in talking about Neanderthals and Denisovans is that when a group of humans first left Africa around 50 to a hundred thousand years ago, they interacted with both of these groups as they spread throughout Eurasia and then on through the world. And they leave traces of their DNA within us now.
7:09
And as we try and understand our past interactions with these archaic groups, it's not just about these different hominine groups, but also: how did these past humans interact with their environment? As well as what types of tools that they potentially create, and how did that develop through time? And there's different ways that we can approach these types of questions. Typically, one thinks of often skeletal DNA, as the type point for ancient DNA, we've also recently shown that we can get DNA
7:39
out of very old sediments. And that actually we could have ancient touch DNA, which is left behind if you touch an object. So, you may have heard about this in forensics -- if you touch a desk or anything, your skin cells are left behind. And this is what we refer to as touch DNA. And so we've seen, we can actually do this also from an ancient setting. And that's what I'm going to to talk about today is the types of questions we can answer with these three different types of source DNA.
8:03
So, one area of great interest in our human evolutionary history is this time period from around 40 to 50,000 years ago when Neanderthals disappeared from Europe and Homo sapiens appeared. Because during this time, not only do we have this changer over, but there's also a change in climate as well as a change in the types of technologies, or stone-tool-lithics artifacts that were found then.
8:28
And one example of this is this type of tool that we see here, which we would say is a nice leaf point. And the reason that we're interested in who created these types of tools is that it seemed as a technological advancement versus the older stone tools that we found before this point. And so this raises the question as to there's something... if they were made by humans, is this something special about us that allowed these tools to be created? Or did Neanderthals create these
8:56
and teach us how to make them as well? And one such area of question was located in Ranis, where there's a technology called the Lincombian-Ranisian-Jerzmanowician, or the LRJ for short. And we want to answer this question as to who made these lithics? Was it Neanderthals or was it humans? And so this site was initially excavated back in the 1930s, but we went and re-excavated, led by Jean-Jacques Hublin, from 2016 to 2022. This is a photo of me collecting sediment samples
9:29
from the site very early on in this excavation. And based on the large team, and a great amount of data that we recovered from this excavation, we were able to say conclusively, it was Homo sapiens, or humans, that created these tools. We're also able to see, though, that combining information from isotopes, zooarcheological analyses as well as radiocarbon dating, that it was short-term occupations of humans moving through this region that left behind these tools.
10:02
And also that it was much colder in this area than we had previously thought when humans were there. And this means that humans interacted with colder climates earlier than previously thought. There was a theory that humans followed warm temperatures north out of Africa. But it seems like that might not necessarily be true based on these foundings, as it was quite a bit colder in this region at that time than it is today. And like I said, this was a huge effort,
10:31
resulting in three different papers, and I highly recommend that you look into them if you're interested.
10:38
Now, in that study, we're associating lithics and the human DNA, just based on dating and associating them through dating. But of course, it would be ideal if we could actually find out who touched these artifacts, who touched these lithics. And so one of my colleagues was able to develop a method where we could actually recover this touch DNA from an ancient pendant.
11:05
As you see here, we were able to determine that a woman about 18,000 years ago handled this pendant and left her DNA behind, and that this woman was from the ancient North Eurasian population, which would later go on to populate the Americas.
11:23
The final source of DNA that we've used to explore the distant past is sediments, where we found that we could recover human DNA from sediments over 200,000 years old. And so this is at a site called Denisova Cave in Siberia. We're covering this timeline as you see on the left. We have four different types of technologies, and we will be able to see the presence of Denisovans, Neanderthals and finally humans. And a benefit of sediment DNA is you can recover multiple taxa from it.
11:55
And so we could also see a change in the types of bears that were present in the cave and the types of hyenas and how this overlapped with the climatic change that happened in the region, really showing and exemplifying this power of using sediments.
12:13
So in summary, we have a lot of different tools for reconstructing human evolutionary history. We can use skeletal data, sediments, as well as touch DNA. And I just want to acknowledge the different groups that I've gotten to work with both of my PhD at the MPI as well as now at Berkeley through my Miller postdoctorate fellow. And I'm happy to answer any questions. Thank you. PRYIA: Thank you, Elena, that is truly groundbreaking work. It looks like we have time for a few questions.
12:46
Let me check the chat.
12:49
One question that Rosette Dawson asked is: "23 and Me said that I have Neanderthal DNA, a tiny amount.
12:59
Wouldn't all humans have some?"
13:05
ELENA: So this depends a lot on your genetic ancestry. So, not all humans, of course, left Africa around 50 to a hundred thousand years ago. And so it's those populations that Neanderthals interacted with that then passed on that Neanderthal DNA. And we actually see that the amount of DNA varies throughout the world, where there's certain sections of the world that have the higher amount of the Neanderthal DNA, also a higher amount of Denisovans DNA than others.
