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Get Ready for Synthetic Biology

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By Meredith W. Salisbury

Two years ago, you couldn’t have attended a synthetic biology conference if you tried. Today, even meetings that are supposed to be about other things — take last fall’s GSAC: Genomes, Medicine, and the Environment, or the International Conference for Systems Biology — devote significant blocks of time to this young field.

You’ve no doubt heard about synthetic biology, but your opinion of it probably stems largely from your own research background. To some dyed-in-the-wool biologists, the concept conjures up images of engineers trying to reduce natural complexity to a handful of Tinkertoys that they can take apart and put back together any which way. For people who come from an engineering background, synthetic biology offers a chance for the kind of standards and predictability that are so infuriatingly lacking in nature.

No matter what your view, it’s time to get familiar with synthetic biology. The field that has been bubbling up off and on for the past five years is now at a full boil, and experts say things are happening so fast now that in a decade the synthetic biology discipline will be unrecognizable to today’s participants. “I suspect it’s going to revitalize some aspects of genetics,” says Drew Endy, an assistant professor at MIT and pioneer in the field.

Put simply, the goal of synthetic biology is to understand —with as much precision as electrical engineers, say, understand transistors and circuits — how organisms function at the DNA, protein, and cell level. Ambitious? Sure, but they’re not through: synthetic biologists will use that information to redesign organisms, build new genomes from scratch, and all in all piece genome bits together as easily as if they were, well, Tinkertoys.

Harvard’s George Church envisions a day when designing a genome is as trivial a matter as sketching out a schematic on your computer, and then pressing a button to “print” or assemble it in real life. What Tim Gardner, an assistant professor at Boston University, calls the grand idea is to “be able to program cells the way we can program a microprocessor [and effect] complex, sophisticated functions at the nano level.”

More immediate, but still complicated, goals are to tweak organisms such as E. coli to produce new kinds of protein therapeutics, or add bioremediation or energy-producing functions to existing microbes.

Whether you’re knee-deep in the field or a curious outsider peering in, Genome Technology offers this overview of synthetic biology to catch you up on its early advances, key leaders, and upcoming challenges.

Where It Began

First things first: where did all these synthetic biologists come from? Many are escapees from that ill-fated buzzword of yore: genetic engineering. George Church is one such early joiner: “In a certain sense I was into synthetic biology because I was into genetic engineering,” he says. “Genetic engineering was, in a way, what happens when you give biologists a few primitive tools and they start mashing together a few pieces of DNA to try to regulate a gene.”

BU’s Gardner says an interest in genetic engineering was also his ticket to this new field. Synthetic biology can be compared to “genetic engineering on steroids,” he says. “It’s a more sophisticated version of genetic engineering from the rational design perspective.” Gardner points to two major evolutions over synthetic biology’s predecessor: scale — genetic engineering was usually performed on two or three genes, while synthetic biology can happen on a genome-wide level — and computation. Rather than haphazardly altering DNA see what happens, he says, synthetic biologists are trying to use computational tools to predict the effects of certain changes, and then perform the experiment in a wet lab to test that prediction.

But the evolution toward genome-scale engineering didn’t exactly spark a new community. It took a new conference, Synthetic Biology 1.0, to bring people together and help them realize that they didn’t have to work on these problems alone. MIT’s Drew Endy, who organized that first conference in June of 2004, recalls, “It was the first time 300 people got together in a room” and recognized that there was a larger community just waiting to get going.

Though it’s still by all accounts a fairly small group of researchers, it has modeled itself on the collaborative nature of exemplars such as the open source computing field, says Church. Jim Collins, a professor of biomedical engineering at Boston University, says, “You have very competitive individuals in the community, and they’re very supportive of each other.”

