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关于"Dark Genome"

已有 2980 次阅读 2022-5-2 18:34 |系统分类:科普集锦

关于"Dark Genome"

昨天看到一段访谈,清晰地解释了我过去多年的疑问,关于Dark Genome,关于DNA损伤,关于innate immunity,关于创新型的新药研发。很佩服Dr. Rosana Kapeller-Lieberman的开创精神,触他人所不能及。和她的团队合作近十年,深刻感受到创新型团队的眼光、思维、策略和勇气,有道是“无限风光在险峰” ,真希望有机会能与这位传奇的CEO有当面交流的机会。

在拓展DNA损伤和表观遗传学平台的时候,让大家的眼光回到了基础的分子生物学原理,经常需要回去翻书查阅一些基本的概念:比如DNA复制、修复、转录、转录后修饰、翻译、入核、出核等等,比如氨基酸、密码子、mRNA,siRNA,shRNA,microRNA,lncRNA,比如操纵子、起始子、启动子、起始密码子、转录终止、RNA加帽、诱导调节,比如crRNA,tracerRNA,sgRNA,CNP,比如DNA退火、连接、酶切、电泳等等,再比如DNA的修复方式、损伤方式、可能的活化机制,如何开发个技术去观察一个过程,这里有太多的细节需要去考虑,也有太多的数据需要给予解释。

访谈中提到一句话,很有意思:We are all part of human, and part of Viruses。我想理解Dark Genome,需要以一种功能性的认识去看到未知领域,存在即合理,随着基因组测序的推进、各个学科的发展、大数据和AI技术的应用,将会有更多有意思的发现。每次想到DNA的反向双螺旋结构,都觉得很神奇,也很智能!如此神奇的DNA,该用什么角度去观察、去思考,其实我们可以多多联想。细胞费了如此多的周折希望准确地复制遗传物质并传递给子代细胞,在广袤的DNA未编码区,到底有什么秘密?该如何去研究?该从哪里下手?和临床需求有什么关系?这里的一些问题,吸引着很多科学家,包括Rosana的新公司,ROME Therapeutics,一家专注repeatome的生物技术公司。

搜索Repeatome,Pubmed收录的文章并不多,有人在研究REPEATOME: A Database for Repeat Element Comparative Analysis in Human and Chimpanzee,这些还是很早期的探索。其实也很容易链接到ROME公司,国际上做这个领域的太少,如此冒险做创新探索的公司更少,希望通过企业引领来影响科学界状态的公司就更不多。

当我看到前两天Theory and Practice发布的讨论内容,我反复听了好多遍,深深的感觉到国内缺少这样的公司,缺少这样的探索,缺少这样的基础研究和技术手段。我深信未来5-10年之间,生物医药领域,会有变革性的进展,不仅仅是药物研发,还有大量的技术、大量的信息、大量的资金、大量的创新、大量的融合与交叉,大量的合作与探索。希望ROME团队在Repeatome的探索之路披荆斩棘,勇往直前,为世界带来更多让人兴奋的发现!

 

                                               DNA.png

The human genome is not packed with ‘junk’ as previously thought, but with regulatory regions that modulate gene activity.1

 

 

如下摘录了部分讨论,以飨读者。

The "Dark Genome" with Dr. Rosana Kapeller-Lieberman

Rosana.jpg

Dr. Rosana Kapeller-Lieberman

President and CEO at ROME Therapeutics

A GV Fellow and the CEO of Rome Therapeutics with over 25 years’ experience in science and therapeutics.

Our guest is Dr. Rosana Kapeller-Lieberman, A GV Fellow and the CEO of Rome Therapeutics with over 25 years experience in science and therapeutics. Rosana discusses her team's scientific approach, and how they have tackled investigating the 60% of our genome that we previously thought was just filler, or repeatable DNA.

Theory and Practice is a presentation of GV and Google AI.

This season we'll dive deep into the languages of life through explorations of the "dark genome", genome editing, protein folding, the future of aging, and more.

Hosted by Anthony Philippakis (Venture Partner at GV) and Alex Wiltschko (Staff Research Scientist with Google AI), Theory and Practice opens the doors to the cutting edge of biology and computer science through conversations with leaders in the field.