13:33
And understanding the dynamics between of that, is actually an active area of research. PRIYA: Thank you. Another question we have from the audience is: What is a good layperson's reference source to understand where all the homo groups come from?"
13:49
ELENA: I guess it depends a little bit if you mean by the definition or their actual origins. PRIYA: Yeah. ELENA: So by definition it's, so, homo sapiens... or homo sapiens Neanderthal, homo sapien sapiens, is all based on just naming to differentiate between these different groups. There is debate as to, if they are species versus group -- and this is also an area of debate. But it's just how we are labeling and differentiating between them.
14:14
PRIYA: Is there a layperson's reference source you might... ELENA: Oh, source. PRIYA: go off?
14:20
ELENA: Not off the top of my head in terms of a book or something, unfortunately. I'm sorry. PRIYA: Yeah. I think that's Smithsonian website has a lot of resources. And I think if not directly at the website, there are definitely links that people can see there, too. Another question we have from Edward Levine is: When did the Neanderthals and Denisovans leave Africa?
14:47
ELENA: So that's a great question. But we actually think that Neanderthals and Denisovans evolved outside of Africa. And so they likely evolved someplace in the Middle East and then spread out West and then East from there. And so there is another ancestor that would have to go further back that would be the ancestor to Neanderthals and Denisovans, and it was that ancestor that left Africa.
15:15
PRIYA: I got a message from one of the other panelists who mentioned that there's this new book by Jennifer Raff, which is called "The Origins," and that might have some resources about the story of Homo also.
15:29
And finally, I'd like to ask you one more question, which is about what is the limit of ancient DNA? How far do you think we can take this technology? It's truly fascinating that we can look into our past 300,000 years ago; but how far can we go with this technology?
15:50
ELENA: Yeah, that's great. That's a constant question as well. And this is very environmentally dependent. And so we do have a Neanderthal from 400,000 years ago that we think it's just very special conditions, those in a type of cave-like vent. But the oldest DNA right now is two million years old, from Greenland. There's also one-million-year-old DNA from Mammoth, up in Siberia. I think it's in these coal climates that we're likely to hit kind of the edges of these limitations.
16:19
And I'm excited each year to see what's pulled out of the permafrost up there. PRIYA: Oh, that's fantastic. That's very exciting. So, with that, maybe, we'll move to the next speaker of this evening -- Associate Professor in Plant and Microbial Biology, Ben Blackman.
16:41
Ben's research seeks to understand how plant development and its ability to respond to changing environment and environmental conditions evolve using a combination of molecular, genomic, and field approaches to connect genes to traits and ecology. His research group aims to address fundamental questions about the genetics of adaptation, the evolution of development, the mechanism of gene environment interactions in two-plant systems -- sunflower, that he'll tell us about today;
17:14
and also, monkey flower. His work in these systems currently focuses on environmental and circadian regulation of solar-tracking movements by sunflower stems and of florid maturation in a sunflower disk transcriptomic and ancient DNA studies of sunflower domestication and ecological genetics of adaptation to local climates along environmental gradients. Professor Blackman, thank you for joining us. Please tell us a little about your research and your ongoing projects. BEN: Great.
17:48
Let me share my screen.
17:51
All right. Great. Well, thank you, everybody, it's great to be here. My lab is really interested in how the great diversity in plant form and function we see evolved over time. And one area of that that we're especially interested in is how humans have driven that evolution of form through the process of domestication. I like to define domestication as the process by which a wild species is changed at a genetic level through generations of selective breeding to benefit the interests of humans.
18:23
And I like this definition and what I've highlighted here in blue, because it really points out that domestication is a very interdisciplinary field and thus, a really rich field to study. It touches on history because it's a process that's happened over time. We have change over time through evolution that's happening through changes in the DNA of these organisms over generations. And of course, this is all change happening due to how these organisms intersect with our culture
18:50
and what we eat, what we wear, and what we live in. And domestication was a huge change for human society. With the ability to grow large amounts of food, human societies could stop being nomadic and form towns or cities. And because everyone did not then have to be involved in gathering or growing sustenance allowed the emergence of political and cultural classes. Crop plants often have really high cultural value to all of us in terms of what we drink, what we wear, and by studying crop history
19:28
and where these crops evolved, how they evolved, and how they followed human society around the globe, we're really studying how humans evolve alongside the crops. So, I've been studying this question in the context of sunflower domestication, and I'm going to start really basic here, because there's honestly a lot of misinformation out there. That plant is not a wildflower. Wild sunflowers are highly branched bushy plants with many small heads and small seeds.
