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The Evolving Nature of Synthetic Biology: A Panel Discussion on Key Science, Policy, and Societal Challenges Facing the International Community

Drew Endy, Stafford University; Rick Johnson, Global Helix; Eleonore Pauwels, Woodrow Wilson International Center. It's great to see such a live audience in August in Washington, and also in the State Department, to talk about a science and technology topic. My name is Bill Colglazier, the Science and Technology Adviser to the Secretary of State.

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The Evolving Nature of Synthetic Biology: A Panel Discussion on Key Science, Policy, and Societal Challenges Facing the International Community

Remarks

E. William Colglazier, Ph.D.

Science and Technology Adviser to the Secretary

Drew Endy, Stafford University; Rick Johnson, Global Helix; Eleonore Pauwels, Woodrow Wilson International Center

Washington, DC

August 16, 2013

E. William Colglazier: Well, good morning. Let me welcome all of you here. It's great to see such a live audience in August in Washington, and also in the State Department, to talk about a science and technology topic. My name is Bill Colglazier, the Science and Technology Adviser to the Secretary of State. I think we're going to have a very interesting session today. The audience includes a number of people from government agencies, but also the National Academies, and nongovernmental organizations. And I think even a few from local area high schools and universities.

I would especially like to thank some of the people who helped put this on first. My good friend Anne Marie Mazza and Steve Kendall from the National Academies. They are part of the Forum on Synthetic Biology. And the National Academies includes the National Academy of Sciences, the National Academy of Engineering, and the Institute of Medicine. Chris Cannizzaro from the Space and Advanced Technology Office in the Bureau of Oceans, International Environmental and Scientific Affairs, and also colleagues from my office, especially Nat Schaefle, who helped kind of bring all of this together. And I'd like thank Richard Murray, who is the co-chair for the Forum on Synthetic Biology at the National Academies. He's from Cal-Tech, my alma mater, so I'm glad to have him here.

And several of the speakers were involved in a report that just came out, the symposium report from the National Academies, called "Positing Synthetic Biology to Meet the Challenges of the 21st Century." It's a very interesting report; I just finished going through it, in fact. And for any of you that are interested, it's available; it's a free PDF if you go to the National Academy Press, nap.edu website, you can get a copy of it. And our speakers include: Drew Endy, from Stafford University, Rick Johnson from Global Helix. Both of them were on the planning committee, I believe, for the three symposiums that this report represents. And the symposia were actually quite interesting and unique, because it involved the science and engineering academies from three countries: from the U.S., from the U.K., and from China. So it includes perspectives from the international side as well. And in our third panelist is Eleonore Pauwels. She's from the Woodrow Wilson International Center.

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Synthetic Biology, in my view, as some people have called it a disruptive technology, is a technology that can potentially have great impact on societies, and create opportunities, as well as create challenges. Certainly, the potential to have impact on international relations and the relations between countries. It's certainly become a topic of interest here at the State Department, because it potentially affects areas of trade, environment, health, and security. The State Department is very much faced with constructively addressing both the challenges as well as the opportunities that are presented from a new technology, like synthetic biology.

The panel today is going to address three issues: first, the state of science versus synthetic biology; second, the policy landscape; and last, what could be the societal response to this new technology.

It certainly is a very fast growing and internationally diverse field of research and development that has the potential to transform the world's bioeconomy. Over the last decade, industry has made significant investments. Governments are investing in fundamental research in this area, and I certainly believe that smart governmental policies will be needed, including to engender the trust of the public in dealing with the full potential of this emerging field. So I'm looking forward very much to learning more about synthetic biology today from our experts.

And lastly, I would like to introduce our moderator and my colleague here at the State Department, Jonathan Margolis. Jonathan is the Deputy Assistant Secretary for Science, Space, and Health from the Bureau of Oceans, International Environmental and Scientific Affairs. So I'm now turning over to Jonathan and he'll introduce the panelists, and then also moderate the discussion.

Jonathan Margolis: So good morning everybody, and thank you for joining us here at the State Department on a Friday morning in August. We've been talking all summer long about how things are going to slow down, eventually, and I'm glad to say that, for this event things have not slowed down. I'm glad to see such a nice turnout here; that's really terrific.

Just to say a quick word about how we all got here: I think folks know that what we're seeing, or the topics that we'll be discussing here today stem from, at least initially, discussions that took place in June of 2009, where the National Academies of Science, Royal Society, and OECD partnered to have an opening discussion or symposium on the topic of synthetic biology. And that led to, as Bill mentioned, the three countries taking a look at synthetic biology and the implications. That's the United States, U.K., and China in a series of meetings taking place in each of those countries. First, in the U.K., then in China, and then finally last year, here at the National Academies. And, so, we're really lucky to have an opportunity to hear, I think, from panelists who were involved in some of that work and look forward to hear what they have to say.

Let me just go over the structure. So we see four chairs here; we'll get to that at about 11:00 today. We're going to ask each of the speakers to come up individually and present their remarks for about 15 minutes or so, and then after that, they'll join me on stage and we'll have a discussion with the audience, with your questions. We have microphones, so please keep in mind that we'll ask you to go to the microphones and say something, if you have a question to ask. And the reason I'm giving you this introduction now, is so you can, while you're hearing these things, think of your questions and then go up to the microphones. So that'll be the format, and we'll try to wind things up at 11:30.

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There are members of the press in the room, so you ought to, all of you just be aware, that any question you ask, there are others who might be listening, and using it for other purposes. So keep that in mind when you ask your questions. And, with that, let me turn now, let me turn now to our first panelist, Drew Endy.

Drew is going to give the overview on the science issues of synthetic biology. Drew runs the world's first fabless genetic engineering lab and the new bioengineering program at Stanford University. And previously, he helped start the biological engineering major at the Massachusetts Institute of Technology, MIT. His Stanford research team developed genetically encoded computers and redesigns genomes. Drew is co-founder of the BioBricks foundation, which is a public, benefit charity, supporting free-to-use standards and technology that enable engineering of biology. He co-organized the International Genetically Engineered Machines competition, iGEM, and the BioFab International Open Facility, advancing biotechnology, BioFab. He is also a new voting member of the U.S. National Science Advisory Board for Bio-Security. Some of you may know that as the NSABB.

Let me introduce, now, Drew, and ask him to come up here. Thanks, Drew.

[applause]

Drew Endy: I've got 15 minutes, and I'll just get started. Genetic engineering, thank you very much, is 40 years old. And so part of what I was asked to do was put synthetic biology in the context of genetic engineering. Is it all done, or, is there more to do? And how does that relate to biotechnology and the bioeconomy. To put that in a quick, larger context, the bio-economy blueprint and Rob Carlson's own analysis notes that recombinant DNA powers about 2 percent of the domestic economy in the United States. That's $300 billion a year split roughly between agriculture, therapeutics, and stuff, where "stuff" might be better enzymes in your laundry detergent. It's growing about, a doubling time of six to eight years, so 12 to 15 percent economic growth historically. And where are we heading? And so synthetic biology sort of fits within an extending context of genetic engineering and biotechnology, but to what end and to what purpose is it really any different? so the next 14 and a half minutes now, I'll try and get to that.

At an abstract level, it basically collapses into science and technology. From the science perspective, we're 70 years into taking molecular biological systems apart and seeing what the components are. We learn about biology, historically, going back to the 1930s, by disassembling living systems. Synthetic biology allows us to reassemble things and see what happens. That is a very powerful approach to learning. It's a complimentary approach to learning. From a State Department perspective, this is a global enterprise. We need to continue to attract the best scientists in synthetic biology, and enable them to work with us or come to the United States, period.

From a technology perspective, as an engineer, we have a long-term goal -- this might sound weird to you -- we would like to make living matter programmable. Not just express a few genes here or there, but partner with biology to reinvent how our civilization works in making the things we need. Not to change ourselves or the world, but just to make things work a little better. Let me give you an example: in Menlo Park, where I live with my tiny family, we have a pine tree in our front yard. At this time of year, it grows pinecones. The pinecones fall off the tree, they get swept away, and they get composted. In the city of Menlo Park, there is about 32,000 people, citizens; each person is responsible for 500 pounds of garden clippings a year that are collected and composted. That's 16 million pounds of state-of-the-art, self-assembling, nanotechnology that's manufactured in Menlo Park every year, that I as an engineer, when I go into work every morning and I go past this tree, I do approximately nothing with.

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All right, so somebody who -- that likes to build stuff, how do I do something useful with this manufacturing capacity that takes natural resources, the sunlight, the water, and the carbon and other things and manufacture stuff? 16 million pounds a year is a lot of matter. The world's chip supply for microprocessors adds up to be about 1 million pounds of engineered matter a year, engineered silicon. All right, so the manufacturing capacity of Menlo Park is quite a bit more than I would need. If I could only get pinecones to grow into wafers and chips, to manufacture very useful things. Now, that should sound like a fantasy to you, because genetic engineering is not powerful enough to reprogram a pine tree to make computer chips.

