This is the transcript from the OVERVIEW OF PROJECT: FROM READING TO WRITING GENOMES This session will present an overview of the Genome Project-write (GP-write) with talks intended to introduce, inspire and anticipate the emerging era of whole genome design, editing and synthesis. Talks will discuss the current progress and future of GP-write and state-of-the-art advances in biological insights that stem from high-throughput sequencing projects, highlighting challenges and opportunities uniquely addressed by efforts rooted in genome-scale synthesis and editing.
The link to the video is at the end of the transcript
Well, thank you Nancy for welcoming everyone and let me add my voice to yours in, in welcoming everyone who’s travelled here today for what I think are going to be a couple of great days of science. Can we, can we get this? Okay. So my talk is titled GP write? What it is, where we’ve been and where we’re going. And so let’s dive right into that. What is GP write? I’m going to start simple because we have a, we have a diverse crowd here. We have some scientists that want to know, you know about individual DNA sequences and we have some reporters that might not want that kind of fine grained discussion. So start very big picture. It is a project as you just heard from Nancy to support technology development in genome writing.
So can be described as genome design synthesis and then evaluation of the biologic impact of genome design changes. This is this quote here is paraphrasing what we’ve written in our white paper as probably our number one aim, which is to reduce the cost of designing, synthesising, assembling, and testing genomes in cells by a thousand fold over the next 10 years. It’s it’s an aggressive goal but we think based on what we saw with the human genome project, the, the reading project, if you will we think we can do this. And we think that such technology improvements will really revolutionise how we as scientists learn about the world and then how we use that information to engineer it.
Nancy alluded to the development of a roadmap for GP write? And so I, I want to talk a little bit about that. First of all GP write? Versus GP read. So GP read is what we have called what we now refer to the human genome project, the sequencing project of the human genome, which, which was of course expanded to include many model organism genomes like the yeast, the fruit fly, the mouse, etc. And so GP write? Is the next phase. And it’s interesting to contemplate the difference between reading and writing. You kind of know when you’re done when you’re reading because you’ve finished the book, you, you’ve read all of it. There might be some interpretation, some complexities of interpretation, but reading is, is very well suited to a purely scientific endeavour because it’s very clear when you’ve, when you’ve finished decoding a document. On the other hand, writing is, it has a sort of element of creativity to it. It has an artistic side, if you will, and you never know when you’re finished because you could write one book or you could write 1000 bucks. So there’s something fundamentally different about it that excites me and others.
Now, what about GP write? Versus HGP write. One year ago, the predecessor of this meeting was titled HTP write? Well, as you’ll, as you’ll see in a moment we, we have defined GP write as the overarching effort to develop technology to write genomes. That’s really what we’re all about. And of course, we’re all passionately interested in our own genome. And the notion that we could actually write a human genome is simultaneously thrilling to some and not so thrilling to others. And so we recognise that this is going to take a lot of discussion from a lot of stakeholders. And so we’ve defined HTP write, as an initiative within GP write? That perhaps we will need to move a little bit more slowly on as we engage with stakeholders. And this is very much dominated our thinking about a very sort of large scale roadmap that I’ll, I’ll, I’ll mention. And a very important component of this that, that has gotten lost in a lot of the writing is that HGP write? We will do in cells only not producing an organism.
So the roadmap here is in the first five years to have a very heavy focus on technology development, but also to develop pilot projects that would have we hope immediate benefits for society. And you’ll hear about more of that in a moment. And during this time period to have intense debate about the HGP write component and engage as diverse a group of stakeholders as possible. And as a designer I’m very interested in identifying what is the worthy design or what are the worthy designs for HTP write? I don’t think we really know yet or maybe there’s an equally or more worthy goal and after that then we could pursue these highly worthy big genome projects while continuing to develop the technology. Cause we’re probably not going to get that thousand fold drop in price just in five years. So GP write in HDP write?
People often ask, why did we change the name? Well, we listened to a lot of you a year ago and we thought that D defining these two components in this way was really helpful to the future of the project. Now, a lot of the journalists I’ve talked to come back to me with one question over and over again when we talk about HTP, right? In particular but also GP write? And that is why are you doing this? And I will offer two kinds of answers. One is I want to know the rules that make a genome tick. I want to learn about it. And this is paraphrased in a quote that was allegedly found on the Blackboard of Richard Fineman after he died. What it cannot create, I cannot understand. And this has become kind of a a manifesto for for our field.