19:57
And it's only in the last four to 5,000 years, the Native American farmers living in the eastern and central part of the U.S. and Canada transforms sunflower through breeding into the crop plant we're familiar with today, much reduced branch stem, big heads, big seeds, high oil content. Sunflower was used for millennia for getting meal or oil out of the seeds for nutritional or ceremonial purposes. And it's really only within the last hundred to 150 years
20:26
that sunflower has become a major agronomic crop, particularly for its oil. So, in modern agriculture, sunflower oil is the number-four vegetable oil worldwide. And of course, it's also a confectionary crop -- you've probably snacked on sunflower seeds or sprinkled them on your salads. And it's also an important horticultural crop, maybe you receive some for Mother's Day recently. And so it's a big crop worldwide. It's also a big crop in the U.S. And sunflower, with respect to its oil,
21:01
is kind of king in one healthy way, which is that of the main vegetable oils out there, it has the highest percent of monounsaturated fats, and these are fats that help to reduce bad cholesterols and also contains antioxidants that can help health as well. And from the perspective of us here in Northern California, the Sacramento Valley is a huge sunflower growth area. If you go out in the next month, you'll probably see so many, because this is where a lot of the seeds
21:32
that are going to be planted worldwide for oil seed are getting made. All right, but in my group, we're interested in what happened during those first 5,000 years. How did sunflower get transformed from this bushy, branchy plant with small heads and small seeds into a crop? And so we study this in several ways. One way is looking at the modern, wild, and domesticated forms and sequencing their genomes and looking in their DNA to infer what happened during the process of domestication,
22:04
either in terms of how population size changed over time during domestication, what we would call demographic change; and also what genes were actually the targets of selection by early breeders. So with respect to demographic change, one thing that we can do is use techniques, like some that Priya works on in her lab, to look at the history of population size over time. And so what I'm showing you here in this plot is we have very old to the right, and the present is to the left.
22:35
And what you see is we have this split between the wild lineage in green and the domesticate lineage in red around 5,000 years ago, as we predict based on the archeological record. However, on the Y-axis here, what we're plotting is population size. And what we see in the domesticate lineage is that there's this big drop,
22:58
an almost sevenfold drop, in population size following domestication. And this is a signature that we commonly see in domesticated species, because not all the diversity that's present in the wild species is sustained through the domestication process.
23:17
We can also use modern genomes to look for regions of the DNA that show signatures indicative that they were experiencing selection during domestication. And when we look at the genes that are in these regions, we see things that in other organisms have functions that would be interesting from the perspective of sunflower domestication. Things related to seed size and seed oil or branching or stem and disk size. And this is great, because one, it gives us targets to look further into,
23:49
if we want to do more breeding of sunflower, because clearly, they're involved in interesting traits from an agronomic perspective already. But also, it's really telling us who all the players were in the domestication process. But what this won't tell us is which of these genes were under selection when and thus, which traits were under selection over time as the sunflower domestication syndrome was assembled over time. And so to get at this question, we turn to ancient DNA.
24:18
And working with an international team of anthropologists and molecular biologists, we have assembled an archeological time series of sunflower disks and seeds over the past 4,000 years from which we've been extracting DNA.
24:34
These samples primarily come from the Ozarks and Tennessee and Kentucky, because in these areas, they've been preserved by desiccation, by drying out. They've been stored, they haven't been burnt up. And so they preserve DNA really well. For instance, from Mammoth Cave or from these rock shelters in the Ozarks. If we've carbonated many of these samples, and what we see in terms of morphological trends, some of it is consistent with what you'd expect and that seed size increases
25:02
as we move toward the present on the right. But interestingly, disk size doesn't show that same pattern and that the biggest disks are from about 1,300 years ago, rather than the most recent disk, suggesting potentially a change in selection on disk size. Now, we've been getting DNA out of these, here's a former postdoc from my lab, all suited up to prevent contamination, as Elena talked about. And we've now sequenced a lot of these samples. And what we are looking at here
25:34
is how the domestication genes have evolved over time and risen in frequency. So, what I want you to consider is if we look at a piece of the genome where domesticated sunflower tends to have one nucleic acid and wild sunflower tends to have another, we can look over time and see how that domesticated variant rose in frequency over time. And each of these pink, sorry... each of these purple curves is a different variant changing over time.
26:06
The highest slope at this inflection point in the curve -- that's kind of a measure that we can take for when selection was acting the strongest on this variant. And so if we take that measure for all of these variants, we get this distribution here on the right, showing that it seems that there was a lot of selection early on during domestication, more relaxation, fewer variants under strong selection around 1,500, 1,300 years ago. And then strong selection again later on toward the present.
26:38
And so if you've been paying attention you notice that I kept saying a lot of things are happening around 12- to fourteen hundred years ago. We have this, like, the biggest disks, but then they decrease. That's when we have the smallest population size after which it rebounds. And then we also have this period where it seems to be that there's less strong selection on sunflower. And so what was going on then? Well, we think what this could be pointing to is there's kind of two major changes
27:06
that happen in Eastern North America at this time. First, the Hopewell culture, which was a widespread trade network that dominated Eastern North America at this time, appears to have collapsed and become less connected during this period. The other thing that happens is that this is the time period when maize is first introduced to the region and it's...