So what would it look like if we advance a synthesis of biology to support manufacturing? Well, it turns out you can grind up trees into saw dust and regrow stuff from that. So this is in Monterey, California, there's a mushroom factory that takes sawdust and with wood fungus, grows mushrooms. These mushrooms are typically delivered to the organic farmers markets and you pay $25 a pound to have a tasty mushroom. But you could also reprogram this molecular machine to transduce matter from cellulose to chitin and other materials. For example, you could begin to add in bio-mineralization. So this is an example of a sponge growing in the ocean that gets silica to organize in novel ways, optical fibers for example, lattices, and so on. This work was done by Joanna Aizenberg, then at Bell Labs, who was interested in the optical properties of natural silicone.

What if I put bio-mineralization into an engineered wood fungus and begin to reprogram how I manufacture an object like this? That would be fully programmable manufacturing, using biology. Of course, I'd need to have program pattern formation, control how shapes grow over time. This worked for Veronica Nagpal, called amorphous computing, where I control systems in four dimensions by programming them with a language that allows me to structure shape as it emerges. To do this, I need implement state logic communications, things you would think of as being part of a computer. But I need to implement that inside a living cell, so that it can control the living program as it morphs into something. Eventually, maybe I could recapitulate what we already see around the world: these double-decker suspension bridges grown in India, from the roots of rubber trees, woven over time from one generation to the next, fixing carbon as they grow. It's just a totally different manufacturing paradigm.

Okay. Well, we're 40 years in the genetic engineering, so this is all working. Except, it's not; why is that? In part, because not everybody's been working on it. So for example, a textbook in bioengineering, my field from only a decade ago, if you start to read this one in particular, the third sentence in the first paragraph reads, "We exclude genetic engineering, that is systematic design of phenotypes by manipulation of genotypes, from the field of bioengineering." There's lots of good stuff in this book around medical imaging, artificial joints, and so on, but many engineers haven't yet engaged in the engineering of biology and synthetic biology represents that immigration within the engineering community.

In the United States, this activity's about 10 years old. Richard Murray and I co-chaired a study for DARPA, literally, in 2003, briefed out on synthetic biology. The conclusion from this study was, if we wanted to get better at engineering biology, we should try out three things. Number one: standardize the components of biology, so that you could reuse them more readily. Number two: separate the design of systems from their manufacturing, like an architect versus a contractor. And then number three: abstract the functions of the biology so it's not so complicated. I know those are technical points, so I'll come to them quickly.

The motivation here was basically to navigate an engineering process cycle, design-build-test more quickly. All right, so could we use DNA synthesis to separate design from fabrication of genetic stuff? Could we standardize how we measure and reuse things? Could we abstract functions to make design more powerful? I'll come to this very quickly. If you haven't seen this before, these bottles represent chemicals called phosphoramidites. There's four bottles. We're talking about biology, so it's got to be the four bases of DNA. If you organize these chemicals in a nice way and feed them into a machine, called a DNA synthesizer, you can then ship information into that machine. The chemicals would be dispensed in a way that assembles a custom polymer that allows you to build genetic material from scratch. Period. You then take that genetic material, if you can put it back into a system, it might reprogram the system, depending on how good you are at designing it. I view as the most important technology for the planet for the century. It allows you to go from abstract information on a network or a database to physical genetic material.

We're getting better at building things from scratch. So in 2004, biggest thing reported built from scratch was 10, 000 letters. In 2010, it was a million letters; not quite sure where that's going to go, but it's an interesting pace of improvement. Why does this matter? To a researcher like me, when we did our first genome redesign project, now almost 10 years old, this is how we had to assemble the DNA. And I won'read the whole paragraph, but what this represents is three person years of work, manually manipulating genetic material, to make a 12 kilo base fragment of designer DNA, cutting and pasting, using the tools of genetic engineering. What DNA synthesis does is it replaces that paragraph with an order through an Internet and a credit card, and says, "Please get me my DNA." That's a big deal. Right. It allows me to focus on being a designer, or a tester, or something else. It's a bigger deal within the context of policy for this reason: when you take synthesis of DNA and combine it with sequencing, that allows you to go from a physical bit of genetic material. You sequence it and now it's information, and it can exist as information throughout the networks. So I could be in Singapore and sequence something, and here in Washington resynthesize that material. And I've now made matter and information interconvertable for genetic stuff. That has the potential to change material supply chains, has the potential to change, excuse me, biosecurity politics.

All right, if you want to keep track of small pox by locking up the physical small pox, that's one thing, but what if the sequence is on the Internet for the genome? Hmm. So recombination of matter and information is a big policy change driver, and I don't know all the ramifications. I just want to try and say that out loud; maybe we come back to it, maybe you can figure it out. I'll give you a funny way to remember it: So this guy here is marketing something that's manufactured in a central location and then distributed as material. In a fantastic future, imagine being able to reprogram the microbes that live on your skin by downloading DNA off the Internet and synthesizing it wherever you are, and now you have a living perfume or fragrance. Right? So instead of shipping physical material, Chanel is shipping information over the network via distributed manufacturing in situ.

That's what synthetic biology can get you. Not that I'm advocating for this particular example, but to give you a sense that you might remember when you recombine matter and information and how that impacts material supply chains, lots of things change.

Okay, standards real quick. This is an object made from standard rocks. Standards are a way of coordinating labor among parties and over time. They're very, very powerful, very soft type of network power. When it works, you enable impossible things to happen. Somebody could pour the rock, somebody could assemble it, we could fix this aqueduct 2, 000 years after it was built. In synthetic biology, there are four areas of standards that have been developed over the last decade: layout of genetic stuff, composing parts to work, measuring things inside cells, and how you share information over networks. There's probably going to be a lot more standards. Who controls the standards, how the standards get promulgated will create a type of network power that we want to be mindful of. It's very important in my position that these standards remain open and scaling and that they're used constructively.

This technology has also been technically controversial within the research community. I just want to call that out and say it plainly. For example, the idea that you can standardize biological parts and reuse them, that you could abstract things, doesn't always work. Biology is too complicated, and you can see that represented within the field. I'll simply report that over the last year, it's now been shown that standard parts can be made to work, including for categories of elements that have been declared to be impossible to standardize. And So Vivek Mutalik, for example, has a series of papers in Nature Methods, coming from the BioFab project, showing exactly how to regularize types of translation controllers.

Okay. Abstraction, this last idea. Wouldn't it be neat if I could design, for example, a tumor destroying bacterium, without having to know that DNA is made of four bases. I would just as a designer say, I need a sensor to this type of tumor. I need some logic. I need some other things. I'm going to call down to the people who are expert at designing those things, and they're going to work with the biochemists and geneticists who can make those functions. Eventually, somebody down there will make the DNA, but I'm just going to be the high-level designer working up-top. Much like if needed to text my mom a photograph of all of you today, I wouldn't need to know how the machine code works to send that over the network, I would use a high-level language through this touch interface.

Could we do something like that? In biotech, examples again showing that this is not impossible, so for example, when logic was bootstrapped in the 1850s and then implemented in computing, that became very powerful. We now have examples, for example, electronic logic based on three terminal devices, like the transistor. Very recently, we've implemented molecular architectures like this for controlling computing within cells; we call it the Transcriptor. And basically what we've been able to do is recapitulate Boolean logic but in a new form that operates in DNA. What's interesting about this work is not just the computing outcomes, but the fact that when we did this work, every DNA design we made worked the first time. We didn't have to go around the design-build-test cycle hundreds or thousands of times. It took us three months to do this work from when we started the project, and we were, from doing that, able to demonstrate amplifying switching and logic gates.

From genetic engineering to synthetic biology. So let me try and wrap up and zoom out a little bit. Here are some of the core tools that powered the last 40 years of biotech: Recombinant DNA for cutting and pasting existing material; PCR for amplifying genetic material and recombining it; and sequencing, for reading it out. What is hidden within synthetic biology are initial and advancing new platforms supporting the design-build-test-learn cycle, and the scientific discovery process. So for example, synthesis of DNA. Although the chemistry for DNA synthesis was perfected in 1982, the process engineering around building larger and larger fragmented DNA hasn't really been invested in until very recently. It's not like the genome sequencing projects where the government said every base pair in the human genome is worth $1, and it's a $4 billion dollar market to bring industry to begin to develop sequencers. We haven't seen that advance until very, very recently with synthesis of DNA.

Abstraction for managing complexity allows more people to implement more powerful DNA programs and standards is a way of coordinating labor across time and over locations. Significantly, there's a dot-dot-dot here, and what also is represented within synthetic biology is now sort of irreversible community of engineers, who are continuing to invent new platforms and tools for engineering biology.

Last slide. As this has happened, we've grown the community. All right, so iGEM was mentioned in the introduction. There's now about 15, 000 students all over the world and at least 40 countries who have gone through a cooperative genetic engineering competition. It used to be run out of MIT, now it's an independent, public benefit. And with apologies, here's the actual last slide. I'll just go right to it, because I know it's running late.

