First SBI forum examines prospects for synbio-based industrial revolution

What can society expect from synthetic biology? A distinguished group of academic and industry experts probed this question at the inaugural forum of the Synthetic Biology Institute, on April 25 at UC Berkeley. Their answers homed in on a common theme: Synbio faces serious hurdles and is not without risk; it could also spark revolutionary changes similar to that of the micro-electronics revolution of the last century.

The event featured addresses by S. Shankar Sastry, Dean of the UC Berkeley College of Engineering, Richard A. Mathies, Dean of the UC Berkeley College of Chemistry, and William P. Sullivan, President and CEO of SBI’s charter Industry Member, Agilent Technologies Inc. They were followed by a panel made up of Nobel Laureate and Stanford Biochemistry Professor Emeritus Paul Berg, Agilent Technologies Chief Technical Officer Darlene Solomon, venture adviser and biotechnologist Douglas Cameron, synthetic biology pioneer and UC Berkeley professor Jay Keasling, and Berkeley Bioengineering Chair Matthew Tirrell. The discussion was moderated by SBI Director Adam Arkin and Associate Director Doug Clark.

Here is some of what the speakers and forum participants had to say on issues that are crucial to the future of synbio:

1) Defining synthetic biology:

RICHARD A. MATHIES: What is synthetic biology, anyway? The definition is the engineering, or re-engineering, of biological component systems and even whole cells to perform improved and novel functions that benefit society and transform technology. … [SBI] will address … this whole discipline via a series of goals that will basically define the field of synthetic biology, develop a deeper understanding of how biological systems work, develop robust, transferrable tools to enable the reliable engineering of these systems, and, most importantly, develop standardized design rules that are transferrable from location to location, that will enable the constructing of enzymes, metabolic pathways, chromosomes, even whole cells, that have the functions and the properties that address society’s needs.

DOUGLAS CAMERON: Metaphors really influence the way we think and how we can be creative … For many years we had this metaphor of a cell as either a bag of enzymes or a cell as a biocatalyst … And then there came this metaphor of a cell as a chemical factory. I think that one of the things that the synthetic biology field has done is sort of broaden the metaphors we use to think about cells, and now start thinking of a cell as a control system or an integrated circuit. I actually like the metaphor of a cell as more of an automobile factory. … One of my pitches I’ll make is, as you go forward, bring the industrial engineers into the field, because the enzymes are like the little robotic machines and the pathways are the robotic assembly lines.

PAUL BERG: We shouldn’t forget that microbes were being used in making compounds and products for a long time. … Monoclonal antibodies are actually grown in microbes … Vaccines are made in yeast. … [Those were] some of the obvious early things to do with the recombinant DNA technology. What’s really different now is …being able to really standardize and assemble components in a way no one was able to do before.

William P. Sullivan

DARLENE SOLOMON: In the last 30 years, biology has really transitioned from what was predominantly a qualitative science to one that today is far more quantitative, and this is indeed going to take it to the next level.

2) Is a new industrial revolution in the works?

WILLIAM P. SULLIVAN: For 70 years Agilent has focused on providing measurement tools for the research, the development and commercialization of products and technologies around the world. One secret that I think that we’ve had for over 70 years is the ability to identify what I call waves of technology changes. What’s happening in the future? What are those measurement tools that we need to allow engineers and scientists and researchers around the world to do the discovery, to do the inventions and the eventual commercialization? … I am absolutely convinced – the company is convinced – that synthetic biology is that next wave.

DARLENE SOLOMON: Synthetic biology is really a disruptive technology, and as such it’s going to enable us to improve some of our existing industrial processes literally by orders of magnitude, whether that’s making them better, faster or lower-cost. But I think that synthetic biology can also contribute to some new industry paradigms. … New industries that will be enabled by synthetic biology, the interesting ones, will integrate electronics with biologically engineered materials and harness the power of both … This integration can transform how we approach everything from information technology – how we write, store and read data – to human health, and how we interact with the world of artificial machines.

S. SHANKAR SASTRY: There are a lot of parallels with the semiconductor revolution. I think that we are where we are because we don’t think about doing semiconductors for entertainment and defense and communications separately. … Gordon Moore and Andy Grove and several others actually had the conviction that developing tools and developing methods which worked across the spectrum of applications was critical. And they did it at a time when a lot of industry – [Texas Instruments], IBM …Motorola – were pulling them in different directions. So we really took a lot of inspiration from this model and really are focusing on not a single application area but really on developing tools for this revolution.

3) Does synbio need more basic science?

PAUL BERG: I worry a little bit about the lack of emphasis on how synthetic biology is going to actually generate fundamental knowledge. It’s going to make products, it’s going to make technology, it’s going to make fuels … but I still think that somewhere we still have to figure out how synthetic biology is going to be used to create fundamental knowledge, something on which the next generation of biological advances will rely.

Jay Keasling and Darlene Solomon

JAY KEASLING: Granted, there are a lot of things we don’t know, [but] there are quite a few things we do know … By thinking about biological components as reusable parts that we can engineer and reuse in many different applications, that we can build different circuits from the same biological components reused over and over again – that gives you, then, a motivation for really understanding those components.

DARLENE SOLOMON: In terms of the fundamental side going forward, today the focus on integrative biology is huge. We think of synthetic biology as kind of a step beyond, which it is, but ultimately synthetic biology is going to drive our understanding of systems and integrative biology.

