Craig Venter: Future Pathways for Synthetic Genomics

Is a Genomic Version of Moore’s Law in the Offing?

J. Craig Venter, Ph.D.

J. Craig Venter, Ph.D., is regarded as one of the leading scientists of the 21st century for his numerous contributions to genomic research. In addition to his past key positions, he is founder, current chairman, and CEO of the J. Craig Venter Institute (JCVI), a not-for-profit, research organization dedicated to human, microbial, plant, synthetic, and environmental genomic research, and the exploration of social and ethical issues in genomics.

Dr. Venter, who is also co-founder, executive chairman, and co-chief scientist of Synthetic Genomics (SGI) and co-founder, executive chairman, and CEO of Human Longevity, spoke to GEN.

GEN: Dr. Venter, you have been on the frontlines of genomics, synthetic genomics, and synthetic biology. Please talk about your research in synthetic biology and synthetic genomics?

Dr. Venter: JCVI’s synthetic biology program started in 1995, when my team sequenced the first genome. That same year we sequenced a second genome, the smallest one known (Mycloplasma genitalium) in collaboration with Clyde Hutchinson, who was then at the University of North Carolina. That led Clyde and I, along with our colleague Hamilton Smith, M.D., to start discussing the concept of comparative genomics and wondering what the most primitive and simplest genome that could exist would be.

That is basically how the field of synthetic genomics got started. We felt that the only way to answer this question would be to make a synthetic chromosome that contained all the necessary genes, and to use that to create a new life form.

That idea took close to 20 years to achieve. In 2010 we recorded the first synthetic cell. It involved making a synthetic version of, mostly, Mycoplasma mycoides. Although it contained a number of significant changes, it was primarily based on a pre-existing species, and with it we were able to show that the creation of a new life form was possible.

Ongoing work at JCVI with funding mainly by Synthetic Genomics (SGI), a company that was spun out of the Institute, and done together with Dan Gibson’s team at SGI, has been focusing on designing a species from scratch on the computer on first principles.

In our final design of this synthetic cell, more than 10% of the genes that are essential for life are of unknown function. That reality somewhat limits what can be done in terms of synthetic genomics. We define synthetic genomics as truly 

• designing biological processes and genomes and then 
• building them from scratch chemically, 

with the process improving as you gain more experience.

However, if we can’t design even the smallest organism based on first principles, because we don’t know what all the components do, the challenge is greater than we initially thought. This, though, should also alleviate a lot of people’s fears about the ease of being able to design super-bugs, super-organisms, and super-species. It’s proving hard to do with less than 500 genes, let alone at a much more complex level. 

GEN: Given this new reality, how are you now moving forward with your synthetic genomics program?

Dr. Venter: We are using a lot of computer metaphors and are in the process of defragging the genome. Two billion years of evolution have not been highly orderly; in fact, they’ve been quite messy. In any genome we have looked at there is not a lot of order to it except, for example, some symmetry around origins of replication that have been maintained. Despite what people used to think, that gene functions would be more organized, they tend to be scattered all over the genome based on changes that genomes have been subject to throughout evolution.

It’s analogous to what happens to a computer hard drive when it gets highly fragmented over time, with information stored haphazardly and not in any organized fashion. You can run a program to defrag your hard drive and organize the information back into files. We have been defragging the genome by rebuilding the chromosome and linking together related genes: for example, grouping all of the genes associated with glycolysis in a single cassette, and the genes associated with cell division in another cassette. In this way, future design can at least start with these cassettes. I suppose we will also have to create a cassette of genes of unknown function, at least until they get sorted out.

We think that this new fundamental cell, largely created by direct design, will be a great experimental tool. We are even thinking of creating a public contest around it and awarding a prize to whoever adds on the best evolutionary functions to the cell. This self-replicating cell represents an early, relatively primitive form of cellular life. If we add genes and complex functions to it we should be able to convert the cell into a much more complex organism.

During research I did while writing my book, Life at the Speed of Light, I came across some of the early history from researchers in the 1800s and early 1900s, where one French researcher said, essentially, give me a basic protoplasm and I will be able to recreate all of life. At that time it wasn’t known what was in the protoplasm—they didn’t know what DNA was or that proteins were discrete molecules—but the assumption was that it contained the building blocks of life.

Now we can attempt to recapitulate evolution on a much faster stage, and certainly use this ability as a very informative learning tool.

GEN: Focusing now on synthetic biology, how would you describe the progress being made and the direction in which this field is heading?

Dr. Venter: I think synthetic biology is more or less a redefinition of the field of molecular biology. And systems biology is, perhaps, a more modern term for physiology. People are largely doing the same things they were doing before, but maybe with a different goal in mind. People who were mainly doing fundamental molecular biology now claim that they are doing synthetic biology.

There are so many directions in which this could go. With the discovery of CRISPRs we have a new tool set to enable things perhaps to go faster and in a different direction than just taking straight synthetic approaches. I think the combination of CRISPRs and synthetic biology is pretty stunning.