What would I want from my colleagues at State? Here's a list and here's my naive academic degree of difficulty scoring. Very important to prevent the remilitarization of biotechnology. You're probably already doing that; I just don't want to take it for granted. Right. It's something that has been underway for a long time. It's very, very important that we don't stumble back into that world view, with better tools. Along with that, there needs to be a strategy for biosecurity, in a world where we get better at engineering biology, and it's not obvious we have that in place yet. It's very difficult to talk about that, politically. We have to absolutely preserve and protect natural biodiversity. As an engineer of biology, I'm really bad at engineering things from scratch. I'm really good at taking things from nature and repurposing them, so I have to be the most powerful advocate for natural biodiversity on the planet. You'll see within the CBD, I'm sure, things happening around synthetic biology and people expressing concern around that. That's important, too. I just want to make a straightforward argument: we have to preserve biodiversity.

There's a thing reemerging right now: GMO versus no-GMO. That's a caring ford of an old debate that's kind of dysfunctional and it would be nice to transcend that; I think there are ways to that. As we get better at engineering biology, it's important, going back to the third point here, to not merely industrialize nature, but to reinvent how our civilization works and partnership with nature. What do I do with the garden clippings from Menlo Park, besides compost them? Standards can be deployed to establish network power. We've seen this with language, commerce, information technologies. Guess what: it's going to happen with the future of biotechnology. We need to be very smart, diplomatically, about that.

Some of the things are actually quite doable. This last one I gave as a easy task. Make human civilization work really well, it's because I'm optimistic, but I think we can do it. Thanks very much.

[applause]

Jonathan Margolis: Thank you, Drew. Thank you for that presentation. I should have mentioned this earlier, but this gives me an opportunity to say this. In case people in the audience don't know this, the views represented by our speakers do not necessarily reflect those views of the State Department or the U.S. Government.

[laughter]

Let me now introduce Richard Johnson. Richard Johnson is engaged with shaping the policy, legal, ethical, investment, research funding, biosecurity, and governance issues related to synthetic biology. He is a member of the Board on Life Sciences at the National Academy of Sciences, and recently co-chaired the comprehensive board review of the National Academy's Science, Technology, and Economic Policy programs. He serves as a director of the BioBricks Foundation and is the Chairman of the OECD BIAC Biotechnology Committee, and Vice Chairman of the Technology and Innovation Committee. He participates in a number of synthetic biology policy and legal task forces, the Human Genome Organization'sGenomics and Society Committee, and the U.S. International S and T joint consultant meetings. Please join me in welcoming Richard.

[applause]

Richard Johnson: Let me try. I may need Nat too, since had a different computer previously. While Nat's doing that, let me just -- two introductory comments here. One is that what I'm going to do is focus on a top, Ricks' top 10 list for why synthetic biology matters to American foreign policy. So this is not a fair and balanced International scope, this is why this matters to U.S. foreign policy. And second is just with the time limits, there are lots of issues that we could be discussing, and so I'm going to be very selective and very subjective in what I have and we can return in questions and discussion or offline, to lots of other issues that are really important, that I'm not going to cover.

So first one. First one, as really, as Drew began to mention, synthetic biology is really emerging in a international context from the start. There are at least forty countries that have significant synthetic biology research programs ongoing. Probably more than fifty at the synthetic biology SB6.0 conference, global conference that was just held in London. We had representatives from more than fifty countries. More than twenty-five countries have national strategies, initiatives, roadmaps about where they're going to go in synthetic biology, and we have a proliferation of new multilateral, regional bilateral initiatives around synthetic biology, in which the U.S. role is going to be increasingly important. And also important to the United States to understand what's going on outside our country.

So let me just quickly mention a few. For example, the U.K., which may have the most advanced program, developed a national synthetic biology roadmap. The prime minister and his cabinet have identified a series of technologies that are viewed as critical to Britain's future. Synthetic biology is number two. At the synthetic biology SB6.0 Conference, David Willis, the Research and Higher Education Minister for the U.K., announced an additional about $190 million of new U.K. Government investment in synthetic biology, including creating a national center for innovation and research at Imperial College. There is a leadership council; there is a large range of activity, public engagement, et cetera, going on in the U.K. And that's being mirrored in a lots of other countries.

The OECD, as Jonathan just mentioned, I have the pleasure to be the chair of the OECD BIAC Science and Technology Committee. And more, probably about two-thirds of the OECD members and key partners have continued to indicate their strong interest in synthetic biology and it's one reason why it is now a new thematic priority in the work program of the OECD. Robert Wells is here, who used to chair the OECD biotechnology programs, and can attest to the interests that the delegations have shown in synthetic biology. The Six Academies' project that has been mentioned clearly indicated the growing interest across countries of comparison. For Horizon 2020, we don't have the budget details yet at a level of specificity, but fair to say that synthetic biology is going to be very important in Europe's new five-year effort around science and innovation. Particularly with its emphasis on challenge-driven innovation and societal grand challenges and the roles of society that synthetic biology can play. And you have countries like Korea that have been developing very actively new programs, so they have an institute for the bio-century, a new intelligent synthetic biology national center, and the list goes on.

But what's really interesting to mention is that some of the greatest emphasis on synthetic biology is occurring in emerging markets, and as part of their national innovation and economic growth strategies. China, obviously, as we learned in the Six Academies' project and elsewhere, this is a major component of China's national technology and innovation strategy. It's a centerpiece of the new, twelfth, five-year science and technology program, which is about midway. Now, what's really stunning about China is not only the level of investment, it's really the breadth and depth with which China is approaching synthetic biology as a means to address a broad range of Chinese needs and interests.

But it's not confined to China; for Brazil, for example, the science board is calling it the next industrial revolution for Brazil. It's taking advantage of a lot of the biomass and activity that's been going on in Brazil, and there's a wide range, there's a new and international conference among emerging markets that just taking place, in that Brazil is hosting. You have a new program at the University of Sao Paulo and around the rest of the country, around synthetic biology.

South Africa's in the middle of developing a new, really interesting bio-design initiative as a core part of its new national innovation strategy, because South Africa sees synthetic biology as central to not only meeting its domestic needs, but also its more global and regional aspirations across Africa and elsewhere in a way in which it could play a significant role. And so the core part here, I think, is really understanding how synthetic biology is really a foundational technology for the bio-economy, both in terms of creating economic value, but simultaneously in addressing a whole range of grand challenges. So you have the World Economic Forum. The Davos people had an expert technical group last year on a global basis, and they rank synthetic biology as the second key technology moving forward, after big data and next generation ICT. Some of you may have seen a new ad campaign in the U.S. by Fidelity Investments. A little overhyped, no doubt, but in which they say synthetic biology is quote: "the defining technology of the next century for global investments."

So the second reason, obviously, that this really matters to State and American foreign policy is around the economic dimension. Economic competitiveness, new export markets, trade policy: there just are a broad range of synthetic biology applications, markets, and business models that are emerging. And, as Drew mentioned, our colleague on the National Academy Forum on Synthetic Biology, Rob Carlson, is part of the development of the national bioeconomy blueprint, has estimated that we already have a significant amount of our economy, two percent, as Drew mentioned, that are bio-based. But, the real opportunities lay ahead. So just thinking about chemical transformations and a lot of things that also are fossil fuel-based, it's estimated that there about $4 trillion dollars of products that are made by chemical transformations and less than five, or 10 percent, of those chemical transformations have ever been addressed biologically. So what Drew just laid out, when you think of the numbers, means that you have huge, potential, addressable markets just in chemical transformations that may be benefitted from synthetic biology. Obviously, the first wave of synthetic biology was heavily oriented and continues to be heavily oriented towards energy, bio-fuels, things like that. And it's really a potentially disruptive game-changer with new production platforms and value chains that may well displace a lot of fossil fuel-based methods of production. But it also from a foreign policy perspective, has a lot of other implications. How does this link to our gas/shale revolution and energy independence in the United States? But also what are the geopolitical and security consequences of countries that may now be displaced or disrupted by the fact that things that have long been important to their economies are no longer as important for us geopolitically?

And obviously, the size of these markets are huge. Nobody knows what the number is. There are numbers out there, that for example, that there may be a trillion dollars in global synthetic biology markets by 2022. Do we know? No. We just know the number is very big, precisely because it cuts across so many domains. Not only of energy and health, but we're already seeing, for example, a huge adoption and rapid diffusion in industrial biotechnology value chains, where synthetic biology processes as well as products that come very important, but there are also a broad range of health applications. For example, and new drug discovery and development, in addressing neglected diseases and responses and more rapid development of vaccines. And also very importantly, just in understanding basic biology in new ways that will advance health.

