Adventures in Synthetic Biology

In the first few panels of Drew Endy’s “Adventures in Synthetic Biology” comics you see a young student with laboratory goggles grabbing Buddy-the-Lifeform. His instructor takes him inside a cell to view the organism’s genome, “the master program that’s running the cell.” The young student remarks, “So this is what we change to reprogram this critter? LOOKS EASY!”

Dr. Endy’s innovative comics attempt to make the nascent field of synthetic biology “look easy” to both student and layman alike. Synthetic biology combines science and engineering in order to design and build (through DNA synthesis) novel biological functions and systems. Endy’s comics made the cover of Nature in 2005.

Dr. Endy’s day job is as an associate professor at Stanford University’s Department of Bioengineering. He’s helping to build a library of standardized biological components for use in genetic research. While his research interests are varied, they focus on engineering integrated biological systems. Here’s a video of his pioneering talk during the First International Conference on Synthetic Biology at MIT in 2004:

As reported in Nature, engineered biological systems have been used to manipulate information, construct materials, process chemicals, produce energy, provide food, and help maintain or enhance human health and our environment. Dr. Endy envisions an open technology platform for engineered biological systems that is component-based, standardized, and reliable.

Drew Endy earned degrees in civil, environmental, and biochemical engineering at Lehigh and Dartmouth. He did postdoctoral studies in genetics and microbiology at UT Austin and UW Madison. From 1998 through 2001 he helped to start the Molecular Sciences Institute, an independent not-for-profit biological research lab in Berkeley, California.

He joined the MIT faculty in 2004 where he co-founded the MIT Synthetic Biology working group and the Registry of Standard Biological Parts. He also organized the First International Conference on Synthetic Biology. With colleagues he taught the 2003 and 2004 MIT Synthetic Biology labs that led to the organization of iGEM, the International Genetically Engineered Machine competition. Teams of students from schools around the world compete regularly in iGEM.

In 2004, Dr. Endy co-founded Codon Devices, Inc., a venture-funded startup that worked to develop next-generation DNA synthesis technology. A year later he co-founded the BioBricks Foundation (BBF), a not-for-profit organization founded by engineers and scientists from MIT, Harvard, and UCSF with significant experience in both non-profit and commercial biotechnology research. BBF encourages the development and responsible use of technologies based on BioBrick™ standard DNA parts that encode basic biological functions.

h+ contacted Dr. Endy at his Stanford University office.

h+: My understanding is that the goal of synthetic biology is to build a biological machine — or modify an existing organism — using standard parts, much like a computer or electrical engineer might design and build a computer using off-the-shelf microchips and circuit boards. Are we close to doing that now?

Drew Endy: I don’t know that we’re close to doing it at all. I think what we’re trying to do is get better at engineering biology. We’re looking to past examples, where, in other types of engineering, people have developed improved capabilities for engineering different types of material such as metals, silicon, and so forth. We’re adapting those lessons to the substrate of biology and seeing which of them might be useful. I think it’s an area of research — which is important to emphasize — because what it means practically is that it’s not at all obvious that the lessons from computer engineering, electrical engineering, mechanical engineering, or civil engineering will directly translate and apply to the substrate of life. They inform us and provide points of departure. It would also be surprising if they didn’t have something to add as well. So, the work of synthetic biology, which as a field in its modern form is only about five-years-old, is an opportunity to work on improving the process of designing, constructing, measuring, testing, debugging, and reworking living components — as well as living systems — to see if we can improve how we work with them and partner with them to do different things.

I don’t think it’s at all imminent that we are going to be designing and building new life forms from whole cloth. What’s imminent are many opportunities to get better at the process of engineering living systems, starting from the ones that already exist, and seeing what comes next.

h+: In your talk at First International Conference on Synthetic Biology at MIT in 2004, you outlined four new inventions that enabled today’s synthetic biology: DNA synthesis, standardization, abstraction, and decoupling. How much have we progressed in each of these areas since the first conference?

Drew Endy: Synthesis of DNA is based on a chemical process that was perfected in 1982. What’s happened over the past five years since the 2004 conference is, from a commercial perspective, that the cost of having a gene synthesized has dropped from about $4.00 to somewhere between $0.50 and $1.00. A four- to eight-fold improvement. That’s a lot, but perhaps not as much as some people might hope for — this means there’s a lot of room for improvement.