27:30
it rapidly expands in terms of how much is being grown. And so, it kind of makes sense that if maize is spreading out then sunflower might be less favored as a crop. And so we have co-evolution between humans and sunflower, but then also humans and the relationships between sunflower and other crops coming out here. With that, I'll thank many people involved and stop and take questions. Thank you.
27:56
PRIYA: Thank you, Ben. That was a fascinating talk. Now we have time for a few questions.
28:04
Let me just check the chat. I encourage you all to post your questions in the chat box. We want to hear from all of you and answer any questions that you have related to this.
28:18
Maybe I'll get you started.
28:21
It was really interesting to hear that sunflower was domesticated in Eastern North America. When I think of domestication, I often think of the Fertile Crest or Mexico or South America, where so many crops have been domesticated. Is there a particular reason that sunflower was domesticated in Eastern North America? BEN: Yeah. So, in Eastern North America for a long time it was thought that basically, the Native Americans living there inherited
28:58
or received all their agricultural knowledge from the south that came up from Mexico and the Southwest. However, a major change in the anthropological field in the '90s and 2000s really showed that Eastern North America was its own crop center. Sunflower was one of those crops, but then other crops such as maygrass and chenopodium and goosefoot and marsh-elder also were domesticated then. And because you can see in the archeological record changes happening over time.
29:31
But many of those crops are now extinct. So for instance, marsh-elder is kind of in the sunflower family, it's closer to ragweed than sunflower. And you can see in the archeological record, its seed size increases in volume just as much as sunflower. But big-seeded marsh-elder doesn't exist anymore, because it stopped being cultivated likely because it was displaced by maize or other crops. PRIYA: Oh, that's very fascinating. Another question we have from the audience is:
30:00
How much of domestication was driven by experiment versus observation by farmers? BEN: Yeah, so... I mean I think that there's a lot of different sources of selection pressure during domestication. So clearly, if there's, like, some mutant out there that's just got the biggest corn cobs, or the change in how sweet versus bitter a melon is, that's something that's going to be very directly selected. However, there's other aspects that can be much more indirect or unconscious. So for instance,
30:40
depending on how wheat was... or barley were being harvested, whether by size or by another method, that would favor or not, whether the seeds shatter from the plant or stay on the plant. And then as these crops move out from their centers of origin to many other places worldwide, they have to face climates that they haven't faced before. And so, as maize moved up
31:11
from Mexico into North America, it really had to evolve to deal with the more temperate climates up here versus the more tropical climates down there. Yeah. PRIYA: This is a good segue into another question from the audience which is: Does the reduction in genetic diversity make the current crop versions more susceptible to pathogens or climate and salts? BEN: Yes, yeah. So, this is a really important question and one that is the subject of a lot of research today. So, part of the goal
31:44
of sequencing the wild relatives of crops is to look at the diversity that's present in the wild that's not present in crops to see whether they can help make crops more resistant to environmental stress like drought or to pathogens. Because our crops, they often are grown in pretty cushy environments with irrigation or fertilizer. And so things that might help them deal with drought or with pathogens, might also make them grow less well, and so they might be less favored. And so a big push
32:20
in the area of plant genetics right now is to look at these wild relatives and identify variants that didn't make it into the crops but that could be very helpful. And sunflower is, like, a case study for this,
32:36
in breeding in a wild allele that helps confer tolerance to a pathogen from related species into the crop and helping to... PRIYA: That's fascinating. BEN: improve yield. Yeah. PRIYA: We have one question from
32:54
another panel member, Professor Koskella. So you mentioned rapid selection. Is there evidence that sunflowers are locally adapted to particular growing regions? Is there variation across varieties? BEN: Yeah.
33:11
Definitely. So, one of the things with sunflower is that in terms of what...
33:23
varieties that haven't been subject to selection for oil or confectionary seed and so aren't part of this, kind of, more modern, elite bread-germ plasm and instead are kind of varieties that have only been kept over time by Native American groups. We don't have very many of those. Many of those were lost, because of the history of how we've treated Native American groups in this country. But in the crops,
33:59
and so, like, there's a lot of work on that in, say, Native varieties of rice or corn or other crops, for instance, but not in sunflower. But in crops, like that's a major focus.
34:10
Like how do you breed a variety that is either robust to whatever context you grow it up in, or do you breed varieties that are adapted to specific areas? And sunflower's grown all over the world. The biggest growing areas are Russia, Europe, and Ukraine. But it's also, there's a lot grown in China, there's a lot grown in Argentina, and they all have very different climates. And so, kind of, selection for different kind of flowering times or abiotic tolerances is definitely part of the work
34:46
of crop breeding in sunflower. Yeah. PRIYA: Fascinating, how we have impacted sunflower in so many different ways. We'll have a chance to answer a few more questions later. But now we'll move on to our final speaker for the evening, Associate Professor of Integrated Biology, Professor Britt Koskella. Professor Koskella is an evolutionary biologist and ecologist, and she's interested in how interactions between host and their microbes influence evolutionary processes,
35:22
agricultural sustainability and human health research in the Koskella lab starts with the assumption that microbial evolution can be a key part of our solutions to societal problems rather than being the problem. They take on this challenge by combining discovery-based science on plant pathogens and plant-associated microbiomes with hypothesis-driven experimentation. By combining field studies on natural populations with experimental evolutionary studies
35:54
performed in greenhouses and laboratories, the Koskella lab is trying to identify patterns of pathogen mediated selection in nature. Over to you, Professor Koskella.