But beyond, sort of, the product and application side, I think it's really important when we think about the economic policy side for the U.S. to realize that it also creates new growth markets that are not related to specific industry applications. So for example, we have a large number of very competitive U.S. companies in computer-aided designs. All of a sudden, as Drew was just mentioning, we now have the development of CAD-like tools and software, with significant market potential. So a company like Autodesk in the Bay area, synonymous with CAD products and services, is making a big move into synthetic biology because it sees the biological space as the next wave for the types of CAD things where it has particular strengths.

Three final points on the economic side, before moving on a couple other issues: one is that, I think it's really important to understand, that a lot of the synthetic biology things have multi-use core platforms and infrastructure as part of the business model. This is Amyris; some of you know of Amyris. They are the company where the University of California-Berkeley and Jay Keasling's lab with funding from the Gates Foundation, came up with a new approach for, precursor for, malaria drug. It's now being rolled out this year at cost in developing countries by Sanofi; huge success story for synthetic biology. The point that I want to make, though, is the same platform that was used for the anti-malarial drug is the same platform by which Sanofi is now trying, and other companies, are trying to develop isoprene for sustainable tire manufacture, new types of jet fuels, farnesene for certain diesel precursors. So this multi-platform basis, and I think it's very important as we think of it, as is what Drew just outlined of the decoupling of design from fabrication and manufacturing. The key point here, besides thinking about the acceleration of sort the design-build-test approach is biology as design space. But just think what happened with semi-conductors over the last 50 years; very striking parallels between what we think biologically and synthetic biology and what has happened in semi-conductors.

And then finally, obviously, potentially the biggest killer app of synthetic biology for the United States is around next generation manufacturing and production. DARPA'sAlicia Jackson's been leading a fantastic program at DARPA on living foundries about looking at precisely that set of issues. And as Mary Oxman at MIT had commented a couple years ago, the biological world is displacing the machine as general world of design. So we have a range of economic issues, but from a foreign policy side it's much broader.

So clearly, synthetic biology very much links to concerns about sustainability. It provides a platform, a set of technologies, new advances that can basically help us address almost all of the issues that John Holdren laid out, in terms of what the Obama Administration sustainability agenda looks like moving forward. A large part, as the National Academy reports, MIT, and others have said in recent years, with this convergence of engineering with physical and computational sciences, and life sciences, in completely new ways. And it also provides a basis, as ARPA-E is doing on the energy side, to really compress and provide a disruptive basis for changing cost curves, for technology frontiers, and scaling options, that can really move us faster to sustainable economic growth.

Fourth area I want to talk about, and this I think is particularly important, and I think has been overlooked to a far greater degree than it deserves to be, particularly in the U.S., which is the role of synthetic biology for U.S. development policies. It's really a problem-oriented, solutions-driven approach. Just think about agriculture for a minute. This a core technology platform that offers one part of the solution for the next green revolution that we need to see in agriculture and food. One of the big issues is sustainable intensification for small-holder farmers, for example, in Africa. Well, the idea of having synthetic biology-produced DNA sensors to monitor soil nutrients, to be able to have disease resistant plant feed stocks that are supplemented with environmentally friendly microorganisms are all something where synthetic biology has something important to contribute and say to that.

And a little further out, is this whole idea that some teams, like Chris Boyd's at MIT and others who are working on, about nitrogen fixation, where we could begin to engineer cereal crops that could fix their own nitrogen, and the decrease in need for fertilizers and ammonia, when all of the consequences of that become apparent. And I very much agree with a comment that George Church made a couple of years ago, that just as when we look, for example, as Jonathan and I were talking about before, about the incredible M-mobile revolution in Kenya in telecommunications. The same way that Kenya leap-frogged landlines and built this incredibly entrepreneurial approach to mobile things, beginning with banking but now farming and what not, is the same approach, I think, that we could see in leap-frogging fertilizer. As George says, "fertilizer wasting, fossil fuel intensive, and disease-rife farming."

But also from very specific U.S. interests, I think it aligns incredibly well with a large parts of the U.S. development agenda. And I'll just use Africa as an example. Obviously, the president unveiled the Trade Africa initiative in June. Trade Ambassador Froman and other people from State have just been returning from the Africa Growth and Opportunity Act forum in Ethiopia, where the theme this year was around sustainable transformation through trade and technology.

The point here is that synthetic biology has something to contribute, whether it's on the global health initiative, on the Feed the Future initiative, a whole range of USAID things that I think we need to explore to a much greater extent than what we have before. And on the development side, it also offers a whole new range of potential toolkits and drivers for development. So thinking about the oceans, and the algae, and the biomass and how both for food and for chemical, et cetera, that that offers a range of new types of activities.

Clearly, the security issues are front and center, and they deserve to be; they're legitimate. But there's a range of them, and we need to be thinking about that in a very integrated and coherent way. On one level, of course, we have the biosecurity issues and particularly the so-called dual-use research of concern. NSABB, Drew, as a member, had a report in 2010, and there's a range of issues about who manages these risks. For some in the room who are in involved with Biological Weapons Convention and the Chemical Weapons Convention, as you know, for example, on the chemical weapons side, OPCW has just created a new synthetic biology working group that's beginning to look at this intersection, and what gaps and what issues may be there.

Beyond the biosecurity side, we have all of the traditional biosafety issues related to biosafety and error domestically, with the NIH guidelines and elsewhere. Be we also and I'm going to come back to the Convention on Biological Diversity, but clearly there are issues around the Cartagena Protocol for biosafety, and a number of NGO's have been making some significant submissions on that front recently. But also there is a broad range of scientific outreach issues around how do we integrate scientific openness and security in synthetic biology in new ways. In terms of educational outreach and opportunities, in terms of ensuring the integrity of scientific research, and scientific norms as a way to reinforce security, and obviously, in terms of transparency, openness, and transforming a range for international dialogues.

And the last point I want to make about security is that we have also a number of nontraditional global security issues emerging around synthetic biology. So the interconvertibility between the physical and digital world that Drew just outlined introduces a whole new range of, sort of, cyber-biosecurity sets of issues. And then on a different dimension, obviously, resilience is one of the major new emerging security issues for the 21st century, and synthetic biology has a lot to say about a range of resilience issues. The U.K., in fact, just did an interesting study looking at the incredible role that synthetic biology can play in the U.K. for pharmaceutical resilience, in the event of disasters. So it has big opportunities for U.S. foreign policy and science diplomacy. It's a huge opportunity to use soft U.S. power in new ways. We have two activities that have been described, so I won't describe them again. iGEM is a fantastic example of using U.S. soft power for young people around the world of science and technology. And with full disclosure of Drew of my own involvement with the BioBricks Foundation, it also in its convening power and it's outreach to the scientific and synthetic biology community, I think, has an important role to play to as well.

And then, because synthetic biology really is a tools revolution, I think it offers huge opportunities for U.S. science policy, in terms of new types of international research collaboration, shared infrastructure, capacity building. Drew heads the Stanford BioFab; why shouldn't we be thinking about developing BioFabs that are open and accessible, to promote synthetic biology in constructive ways, on a much broader basis, outside of the United States, as part of a global network?

Very briefly, just all of the types of issues we have here are also transforming a range of other policy issues. Obviously, we have a new set of regulatory conflicts and disconnects, not only domestically among our regulatory agencies, but internationally. We're going to have a new wave around precaution. We're going to have issues around whether or not regulating the technology in synthetic biology exceptionalism. There's lots to trade policy and regulatory things around techno-protectionism. We obviously are going to have turf wars and jurisdictional issues that are going to, from an international side or, have to be addressed. We have this big lag between the regulatory science and where academic and commercial science, technology, and engineering are today. And then finally, I think, we also are beginning to see early stages of some countries and some groups who really want to use regulation and risk management techniques as a way to constrain or to slow down perceived American leadership, economically, and scientifically in synthetic biology.

And so for example, there are going to be a range of new regulatory foreign policy things around international treaties in the conversation and later we can come back to, but for example, there's a whole range of activities on the Convention on Biological Diversity. There's a range of intellectual property access ownership diffusion issues. The National Academy Forum on Synthetic Biology has just had a meeting in London on this issue, and there is a range of interesting issues that are emerging there. And particularly in terms of how the engineering of biology may well exacerbate some of the already existing tensions that exist in property rights frameworks. And particularly, when we try to shoehorn this into existing frameworks, whether it be WTO trips, whether it be world intellectual property organization, CBD standards; Drew has covered very well. This is an absolutely, critical issue for how we think about internationally keeping the synthetic biology movement forward.

And then, finally, I think that we need to be thinking, we tend to forget the investment side. And the international investment, public-private partnership funding issues are absolutely critical if we're going to successfully scale synthetic biology for beneficial applications, and also to de-risk synthetic biology investments. So again, very quick whirlwind, and I hope we can return to a number of those issues in the discussion. Thank you.