In terms of standardization, there is a first generation of standard biological parts called the BioBricks parts collection out of MIT. It probably numbers about 5000 parts. It was motivated by naive allusions to the Transistor-transistor Logic Data Book that Texas Instruments and other electronics manufacturers might provide.

No one should be under any illusion that standard biological parts collection as it now exists is of the same quality or maturity as what people might be familiar with in electronics. Nevertheless, it’s a fantastic success story. It’s growing exponentially with the number of parts being added to the collection year-after-year. It’s also become a world resource that’s unparalleled and quite valuable. Students and others who are starting genetic projects today don’t have to start from scratch. This allows a lot of projects to happen much more quickly than was possible five years ago.

The next step in my mind around parts collections is to professionalize them so that they support the worldwide diversity of folks who are identifying all sorts of new natural genetic functions that might be adapted for technology purposes. We want to support those folks with core, professional teams that are working for public benefit while making very high quality standard biological parts as best as anyone now knows how and giving them back to the world as an open technology platform for the future of cellular and genetic engineering.

h+: This begins to sound very much like Open Source software in the computer domain.

Drew Endy: Yeah. And to speak frankly, I think synthetic biology is informed by the transition in computing from AT&T and Unix circa 1971 to today. If you look at the transitions in computing over that period of time, some of the first software that AT&T wrote is word processing software for writing patent applications. There was a move to use copyright as a legal mechanism for defining and sharing innovation frameworks in software through the 1980s up to this day. For a period of time that led to a split in the software development community where some folks decided to use copyright to define proprietary software and generate significant revenue streams around that — Bill Gates and Microsoft is a leading example. Other people decided to use copyright to enforce standards of freedom around software — that’s Richard Stallman of the Free Software Foundation.

But from the 1980s to today it took about two decades to have a rich ecology of software innovation. Today you find quite a vibrant ecosystem of software that includes open technology platforms comprising Linux, mySQL, Apache as a web server, and so on.

I think the opportunity that presents itself to the biotechnology community is that we can transition to a richer innovation framework — and I mean richer in many ways — and get to open technology platforms without a whole lot of dysfunction as an intermediate stage.

Coming back then to your bigger question [about progress since the first conference], we’ve talked about construction and we’ve talked about standards. Abstraction as an idea came into existence for genetic circuits based on transcription — that is, the reading out of DNA — and it’s been extraordinarily powerful as a first step, but it hasn’t gone much beyond that. The PoPS (Polymerase Per Second) standard, while not yet widely understood, is quite powerful. But the reading out of DNA is just one type of cellular function. There are many others, and it would be good to see the ideas of abstraction explored against different categories of biological function.

h+: The fourth area that enabled synthetic biology is decoupling, right?

Drew Endy: Decoupling is a consequence of the success of the other areas. For example, if you have the ability to print DNA on demand, this means that one person can be a designer of DNA and another person can be a builder of DNA. That’s a type of decoupling, like an architect and a contractor. However, if the designer of DNA does not have a language or a grammar that supports the programming of many genetic systems, then the decoupling between designer and builder will be useless. Where do these languages and grammars come from? They come from advances in standards and abstraction and any other idea that might apply.

I think there’ve been some good steps towards decoupling — we’re seeing teams using DNA synthesis and acting as designers — but we still have to do a lot of work because the component sets themselves are not very mature. What the sets are calling on are not reliable objects; they’re research projects basically.

h+: A number of these ideas were encapsulated in your “Adventures in Synthetic Biology” comics that made the cover of Nature magazine. A comic book seems like an innovative way to communicate complex ideas to a younger audience. Has it been included in educational curricula? Do you have any plans to make it into a series?

Drew Endy: I would love to take it forward as a series of comic books. To be fair, it was a lot of work as you might imagine. You’re highlighting quite sharply many of our motivations around doing it. It was a project that we took forward as an educational project, meaning that we were really struggling to communicate certain ideas to our students, specifically the idea of a common carrier for genetic circuitry. In drafting the comics, what we tried to do — and this is manifested in the last chapter of the comics with the title "Common Signal Carrier" — is insert a dialog between student and teacher that would lay out on one page all the questions and puzzles that we found students to be wrestling with when we tried to explain this sort of idea. And I think we did a good job of that, to be frank.

h+: I think you did too. I was very impressed.