 

Transcript(节选)

Anthony  00:14

In this series, we'll be exploring research that we think may be impactful in the next 10 to 20 years. We focus on research in the life sciences, particularly where it intersects with the data sciences. Today, we'll be exploring a new area called the Dark Genome. And by that, we mean the part of our non-coding DNA, which is the repetitive filler sitting between our coding genes, and the regulatory elements that control them. For a long time, people have referred to it as “junk DNA,” or the colorful phrase, the repeatome. It showed up as long dark patches that were hard to analyze with existing methods.

 

Alex  00:50

Since the development of long read genomic sequencing combined with machine learning, some extraordinary findings about this part of our genome have come to light. Around one in 12 of those repeated segments of non-coding DNA are recognizable as ancient and current viruses that have been incorporated into our DNA. They're passed on through the generations and picked up as we live. We are all part-human, part-virus. Complex mechanisms lead to these parts of our dark DNA being reactivated under stress. For example, when the chickenpox virus lies dormant in the peripheral nervous system, under stress, it is reactivated as shingles, at least partly by the Dark Genome.

 

Anthony  01:33

We know that about 60% of our Dark Genome is composed of things called “transposable elements.” These transposons can duplicate themselves hundreds of times and move around the genome. There's more and more evidence emerging that these transposable elements are implicated in the regulation of our innate immune system, and hence our initial response to attack by viruses and bacteria. Ongoing environmental stress can also challenge this part of our DNA, and potentially promote the development of cancers.

 

Alex  02:03

To help us work through the complexity of this topic, distinguishing between hype and real potential is Dr. Rosana Kapeller-Lieberman. She is Google Venture (GV)’s, first Entrepreneur in Residence, CEO of ROME Therapeutics, a medical doctor, and she has a PhD in Molecular Cellular Biology. She also has a deep expertise in computational approaches to biology.

 

Anthony  02:28

Hey, Rosana, welcome to Theory & Practice. It's great to see you here today.

 

Rosana  02:32

Very nice to be here, Anthony. It's a pleasure.

 

Anthony  02:35

So, you and I are both on the team at GV. Over the last few years, we've had some wonderful talks about the Dark Genome. And now, I think it's a chance for our audience to hear a little bit more about what you think it's about and why you think it's important. So maybe you can start off and say, what is the Dark Genome and what is the repeatome?

 

Rosana  02:55

So, the Dark Genome, the best definition I have seen is: everything in our genome that does not encode for proteins or regular proteins. And if you think about it, only 2% of our genome is responsible for basically encoding for the proteins that we are aware of, and about 20% of our genome are part of the regulatory mechanism that basically modulates the expression of these proteins. So, if you think about that, it leaves about 70% of our genome that's considered the Dark Genome. We don't really fully understand the function of it. And for the longest time, this Dark Genome has been ignored; it has been thought to be: “Oh, maybe it just plays a structural motif. You know, it's important for chromosomal structure; it doesn't do anything. It's dormant, you know, we just carry it along for the ride.” And that doesn't really make a lot of sense from a biology evolutionary perspective. And I think in the past five to 10 years, with the advent of new technologies, especially next gen sequencing, long read sequencing and machine learning, etc, we are starting to understand that this Dark Genome is not as dark as we think; there is light there; a lot, actually. And we see bursts of it in adult normal, healthy cells; it's usually dormant. But during certain conditions, it gets reactivated and plays a very important role in both human health and disease.

Alex  04:25

I just want to be clear about what we're calling this. So, you didn't mention it, because I think you're avoiding the term, but I don't think you like the term “Junk DNA” for the Dark Genome.

Rosana  04:35

No, I don't like that term “Junk DNA.” It's not junk. You know, people call it junk just because they didn't know what to do with it. And to be completely honest, when we didn't have the technologies, we developed ways to mask it, and basically throw it out, so it's like the proverbial “throwing the baby with the bathwater.” I think that has changed and I think people are now paying a lot of attention on what is inside this Dark Genome, that “junk DNA.”

 

Alex  05:02

So it's kind of, “One person's trash is another person's treasure.” It's your treasure, I guess!

 

Rosana  05:07

It's definitely my treasure. You know, I am absolutely fascinated with the Dark Genome. And I think there's so much there.

 

Anthony  05:15

“Rosana Kapeller, dumpster diver. Genomic dumpster diver.”

 

Rosana  05:21

I never thought about it this way. You know, I think that from rags to riches, you know, what is? Yeah. Dumpster Diver? Okay. I'll go with that for the moment.