Supportive though scientists may be, it’s still hard to explain why synthetic biology is seeing such fascination right now. The concept of extracting an engineering discipline out of the wilds of biology is as daunting as ever. “There really are no organisms for which we have a complete understanding for how they’re wired together,” Gardner says. Engineering is largely based on the idea of taking modules you understand and assembling them into new but still predictable creations — but in biology, those modules are hard to come by. “We haven’t really figured out how to break cells down in that way yet,” he adds.

Endy says he arrived at synthetic biology for just that reason. Previously a systems biologist, he was frustrated with trying to understand and predict the behavior of natural biological systems when he realized that those systems “aren’t optimized to be easy to model. You should be building the systems that you’re trying to model.”

Tom Knight, another synthetic biology leader at MIT, says one of the challenges to even beginning a DNA-level engineering discipline is the lack of standards in biology. Biological pieces, such as genes, promoters, and proteins, have been named for the most part without rhyme or reason — making it difficult for outsiders (and sometimes even insiders) to speak the same language. Standardizing names for parts — Knight suggests a number-based identification system — would be a good step toward whipping biology into shape for an engineering sidekick. Another challenge Knight points out is the lack of a regular interface between pieces of DNA: unlike our Tinkertoy metaphor, there’s no one linker piece that can connect any two chunks of DNA you want to smoosh together. If each block of DNA needs to be custom treated, synthetic biology doesn’t have much hope of getting past the cottage-industry stage.

Despite the significant hurdles, enough incremental advances have happened in the last few years to fan the flames for synthetic biologists. Though there was no “sharp transition” in the technology, Church credits general improvements in DNA synthesis for helping jumpstart the field. “DNA synthesis has gotten better and better and to some extent has been pushing aside recombinant DNA,” he says. Jay Keasling, director of the Berkeley Center for Synthetic Biology, says having a good number of available genomes, better computer algorithms, and longer products from DNA synthesis have all contributed to the uptick.

Meanwhile, the cost for synthesis has been dropping — by a factor of two each of the past four years, according to Drew Endy. “That’s a collapse in price from $16 to $1 [approximately per base]. A project that when I started my lab at MIT was the entire budget of the lab is now essentially noise.” Steadily improving technology and dropping costs — sound familiar? It does to Endy, who contends that DNA synthesis is where DNA sequencing was 15 or 20 years ago. “You can probably just play the tape forward with synthesis,” he says.

Building Blocks

As in sequencing all those years ago, a few early technical advances in synthetic biology have helped to shape and lend credibility to the field while luring former skeptics. Around 1999, BU’s Tim Gardner, then a PhD student in Jim Collins’ lab, hit a milestone by engineering a genetic toggle switch. This technique relied on two linked genes, each designed to want to shut off the other. Providing the proper stimulus allows one gene to shut off the other, or to temporarily deactivate one and turn the other on. That paper was published six years ago in Nature, says Jim Collins, at the same time as a paper from Michael Elowitz’s lab that showed a similar advance — an oscillating system with three genes arranged in a ring.

These early triumphs and others like them, says Knight at MIT, were not necessarily ones that “anyone would consider interesting science, but it was starting to be some interesting engineering.” Still, they served to prove the point that it was in fact possible to do at least simple engineering within a biological system.

But the field still needs a stronger foundation to really make synthetic biology a robust engineering discipline. For his part, Knight has undertaken a project he calls BioBricks, which aims to build a repository of open-access, standard biological building blocks. Knight says the impetus to do this came from watching biologists struggle with assembling DNA to run their experiments. “The assembly process was out of control,” he says. “We are developing high-throughput, high-productivity, always-work kind of mechanisms which allow us to assemble pieces of DNA.” The idea is to make DNA assembly a routine conglomeration of standard components, so that it becomes a simple, quick part of the pre-experiment work, rather than a  time-consuming experiment unto itself. “That’s what BioBricks is about,” he adds. “Understanding the assembly process in absurd detail, and optimizing that process so that no one else has to ever do that again.”

A related effort is the Registry of Standard Biological Parts, also hosted at MIT. This program is a public index of available and in-progress biological components, and also offers a service for assembling new parts or systems out of those building blocks. “It’s a way for us to all share these parts that we make,” says Keasling at Berkeley.