36:09
BRITT: Thank you very much. All right. Let's make sure this is the right view.
36:15
Great. All right, well, I've learned a lot already in this session. It's really wonderful to be here. I'm going to start by thanking all of the folks who do the research here. One of the great privileges of being a professor here at Berkeley is the amazing people that come to work with you as undergraduate students, graduate students, and postdocs. And they really are incredibly inspirational to work with.
36:41
So, so far today, you've heard about evolution on the million-year timescale. This really long, beautiful evolutionary history that has generated this incredible diversity we see. And then we zoomed in a little bit and heard about things happening on the order of 10,000 or thousands of years and seeing how quickly with artificial selection and breeding, we can change crop species, agricultural species, and animals. And so this is a really beautiful evidence
37:11
of the speed at which evolution can occur and really the amazing variation that can be leveraged to create new varieties. But I'm going to zoom you in even further to something that you're going to see, sitting here right now -- evolution in real time. So, this is a large Petri dish grown by my colleague, Michael Baym. This was his brilliant idea where he created a Petri dish the size of a pool table and he inoculated both sides with a pseudomonas bacteria.
37:45
And where it's grown so far, there were no antibiotics. But the next block, the next rectangle on either side of your screen, has a bit of antibiotic in it. And what you've just witnessed is real-time evolution by mutational change of this bacteria, evolving resistance to antibiotic and then it hits another wall, and that's a higher antibiotic concentration. And for a while that stops the bacteria. But then there are mutations and each of these little rivers that you see
38:15
is a single mutant, a variant that has evolved to resist antibiotics and grow in that next concentration of antibiotic. And then right in the middle is the highest antibiotic concentration, where they didn't expect the bacteria to be able to get. And sure enough, without wasting much time, this is all in the course of about a few days. You see the antibiotic resistance evolution at that last stage. And so, this is one of my favorite videos to show.
38:45
I think Michael is a genius to create this visual, because it's so clear of the power of evolution. But of course, this beautiful display here is of course a very real-world problem. So, we are currently living in an antibiotic crisis. And what you're looking at here is an image of different antibiotics that were, this is showing both when they were first discovered and introduced clinically to treat bacterial pathogens, versus when resistance first evolved against those antibiotics.
39:19
And so you'll see that most of our favorite
39:23
and well-used antibiotics have resistance mutations out there. Many of these live on plasmids and can rapidly evolve even multi-drug resistance. The other thing you might notice is if you move to the right, we're moving into more recent times, then the speed at which resistance is occurring seems to be accelerating. And this has made many in the medical field very scared. And so it has led to a big push to think about both how we use antibiotics and to really drive antibiotic stewardship,
39:58
which is a critical part of this, but also to think about alternatives. What can we do as we move back in time to the pre antibiotic era? And so one of those possible solutions are bacteria phages. And if you haven't heard of a bacteria phage, it's a virus that infects bacteria. So, this is a virus like any other virus, it has to recognize its host cell and injects its DNA, its genome, into the bacterial cell and then hijacks the replication machinery
40:28
so that the cell is now producing little viral particles. And once those are assembled, the bacterial cell bursts open. And so this is a killer of bacteria. And this was the first discovered killer of bacteria and its discovery predates antibiotics. Indeed, bacteria phages were co-discovered by Felix D'Herelle. And this is one of my favorite diagrams from one of his recent publications where he was studying cholera patients in hospitals and he was taking fecal samples through time
41:01
and measuring how much cholera bacteria they were shedding in their feces. And that's this dark line, the solid line, is telling you how much of the bacterial pathogen he was finding in these patients over time. The dash line are bacteria phages. And he was able to enumerate these bacteria phages because they form something called a plaque, which is a little local area where you can see, almost like bullet holes, where you can see that the phage has eaten or killed the bacteria.
41:32
Now at the time he didn't know they were viruses, but he did coin the term of bacteria phages, eaters of bacteria. And the key point of this paper is that for the two patients that died of cholera, they either never had any appreciable bacteria phages or that phage started to increase and then failed to take off and the bacteria took over. In contrast, the three patients here who recovered had appreciable phage densities through their entire time in the hospital.