 

Alex  05:32

But going back to the science here; this is a major part of our genome by bulk. And we couldn't see it before, until, as you mentioned, long read sequencing was developed, because of how repetitive this is. And maybe also some statistical techniques here too, absolutely. Could you maybe give us a tour of what we have learned about it that's made you excited about the Dark Genome in the past five or 10 years?

 

Rosana  05:58

Absolutely. So, before I go there, I want to make an analogy of the problem. It's like having a 100,000 piece puzzle or a million piece puzzle with no edges. They all look the same, no picture on the box, and then being told, “Okay, put the image together” - it's basically almost an impossible task. And that's what we're faced with, by the nature of the elements in the genome, that are repeats. So these are repetitive sequences, repetitive elements, that have basically integrated our genomics revolution, through actually viral infection. So in a way you think about this as our genome parasites. So if you go and look into the Dark Genome, 20% of it is LINEs, which are long interspersed nuclear elements that basically are transposable elements. It’s the only active transposable element that we have in our genome. And there is more and more that we're learning about that, in terms of genomic plasticity, embryogenesis, and very much the role it plays in pathogenesis and a variety of diseases. 8% is comprised of HERVs. These are human endogenous retroviruses that also have activities. You know, if you look at these retroviruses, some of them are incomplete. But some of them are complete pro-virus that have gag, pol, and env. What are they doing in our genome? Many groups think that they went there to die. But are they responsible to help us defend ourselves against viruses? You know, what is their role in our genome? I mean, they comprise 8%. It's a big number. If you think that only 2% code for proteins, it's incredible.

 

Alex  07:49

So I'm curious about that, Rosana. You kind of allude to many different functions. But, should I think of these sequences from HERVs as scars in our genome? Should I think of them as little badges or medals of achievement that we beat them? Or are they hitching a ride? And you use the word parasite? Is that the right way to think about them?

 

Rosana  08:09

I think it's all of the above, Alex, because I think it depends when they integrated into our genome’s revolution. The most ancient ones are definitely fossils; they don't do anything. They're like battle scars. But there are more recent HERVs that seem to be active. And the other thing about HERVs is that we have co-opted some of the HERVs proteins. For example, the most famous one is Syncitin 1, which is the envelope protein of HERVs-W, which is important for placenta formation. So, if you think about that, without Syncitin 1 mammals would not exist.

 

Anthony  08:46

Well, you know, it's fascinating on so many levels. And again, let me step back, especially for some of the listeners that maybe are not as close to genomics. I'm curious; I think of repeats as being like the following: you have two kinds of them; imagine your genomes as a book. And imagine that there's a page of that book that just gets repeated, reinserted over and over again, throughout the genome. And you'll see 100 copies or 1000 copies of that one page, just at random places. And then there's a second kind of repeats, which are like in the old movie, The Shining, where, you know, there's like, “All work and no play makes Jack a dull boy, all work and no play makes Jack a dull boy…” And so there are passages in the genome, where you see the same sort of short string repeated over and over again. So that second class, we've known a long time that they could cause disease like Huntington's diseases is “All work no play, Jack…” But I think one of the things that is so fascinating about your work and the work of a lot of your colleagues, is this idea that these other classes of repeats, the pages that are just randomly reinserted over and over again in the book can actually also cause disease.

 

Rosana  09:54

Absolutely. And just before I got there, just want to finish with some of the elements just so that we understand that what this is comprised of. So I talked about LINEs I talked about HERVs, you have also SINEs and Alus, and satellite elements, all of them play an important role. Some of them still have high CpG content. So they look like viruses. And I think that the breakthrough that happened is when we understood that these repetitive elements are not always dormant, okay? They're very active during embryogenesis. Then once you're born and you're healthy, these repeats go dormant, that is true. But upon certain stages, like for example, if your cells are submitted to environmental stress, smoking, irradiation, UV, whatever it is, you know, there is an epigenetic control of these repeats, and these repeats get reactivated – it’s basically hyper methylation of the areas of the genome where they are located. And these repeats actually get expressed; we have transcripts of these repeat elements or RNA. And what happens is that these transcripts, now, they can go and activate our innate immune system. So in a way, think about it as sort of our first sentinels, our first army to say to the rest of the organism, the cell is sick, let's kill the cell. Because it's sick. It's like having an endogenous infection. And basically, you kill this out and you establish homeostasis. So if everything is going well in your organism, you just have a healthy organism and the cells. But what if this mechanism goes rogue? In a way, you have to…it's very similar to what happens when you have a viral infection, you can have hyper activation that leads to a cytokine storm and damage to the whole organism. Or you can have hyper activation or latency that leads to diseases like herpes zoster, you know, you get chickenpox when you’re a child, and 50 years later you've developed herpes zoster. And the same thing happens here with the repeats. If it goes wrong, and you have hyper activation, you can get autoimmune diseases, you can get neurodegeneration, you can get aging, which is something very interesting. But also if you get hyper activation or certain types of hyper activation that can underlie some of the proliferation that we see in cancers. So what is happening here, and it could be both intrinsic factor in tumor cells as also an extrinsic factor in the tumor microenvironment. And that's what we're studying right now: the role that repeat plays in the pathogenesis of these different diseases. And where we're focusing right now is ultimately diseases and cancer, but also have a pretty healthy interest in neurodegeneration and aging.