[applause]

Jonathan Margolis: Thank you, Richard. Thank you for those wonderful remarks. Let me now turn the floor to our final speaker this morning, Eleonore Pauwels. Eleonore is a public policy scholar with the Science and Technology Innovation Program at the Woodrow Wilson International Center for Scholars. Her primary focus is a comparative and critical analysis of the EU and U.S. approaches towards the societal governance of synthetic biology. She is also examining the challenges that the new forms of biotechnology pose for political and public policy organizations, and the regulatory innovations that emerge alongside developments in cutting-edge technologies. In 2006-2007, she was part of the Governance and Ethics Unit of the Director General for Research at the European Commission. Eleonore.

[applause]

Eleonore Pauwels: Good morning. It's a pleasure to be part of this panel in such good company. So let me start by saying that we have devoted about six years of our time at the Wilson Center, trying to essentially bring the voices of the public into the conversation about science policy on emerging technologies. And this part of my long-lasting interest in the cultures and mechanism of knowledge sharing within and outside of the lab.

So it all started when, a few years ago, I began to listen to researchers at MIT talk about the hopes, successes, and failures. And from there, I began to question their ways of knowing, and their ways of dealing with uncertainty. And I use this same method outside of the lab. I talked to lawyers, policy makers, NGOs, and members of the public. So the sources I use today, there are two kinds: interviews with scientists in the lab and years of studying U.S. public perceptions and press coverage about synthetic biology.

So let me jump in and tell you about my first visit at MIT. You know, I had come to talk about biology, but quickly felt like anthropologist trapped into the backwaters of the precedent forest with an outdated dictionary. Students were speaking about genome barcodes, gene shuffling, BioBricks, cells as hardware; I was looking for the jargon file. The one they provided old hackers in the seventies, I couldn't find it. That's when I started to think about what we lose in translation when we communicate about synthetic biology. First big question: what is it? This new science is not easy to define. It's at the crossroad between computing, engineering, and molecular biology. It's in the work of enabling technologies like cloning, stem cells, and GMOs. And to add to this complexity, as you can see on the slide, the field is suffused with metaphors. It's about metabolic machines, and engineers who have invaded genetics. Then the next issue is what happens in the lab, what you and I cannot see.

Well, scientists are constantly questioning their computing and engineering models. They are dealing with high uncertainty and high complexity. Just have a look at this quote from interview with a scientist at MIT. "The misconception is that you think what we do is easy, we make Legos. And that we are able to design organisms in very predictable ways. The misconception arises by invoking these engineering concepts which are not yet practices. As we start building stuff, we are finding in general that our designs actually don't work very well. And in part, the designs don't work very well because we don't understand the biology as well. We need to accommodate the biology. What could go wrong? What makes the system fail in the biological setting?"

And the next issue is what happens outside of the lab. And outside of the lab in the public sphere, we don't measure the uncertainty and the complexity. This cartoon was published in the Washington Post a few weeks ago and it goes for creative tension, instead of uncertainty. But what happens in the lab is definitely about dealing with the complexity of biology. So there are two problems I see coming: media interpretation and public perceptions.

Let's start with the media. Since 2008, press about synthetic biology in Europe and the U.S. has more than tripled. And what you see most of the time in media is that notions of uncertainty and complexity are replaced by hype and narratives of control. And the hype built on this notion that biology is becoming a technology and will produce better value. So from there what you often read are stories about bacteria factories that will save the world by producing just about everything, from fuels to plastics to medicines. And this not only simplified in terms of technological visibility, resources, and safety, but also in terms of ownership. I have a few examples here.

On NPR you could hear a little while ago, "bacteria will create electricity: clean water from waste, produce blood, vaccines, fuels, or whatever we fancy." In the New York Times Magazine 2012: "Tiny bugs will save the world; custom bugs, designer bugs -- bugs that only Venter can create. Bugs will have a mission: devour things like pollution, generate food, and fuel." Now, at the same time, these visions of promissory features are coupled with narrative of control and failure to control. And in the media, the narrative goes this way: "Life sciences are becoming information sciences," with metaphors like "DNA is the software of life, emphasis on hardware, like programming or rebooting a cell." And so again here, you have important detail lost in translation. While the scientist ambition is to, step-by-step, be able to read DNA sequences, write them, and one day be able to design, predict, and control DNA functions, what an average person gets out of this news article is that we do logic. We make computers in the cell. It's going to be safe and predictable.

So let's give a closer look at some of the narratives of control as they are used in the media and sometimes in policy discourses. In the New Yorker in 2009 you had, "cells has hardware," "genetic code as the software," "to write programs to control genetic components," "alter nature", "guide evolution". In Nature, "what can synbio do for us? Move genes around cells, create biological circuits, write new genetic programs that will change the world." Then, at a Congress hearing in May 2010, you had expressions like: "because you have standardizations, you know can get Legos from anywhere and they are going to work together." Similar notions like, "booting a genome in a cell," "writing the software of life." And then interestingly, you see Congressman Waxman picking up the metaphor and using it to say, "We are now able to reprogram a bacterial cell." So there is a kind of transfer of language between the scientist and the congressman, which might actually widen the gap between scientific realities and the expectations of policy makers and the public.

Now, let me gloss over a few variations of this narrative of control that I find interesting for two reasons: first, because they got international coverage; secondly, because they use the distinction between an old way of doing science and a new generation of biohackers in synbio. So the first one is what I call the entrepreneur-scientist. In May 2010, Craig Venter announced that his team had been the first to build a self-replicating bacterial cell. And in this world, a complex biological process became a top Sci-Fi storyline: "This is the first self-replicating species we have had on the planet whose parent is a computer." More than 200 articles covered in the U.S. press covered Venter's bacteria, and all the headlines were asking the same question. "Did Venter design artificial life?", "Is he playing God, or is he going to save the planet?" Then another international press birth happened early 2013 when another entrepreneur-scientist mentioned the possibility to clone Neanderthal gene. [laughs] And as you can imagine, that dream led to a few hot debates about using synbio to restore biodiversity and extinct species.

Then the last variation is what I call the biogenius. So opposed to the Venter model, funded early on by big corporations like Shell, Chevron, and BP, emerged a new profile. Engineers who used Kickstarter, to get in two months half million dollars to design glowing plants that would shipped all over the U.S. Now, here is the problem: while they used all the appropriate federal channels, their project did not fall under any U.S. agency's oversight. And NGOs were quick to react with a campaign against untested, unregulated, uncertain, synbio pollution. And they have a pretty punch motto, which is "There is no undo for genetic contamination." So Kickstarter decided to stop funding gene projects, and once, the bottom line, when this story got a lot of coverage and showed weaknesses in the U.S. regulatory system.

So what do these stories have in common? They all leave a potential failure to control for implications of emerging technologies. Failure to ethics, failure to anticipate, failure to control; these are deep, deep control narratives. And they are deep because they're built on precedent failures, like DDT, Chernobyl, the oil spill, recent flu outbreaks. You have to remember that narratives are key in human cognition. We are the species' storytellers, and the stories we tell shape our perceptions. People trying to make sense of new technology will fall back on narratives long before they pick up a biology book and try to learn about the science.

So that leads us to U.S. perceptions. I summarized four years of U.S. perceptions to these and here are the take-home messages. People know little about synthetic biology, with 23 percent in the U.S. and 17 percent in Europe who have heard about it. But they usually make quick analogies to cloning, stem cells, and GMOs. So you are in the very interesting space right now where people don't know much. And who they hear from and what the message is will have a huge impact on the future of the science. Then, initial reaction to synbio are kind of mixed, but usually people tend to get more polarized as they -- as we discuss the science behind it. So it goes from 15 percent of people initially concerned by the risk to 33 percent post-information. Which was, you know, the importance of how you frame the risk and benefits of that information.

On that note of course, applications matter. People mostly care about applications which have a significant duty for society, medicine, and the environment. So flu vaccine, cancer research, biofuels are more compelling than trivial projects. When it comes to risk, biosecurity raises a lot of concern in the U.S. People fearing dedication to bioweapons. But they also have concerns with biosafety. So they would say, for example, could see moving to horozontal gene transfer. Something of that sort. In general, what they emphasize are failure to control for long-term implications, "what if" scenarios, and governance failure. So you could get a question like, "If a disaster happens, who is in charge? Can they fix it?" and, "How much is it going to cost?" If we glance over a few comments we got from our focus groups, you get: "I am worried about self-replication." "How do you control that technology? How do you stop someone from cloning a human being? How do you regulate that?"

"There are no safeguards. There are no understanding of the repercussions." And then this one is really interesting: "If there is not someone in their group who is asking, 'should we do this?' they need to include that person." So they are not asking for banning the research, they are asking for continuing oversight, transparency, and regulation. And they are also asking for benefit-sharing. And when it comes to benefit-sharing, the level of trust and cooperation was usually pretty low, but in 2013, the level of trust in the government and in NGOs dropped significantly. As you can see on this graph, it's kind of, it's pretty low. So I mean, what they are telling us is go for what was designed, but anticipate implications upstream in the process, and take responsible measures. And indeed a key issue in synbio will be trust, whether we trust the people who are essentially developing the technology, promoting the technology, or doing oversight on the technology. And then we have a lot to do with how much social capitol is in your society; there are huge variations. There might be much more trust in China right now in government cooperation than there is in the U.S. I don't know. But the trust issue is kind of floating in the background.