42:04
And so this led to great excitement, but was quickly replaced by antibiotics and there was a lot of lost interest. But here we are now back at a time where we need alternatives and we need new solutions. And so, much like phages can be used to treat human pathogens and there's still very much interest in using phages for human pathogens, my lab studies the use of phages against plant pathogens. And so this is just a really nice example of how this works. This is worked by Cathy Hernandez,
42:37
who's now a postdoc at Yale. And what Cathy did is inoculated tomato plants, these cute little seedlings, with our pseudomonas syringae pathogen. It's an important agricultural pathogen. And when we inoculate our seedlings, we can track how disease symptomatic they become over time. And we call this a disease curve. So, you inoculate them and then you can track how diseased they get. And this green line at the top is when you just have the pathogen there.
43:04
And you might see that when you have a bacterial pathogen plus its bacteria phage, when you inoculate the phage onto the tomato at the same time, there's no disease. It's essentially exactly as healthy as a plant that never saw the pathogen at all. So, just to say that these phages absolutely can reduce disease symptoms, they work as a therapeutic or a biocontrol agent. But the other really neat thing about phages is they're everywhere. They're incredibly abundant to nature.
43:34
And this is another push in my lab. So think about what phages are already doing. And so, my group studies led by Dominique Holtappels, who's a postdoc in the lab. He leads a large team of undergraduate researchers and you might see them sometimes walking around campus with a tree trimmer, because every few weeks they set out to cross the city of Berkeley and sample Bradford pear trees. And the reason we're doing that is because these trees have this disease that you see here.
44:04
Two, actually -- blossom blight, which is caused by pseudomonas, and fire blight, which is caused by erwinia -- both bacterial pathogens. And what we can do is we can isolate bacteria from the leaves around here in Berkeley and then we can take those bacteria, grow them up. This is called a bacterial lawn, here on the bottom left. So, it's a beautiful lawn of bacteria, but we can take those leaves, filter them through a small filter and put any potential phage onto that same Petri dish.
44:35
And here are the beautiful plaques that Felix D'Herelle first saw. And so these plaques are a single virus that infected a single bacterium, bursted open, infected the neighbors, and so forth, until you can visually see the virus, the phage. And so from this bacteria that we found here in Berkeley and this phage that we found here in Berkeley, we can do tests. So, for example, if we take a pear fruit, an immature pear, which is what you see in here,
45:03
and we inoculate the pear with only the pathogen. So, those are the two middle pears. Or with the pathogen at its phage on the outside, we can see that the presence of this phage that's naturally circulating does indeed stop disease. And we have this, my favorite assay that we've ever done in the lab, the most beautiful experiment is here where we have these pear blossoms on the bottom. We can take pear blossoms from trees around campus, bring them in, and inoculate them with the pathogen.
45:32
And you can see on the right, we see a lot of oozing brown disease or with the pathogen and the phage, where we see no disease. So, these phages are abundant and incredibly effective at controlling disease. But there's a slight problem, and that is that there's evolution. So, bacteria and phage rapidly evolve and co-evolve. And so if you were to take a bacterial lawn and spot in the middle of it, a lot of bacteria phage, so that you get a big zone of clearance where the bacteria has been killed
46:07
and you forget about it for a little while. So you leave it on your desk and you come back a couple days later, you'll see that right in the middle, there are these bacterial colonies and that is real-time evolution. This is a bacterium that's evolved resistance to these phage. And what Reena Debray who was a graduate student and is now a junior group leader at the Max Planck in Leipzig. Reena took these mutants and she whole-genome sequenced them. So, this is basically a way of understanding
46:35
which mutations caused this resistance. And what we find is this is the LPS molecule, which is a molecule on the outside of the bacteria. And we found that the phages that attach to these molecules could no longer recognize the bacteria, if the bacteria changed the confirmation of this molecule. But there's a catch: every one of these mutations that conferred resistance to the phage came at a cost to the bacteria. So, on the right here, you're seeing the growth of the bacteria
47:07
relative to the sensitive ancestor. And every time these resistance mutations happen, the bacteria cannot grow as well. And I'm not showing you the data here, but they're also not as virulent of a pathogen. And so this is a kind of win-win where if you use phage, you might stop disease or you might have resistance evolution. But in doing so, you end up with a less pathogenic, a less nasty bug.
47:34
And one of the most creative ways that we can use this kind of directed evolution or this consequence of evolution, is work led by a colleague of mine, Paul Turner at Yale. And what Paul has been doing is finding bacteria phages -- so, here's a panel of phages -- that when he selects for resistance, those resistant bacteria are now once again susceptible to antibiotics. And this is because he has found phages through phage hunting that combined to the efflux pump that is critical for bacteria
48:11
to resist antibiotics in our system. And so by using phage and selecting for resistance, we can actually reverse antibiotic resistance going back to the original problem we're trying to solve. And I think this idea that we use evolution, we don't fight evolution but we use it as part of our solution, is incredibly exciting and really untapped in terms of potential. And so, we are taking very similar approaches. I'm not showing our data, because it's not quite ready yet,
48:42
but we're taking very similar approaches to ask whether we can reverse resistance to common pesticides used in agriculture as a way towards moving towards more sustainable agriculture. And so with that, I will once again thank the group and all of the funders for this great work and you all for being here this evening. Thanks so much.