Once scientists have a reliable collection of biological components, “then we’re going to build circuits and devices that will allow us to build almost any three-dimensional [object],” Church says.

Different Avenues

Even as scientists make progress in establishing standard, interchangeable DNA parts, research programs within synthetic biology are shooting off in all different directions.

One of the longest-running paths — and possibly the one with the most adherents — involves adding or changing functions in a system or organism. Jay Keasling has garnered considerable attention for his work in this area, not only in the scientific realm but in the funding arena as well. Keasling’s effort to engineer E. coli and yeast to produce a new antimalarial drug won his team a $42.6 million grant from the Bill and Melinda Gates Foundation. Right now, he says, the research has approached but not conquered the last stage needed, which is being able to produce artemisinin. “Pulling this gene out for the last step in the pathway — that’s going to involve quite a bit of science,” he says. “And getting the yields up [to make it economical] is a lot of engineering.”

Chris Voigt, a scientist at the University of California, San Francisco, managed to tweak E. coli to make the bacteria light-sensitive — what he calls “programming sight” into the organism. The bacteria were engineered so that their gene expression would alter when exposed to light. The project was tested by covering the E. coli with an opaque mask that had a pattern or image cut into it; a light source was then placed above the mask, and at the end of the experiment the E. coli that had been under the light had one pigment while those that were kept in the dark did not. Voigt, who presented this work at last fall’s ICSB meeting, says his team has also been working with heat- and cold-shock promoters to engineer a temperature-sensitive organism.

Other synthetic biology groups are trying to delete pieces from genomes. Fred Blattner’s team at the University of Wisconsin is aiming to get down to the minimal genome for E. coli and has been slicing hundreds of genes out of the bacteria’s original 4,400, with plans to keep cutting. “We’ve removed roughly 750,” Blattner says, “and we’re working on another 500 to 600.” The project began when Blattner was studying seven or eight strains of the pathogen and realized that “there was a common core in all strains, and then islands” of DNA unique to each. “I began to wonder, what if we just stripped away everything that was horizontally transferred and got down to the core genome?” Early on, Blattner saw that much of what his team was stripping out turned out to be transposable elements. “When we got to that point, we began to see some more stability in the genetics. … Everything seemed to start working better: protein synthesis was stronger, electroporation efficiency became better,” he says. “In some cases … genes that you couldn’t clone were rendered clonable.” Based on these improvements, Blattner has started a company called Scarab Genomics to commercialize what he’s calling the “clean genome” of E. coli.

Still other groups see synthetic biology as a way to start fresh, building genomes from the ground up as a way to exert more control over what goes into the model. Craig Venter recently launched a new startup around this concept, calling it Synthetic Genomics, with a goal of designing a modular system that can be given specific functions — in the interest of energy production or bioremediation, for instance.

George Church has also embarked on this approach to synthesis. “The initial exercise is to try to model [biology] on electrical engineering, where you try to reduce complexity and only use parts that you trust and don’t allow them to evolve.” In a talk he gave at last fall’s GSAC meeting showing the technology he’s developing to assemble genomes from scratch, Church said that one advantage to starting at the beginning was being able to prevent unwanted events such as functional DNA exchange with the environment.

And finally, there are plenty of people using synthetic biology as a way to learn more about biological function. At BU, Collins says some of his team studies synthetic gene networks to explore “the role of positive and negative feedback,” for example. “There’s an increasing number of groups turning toward these synthetic gene networks” to gain insight into how organisms work, he adds. “That’s helping to move synthetic biology into the mainstream of molecular and cell biology.” Gardner, who works with Collins, is continuing to use reverse-engineering methods to understand gene circuits and metabolic models.