So where does that leave us? Well, people are going to ask pretty hard questions about who is doing science, who is funding it, who wins, who loses, and what can go wrong. So in that context, there are a few pressing societal and communication challenges we need to tackle. First, it's never too soon to tell. We need to address the potential for failure to control. From the lab to the federal agencies, we need to get better at anticipating implications, biosecurity, and biosafety, upstream in the process. Ideally, at the level of design, but for sure before commercialization. So to that end, at the Wilson Center, we had a few experiments with what I call trading zones. These are open spaces where scientists from different disciplines and policy makers can share knowledge and question their designs to better anticipate implications.

Then secondly, well, we need to address narratives. We need to get better at communicating what an amazing revolution synbio is, but be open about uncertainty and complexity. And it's not a question about of public acceptance, it's a question of transparency and knowledge sharing. It's about a future where knowledge and funding can begin for crowdsourcing. It's an open future. Finally, we need to be thinking about ownership models that promote openness, innovation, benefit-sharing, and avoid inequality. And that has to be done in an international context. Just to give you an idea, two of the biggest genome sequencing facilities are in New York and in Beijing. So to that effect, all teams at the Wilson Center just got a new grant funded by the EU. It's a total of 4 million euros, to be doing just that -- international collaboration on synbio progress. We also committed some funding to work on synbio ownership and the Convention on Biological Diversity.

So to conclude, I would just we still have time to address narratives, but that requires vision and engagement, not false promises. The public must believe that effective regulation, technology assessment, and public engagement is part of our science policy and not an afterthought. Thank you for attention.

[applause]

Jonathan Margolis: Thank you, Eleonore, for that speech. I'd like to ask the three panelists now to come up on stage and join us in these chairs, and we'll start the question and answer period. So Drew, Richard, and Eleonore, if you're available. Right over here. And I'd ask also while they're coming up, if folks in the audience have questions, we have two microphones here, as I pointed out earlier. And please do step forward to those microphones.

First question; please identify yourself when you ask your question.

Tim Trevan: Tim Trevan from the International Council of Life Sciences. I thought I'd come up, because I didn't see anyone else moving up. First, to pick up on a comment that Richard made about the potential for standards to be misused against the U.S. or to create competitive advantage or potential barriers to markets; it's interesting that that's not a concern of just the U.S. I was talking to one of the Brazilian presenters in SynBio 6.0, who is concerned that the application of best standards to synthetic biology is so expensive, it excludes innovation from the third world, and that's an issue that needs to be addressed as well. But the question I wanted to put to the panel concerns more the security aspects. We held a meeting in Heidelberg in March 2012, sponsored by the British Foreign Office Sloan Foundation and the FBI, trying to look at how the codes of conduct were being implemented by the gene foundries could be implemented to best effect, and what barriers there were to effective implementation. And one of the issues that came up is this issue of who is denied access to the market, based on gene sequences being of concern. And the question was asked of the companies in the room, "Do you fulfill orders from countries like Iran?" And the answer was immediately, "No." And this isn't a security response from the companies, it's just a cost-benefit one. If the order's small, and the costs of due-diligence are high, there's a commercial disincentive to even consider fulfilling those orders. The concern that came out of that discussion was: are you then from just the economics of the market, creating a black market potential for gene sequences of concern, for synthesis of genes of concern? And if so, how do we then change our policy to reduce the size of that market you're creating? And one of the issues that came up was, or, one of the potential solutions that came up, was can we actually license those who are legitimate players? Whether they're small institutions that don't have a track record yet of synthetic biology that gives the gene foundries confidence that they are bona fide players, or whether it's citizen scientists, or whether it's legitimate entities from countries with which the U.S. doesn't have good relations, like Syria or Iran. So I throw it to the panelists, what do you think about the idea of creating a licensing system to reduce the cost of due-diligence for the companies?

Drew Endy: Yeah, we looked at licensing and the options for governance report back in 2005 as one of the options for governing access to synthesis of DNA technologies, and scored it as being potentially useful but very expensive to implement. And so you know, it's one thing if the burden of looking into who's ordering what is hitting the company, but it's a whole other thing if that's hitting a licensing scheme that implemented by "who?" Right? And that takes real work and Jerry Epstein and colleagues who helped -- drafted that, you know, might want to comment offline about why exactly we weighted not so highly the option of licensing. It's not that we were against it, and others have argued for it. I guess would I offer as an option to consider would be things like MoSys in the world of silicon manufacturing, where you can, in the world of silicon manufacturing, see the requirement of having significant capital investments to get state-of-the-art manufacturing technologies implemented. All right. Huge investments. Yet, MoSys has an implementation service, provides access to those technologies, throughout many communities that otherwise would never be able to get to the silicon wafer Fablabs. So an idea that came out of the Weiss Institute at Harvard was called Symbiosis, Synthetic Biology Shared Implementation Service, that would be a way of coordinating access through a central, almost public benefit service that would do some of the checking about who was ordering what and not having that hit industry. Especially when you have a very small industry, you know, the worldwide genome synthesis market is probably now approaching only $200 million a year. It's growing quite a lot but it's not that big, so it can't really afford to take on the burden of checking everything. So licensing is an option but I think there might other creative options if we could learn from other sectors that might be better. It's a good question, though.

Richard Johnson: And just two additional points on that. You know, I think it may not get us to a couple of the other dimensions. So for example, our colleague on the National Academy Synthetic Biology Forum, Rob Carlson, for a long time, has been talking about the problems of black markets and has done some recent work trying to quantify. For example, in China, there are a large number of mom and pop operations who are working outside of the gene synthesis agreement. And interestingly, the Chinese Government, Chinese Academy of Sciences, are every bit as worried as we are about what they are doing and what that may do. And the point is, you know, are we going to catch -- get those under control by a licensing process, and my guess is not. But could licensing do some good? Perhaps. But then we also have to think of the full range of the activities. We have obviously a very vibrant, growing DIY, do-it-yourself synbio community in the United States and elsewhere. Interestingly, a number of you know Ed You at the FBI who has been doing fantastic work with outreach in terms of domestic security issues around this field, and that's one of the communities that have been most responsive to understanding responsible norms so far. And so my point is, if the licensing concerns are, to what extent do we constrain new entrance, new ideas, by saying that only certain universities, only certain labs who have the wherewithal to get the licenses can participate in synthetic biology. And I think that's a difficult balance to strike so that we have both the security concerns integrated well with the open science, as well the potential benefits that we're talking about.

Tim Trevan: Could I come straight back on that, because that's somewhat the wrong way around from the meeting in Heidelberg. It was the current system is effectively dictating who could get access to the stuff, and it was actually the -- those who were excluded from the markets who were actually proposing licensing as a way for them to get access. So that was a way around that. Interestingly, on the Chinese Academy of Sciences, I went and talked to them and presented on the security aspects of synthetic biology. Their conclusion seems to be that, for the moment, pop shops the way is regulation because that's the only way that they don't have the market incentives to do self-governance. So it will take government regulation to actually get to them. Thank you very much.

Jonathan Margolis: Eleonore, any views on licensing and narrative? No? Okay.

Diana Mott: I was just going to make two points, which is that I really enjoyed the last talk --

Jonathan Margolis: Could you introduce yourself, please?

Diana Mott: Hi! I'm Diana, Diana Mott --

Jonathan Margolis: -- from which organization are you representing?

Diana Mott: I don't represent the State Department, but I work here. [laughs] Anyway, I was just going to say that I really enjoyed the whole symposium, and I wanted to sort of bring to -- I wanted to bring up two points, which have, as a biologist, have occurred to me several times. The first one being the person that brought up the question, "should we be doing it?" I think is a very, it's a very good point, but I think it's probably a little bit hard to implement in policy. So the challenge that I would give to the educational community would be to put more emphasis on bioethics education and to integrate that a little bit more into the teaching of these tools and use of these tools. The other thing is that, calling to mind the fact that RoundUp Ready Wheat was recently found in a field in Oregon unexpectedly, and that fact that these technologies can get out, and can get out of our control, I'm wondering whether there is any value in your mind to developing more rapidly programmable and deployable synthetic immunity. So a system which can track down the synthetic DNA that you've created, to destroy it once it's been created.

Drew Endy: Just, let me take the second one real quick, is that talking with the Google Maps team recently that opened up access to a lot of mapping data and was asking them for the spectrum that they're getting, and looking for gaps in the spectrum that might not be of synthetic immunity but just would be within any engineered crop to build within that a biosynthesis of a pigment or reporter that would show up as a very clean signal that could be observed remotely. Such that you wouldn't have to rely on, on the ground, in the field, pop-up assays. Say, "Oh, look. It's in that weird spot in Oregon." You'd have much more powerful indirect observational capacities. And that seems something that's pretty quickly doable --

Diana Mott:

[affirmative]

Drew Endy: Coming in with other types of more sophisticated control systems is probably doable too, but that gets complicated in the context of engineering those systems for reliability. Which I think we can do in biology, but the fundamental investments around how to engineer for reliability and the context of evolution haven't really been stood up yet. So we've got a long way to go to implement some of the more sophisticated control systems in a way that you would feel comfortable --

Diana Mott: --Oh, I certain. I --

Drew Endy: -- for a conversation with the public.