And an example of something that we, we learned by doing this as the three dimensional structure of synthetic chromosomes in the nucleus of the yeast cell. So on the right here you see maps of chromosomes taking trajectories through the nucleus of a cell. This is the, this is done using a technique called high C, and this is one such chromosomes synthesised in Tianjin university, the fifth chromosome. You’ll hear more about that later. This is the native version. And this is what happens when we make a synthetic version, which has a whole bunch of thousands of changes to the DNA sequence. We’ve removed all the repetitive DNA, we’ve removed all the tRNA genes, and yet there’s only a minimal impact on the trajectory of the DNA through the genome and the overall structure. And secondly we want to do good things, not bad things. Y well, I thought I’d go biblical on you. Okay. There’s the 10 plagues, right? From Exodus here. They are water to blood, frogs, lice, etc. And so, yes, today we have environmental destruction. We have invasive species, we have emerging pathogens, problems with food security and climate change. And all of these things have you know, potential biological solutions that GP write, we think could be an integral part of.
I’m getting a signal that I need to stop, but I can’t resist telling you a little bit about writing. Okay? Here’s the history of writing. And you can see it goes way back. And you know, George will tell you that he’s already like encoded an entire movie in DNA. You know, every, every pixel. But actually on this here, when we talk about DNA writing in cells, we’re kind of, we’re kind of in this Gutenberg phase. We can write millions of letters of DNA, but that’s about it. So we have a long ways to go. We’re actually just at the very beginning of this project. In fact, the history of DNA writing in cells started around 1976 the year I graduated from college with kiranas synthesis of the transfer RNA gene and it’s extended recently. You can see here virus in 2002 Venter institutes mycoplasma in 2010 and this year, 2017 third of the way through yeast and maybe human by 2027.
And note that this is enlarged 100 fold, this one a thousand fold and this one almost 500,000 fold. So I’ll wrap up by telling you our recent activity in the past year. Our SC 2.0 project, which you’re gonna hear a lot about, has generated a lot of global excitement for the project. We have participants here from Australia, China, a new participants from Japan and new funding various types that George will go into in more depth. But I especially want to emphasise this international nature of this project. And, and this whole project has essentially been invited to become part of GP write? That’s one important decision that we made over the past year. And finally we’re launching something we call the dark matter project with a number of people you’ll hear from later on today. And in case you don’t know what that is, you can turns out, you can just look it up on Amazon. So if you forget you can, you can learn more about it there. And with that, I’m going to ask George to come up and we’ll take questions at the end of his presentation.
So my conflict of interest slide I will be talking about one pilot project that Jeff has already mentioned. First the funding this, I think that we have to put this in the context of past funding and recent academic and commercial. Not all of them focused on the same goals, not all of them brought about by this initiative. But I think any of you who feel like you have funding that is related to this, and I’d like to join the club, feel free to let me know. Or if I’ve accidentally included you and you don’t want to be included, please let me know. This will be publicly available information. You all know about this super exponential curves. This is factors of 10 on the Y axis. So when it goes hockey stick up, that’s a double hockey stick. And this is for both reading and writing genomes. And I think it’s important to do both interconnected with each other, reading, writing, and testing.
Most importantly. We’ve got 3 million fold improvement in sequencing and a billion fold improvement in synthesis of oligonucleotides on ships. Now but we want to turn that into testing in cells and in organoids. This particular example here, this is I just can’t stand the typos there. This particular pilot project is on so-called Ultrasafe cells for manufacturing and therapies. These could be any mammalian cells since those are used for making protein, pharmaceuticals and vaccines. Probably it will be humans so that we can also use them for STEM cell therapies and transplants. But we want it to be virus resistant, prion resistant radiation resistance, senescence resistant. We’re just getting warmed up. Endogenous retroviruses, Lu Han yang, we’ll talk about that later in this meeting. And the virus was insulation mentioned nilly. Ostrava will be giving a presentation on, on that. So I won’t go over those. Triplet repeats. We want them to be germline negative, but pluripotent want to have failed proof self-destruction, which we’ve already demonstrated using non-standard amino acids in Ecolab. We want to transfer this over to the Malian cells, cancer resistant, immune negative, you know, swap regimes and so on.