For his part, Drew Endy at MIT has been redesigning the genome of bacteriophage T7 to make it easier to model. The engineering has taken the shape of “unstuffing and insulating the primary genetic elements” — separating genes that overlapped sequence, for instance, so that each gene can be studied and analyzed individually. At this point, though, Endy says that while the research seems promising, so far it hasn’t proven that the new genome will be truly easier to work with. “We think we made the design of the car better,” he says, “but we don’t know if it’ll be easier to drive.”

Stay Tuned

As research continues, so too must technical and other improvements if synthetic biology is really going to take hold as its own discipline, say experts. While the quality and cost of DNA synthesis have gotten better, Keasling points out, it can’t stop where it is. “We’re now down to $1.40, $1.25 a base,” he says. “I look forward to the day when synthesizing really long genes is really cheap — a penny a base.” That would facilitate much higher-throughput and larger-scale experiments that are now beyond most scientists’ budgets.

Also, the collection of biological components has to grow. “We’ve got to get some foundational technologies in place,” says Drew Endy. “We don’t have standard DNA binding proteins. What would a standard DNA binding protein look like?” In the long run, many hope to see the assembly of these pieces completely automated.

Tom Knight says the field could benefit from an increased sense of urgency. “Engineering in this discipline, by and large, is happening at a gentlemanly pace,” he says. “No one really has worried about the speed with which these experiments get done. That has to change, if for no other reason than we have to learn how to respond quickly to some of the natural and non-natural threats that are coming from the biological world. The idea that you can take a year to manufacture a flu vaccine is quaint and nice, but gee, it would be better if you could do that in a week.”

Other challenges loom, such as taking the simple circuits and switches that have been built and using them to design more complicated networks. Endy, who is credited with popularizing the term “synthetic biology,” says he worries about sustaining investment in DNA synthesis technology, which will be a linchpin for the continued evolution of the entire field.

There are also plenty of social and cultural hurdles for the nascent discipline. “You’ve got the issue of engineering biology, which is a big one,” Endy says. “That’s a brand new relationship with the living world for many people, so we’ve got to broker that.” He argues that it’s time for synthetic biologists to form a professional society and develop a code of ethics. George Church, who is also concerned about forming an ethical and safe community, says that “one of the top priorities is making synthetic biology safer than any previous biology.” He encourages anyone who is worried about what may be seen as risks in engineering organisms to get involved now, while so many aspects of the community are still taking shape.

Endy rattles off the challenges he sees for the field: “Naming issues, society understanding issues, legal issues, risk issues, community development issues. It is starting something new — we’re going to basically have to bootstrap this whole thing.”

But somehow, optimism still reigns in this rapidly evolving group. “We’re at the cusp of making this happen,” says Knight. “I will be shocked if there are not some interesting engineering artifacts coming out of this community in five years. And I think that the field will not be recognizable in 10.”



How Do You Get the Word Out? Start a Competition

Now a competition respected enough to draw 150 students, iGEM — or the Intercollegiate Genetically Engineered Machine competition — had humbler beginnings as the outgrowth of a month-long session at MIT. Taught by Drew Endy, Tom Knight, and Randy Rettberg, the idea was based on Michael Elowitz’s oscillating circuit work and challenged students to program cells to do something useful. Now an annual affair, the most recent iGEM boasted 13 participating schools after just five the year before, Endy says. The students, mostly undergraduates, “are absolutely formidable,” he says. “They’re just completely bringing it.”

Projects have included work like the light-sensing bacteria designed in Chris Voigt’s UCSF lab and the biowire from George Church’s group. Students have worked on building cell counters, temperature sensors, caffeine detectors, and a host of other things. Awards are given out for such accomplishments as the “Nothing-Will-Stop-Us Award,” the “Best Simulation of a Simulation,” and the “Best Device Award.”

Church says iGEM has been responsible for generating a tremendous amount of interest in the field, adding that this has been “possibly more important than the technological ripeness” in drawing people to synthetic biology. “iGEM gave the field a focus, a vision, and an energetic set of young individuals.”

 

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