Eleonore Pauwels: Yeah, thank you for your comment on the scan of consciousness. I mean, the person who are presenting that kind of voice from outside were saying, "Should we be doing this?" The whole point is to not to have it at the level at policy, the whole point is to have it before, upstream. So maybe in the, maybe in the lab, those few experiments I described in my speech, those trading zones are experiments we did before having something on the market. So we did one a biosensor for arsenic, we did one on algae that would be used for biofuels; those discussions happened before even have designed the product. So we had, for example, meeting with synthetic biologist and people who do ecology, who work on specific organisms, who work on plant sciences or soil sciences. Those people can actually share knowledge, question their designs, you know, have questions; think about gene transfer, think about all of these questions that one field cannot answer. That has to be done before you of course design the product and have it, you know, in the policy sphere. So the whole point is to actually gather enough disciplines and enough creative minds to be able to work upstream.

Richard Johnson: And I'd just add one additional point, which is, in terms of your question and comment on bioethics and should we do it; obviously critically important, very important that we consider that. The other dimension, I think, that we need to include in that calculus, however, is: what are our obligations and what are the ethical ramifications of not doing things? When in fact, if in fact, you have the science, and the tools, and engineering that you could use for certain purposes, that you would want to do. And so I think adding the cost of not doing need to be as prominent as, sort of, what are the concerns of doing them.

Drew Endy: Can I just add to that? There's something I want to highlight. I think for a field of esoteric research that somehow leaps out and says we're going to do something about saving the world, we tend to know very little about the world, as the practitioners within the laboratory. And one of the things that Eleonore's response to your question brings up is how important it is to represent what's desired and to give standing, fairly, to diverse people in representing what might be desired in the future of biotechnology. And within this community, there's a lot of capacity for channels of learning, and interaction, and engagement. One of the neat things within synthetic biology, for example, that's risen is when, for example, the Royal College of Art partnered with Cambridge and Imperial in bringing designers into the space of biotechnology and asking anew, "What do you want? What could we make? How would we change the relationship between ourselves and the rest of the living world, and do we want to change that relationship?" So I just want to really champion an element of the dialogue just there. I think it's critical and I think, from what I see within the scientific and engineering community, we're desperate for more diverse drivers about what the goal should be. All right, biotechnology, in other words, is almost too important to be left to the biotechnologists.

Diana Mott: So if I could just throw back into that discussion, I should say that I'm not advocating for us not doing this research. I -- my position was just to, just to sort of guide it with ethics. But, regarding rapidly programmable and deployable immunity, one, I was considering it more as a dual-use thing. One as to, one to hunt down rogue DNA that's created that may be doing something that you don't want it to do; but the other thing is that we also have worry about pandemics. And so one thing that can definitely, you know, it seems like a useful line of research that would be useful for the next pandemic to be able to rapidly engineer immunity.

Drew Endy: Yeah, and there's, you know, when Eckhard Wimmer caused some trouble back in 2003 by doing polio virus synthesis from synthetic oligos [oligonucleotides], what got missed, what didn't get as much attention, was just a few years later they did rapid computer-based design of attenuated vaccine candidates using synthesis of genomes. Where you make almost a thousand changes to the DNA of a virus that don't change the immunogenic properties of the peptides, but greatly reduce its capacity to replicate, and anyone of the changes is not fully responsible for the attenuation. Such that in a manufacturing context, you don't get a single point mutation relaxing back and leaking through, and creating a fully infectious agent that hurts somebody in a vaccine program. So super-impressive, immediate use of a synthesis technology to improve vaccination platforms and to literally create a platform that would give us a chance of doing rapid development of vaccines, in response to emerging and infectious diseases. More recently, the partnership between synthetic genomics and Novartis has modestly improved the turn-time around manufacturing of the flu vaccine. There's a lot more work to do there and it would be great if we could figure out how to make total DNA vaccines work in humans. Hasn't quite worked yet. But I think you are pointing to something that the field has been responsive to. There's a lot of upside still to be explored.

Chris Hoffman: Hi, I'm Chris Hoffman, also from the Department of State, and I was just curious. I have a question and a following question. You had mentioned the number of, or the economic implications, of synthetic biology as being, you know, around $4 trillion. And I'm curious because a lot of your examples were replacing existing technologies or products, So you know, synthetically creating fossil fuels, for example. And I'm wondering, and not just replacing existing markets, but in terms of sort of transforming existing markets, what are the potentials there that we're not seeing? And I'm thinking based on how the Internet has sort of revolutionized all aspects of our life and created markets that we couldn't even foresee a decade ago. And so I'm wondering, for you, how, as leaders in the field, where do you see this going? How -- what would be one just completely wild implication or application of synthetic biology that could totally transform society as a whole?

Drew Endy: So programmable living scents and fragrances didn't do it for you?

[laughter]

But, appreciating that's a displacement. All right, you know, if you think of Samsung Electronics as a consumer electronics company in part, right, and one of the things they sell is a bread machine; and within bread machines are organisms called yeast. What happens when yeast is capable of doing biosynthesis of anything now found in plants? What happens when yeast is capable of doing biosynthesis of not just chemicals now found in plants, but other things? And you have a distributed manufacturing capacity where a loaf of bread is now capable of making a number of interesting things. Right. I don't want to unpack all of that here. And a lot of it does, I think, fall to a resetting of material supply chains as much as anything else and there's a long tradition of that, starting with indigo and things before that in synthetic chemistry. If I wanted to point to some other things, again, maybe you'd view this as replacement, but I still find it interesting.

Two papers published in the last year show using synthesis of DNA is archival data storage. Right, so for about $10,000 you can write one megabyte of digital data into DNA That's quite expensive, but the price is on a very nice cost-down. The neat thing about storing data in DNA is around a five-carbon ring, which is quite tiny. You get two bits of data storage and it lasts quite a long time, and it's a tape, a physical tape, which is relevant to human beings and will be as long as human beings are relevant. So we can rely on the physical media storage for quite a long time. A lot of people initially looked at these papers as being a stunt, but the archivists who are responsible for storing information for 500 years showed up pretty quickly and said, "Wow, this gets us off the trap of having to upgrade our hardware and readers every three to five years." And it might be really, really expensive now, but we can see it bounds that by stabilizing what the physical material is. Now, is that a replacement technology? Is that a lateral of synthetic biology into a new space? It's probably both of that. What comes from that next, I'm not quite sure.

Drew Endy: Do you see this, Rick, as a replacement or --

Richard Johnson: I think it's going to be both. I mean, I think in some cases we're going to basically see a replacement for existing processes. We're also going to see certain areas where it doesn't work that well. And so traditional methods will still be needed or still sources. We're not certainly getting away from fossil fuels completely. But the point is, and I'm not smart enough to figure out what the next thing is going to be. If I were, I'd be an investor and doing some other things. What I can say is that, you know, I think that when we look, as your question implies, if we look at the history of how the Internet and it's

Nobody at the early stages of ARPANET clearly could foresee the power it was going to be. I was very involved, being so old, with a lot of the government semiconductor issues in the late seventies to the early eighties. And you know, even Andy Grove didn't foresee at that point the incredible power that new approaches of how semiconductors or other things would be driving productivity, be driving all sorts of new applications. What I think we can see is from those historical examples, the things that Drew laid out and I mentioned very briefly, around abstraction, around decoupling fab from design. Around standardization are powerful, powerful tools that we have seen in other spheres used repeatedly for how engineering combines with science to really create brand new things. What those are going to be, I wish I knew. And -- so my only think I can say with confidence is, I fully expect the power of these new tools and these concepts are going to completely drive things that we don't; in five to 10 years, we're going to look back and say, "Wow. We had no idea that this is where it was going to go."

Eleonore Pauwels: I don't know if that's going to be a leader in, you know, economic costs, but at least there are. I mean, synthetic biology is a revolution in terms of how you think of some of the health issues. I mean, cancer research, it's, you know, it's really kind of importing an engineering mental model into how you understand biology. So you might understand that this is like cancer in a different way. How does it migrate? How does it work? Why does it work so well in some bodies, in some system? And, so that, that might not make so much money, but in terms of expectation and in terms of intellectual developments, it's quite interesting. So there are, there is a lot to expect for and in that field and, I mean, in that specific part of the field. And there are diverse mammalian cells synthetic biology kind of meeting at MIT a few months ago. And actually, you had some of what I described before; you could see people, you know, doing synbio at MIT but also meeting with people who do cancer research at MIT and having breakout session where they talk about that new model, that revolution. And that says, really, I mean, that gives a lot of hope for that.

