HGP-write project overview


video: https://www.youtube.com/watch?v=6nirrqtUSUk&list=PLHpV_30XFQ8R2Kpcc1pwwXsFnJOCQVndt&index=2

Andrew Hessel

AH: Good morning everyone. I'll keep this fairly short and sweet. My name is Andrew Hessel. As George just pointed out, I've been thinking about whether it's time for a new human genome project for some time. I wrote that little piece in Huffington in 2012. It wasn't the first time I thought about it. My history in genomics started really quite early on, although not as early as George. Most people, a lot of the early history of the first human genome project has kind of been forgotten but it was a really radical idea that began to be proposed in 1984. It started to pick up some energy in 1985 as people came together and started talking about the technical feasibility of the project, and starting to consider whether it should be done, and of course how the project would be funded. I first heard about it, really, when it launched. When it started to get the attention in 1990 with James Watson and various folks and large dollars being thrown into genomics. It inspired me to work in the area of genomics. I don't know what your entrypoint into this field has been, but really it was the idea of being able to sequence organisms and look at their code and really the instruction set for these creatures that just completely thrilled me. And at the time, it was a slow process to read DNA. It was difficult to analyze and interpret. But it was just incredible watching the acceleration of this technology over the next decade. They have really put this science into the public perception. Of course there were debates about the technology and how it could be used; it turned into an incredible race between public and private and some very charismatic and newsworthy scientists. It made it accessible to the public. And of course when President Clinton brought the public and private groups together and essentially declared the draft genome complete, at 93% at that point I think, that was kind of a moment of closure at least for the public. The work continued, and is continuing, but now sequencing is just taken for granted.

What was incredibly provacative pushed everyone's capabilities, made careers and inspired humanity. Over the last, since that time in 2000s, we have seen the emergence of being able to write DNA faster and cheaper. This is, it's shaped my career as much as the first genome project. At the time I was working for a biotech company. I said reading the human genome is complete, why don't we think about writing technologies? They weren't interested. DNA writing wasn't a bottleneck for their drug development process. And I thought to myself, well, I don't want to work for a biotech company that doesn't want to write DNA. I left the field, then explored the world of synthetic biology and I've had the great pleasure of watching this field emerge over the past 10 years in particular. I know many of you in this room.

I don't know where this goes. I know we're at very early days of synthetic biology. Today I do a lot of public speaking. Most people haven't heard about writing DNA. They have very little understanding about what the potentials of this technology are, what it means to society, what it means to medicine, what it means to humanity. This has always disappointed me. This means that maybe as scientists we are not doing a very good job communication, or maybe it just means we need a better marketing department.

In 2009, I joined Singularity University. I wrote the life sciences program. This is a group of people that are really forward thinking that propose dangerous ideas every 20 minutes. In my first presentation, to the executive program I was teaching, I mentioned that it's probably time to write a human genome and they said-- you should probably not talk about that, it's a little too dangerous of an idea. So I put it on the backburner.

[When I wrote the Huffington Post article in 2012, ... up until a few weeks ago, if you googled "human genome synthesis", you got nothing. There's a void out there. Yet it's, that we will go down the path of writing more complex genomes and ultimately human seems to me inevitable. It's a journey that we are exploring here today. It's not going to end here today. This is the start of many different things, I'm sure. I just want to say thank you for having an open mind. Thank you for being here, thank you for bringing your skills to the table. I hope that in 10 or 15 years when we look back at this moment, we'll realize that we might be making history today.

Jef Boeke


Welcome. I'm more of a detail guy. If you could put up the slides please. Oh. I'm going to offer up some thoughts on HGP-write as we like to call it. Designing and synthesizing modified versions of the human genome. I need to disclose my engagements in a couple of companies here before I talk: Neuchromosome Inc., CDI-Labs Inc., Recombinetics Inc., NYU Langone Medical Center.

So, I think one of the biggest questions on everyone's minds and is certainly was on my mind the first time Andrew sprang it on us last July, was why? And should we synthesize a human genome? I add to that, in cells. That's very important addendum. So, just a few thoughts before we dive into the details of what we've been discussing and what we hope you will discuss with us. As you've heard already, we seek to do this responsibly. We don't want to use defecit model thinking, so-called, which is I've learned is telling people why what you're doing is important and then doing it. A good example of this is the widespread rejection of vaccines by a substantial proportion of our population. They were told it was important, but there was no real engagement around it at all. In contrast, a good example of responsible innovation is the arsenic biosensor, one of the first synthetic biology projects, where the people in the project widely engaged government officials and most crucially the potential end users to help understand the problem and heard them.

Another really important point is that we're talking about doing it in cells, so that there is no confusion on this. We are looking at somatic applications. We don't anticipate that there will be a major discussion about germline modification, here. That discussion is already out there and we have decided that our involvement in this is strictly somatic not germline.