 

Anthony  12:46

In going back to kind of the taxonomy of the repeats, you have HERVs, and you have transposons, you have SINEs and Alus, which map those on to the different disease processes you talked about which ones, for example, trigger the innate immune system…

 

Rosana  13:00

In terms of the transcripts that induce the innate immune system, what folks have shown is that LINE1, Alus and SINEs seem to be activators of the nucleic acid sensing pathways, like RIG-I, MDA5, and also cGAS in this tank pathway. And what is interesting is that repeats like LINE1 and HERVs encode for reverse transcriptase. So one of the things that fascinates me is that the repeating coded reverse transcriptase plays a big role in reverse transcribing, repeat RNAs into RNA DNA hybrids, and then double stranded DNAs. And now we can show that this hybrids and the double strand DNA activates cGAS-STING pathway. So, in a way, we're starting to interrogate whether those repeats are the genesis of sterile inflammation that has been implicated in a variety of autoimmune diseases. So again, it looks like an endogenous infection. Nobody knows where it comes from. But now you can sequence like if it takes cGAS, you can now sequence these DNA-RNA hybrids and double-stranded DNA and cGAS that are derived from repeat motifs.

 

Anthony  14:22

Let's deep dive a little bit on cancer because I know that's one that you followed really closely. And so I remember you telling me an incredible story about the HERVs and actually treating cancer patients with anti retrovirals. Maybe you can kind of connect the dots a little bit on that.

 

Rosana  14:38

Sure. So this is work actually from one of our scientific co-founders, David Ting, that started exploring that, where basically he saw the repeats and he saw the high expression of repeats in cancer and he hypothesized that if you actually would block the reverse transcriptase of those repeats, you would have an effect in cancer. The answer is that the jury's still out. I was mentioning before, whether there is an intrinsic effect or an extrinsic effect. And I think that it's going to be very much context dependent on whether inhibiting CAR-T is going to be beneficial or not for cancer, I think that for certain cancers, the answer is yes. For other cancer, the answer is no. And the reason for that is that if the cancer requires pro inflammatory signals to proliferate, then the answer is no. If the pro inflammatory signals actually blocks that particular cancer, like what you have with checkpoint inhibitors, the answer is yes. So one of the things that we're very curious about and researching right now, is whether you can use antiretroviral therapy together with checkpoint inhibition, and basically enhance checkpoint inhibition, because they should work hand in hand, because you're going to be activating the adaptive immune system and also regulating the innate immune system. I think with cancer, the story that's emerging right now, it's not so much about whether it activates innate immune system or not, but it's more about genomic instability- it’s the ability of repeats to integrate into the genome. And the other thing that I want to mention is that tumor suppressor genes, also regulate repeat expression. So when you have mutations in BRCA1 and p53, you have upregulation of repeat expression. 

 

Alex  16:33

So, Rosana, the use of what you're learning in regulating or responding to changes to the Dark Genome and cancer seems really complex. And is that a reflection of just how complex cancer is as a constellation of diseases?