We are engineering mammalian. Oh, I forgot to mention in that second column are some of the people that, that are taking this on as postdocs and graduate students. The same thing for mammalian repeats, assemble sequence proceeds, tailor mirrors, central mirrors, rubs, Stonewall DNA signs like aloes lines and endogenous retroviruses. We’ve already knocked out 62 and Dodgers retroviruses. In fact, we’ve done it more than one different pigs. Strain instead embolden us to take on all these other categories of repeats. Some of we haven’t even sequenced yet. It’s, it’s a a dirty little secret that there is never been a human genome or for that matter, a mammalian or vertebrate genome that’s been sequenced anywhere in the world. To my knowledge. You heard it here. If you didn’t hear it before I will not declare victory until we have many human genomes sequenced all the way through to Yomiuri tumor and engineered as well.
So nilly will tell you more about engineering. A 4 million base pair genome for four goals, nonstandard amino acids, genetic and metabolic isolation. This bio-containment, that’s one of the goals of the safe genomes and multi virus resistance. I think it’s very profound that we can be resistant to all viruses. These cells can be resistant all viruses without even some we’ve never seen before. We want to be able to use these cells in two directions, in one direction or in many directions, but one of them is developing gene therapies where we take a deleterious Julio and turn it into a normal one. And the other is going from a normal wheel to deleterious. So we can determine cause and effect for the millions of, of new unknown possibly disease causing alleles that we’re finding as we’re starting to sequence everybody on the planet.
Hopefully all of you have been sequenced them. I’m sure you have. And then for this we need properly consented cells and we turn to the personal genome project for those. And Jason Bobe we’ll talk about that. We have genome and epigenome engineering. I’ve already mentioned some of our genome engineering tools and we’ll mention it again in the like speed thing late this afternoon. But I just wanted to take a moment about epigenome engineering. In order to do the Read-write and test the testing needs to have almost any kind of cellar organ in the human body without actually making a human being. And and also sequencing is really important. It’s hard to edit or write a genome if you’ve never read one or if you haven’t read one that’s relevant. And once you’ve made it, you want to sequence it. And so we constantly sequence the genomes that we’re engineering.
It’s, we take it for granted that it’s trivial to sequence the human genome. It’s just something you check a box and it happens. So this had this variance of unknown significance pipeline and if this foe finally a, there is a full transcription factor library for all the human transcription factor genes and, and including multiple alternative splice forms so you can actually determine the causality there. And we’ve used it for making almost any cell type. We set our mind to I don’t know of a, of a failure since we finished getting this full library. This library will be distributed through add gene, as many of our other genome project, right tools have been distributed through add gene, which is a nearly, you know, as a nonprofit, great way to distribute things. Here’s some of the cell types that we’ve new ways of getting neurons, muscular musculature endothelial blood vessels oligonucleotides for glaucoma Anglia.
Here’s how you can use it for variants of unknown significance. Here we take one of the personal genome project cell lines, which is freely available and it’s a STEM cell line. It can be engineered with any of the genome project, right tools to make one base pair change. You then sequence the genome to make sure you change that base pair and nothing else. This is in a clonal salon. So the issues about off target and on target problems disappear when you, when you sequence clonal cell lines. And then you can, you can epigenetically reprogram these from fibroblasts to STEM cells where you do the genetic engineering to cardiac tissue. Here you get this beautiful cardiac repeat structure here and you can, with a single base change, you can alter the lipid biochemistry and mitochondrial function, the morphology and the, and the contractile nature.
And so showing that ever in a, in of one one patient, not necessarily just some gigantic correlation, you’ve got something that’s more, possibly more convincing, which is cause and effect. And you can compliment that with a messenger RNA. You can extend this to a broader set of genes vaulting, ageing reversal. This might be something that would be appropriately genome wide. We want to have pathogen resistance senescence resistance and cancer resistance. And there’s a G date database that one of my previous postdocs, Pedro de McGallows has maintained ever since then. That includes 300, five human ageing-related genes and we’re tackling these both in a gene therapy form but also in a cell and tissue level. And so I just want to wrap up with this slide. I’ll come up, oops, that’s kinda tight it. And thank you to some of the people, and this is just a small set of the people that I’ve mentioned along the way and the slides that have working on the genomic-ally engineered organs, which I consider a significant part of this genome project. Right. So I’ll just leave it. We’ll have Q and A for all of us now. All three of us
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