4) How might synbio affect America and the world?

JAY KEASLING: Let’s take the example of petroleum. We burn 225 billion gallons of transportation fuel [each year]; two thirds of it comes from imported fuel, roughly. If you look at a barrel of oil, 15 percent of it goes to all chemicals that we use, which is almost everything that we’re touching here today. And you say now that we’re going to use synthetic biology to replace, say, a third of that petroleum-based fuel and a large fraction of those chemicals. That’s an enormous industry. It’s an enormous industry in terms of its total volume, and its societal implications are also enormous in terms of transforming American agriculture.

DOUGLAS CAMERON: If we do go to a more bio-based, microbial-based chemical industry and fuel industry, I think it will be more distributed, and the plants will be smaller. Right now to get economy of scale of a chemical plant or petroleum plant, it has to be very big. So you build one great big one in the Gulf of Mexico or something. I think that these biological processes scale differently. You don’t want to build them as big. You want to build multiple units smaller. And you want to put them closer to their feedstocks. So I think that will have an interesting influence on the economy in the rural parts of the United States and developing nations. I think that this whole technology could have major, major implications, for example in places like Africa that have huge biomass resources.

5) What does synbio need to succeed?

Douglas Cameron, left, and Matthew Tirrell

MATTHEW TIRRELL: There’s certainly not a widespread infrastructure [for synthetic biology], but I think we can and should and will have to create one. … If you look at device technology or materials technology in general, these things have been driven by investments in large-scale facilities where people can try things out, where there can pilot plants, where there can be test runs and that sort of thing. I really think we have to lead a drive that produces the right kind of investments in large-scale facilities to enable the field of synthetic biology to take off the way we’re talking about.

ADAM ARKIN: The ability to test and construct has to be in students’ hands as well.

PAUL BERG: Around the world, around the country, how many of the very bright young people who are looking for new worlds to conquer know that there is something like synthetic biology? … It isn’t like it’s on the lips of everybody. So the question is, if you’re really looking for building a …following, and someone who really wants to move this field ahead outside of where you’ve created this institute, that’s a challenge, and how is that going to come about? Well, very likely through publications that really knock your block off … not just in the industrial journals and so on, but in Proceedings of the National Academy of Science, and Science, Nature and so on, where it’s going to really have an impact who are not yet familiar with it.

JAY KEASLING: I would argue that the scientists should be just as enthusiastic about [synthetic biology]. Just as it will reduce the cost of producing molecule X, it will also reduce the cost of doing science. Imagine now you have this set of circuits that you can use to turn genes on and off and discover their function inside the cell, to send cells down a certain developmental path; I think you can reduce NIH’s cost of doing biology substantially.

6) Dealing with the fear factor:

Paul Berg

PAUL BERG: Not so long ago I did a talk on synthetic biology to a group of economists [and] some engineers ... What astonished me was the very strong negative reactions that I got from many in the audience. I shouldn’t have been surprised because, in fact, it’s very similar to what happened 35 years ago. The general thing is, “How do you guys know that the stuff you’re going to be making is safe? How do you know that somebody’s not going to use the technologies that you want as an open source to do some nasty things?” And the answer is we don’t know. So we have to devise ways of anticipating or detecting or creating barriers to some of these kinds of things.

DARLENE SOLOMON: I often use the analogy that beyond biology, if you look back several years, something as simple as an airplane can be used as a weapon as well. … If somebody wants something not in our interest to happen, they’ll usually find a way.

DOUGLAS CAMERON: Clearly there are bad things that bad people can do with this, but on the positive side there are small molecules and specialty ingredients from plants that, if we didn’t use this technique, we would be destroying the fields. …There are some specialty spices, some unique sweeteners – there was a sweetener project I worked on, a very, very rare plant from the mountainous regions of South Africa -- and without coming up with these techniques to make these things better, what ends up happening is that these endangered species just get destroyed. So there are some positive factors to this as well.

Adam Arkin

ADAM ARKIN: Synthetic biology gives you the opportunity to engineer for safety. One of the things that we can say about natural systems is that they are evolved not to do that; they’re evolved to compete. You look outside and there are California grasses that are all from someplace else. You move a cane toad from Hawaii to Australia and it destroys the ecology as it moves across that continent. It’s not that the things that exist that we use for our own purposes are that much safer. With engineering, you have the possibility of perhaps trying to think ahead as to what might happen and engineer the safety in. Now I’m not saying we’re anywhere close to that yet … but we’ve done pretty good for the last 40 years for things like crops and for things like medicines.

7) Is there a “Moore’s Law” for synbio?

PAUL BERG: Well, there are two things on an incredible slope. One is DNA synthesis. And the other one is sequencing. … To me, one of the things that is a real challenge out there is being able to sample this huge reservoir of sequences that are accumulating at an incredible pace. At what point do we need Google to come in here and organize this whole mass of information? Because it’s almost, I would say, approaching inaccessibility in a way, and if inaccessibility is a problem, than interpretability is even a bigger problem. … That’s a huge challenge for this field, because that’s where the raw material is … the genetic information that’s out there, and what it

ADAM ARKIN: Following on that, summarizing in a sense, the amount of properly functionally annotated sequence of use to mankind will double every couple years.

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