 

Rosana  16:49

I think that you hit the nail on the head. Yes, I think that's part of it. And I think that's also because we're just learning about the role of repeats in cancer, and it's multi dimensional. So we have been talking about the role of the transcripts activating the innate immune system. Okay, so this is one aspect of it. The other aspect that we didn't talk about, I mentioned that LINE1 is an active retrotransposon transposable element in what several groups have shown now is that LINE1 is highly active in cancer. And that actually, you'll see more LINE1 insertions as the cancer progresses from the primary tumor into metastasis. The question for us, is that is that cause or consequence? Correct? Or people ask me this question all the time is, you know, the, the repeatome driving, or is it a passenger, and the way that I always like to refer to it, is that I believe it is a passenger with the foot in the gas. So there may be something else that initiates it, but without the repeat activity. For progression of the cancer, you're not going to get the type of proliferation metastasis that to get in the presence of an active LINE1 element and other elements. The other thing that I want to add is that LINE1, not only retrotransposons itself, is also responsible for retro transposing elements that don't have intrinsic retrotransposition capacity. So it can retrotransposons, SINEs and Alus, and so on, and also reverse transcribe them all. It seems that one of the day jobs for tumor suppressor genes like p53 and BRCA1. One is to basically keep repeat expression under control. So in cancers that have a p52 mutation or BRCA1 mutation, you see any increase in repeat expression. Again, is it cause or effect? And this is another piece that we're investigating right now, with our academic collaborators.

 

Alex  18:53

It seems like there's a lot of open fundamental research threads here. And I would like to return to that, like how you think about doing fundamental research in the context of a company. But you also mentioned something I want to double click on now, which is the relationship between aging and the repeatome. And it's an interesting link, because at least I think of aging is much more complicated than cancer and cancer is a disease state. There are many, many different types of cancer, but I don't even know how to name the types of aging or the ways in which we age or it's accelerated or decelerated. So, for me, it's strange that aging could be related to the repeatome. But is it more or less complex in that relationship than cancer?

 

Rosana  19:36

I think it's more straightforward. I think that the seminal work from John Sedivy has pointed to a path in which there is a failure of the repeat surveillance system in aging, so that you get more active repeat expression as you age. And because of that, as you express more repeats, you activate inflammatory pathways that become chronic. And that's also part of aging. Also this: over active repeats seem to be involved in senescence. And what John has been able to show is that if you use antiretroviral therapy to be more specific nucleoside reverse transcriptase inhibitors that block LINE1 activity, you can also block senescence, at least in vitro. So this is an area of active interest in academia, in how antiretroviral therapy may play a role in basically delaying the progression of senescence and aging. This is still an emerging field, but I think it's going to be much more straightforward for cancer in that regard.

 

Anthony  20:50

One of the things that I've noticed over my 20 years in life sciences is that there are some fields and some moments in time, where a community is able to organize itself and create a coherent, intellectual agenda. I remember last year on Theory & Practice, we had David Altshuler and it was just breathtaking, to watch how you had the Human Genome Project, and then the HapMap project, and then GWAS, and then sequencing. And you know, it was just this kind of amazing period of progress, because that community was able to organize itself. How do you see this playing out in the world of the Dark Genome? Do we have a set of organizing principles and efforts that are guiding the field? And if not, why not? And what would it take to get there?

 

Rosana  21:38

You hit the nail on the head; I think this is going to be required for us to advance this field where it needs to go. Right now, there are different groups of people focusing on their little space, you know, the LINE1 folks organized through meetings and they talk about LINE1; and HERV folks organize meetings and talk about HERVs; the LINE1, folks don't talk to the HERV folks and vice versa. So there is no organization in terms of what are the overarching principles, as you say, and then how we can organize the different disciplines so they can collaborate and converge into a common arena. And that needs to happen now, so that we can actually get to an explosion of knowledge around repeats. And, you know, we call it the repeatome. Others call it the mobilome. I think that the technologies are here today that can help us investigate those repeats to help investigate their role. But if we don't get the community to really engage and create that very unified front, this is still going to continue to progress very slowly.

 

Anthony  22:52

And you know, just to kind of dig into that for a second. How much of the lack of kind of coherent intellectual agenda is due to a lack of leadership? Is it that we're missing a small number of people that can really paint the vision and rally the community? Or is there something more structural or fundamental that's missing? 

 

Rosana  23:15

I think it's because people came into it from different aspects, and people haven't connected the dots yet. And the other piece is that there hasn't been a real effort, maybe now there's going to be an effort, let's unlock the Dark Genome, and understand its functioning human health and disease and make this a mandate. You know, I mean, if you think about the Human Genome Project, that was a mandate; we got to all the greatest minds in the world and say, “We want to sequence the human genome, we want to understand what's in there.” And I was at Millennium at the time. And I have to say, it was amazing to watch how it was done. And I think that something like that is required right now. And I think the ENCODE project was a great start. I think that there are other programs that are happening right now. The telomere to telomere consortium now has mapped a lot of the Dark Genome with something that we needed, you know, we don't even have basic things. We can't even map the repeats into the genome, you know; this is basic, you know, we saw that you cannot even start discovery. And I think this is going to change a lot, but we need to organize the community, this is a call to arms, and let's break darkness and bring light into the Dark Genome.