49:04
PRIYA: Thank you, Professor Koskella. That was really groundbreaking work. We have time for a few questions.
49:13
A question by Dennis Meister
49:18
from the audience is:
49:24
Will most phages used in the future be from natural sources or synthesized or engineered? BRITT: Oh, really great question.
49:34
I'm an ecologist by training and evolutionary biologist. I think evolution is amazing and the amount of variation that evolution has already created for us as a playground out there that are already optimized to be incredibly effective killers of bacteria, makes me feel more comfortable and excited about hunting for phages that do the things we want them to do. But that being said, that's one person's view, and there is a huge, burgeoning field of both
50:04
researchers, at Lawrence Berkeley National Lab and here on campus, as well as biotech companies who are very much investing in engineering phages to do things that natural phages, at least the ones we've found so far, can't do.
50:20
PRIYA: I think what's truly fascinating to me is the interplay between the phages and the antibiotic resistance.
50:29
But what's intriguing is if phages are already everywhere, why aren't all the bacteria already resistant to them? Like, why do phages still work? BRITT: Yeah, that's a great question. So, I will say that the same is true for antibiotics. So, we use antibiotics in a clinical setting, but antibiotics were not invented by us, right? Fungi, other bacteria use antibiotics. And so if you go into deep caves that have never had human contact, you will find antibiotic-resistant bacteria.
51:02
It's a natural phenomenon. And same is true with phage resistance. When we look at bacteria across the planet, we find that they vary in phage resistance and it is absolutely out there in widespread. The difference is that with a little bit of a tweak, and with a clinical eye, we can change it from something that might be at lower density and just having a small impact, we can increase the numbers and treat... turn it into a therapeutic agent.
51:30
But it's true that, and I guess maybe I'll just continue for a moment to say that the other side to that is that unlike antibiotics, the phage that are in the environment, when bacterial evolution pops up, unlike antibiotics, phages counter-adapt. And we see this, we can do path... we can take a test tube and over the course of a week, we can watch multiple rounds of evolution, where the bacteria evolve resistance and the phage break that resistance. PRIYA: Oh, wow.
52:01
BRITT: And then the bacteria evolve resistance again and the phage break it again. And we can watch that cycle in real time and in nature. PRIYA: That's truly fascinating. It's like the red queen. BRITT: Yep. PRIYA: Yeah. The further I run, the further it go... Yeah. [Britt Chuckles] I know there's been a great deal of focus on how bad antibiotics are for our microbiomes. I know your lab also does a lot of research on microbiomes. I was wondering if you can comment
52:32
on should we worry about negative impacts on our good bacteria? BRITT: Yep. So, this is a rapidly changing question and answer. I will say that one of the appeals of phage, and I didn't mention this, but unlike antibiotics that are a bit like a wildfire, they go through and burn everything including all of our good-gut microbiome and flora. Unlike that, phages are quite specific. So, phages will target a particular strain and only kill that strain. That being said, though, a big push in my lab
53:08
is thinking about phages as a more holistic...
53:13
they've been called puppet masters, it's a nice way of thinking about it. Engineers of the microbiome. So, I've focused today on phages of pathogens, but we really think about phages as being a critical part of our gut ecosystem and actually quite the opposite of antibiotics. Phages seem to be very good for our gut health. And we have a lot of evidence to suggest that without phages our gut microbiome would be a mess.
53:40
PRIYA: That's very interesting. A couple more questions from the audience. Barbara Monette asked: Do you anticipate unintended negative consequences from manufacturing synthetic phages?
53:54
BRITT: My feeling is no. Again, I believe evolution has optimized many things through time, through millions of, in this case, billions of years of optimizing phage. And so, I actually think almost the opposite where a lot of what we try to do when we engineer is create a super phage or a super bug. But of course, the reality is that an organism can't do everything. And so when we create a phage that has the capability to do a lot more than a natural phage might do,
54:27
in that case, selection is typically working against us and evolution is working against us. Where over time, selection will probably reduce the functionality of that engineered organism rather than the opposite. So, this is not of the things that keep me up at night. This is very, very low on the list. PRIYA: Yeah. Another question by our Dean Botchan: CRISPR arose in many bacterial species to defeat viral and phage growth. BRITT: Yeah. Yeah, we should make a big nod to phages and bacteria
55:00
for bringing us the latest and greatest genome engineering capabilities, because the CRISPR system was discovered because people who really want bacteria to grow, for example the yogurt industry and other places where fermentation and bacterial cultures are incredibly important, they needed to find ways to stop phage, and phages are pretty unstoppable. So that's how we ended up in this beautiful place where we have the IGI and CRISPR as a new tool. Yeah.
55:32
PRIYA: Another question from Rosette Dawson is:
55:36
Have there been a clinical trials using phages on human bad bacteria?