One of the most important programs at Synthetic Genomics is the company’s collaboration with United Therapeutics, in which it is literally rewriting the pig genome to create pig organs that will survive in humans as replacement organs for transplantation, e.g., hearts, lungs, kidneys, and livers. Similar to what was done with monoclonal antibodies early on, in which they were humanized and replaced with human gene constructs, making it possible to grow human monoclonal antibodies in mice. Obviously, changing everything associated with rejection of allogeneic transplants is much more complex, but we have already had some limited success. We are literally starting at the design phase.

We have created a new, highly accurate version of the pig genome that we’ll be working with, which carries all of the genes that we have identified as being important, and we are going through and systematically changing those in the pig genome. For some of those we rewrite the gene and put a wholly new synthetic construct and a landing pad into the pig genome; whereas for others, when there are only minor edits needed between the pig and human genes, we use CRISPRs just to edit the genes and convert the pig sequence to a human sequence.

Dan Gibson at SGI made a big breakthrough early on in this process when he found that he could combine all of the different enzymes for all of the different processes in a single tube at a single temperature. This is called the “Gibson assembly,” and it allowed the process to be carried out by a robot. SGI has an instrument called the BioXp™, which is an automated DNA assembly robot that takes oligonucleotides or subsets and builds them into larger constructs. It is a commercial instrument currently being used in several labs. If we are not able to write large pieces of DNA, then there won’t be a lot of development in the field. 

"Future Pathways for Synthetic Genomics" is part 1 of a 2 part interview with Craig Venter. Part 2 will appear in the April 1 issue of GEN, and will focus on tools and technologies needed to advance synthetic genomics research.

ORIGINAL: GEN

Mar 1, 2016 (Vol. 36, No. 5)

Janine Benyus: Inventing the Eco-Industrial Age

Could a large-scale industrial factory actually be designed to be good for the environment and for the ecosystem that surrounds it? And could that, in turn, generate long-term economic value for the population of people connected to that factory? Author and global bioengineering guru Janine Benyus doesn’t just believe it’s possible—she’s partnering with the world’s biggest carpet tile manufacturer to set the example to follow. 

Atlanta-based Interface is already on track to hit zero-waste status by 2020, thanks to decades of sustainability initiatives, such as operating four of seven factories with 100 percent renewable energy and using simulation technology to replace physical carpet samples. The next step, which Benyus and Interface are plotting, is a project they call “Factory as a Forest,” which entails remaking one of Interface’s 10 factories, in New South Wales, Australia, using the local ecosystem as the new foundation.

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This isn’t just the next flavor of the month in corporate social responsibility. Benyus, founder of the Biomimicry Institute, helps clients such as Nike tap into biology and planetary science as a new source of tech innovation. For example, her consultancy studied how nature captures fog and wicks moisture to help an aircraft manufacturer reduce moisture and the spread of germs within an airplane cabin. With Interface, she and her team are helping define the region’s specific “ecosystem services” —how much water it stores, how much carbon it sequesters, how many pollinators it supports. Interface, in turn, will use those guidelines to ensure that the ecological “output” of the new factory operates in the black, not the red. 

We asked Benyus to explain in greater detail how this concept can work, and for her thoughts on a tech-enabled future. 

What excites you about where technology is taking humankind?

I’m excited by the fact that we are probably the first generation to actually be able to gather biological intelligence and distribute it to the people because of the Internet. Our understanding of how nature works is just increasing exponentially. Now we have a way to gather it and to actually make it available to people. Our experiment is AskNature.org to try to get that biological intelligence out. That’s exciting to me—understanding how nature works, and then possibly being able to emulate it. 

What scares you about where we’re headed with technology? 

What scares me is that we might actually believe that we truly can create life before we fully understand its complexity. I’m very much a believer in the precautionary principle when it comes to creating life forms—synthetic biology. What worries me is getting ahead of ourselves. I think we should emulate many things, but I don’t think we should emulate self-reproducing organisms until we understand a lot more of what we’re doing. 

Companies that preach sustainability often focus on mitigating damage. How does the “Factory as a Forest” concept flip this around? 

The next evolution of “do no harm” is to produce beneficial services.

• The way local ecosystems actually function, 
• the way you know they’re healthy, is that they’re producing services that are beneficial to us as human beings and to all life. 
• They’re cleaning water. 
• They’re cleaning air. 
• They’re building soil. 
• They’re supporting biodiversity and pollinators. 
• They’re holding sediments during flooding. 
• They’re mitigating climate change. 
• They’re protecting against pests. 
• Even providing food and fiber, and cultural experiences like recreation and inspiration. 

These services are called ecosystem services. 

We thought this would be an amazing framework for the next aspirational goal for Interface—once they had reached do no harm, to actually become a generous company, in the fact that their facilities were functionally indistinguishable from local ecosystems, meaning that they actually performed like the ecosystem next door, meaning they would meet the same metrics that the system next door would. 

How do you get from studying an ecosystem to recreating its benefits in a factory? 

At Biomimicry 3.8 [Benyus’ biomimicry innovation consulting firm] we’ve been working with city planners for several years now, working to figure out how a city could produce ecosystem services, giving city managers these kinds of metrics—purify this much water, purify this much air, store this much water, store this much carbon. We call them ecological performance standards. When you have those metrics, they become an organizing framework to cumulatively gather what are now fragmented technologies and put them together and then start to count what it is they produce. 