 

Anthony  24:39

So let's switch gears a little bit from talking about the Dark Genome and actually talking about you as a person a little bit. You know, tell our listeners a little bit about how you actually came to be an entrepreneur in residence at GV. In fact, you were our first EIR, so what brought you to us?

 

Rosana  24:57

So, before joining GV, I was the founding CEO of Nimbus Therapeutics and all my career has been about bringing new medicines to patients. And do that using technology. I was always very interested in cutting edge technology. So Nimbus was all about computational chemistry, how can we use computational chemistry to drive the drug discovery process. And after eight years at Nimbus, and quite a bit of success, we have now three drugs in the clinic partnership with Gilead and Celgene and all kinds of good things happen. I was really interested in what's next. And I was interested either in doing something with new technologies, so - machine learning. And the other part I was very interested in is what is out there that nobody is working on, that can be, sort of, the new area of research that we can find novel targets, and really create new medicines to treat underserved diseases right now. And when I was leaving Nimbus, I called Krishna Yeshwant, who I had met, you know, when we were trying to finance Nimbus. And the first was a GV, I basically told that the whole GV team how Krishna did not decide to invest in Nimbus, you know, and how he missed the opportunity to have a 10x return. And I didn't realize how embarrassing this whole conversation was. And I didn't also realize why they hadn't invested on it, and which now makes complete sense to me. But over the years of trying to convince Krishna to invest in Nimbus, we developed a relationship. So when I was leaving Nimbus, I called him up and I said, “Look, I'm looking for my next opportunity, I could go and join another one of the traditional VC groups, but I would love to hear more about what GV is doing.” And we went for dinner, and we had a wonderful conversation at dinner. And I said to him, why not bring me in as an EIR. And Krishna turned to me and said, “We don't have an EIR program.” I said, “What a great opportunity to start one,” you know. And that conversation evolved for about nine months. And then at the end of it, I did join GV, and I never looked back. I mean, that was the best decision ever in my life. And I think that you guys have really built a tremendous team and are doing things in a in a quite different way. And I really appreciate that.

 

Alex  27:41

It’s speaking truth, you know, which, which certainly is something that you do extremely well. And I appreciate. So, some more about you. You know, I read that in 2012 viewer on the Boston Business Journal, Women to Watch list and you know, they were right, like, for you to be watched, because you've done incredible things. And I think, at least from where I sit, it's because you like taking on new challenges, right? I mean, you mentioned explicitly, what's something that literally nobody is doing, I mean, how much more audacious and ambitious and scary is that right now you're the CEO of a company that's, that's doing that with a mission to unlock, you know, even the word “unlock” - the Dark Genome implies, like level of ambition, and passion. And right now you're a CEO in a small group of just 10% of female CEOs of biopharma companies. Why do you think that this lack of gender diversity is persisting, even today?

 

Rosana  28:38

Complex question. Let me take a step back here, because I think that we need to understand the evolution of gender diversity in our industry. 20 years ago, there were very few women, basically, you counted the Vicki Satos of the world and Deborah Dunsires of the world, basically, they would go into a room and have a lot of men around them. I think that with my generation, you started seeing more and more women rise to the top, you know, and nowadays, if you look around, there are more and more women in the C suite. I think that when it comes to the CEO level, it’s a question of, how are the investors going to trust women to basically return on their investment? And I think this goes back to the basics that, “like hires like,” so if you look at the investor community, most of the investors are men. You count basically in two hands, the female investors in R&D, it's actually improving. I have to say that. I think that the number of female CEOs will only increase when the number are female investors increase. I don't think there's any other way that this is going to play out. And I think that investors are making a lot of effort to go out there and recruit female CEOs and female CSOs and female board members. But I don't see the same level of interest in recruiting female investors. And if that doesn't change, the field is not going to change. I think that the idea of a glass ceiling that is not there anymore, but it's this idea of convincing people to trust you with their money. I think that's why you don't see a large number of women CEOs out there.