55:42
BRITT: It's a great question. Yes. Clinical trials a bit less so. So currently, it's not phages as in a clinical setting are not FDA approved. They're only used at the moment as compassionate care. Now that being said, because of the increasing threat of multi-drug resistance, there is a lot of compassionate care use for phage. So, these are folks who have tried the traditional medicine and cannot clear their infection. And then absolutely, there's a whole slew of phage researchers
56:11
who share phage strains and ship them across to doctors and attempt to cure. In fact, Paul Turner, who I mentioned earlier, he saved a very large turtle at the aquarium there in New Haven that was dying of a bacterial infection. It was one of the most famous turtles in the aquarium and they sent him the strain, and he's found a phage, sent it back and cured the turtle. But in more serious, yes, they're being used in humans. And so far, everything that we were worried about like toxic shock
56:45
or other negative consequences have absolutely not... there's been zero evidence of it. PRIYA: Oh, that's incredible. BRITT: Yeah. PRIYA: As you know in India, antibiotics are overprescribed, and I've had relatives who have tried five or seven antibiotics before they can get one to work. And it's really a major problem in the subcontinent. BRITT: Yeah. PRIYA: I think with on that note, I will bring back all the presenters. This has been a really exciting session
57:22
and we'll open it up to questions to all of the speakers. So, audience, we want to hear from you. We want to hear your thoughts and comments
57:35
and feel free to ask any of the speakers questions now. There are lots of comments in the chat with Bravo
57:46
and fascinating work, breathtaking work.
57:53
BRITT: And go Bears, I agree. PRIYA: And go Bears, yes. [Priya and Britt Chuckles]
58:05
I mean, it's just incredible to see how evolution at every scale has
58:13
really shaped everything that we see around us.
58:18
And it's just fascinating at long time scales and short time scales related to disease and adaptation, how it's been this one answer to almost all the questions and problems.
58:39
I'm going to check again.
58:42
We have a question from the chat,
58:47
from Rick Reader who asks:
58:51
Will we be able to get wilds or phages for our infection at the pharmacy? So, this is for you Professor Koskella.
58:59
BRITT: Well, at the moment, you'll have to go to Tbilisi, Georgia, but this is indeed a vial of phage that I got at the clinic. In Tbilisi, they have had phage clinics since the '20s, and this is if you were having diarrheal symptoms, this would be a phage tonic you could drink with phage cocktails against the known pathogens that cause diarrhea. I think we're probably quite a long way from having a vial of phages that you could have over the counter. But time will tell,
59:34
things move quickly and surprise me every day.
59:39
PRIYA: Yeah.
59:41
BRITT: I think, maybe, we'll unmute and take a question directly from the audience.
59:48
Barbara Monette has a question.
59:52
BARBARA: Yeah. Yeah. I was just wondering how do I get a recording of this session?
1:00:00
PRIYA: The recordings will be posted in a couple of weeks. And so just check back at the website.
1:00:12
Ben, I have a question for you. I've been thinking about why population sizes that you showed us in your study, why they rebounded after 1,300 years, and how that was impacted by the other crops? BEN: Yeah, it's a good question. Because you'd expect like if Sunflower was getting less grown as a crop and corn was taking over, then why isn't population size just continuing to decrease? And what I think is going on there, and this is something that we need to do more analyses to prove,
1:00:51
is with the relaxation of selection on these, like, really important domestication traits in sunflower, it creates an opportunity then for more just cross-pollination between wild forms and domesticated forms. And so we may have a resurgence of gene flow moving diversity in from wild forms into the cultivated forms at that time, which would increase the overall population science. PRIYA: Thank you. I thought your study was really a fascinating example of how evidence from various
1:01:27
different analysis came together, sort of highlighting the same time period. And I think this is really where how scientists learn about different processes that have happened. Usually, we don't focus on one evidence, but like try to learn from different analyses. And so, with that, and sort of a nod to the scientific method, I will turn it back to Dean Botchan. Thank you, everyone, for joining us and also to all our speakers. MIKE: Okay. Well, thank you, Priya
1:02:07
and thank you, all of our speakers, for sharing their research. Tonight is the final Basic Science Lights the Way event for the semester, and it turns out my final event hosting as Dean of Biological Sciences. For those of you who don't know, I'm retiring this summer, which is fast approaching. But these events have been a highlight of my tenure as Dean, allowing me to connect with so many of you. I've found these events and our speakers to be remarkable and I hope you have, too.
1:02:39
I want to thank our audience for joining us and encourage you to reach out if you would like to learn more about anything we've covered. And I think Priya's already answered a question, but I'll just repeat it for those of you who weren't paying attention. We'll be sharing additional resources with you by email about today's topic and speakers and about future Basic Science events. Also, a video of today's session will be available at our Basic Science Lights the Way website,
1:03:11
which will be approximately two weeks from now Until we see you again: Stay curious, fiat lux, and go Bears!
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