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hgp-write Scientific Executive Committee: Roundtable discussion
* Jef Boeke, NYU Langone Medical Center
* George Church, Harvard Medical School
* Pam Silver, Wyss Institute
* Farren Isaacs, Yale University
discussing:
* scientific roadmap and milestones
* evaluation of pilot projects
* composition
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This is not going to be about roadmapping or how to evaluate pilot projects. We're just going to have some fun for a few minutes. Relax. We want to engage you a little bit and so, I just thought, to get the energy in here late in the day, maybe we could all talk about what excites us about this, or one thing we would like to see happen. To kick that off, we're going to start and then we're going to open up to you.
JB: What would you do if synthesizing assembling and delivering DNA to your favorite organism doesn't matter what it is, were no longer a constraint? If you had infinite resources, do anything you want, this is one of our biggest challenges, it's one of the most fun parts about this problem-- no writers block. What are you going to write? I'm going to kick it off with a really fun one that came up a few months ago, I was visited by a new colleague who was telling me about lupus and telling me about genomic region that always confers risk to lupus, and it's not well understood, it almost always comes as haploid type block. A whole bunch of changes that always travel together. We don't know which of those mutations is primarily responsible for lupus susceptibility. When he heard we could assemble large chunks of DNA and put it in, but I got even more excited when I heard that this particular variant in this gene is actually derived from neanderthals. And so, those of us who have neanderthal heritage may be the carriers of this. And, we're going to learn something about it.
FI: I guess the idea that most excites me about this project is first, rediscovery, building up, being able to create complex genetic variation and then elucidate the diseases and phenotypes and realize some of the promises and goals of the original human genome project. Full genome writing efforts, like codon recoding, is to impart biological function, like genetic isolation, biocontainment, and I'm really excited about the interface of leveraging organisms that have been redesigned and recoding to be able to develop new classes of polymers and proteins and really establish new types of therapeutics and materials that could go beyond what exists today in chemical synthesis and go beyond what biology could do as well.
GC: I see Jef's scenario of genome synthesis being so cheap that there's a lot of pressure on you for writing. In our experience already in the ecoli recoding project, is actually testing and debugging. That fantasy is not so far away. I'd like to put-- I don't think there's much writer's block. There's all sorts of things that we want to write. It's going to be highly packed-- all the manuscripts we want, into really tiny space, ... and, but, it has to be done inside of cells and even though Jef constantly reminds us this is about cells, we're also doing organoids. Testing unknown variants-- we better be able to do organoids, and eventually organs and organisms. A running joke in my lab is asking "hae you tried multiplexing?".
PS: I am going to take this in a slightly different direction. Since starting this and for several years now, I get these amazing letters from 5th graders and they are fascinated by this. I think back to my own experiences as a 5th grader thinking about this. The big thing was, how do we go to the moon? And things like that. I think this will also help with the ethical issues of bringing this to people's homes. Elementary schools and high schools-- it will become routine to think about doing DNA synthesis as a project. I want that to be the norm. It's a perfect education tool. That's my dream. Now, I want to see, we've beared our souls to you... oh, I had another dream at one point, to make the minimal Y chromosome.
GC: The minimum is zero.
Q: I would like a multiplexed photosynthetic system, to manufacture fibers like cotton, grown in food instead.
Q: Bottom-up design of DNA chunks, and chromosomes.
GC: Automation doesn't necessarily by itself-- if you have to do a billion pipettes, it's not so different. Capillary sequencing to next gen sequencing, that's a good change. Sometimes that's what happens with really good automation.
Q: I think it would be interesting to think about designing neochromosomes that basically contain the instructions to launch a genetic program once they are introduced into the cell. Entrypoints... for example, contain the steps necessary to differentiate the embryonic stem cell or haploid human cells and so on. There are already lots of examples like oscillators, let's just see whether they work.
Q: I think it would be interesting to try to reengineer cells to tolerate extreme environments like temperature, UV radiation, freeze cycles, or to send them to space
Q: I would vote for figuring out a way to assimilate carbon very fast.
Q: I would like it to be way easier to build complex information processing and control circuits so that all of these projects where if you could just get a little bit of control, like the embedded control revolution in electronics. I want embedded controllers to be cheap and easy.
Q: I would like to see unicorns-- not the mythical creatures, but billion dollar companies.
PS: What's the killer app?
Q: In terms of killer apps, one of the things that got me excited about genome recoding-- at first a money grab maybe, but then I went to one of many IGEM meetings that have students presenting 100s of ideas and maybe out of those 200 ideas maybe 10 or 20 are pretty good and I would go to the posters and talk to the students. They would all end by saying we engineered hte organisms, it would solve the problem we want to solve, but we can't use it because of environmental issues, we can't give it to people, we can't spray it on trees or wheat plants or whatever they want to do, because of environmental issues. The idea of a genetic firewall solves that problem. There are actually well-thoughotut ideas. In these brainstorming sessions, people tend to say what they want rather than what they would do... What exactly are you going to do? But over the years, IGEM students have picked very particular biology problems and have come to the same solutions or walls.
Q: Could you synthesize the inferred genomes of ancestral organisms and use it to study ancestors of life or apply selective pressure and evole enzymes at different specifities than the ones that happened to evolve at natural evolution?
GC: Some people say it's limited to 700 kya, oldest discovered DNA. But we have reconstructed old DNA because of epiphylogenetic tree. There are a lot of things that are not lost. That list will almost certainly grow. You're not going to get it out of the freezer somewhere, though.
Q: The proteins have enough information, but the non-coding sequences will be the challenge.
Q: Although we can do all the writing and everything, we haven't solved the holy grail for biochemistry. I would recode every protein and try to find out how and why folding works to kind of add this complexity on the writing level. It's a very basic problem but very important.
Q: 3d shapes of chromosomes. I would love to see if we could change the shape of chromosomes.
JB: We have already done that. In yeast, you can torture the genome a lot with no apparent effect. This is pretty shocking when you consider how complex the three dimensional structure is, in mammalian cells. It does cause certain segment of us to say, is that just you know energy minimization or is it really something there in terms of folding of chromosomes? In yeast, maybe it's a really small number of constraints like energy minimization.
PS: There's a large project called the 4d nucleon that is trying to solve these challenges. I proposed that they should look at synthetic chromosomes, off the table.
GC: The possibility of actual visualization rather than HiC, which should be interesting. We should try to mess up the chromosmome-- so far it's accidental. but how do we fold it to get a different shape intentionally?
Q: If this project want sto change the world in terms of applications, ... I haven't seen a lot of work of people trying to create orthogonal systems in plant cells, so presumably if you can start to make plants that have such a system then a lot of the worries... concerns about biocontainment go away.
GC: Cisgenics is the opposite of orthogonal, they are similar to existing species that they might get classified as non-GMO.
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