 

Alex  30:42

So it's structural in how these companies are financed in the first place. That is the problem.

 

Rosana  30:50

I think so. And I think it's human. It's…look, everything we do. It's about our tribes. You know, we're talking a lot about inclusion. And we talk a lot about diversity. But let's be honest, look at your circle of friends, they all look like you. You know, your family looks like you, we still haven't done a good job, even in our personal lives, to diversify. When you get into a job, it's even more pronounced. So I think that once you have more female investors, more investors of color, you're going to see that diversity at the top change. Because “like hires like.” Look, look at my company ROME. 70% of my management team are women. We have to make an effort to hire man. It's serious. We actually made that concerted effort.

 

Alex  31:41

Yeah, that's so interesting. It reminds me of this quote from E.O. Wilson. The real problem with humanity is the following: “We have Paleolithic emotions, medieval institutions, and godlike technology.”

 

Rosana  31:55

Yeah, agreed, agreed.

 

Anthony  31:57

Rosana, I kind of want to just close out with a little bit about the future and where you're going with building ROME Therapeutics. And in fact, you know, how you're trying to take the theory of the Dark Genome, and then translate it into practice. So you know, when you actually think about trying to make a drug that goes after the Dark Genome, how do you approach this question? What are the modalities that are most promising? Is it gene editing? Is it small molecules? Is it antibodies? Is it something else?

 

Rosana  32:26

That is a great question. So this is a new field, but I'm super pragmatic about how you get medicines to patients. And when we started ROME, we already started with that idea. And I have to say that we are currently focusing in small molecules and antibodies, because a lot of the targets that we have now are, in a way, traditional drug targets, even though it's the first time they're being drugged in humans. So for example, we are focusing right now in drugging LINE1 reverse transcriptase. And the reverse transcriptase activity is very similar to the reverse transcriptase activity that you see in viruses; we just have to generate compounds that are potent, specific and selective against the LINE1 RT versus the viral reverse transcriptase inhibitors. That's what we're doing. So being very pragmatic, we are going after antigen targets, because as I mentioned before, the HERVs make envelope proteins that are overexpressed in certain types of cancers, we are going after host targets, you know, that are responsible for splicing of this transcript. So there is a variety of the low hanging fruits that we're going after. This is going to give us the space to basically do a lot of work in finding novel targets that are repeatome based. And to do that, we're building a very strong data sciences team. So the way that I see that this is going to go hand in hand, is that ROME is the intersection of a therapeutics company with a data sciences company. That's the only way that we're going to be able to do that both in terms of identifying novel repeatome targets, but also identifying the right patients for which these medicines will have an impact. So that's how we are translating the theory to practice. Our first drug is going to be based or modelled in anti retroviral drugs that go after reverse transcriptase as a target. And the beauty of that is that we have 40/50 years of experience with reverse transcriptase inhibitors.

 

Alex  34:31

I think it's interesting to keep the risk focused on just the unknown part and be as pragmatic as possible about the rest of the therapeutics story. But if I could ask you to leave pragmatism behind a little bit and look forward like 10 or 20 years, do you think that we'll see interventions in the Dark Genome not for disease treatment, but for disease prevention?

 

Rosana  34:53

Absolutely. I think that this is going to be the big future here is that we could use it to prevent diseases, like for example, David Ting and I, in the very beginning of our collaboration on the ROME idea and so on, he used to tell me that if you could modulate repeats that may be blocking reverse transcriptase -  the repeatome called reverse transcriptase - that could be the aspirin for cancer, because if you can block insertion to the genome, you can block activation of the innate immune response or whatever it is that is involved in the pathogenesis, you could see that could be used prophylactically to prevent. And I think that this is going to be true, not only for cancer, but autoimmune diseases and neurodegeneration, and maybe possibly aging.

 

Anthony  35:42

Rosana, thank you so much. This has been a fascinating conversation. You know, over the last few years at GV, you've been one of the people that I am most valued as a friend and as a thought partner. And you know, I think this is just a wonderful chance for our listeners to get to know you the way that I have. So thank you so much for doing it. 

 主要访谈内容来自:

The "Dark Genome" with Dr. Rosana Kapeller-Lieberman | Theory and Practice (gv.com)

 

1          Chi, K. R. The dark side of the human genome. Nature 538, 275-277, doi:10.1038/538275a (2016).

 




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