Richard Johnson: And I'll make one prediction. I mean, in terms of the production economy, obviously we're spending a lot of time thinking about the Internet of things around 3-D printing, and the things that Drew was just mentioning about potentially on storage and things. When we start to move that, those concepts that are right now in the physical world of the Internet of things and the factory floor and the new production economy, into the biological design space. I think the potential there is enormous.

Jonathan Margolis: So we have time for one last question. I noticed someone standing over there. I'd also like to add I'm torn because I'd like to exercise moderator's prerogative and ask a question, so I'm going to combine those. And we'll take the question in just a second, but I'll also ask. The activities that took place, took place not only in the United States, but U.K. and China. And if the panelists would be willing to just give their reflections on, not only what, we heard quite a bit about what might be done in the United States, but where the discussion stands in the U.K. and where the discussion stands in China; especially the narrative in a public discussion; that would be useful to reflect upon, if you would.

Jessica Petrillo: Jessica Petrillo, State Department. And I had a just quick question about timeframe, because I think one of the things that iGEM. has really illustrated is what the, you know, the disruptive innovation, the innovation that can occur when it is in, kind of, the hands of people that are just trying to say, "Hey," you know, "what is this?"; just come up with ideas. And so my question is sort of this: where is the technology now? How quick is it moving to having what type of capabilities in which people's hands, type thing, to get a sense if we're talking, you know, 30 years out, the next three years? That sort of sense. Thank you.

Richard Johnson: Well, I'll just start and then let Drew pick up on some of things. But I mean, clearly it's already being used, for example. Let's it put it, for example, within commercial spectrum. You know, it's already being used in areas like cosmetics and enzymes for food. It's being used with a number of examples that I was showing. So we're really in a phase one thing, both in terms of process and then of course we're beginning to see some companies, like the gene synthesis and others with new products and services. But I think it's in a very short period of time that we're going to see a number of the new SME startup companies' benefits of their collaborations with both universities. And one of the interesting things in this space, certainly in the United States, is we tend to be focusing on a lot of the synthetic biology startups, is how the large companies, whether they be the large integrated energy companies, the large food companies, et cetera, are immediately engaged. They may not be publicly out there explaining all the things they're going, but they are deeply engaged immediately. But, you know, a number of these things are clearly going, and I think that's a really good question. Because, I think, when we talk about risk, when we talk about regulatory issues, when we talk about what we're going to deliver to policy makers and politicians, we have to be very careful about the temporal dimension here. And we tend to conflate that and, I think, beginning to sort out over what timeframes it may occur is an important task, I think, for all of us in the community to be doing more of. But I'll let Drew get more into when he thinks a couple of these major things are likely to move along out of his lab.

Drew Endy: But I want to return to the aspect of the question around what's happening in the other countries and how is it being perceived publicly and politically. And you know, Steven Kendall and Anne Marie Mazza as the engine of pulling these meeting together across the globe, really did something extraordinary and an experiment, in terms of looking at an emerging technology and how it's shaped across the world. You know, the first meeting was in London and the sense there was not much is organized, we're a little bit behind; we've got a lot of things to do and we better get going. And then just last month when, as Rick mentioned, there's Minister Willetts as a ranking conservative politician, getting up and speaking quite plainly to the effect that getting better at engineering biology matters. "England cannot be a museum of 19th and 20th century technologies. Yes, there's something associated with genetic modification here and we should be mindful of that, but let's get on with it. And, oh by the way, since I'm spending almost another $200 million right now, you researchers better deliver."

So the impact of that on the U.S. graduate students and post-docs is quite impressive. We don't have a political leader like that standing up for biotechnology in the United States. That might be a bug or a feature, but I'd encourage folks to watch the video of Minister Willetts and his remarks. It's quite impressive. So they couldn't believe that the political leadership was showing up and organizing aspects of their field, and then feeling the pressure when that shows up and wanting to deliver. That's quite empowering and helpful. China is very impressive. They are challenged, at least what I hear within the research community there, to solve some problems around food and energy in the environment, and the way that impacts the research community is even more powerful than how it shapes research in the United States. I think one of the most significant things represented by synthetic biology in the United States is the first time within our research community, where there's been a critical mass in biotechnology research, allowing researchers to take a half-step back from the immediate applications for biotechnology. See, when we turn to biotechnology to solve problems, they're really pressing problems. Cure the disease. Save the environment. Do something else. And we'd like the answer; my representative, Anna Eshoo in the House would like to drop in biofuels yesterday. Right? And the fact that we might need to invest for the next 10, 20, 50 years in tool platforms is a new story. China feels that more strongly, I think, the research community does. And that sort of came out from the Six Academies. In terms of timing of when things happen, you saw just the delta between my remarks and Eleonore's relations of comments from colleagues. Right? If you talk to me a year ago, we were shipping products that took us 700 attempts to get systems working. If you talk to me this year, we've now had the first time ever for us experience of getting our first designs working. That's represents 10 years of fundamental engineering research. Working on things have been very, very difficult. So it's hard to project where that goes next. We simply know that some of the core ideas are not impossible to make true. They mostly haven't been built-out or scaled; and it would be false to represent that we don't need to lay in preparations to sustain decades, and decades, and decades of fundamental investments, to make this really realize what Rick represents in terms of economic and other type of impact.

Richard Johnson: And I'd just add two things about impressions and clearly agree with Drew's on both the U.K. and China. On U.K., I was really struck in the course of our Six Academy initiative of the way in which the U.K.'s breadth across the country is not limited to the research community. So the research councils in the U.K. are doing an extensive amount of public engagement. Civil society is completely engaged initially, and so it's not an afterthought. And basically, you have British society very much engaged with synthetic biology from the outset, which I think echoes one of the themes that Eleonore is making so well. China: the thing that really struck me beside the scales, the breadth, and the depth that I mentioned before, was the youth. I -- we, I think, we're really struck by the incredible interest and vitality of young researchers in China in synthetic biology. And what was really interesting is, and many of the thanks go to Anne-Marie for putting the program together, insisting that basically some of the issues around ethics, some of the issues around policy and public engagement, which were not, were new to the young Chinese researchers, were on the table. And I thought that was an incredibly powerful discussion that we had, both on and offline with young Chinese researchers, around sets of issues about their research, that perhaps they may not have had outlets to explore before. And that to me was another benefit but also really interesting component of the overall project, of which there were many.

Eleonore Pauwels: Yes, I would confirm what Rick said about the U.K. The countries in the EU have kind of taken on that challenge to try to develop public engagement with their populations as much as they can. And you just look at the recent history: medical disease, Chernobyl other disaster of that sort; they really need to tackle that dimension. Now, the problem is that those, some of those demonstrations of good will are only demonstration of good will. They don't lead to any new step in how you anticipate about implications and how you think better about regulation in how you answer some of the expectations of the public. So it's a, it's a sole question of management of expectations and more than a public engagement show that you give once a year. So I think, I mean, to me it's more question of education, not in terms of we need to educate the public and you know, just give them a lot of information. It's a question of getting into that synbio revolution some of those new generation. Let them understand what this revolution is about. Being open about the uncertainty and the complexity, not promoting hype and notions of control. And by showing knowledge that way, you know, the world is going to change in terms, you know, as I was demonstrating with the Kickstarter.

Things are going to change in the way we talk to each other and the way we share knowledge, and the way we use funding. With crowdsourcing you could, you could actually use a lot of energies in country like the U.S., which is pretty crazy. So it's a question of education at the level of those young generation to include them in this innovation journey. You don't want to leave, you know, people at the margins of this change. And I think by showing them how much of a revolution it is, in the mindset, like I was saying for cancer research. I mean, You know, some researchers they work on T-Cells and made a lot of progress very quickly by showing those things and by getting this new generation in the move; I think we can go much further. But do not forget the anticipation; we are really bad at anticipating in different cultures. In the U.K., in the U.S. As for China, I mean, it was, it was pretty eloquent when they had to talk about, you know, public engagement and those dimension. They couldn't really show us any work they would have done in that realm like we do in western societies. Not, of course, to blame their way of working, but I think that's really something to address with them, and you have to address those questions in a cultural context anyway. So that's definitely a conversation to be having with people there, the scientists and policymakers, and people, you know, who do ethics.

Jonathan Margolis: Well, what I'd like to do, just in closing, is I'm going to ask you in the audience just to thank some people. Obviously, our panelists, who are just superb from my perspective: Eleonore, Richard, and Drew; but I'd also like you to just reflect on the fact that what we heard was not only the science of the politics, but also how you have a public discussion about this. And I want to really thank the people, the organizers who put this together: Bill Colglazier and his office at the Science Technology Advisor to the Secretary, and of course Chris Cannizzaro, who did the yeoman's work in putting all this together at our Science and Advanced Technology Office. Absolutely, the whole crew. Thank you very much. Terrific work. So if you would put your hands together for the panelists and the organizers.

[applause]

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