I am a skeptic by nature, it took me a while to warm up to this project. Over the past few months, I've recognized several big drivers for me to say yes and also enthusiastically participate and be a proponent. This is an incredible tool for learning the fundamentals of genomes. As you have already heard, technology development will come out of this. There will be many spinoffs for global problems beyond genome, such as gene drives to revolution health in the tropics, zika, malaria, dengue, chicken miga, -- crop engineering for pest resistance, and the field of synthetic biology obviously is to some extent limited by how rapidly and efficiently you can make DNA and put it to use. I'm at a medical center, so finally, the biomedical applications seem real to me, such as engineering universal T cells, T cell therapies, organ and tissue transplantation, and perhaps the next generation of gene therapy.

Some of my colleagues have been talking about a stepping stone project. One of the most fascinating aspects of the human genome today is that we've discovered all of these loci on the map that are associated with disease and human traits, but we don't really understand them, because these variations are in the dark matter in beteen the genes. So here's a picture of a human genome.. and, is there a pointer here? As most of you know, the human genes are made up of tiny little blocks, they are split by much larger regions called introns, and then if we zoom out, here's that same gene, we see very large gaps between the genes. And thanks to large support by the NIH, there's lots of clues about places in the dark matter that are important for controlling the expression of these genes and therefore a better understanding of how they work and how the cause of disease. So we're proposing a project ew call stepping stone project... here's a gene, call it your favorite gene, where we would make 10 to 1000 synthetic variants of that gene, assembling them in yeast cells, and then incorporating that very efficiently into a specific human cell line so that we could then evaluate the specific effects of the variations in the dark matter on the expression of the gene and ultimately the function of that gene.

So how should we start a larger project to understand the human genome? You will hear about pilot project. We have decided to promote the concept of 1% of the human genome, although a very informative 1% of the human genome. Not a random 1%, as has often been done in other genome projects, including our synthetic yeast genome project. These are designed to teach us more biology, to develop important tools for therapy, and engineer other non-human genomes. And in parallel with this, technology development will proceed and make the ultimate synthesis of the human genome much more practical. New technology, new tools, new ways to handle big DNA, integrate it, better defined cell lines, etc., and very importantly, to do this efficiently, we will need to employ automation in order to make this really fly. And so, this is our genome foundry that we are setting up at NYU showing how we are automating one bottleneck in this process.

So where do we start with this? As I've said, we're talking about a cell line, engineered for safety, this would be presumably an IPS cell so that it would have the capability of being differentiable into different types of tissues, and it would be engineered to have a strict germline firewall. For example, removal of one of the sex chromosomes, an XO cell line, would be a simple way to ensure that this would not be able to become a germline. These cells can be differentiated into tissues and organoids, models of human organs, to evaluate the functional effects of any designer changes that are introduced.

Here in Boston there's these so called organs on chips that provide excellent models for lots of processes that happen in the body.

How would we build a genome? This is obviously a longer discussion. Dpeending on what exactly we plan to do, that will dictate the ultimate design. The 1% pilot, you will here me talk about those in a bit. We might engineer just the short small blocks, the exons, which require small pieces of DNA but not giant pieces of DNA. Whereas, if we were to do an entire genome synthesis, it might benefit from a strategy used to synthesize a modified version of the yeast genome, called "SwAP-in" where potentially 100k DNA letters at a time could be introduced and used to replace the indogenous 100k DNA letters. So to make a 3 billion BP genome, would require 3000 rounds of this procedure. That sounds like a lot, but it's not inconceivable by any means, and there are surely many ways to make this more efficient. One very interesting publication that came out recently was the development of haploid stem cell lines, which could make projects like this much easier. You'll hear about those later today.

To wrap up, there's two last points I'd like to make. They have to do with community. The first one is that we don't think this should be a human genome project to the exclusion of other organisms. As the leader of the yeast genome project, I'm keenly aware of this and a huge proponent of appreciating our biological diversity and bringing this tech to other organisms on the planet for practical reasons and also reasons of dissecting fundamental biology. I think we're already learning a lot from microbial engineering. Secondly, the scientific community, this is a grand challenge, and as such it demands global participation. We have interested parties here today from Australia, China, Singapore, the UK and more. I think this is a fantastic way to educate an international workforce in genomics, to promote an understanding of the field, and in the words of Huanming Yang, chair of BGI (Beijing Genomics Institute), "it is more fun to do it together, we make new friends".

Thank you. I'd be happy to take questions. Stunned silence?

Q: ...

A: Right. There are versions of.. syndrome, where the whole chromosme is not deleted. XO.. as far as I know.

Q: ...

A: Yes, Richard? Sorry, we can't hear.

Q: I wanted to get your opinion on you and George's opinion on how easy it is to hack that firewall.

A: Well, that's an important question. It would depend on how the firewall is constructed. I can't really answer that. But obviously, since biosafety is an integral part of this, we're going to hear about that later on today. I expect that, the firewall will be improved as the project progresses and it will get better. The details of that are to be determined. Therefore the security is a little hard to predict.