Drew Endy: But, if I then try to assess the impact of the comic book in teaching these ideas, I don’t know if it was a success. Often it’s difficult for people to imagine that they might learn engineering theory from a comic book. Maybe they don’t get to the third chapter. They just read the first chapter which is simpler and meant to explain what’s happening to a person who might not know what DNA is. I’d be curious if you or any of your readers might have some insight on that. I recognize that the comic book form is very powerful. But as a pedagogical device, I’m not convinced that it is as impactful as we might have hoped.

h+: It seems like a great approach to communication, and I’m curious to know if you think that the comic idea will go anywhere as an educational device.

Drew Endy: Well, we don’t have a communication strategy for it (laughs). But I think it will. I’m speaking from my own perspective. One of my colleagues at MIT extended the comic idea via a web site called biobuilder.org You’ll see that he uses comic-like animation around specific aspects of synthetic biology.

h+: I see from your web site that there are quite a few projects being pursued by the Endy Lab at Stanford — genetic memory, computational modeling, electronic counter review, DNA sequence refinement, synthetic biology data transfer protocol, to name a few — can you talk a little about your current research focus?

Drew Endy: The lab at Stanford is for the students. The research at the lab is really being defined by the students as they learn to become better researchers. The meta-level framing of the lab is focused on getting much better at putting together parts to make integrated genetic systems and having those systems work as we expect. So, for example, the types of systems that synthetic biologists are building today might contain ten to twenty different genetic components. But the pieces of DNA that people can construct are capable of containing thousands of components. So researchers can put together eight million base pair fragments of DNA that can have 8,000 different genetic parts on it. But these are not novel engineered systems, they are recapitulations — we’re “plagiarizing” the natural sequences. Meanwhile, we engineers can design, build, and get working 10,000, 20,000, maybe up to 60,000 base pair fragments. This means that we have an opportunity to get between 100 to 800 times better at genetic engineering.

And how are we going to get better at putting parts together? The answer is that we don’t know, so this becomes a research topic in itself. One of the reasons we’re interested in implementing scalable information storage systems inside cells is that the scoping of these systems is about ten times more complicated than anything anyone has been able to build today. So by targeting that sort of system, we’re challenging ourselves to get better at integrating genetic components into many component systems.

All the specific projects in the lab are exploring ways to take forward the opportunity to get better at putting things together, specifically, the integration of genetic components.

h+: Your startup company, Codon Devices, closed its doors recently. Can you talk a little bit about what happened? Is the market not quite ready for synthetic biology devices?

Drew Endy: Codon Devices went to market as a gene synthesis company. It did not compete successfully as a gene synthesis company and so we shut it down and went out of business. We didn’t go bankrupt, which I’m proud of in some strange way. I think the gene synthesis marketplace generally is doing quite well and has a lot of competition. This marketplace continues to grow, and there seem to be many opportunities for improvement in gene synthesis technology. People are continuing to work on it.

h+: One last question if I may. What is your vision for synthetic biology over the next five to ten years?

Drew Endy: The things I’m anxious to see over the next five years include getting the construction technologies to be much more powerful and practical. If we could drop the cost of gene synthesis by a factor of 100, that seems within striking distance. It basically requires obtaining oligonucleotides [short nucleic acid polymers, typically with twenty or fewer bases] for building genes in some reliable fashion from oligo chips [chips containing several thousand oligonucleotides]. People have demonstrated that this is possible, but no one has made it reliable as a commercial process.

A second goal for me over the next five years is to see a very professional biological parts collection, complementing what the student competitions are now producing. These collections can be used to form an open technology platform that future biotechnology can draw upon for free to more cheaply and effectively deliver solutions that address the problems and opportunities that the world presents to our civilization.

So, in summary, about a hundred-fold improvement in the cost of construction would be nice, and a professionalization of the parts collection, so that, for example, the central dogma in microorganisms like E. coli and yeast no longer present themselves as research questions for genetic engineers. I’m sure there will continue to be scientific research into these microorganisms, but I don’t want future genetic engineers to have to debug the equivalent of a “print” statement. The other big goal for the next five years is to see if we can catalyze an open technology platform in this sector that brings industry and academia together in a new venue to do a lot more and more effectively.

In terms of the applications in the field [materials, chemicals, energy, food, human health, etc.], it’s actually my job not to speculate. The whole significance of synthetic biology is that we’re not trying to overdrive it with any one application. We’re trying to invent and practice new technology platforms and languages and grammars that enable biotechnology quite broadly. I’d look instead to what the students in iGEM and other educational programs are exploring as leading indicators of what the future of biotechnology might hold.