Before, [Interface CEO Ray Anderson] set metrics for reducing energy use, reducing waste. Now what we’re doing is saying, “What positive effects can we start to count up?” Once you have an aspirational goal like this, and you have numbers, you begin to gather collections of design changes. For instance, we can go next door and look at relatively untouched areas and figure out how much water they purify and store per hectare. Then you say, “OK, we can start to meet or exceed that metric in different ways. 

• We can change our water use. 
• We can purify the water from the manufacturing process even more than we have before. 
• We can use constructed wetlands. We can store water with rainwater harvesting.” 

Suddenly you’re not doing those things in a fragmented way. You’re actually trying to meet a metric. 

How will quantifying nature’s benefits change how the factory operates? 

What we’re doing now is basically understanding the habitat type. We look at the system and what makes it tick. We look at the ecological realities of that river flat eucalypt forest [the ecosystem where the factory is located]. Which ecosystem services are most important to this company in terms of its business model and what it has to accomplish as a business, and then how can we reduce risk and make the site more resilient? 

For instance, if you were to increase carbon storage on site, you were to increase the fertility of soils and the cycling of nutrients in the soils, and slow water and sink it and store it, the landscaping would be more resistant to drought. You want to store more carbon or more water, so you want permeable pavement wherever you possibly can, changing the parking lots. You may incent your employees to commute and not bring their cars to the factory. 

How can the concept of a factory that produces these ecosystem services change our human relationship to manufacturing? 

Nobody wants it in their neighborhood. In fact, there’s a social justice component of this, because poor people have tended to live closer to the chain-link fence with the factory on the other side, right? Now what we’re saying is how can development, or manufacturing facilities, actually be welcome neighbors in a neighborhood? That’s a radical thought. 

If you think about the factory as having a metabolism, the exhale—the outcome of a factory has been pretty nasty pollution—air, water, and soil pollution. Does it have to be like that? This is an idea of re-envisioning what it might be if a factory actually released water cleaner than what came into it or released air cleaner than what came into it. 

I expect that there will be cascading benefits, and that the benefits will be—to the business, it’ll be healthier employees, lower healthcare costs, more happiness, more productivity, the ability to recruit and retain. Then also for the company, it’s reduced risk in terms of liabilities and regulators. You’re suddenly producing cleaner air. You’re not wrangling with regulators. 

You’ve said that “heat, beat, and treat”—heating up materials, beating them with high pressure, and treating them with chemicals—is the de facto slogan for our current industrial age. What should be the slogan for the next era in manufacturing? 

I think manufacturing will be local, safe, and cyclical. I’m doing a lot of work as to how nature’s models can help 3D printing or additive manufacturing. I actually think manufacturing’s coming home. I think manufacturing is going to be coming into neighborhoods in the form of print centers. 

This is a really key moment for biomimetic chemistry inside the printer, biomimetic designs of adding function to very common raw materials. [Nature uses non-toxic building materials like keratin and chitin to create forms, while 3D printers currently rely on toxic plastics and resins.] That’s what nature does. It doesn’t use very elaborate materials. It has very good designs that make it tough and strong and resilient. And then, of course, nature is able to easily disassemble at the end of its life and be reassembled into new product. These are all things manufacturing needs. 

That’s very different than what we’re talking about here. We’re talking about an industrial process, where you wear hard hats and eye guards. We’re a long way to go before it’s local raw material, safely produced, and then recycled at the end of its life—put back into the printer, if you will, as the raw materials for the next product. We’ve got a long way to go. 

ORIGINAL: Wired

MARGUERITE MCNEAL

Luke Muehlhauser on Singularity 1on1: Superhuman AI is Coming This Century

Last week I interviewed Luke Muehlhauser for Singularity 1 on 1.

Luke Muehlhauser is the Executive Director of the Singularity Institute, the author of many articles on AI safety and the cognitive science of rationality, and the host of the popular podcast “Conversations from the Pale Blue Dot.” His work is collected at lukeprog.com.

I have to say that despite his young age and lack of a University Degree – a criticism which we discuss during our interview, Luke was one of the best and clearest spoken guests on my show and I really enjoyed talking to to him. During our 56 min-long conversation we discuss a large variety of topics such as:

• Luke’s Christian-Evangelico personal background as the first-born son of a pastor in northern Minnesota; 
• his fascinating transition transition from religion and theology to atheism and science; 
• his personal motivation and desire to overcome our very human cognitive biases and help address existential risks to humanity; 
• the Singularity Institute – its mission, members and fields of interest; 
• the “religion for geeks” (or “rapture of the nerds”) and other popular criticisms and misconceptions; 
• our chances of surviving the technological singularity.

My favorite quote from the interview:

“Superhuman AI is coming this century. By default it will be disastrous for humanity. If you want to make AI a really good thing for humanity please donate to organizations already working on that or – if you are a researcher – help us solve particular problems in mathematics, decision theory or cognitive science.”


ORIGINAL: Singularity 1 on 1
from Nikola Danaylov