Implications of advancement: Synthetic biology researchers consider peril as well as promise
By Susan Bland, Virginia Bioinformatics Institute
Related story: Students compete to safeguard synthetic biology use
While synthetic biology grabs headlines, as well as the attention of drug makers, energy executives, bioethicists, and high-ranking government officials, including President Barack Obama, the Virginia Bioinformatics Institute (VBI) at Virginia Tech is thinking ahead. VBI’s Synthetic Biology Research Program, which was introduced in 2006, is creating safeguards as it creates a program language out of DNA code.
Synthetic biology is a rapidly emerging area of biological research that uses methods developed in engineering to design artificial biological systems for useful purposes, as well as to re-design natural systems to better understand the fundamental properties of living organisms.
On May 20, 2010, the journal Science released a study outlining the successful creation of a bacterial chromosome and subsequent transfer of the chromosome into a hollowed-out bacterium, where its original DNA was replaced with the synthetic genome designed in the lab. The synthesized genome breathed new life into the disabled bacterium, providing the parts it needed to once again replicate and produce proteins. The team responsible for the creation of the cell made entirely of synthetic genes was led by Craig Venter, founder of the J. Craig Venter Institute, who is most widely known as one of the first researchers to sequence the human genome in 2001.
Potential applications of synthetic biology are vast. By genetically engineering microorganisms to perform specific functions, researchers will be able to develop medications, create alternative forms of energy, and detect deadly chemicals in the environment. But, so far, headlines have been more like “Man-Made Life a Boon With Risks for Terror and Error” (BusinessWeek, July 8, 2010).
Evaluating the potential and the risk
Government interest is increasing. The Woodrow Wilson Center’s Synthetic Biology Project reported that government funding for synthetic biology projects is growing, with the U.S. government spending $430 million since 2005, compared to $160 million spent by the European Union and several countries in Europe during the same time period. The Defense Advanced Research Projects Agency (DARPA), the U.S. Department of Defense’s research and development office, has allocated $20 million for general synthetic biology for 2011 and will invest an additional $6 million for BioDesign, a new program to create immortal synthetic organisms genetically designed to perform specific biological functions.
Regardless of the source of investment, the federal government is keeping a close eye on the implications surrounding advances in synthetic biology. Just as with any emerging area of research, there can be potential health and environmental risks, or even opportunities for intentional misuse. Since synthetic biology is still fairly early in its development, there may be risks that cannot be predicted.
The same day the results of the Venter team’s efforts to create the first synthetic organism were released, Obama asked the Presidential Commission for the Study of Bioethical Issues to examine other potential advances in synthetic biology — both the benefits and the risks. One week after the research was made public, the U.S. House of Representatives’ Energy and Commerce Committee held a hearing about developments in synthetic biology and its implications for health and energy. Venter and other scientists discussed the potential of synthetic biology research with members of Congress and agreed that while the technology offers many benefits, there must be regulations in place to guide scientists. This is the challenge government officials are currently facing.
VBI’s Synthetic Biology Research Group is working closely with various government agencies to help ensure that synthetic biology moves in a safe and useful direction, while continuing to make major strides in the field.
Streamlining the bioengineering process
VBI Associate Professor Jean Peccoud and the Synthetic Biology Research Group he founded are developing a design automation framework for engineering biological systems. New DNA molecules have been assembled primarily from existing DNA fragments. However, as the process of chemical gene synthesis evolves, the design of synthetic DNA molecules will increasingly become a bottleneck for biotechnology projects.
The framework being developed by Peccoud and his team will improve productivity for the biotechnology industry in the same way the electronics industry has successfully automated the design and fabrication of electronic circuits. The VBI team is integrating new computer languages to design DNA sequences, coupling DNA fabrication and design, and engineering a custom imaging platform to evaluate the performance of synthetic DNA molecules.
Abstract representations of synthetic genetic systems make it possible to reuse simple components to build complex systems or break down a complex engineering problem into manageable tasks. Several fields of biology have adopted the idea of genetic parts — associating certain biological functions with specific DNA sequences. The benefits of this have been limited by a lack of formalism. The synthetic biology group at VBI is developing new computer languages to represent the complex phenotypes that are encoded in long DNA sequences composed of these genetic parts.
Understanding the language of life
There are many words in the English language that are spelled the same yet have different meanings. For example, “bow” can mean the stick used to play a string instrument, the front of a ship, or a ribbon used to decorate a gift. “Bough” and “beau” complicate things even further. It is sometimes difficult to comprehend the intended meaning of the word by just looking at its definition. An examination of the surrounding words in a sentence, or sometimes even several surrounding sentences, is needed to understand the message being conveyed. The same is true for understanding biological systems. Just as the context of the word “bow” helps determine its meaning, the entire structure of the DNA molecule must be considered to understand its function. One idea is to extend the linguistic metaphor — the grammar of DNA — to formulate the transcription of DNA to RNA to protein by using the concepts of genetic code, transcription, and translation as a linguistic representation of biological sequences.
Attribute grammars are used in computer science to translate the text of a program source code into the computational operations it represents. A few further refinements of the grammar of DNA allow scientists to translate DNA sequences into molecular interaction network models. Attribute grammars represent a flexible framework connecting parts with models of biological function and are a key component in the process of building mathematical models of libraries of genetic constructs synthesized to characterize the function of genetic parts. This work serves as the foundation for GenoCAD, a Web-based Computer Assisted Design environment for synthetic biology developed by Peccoud’s group. The open-source software tool allows the non-specialist to design and validate large-scale genetic systems for use in basic biological research or product development programs.
“The idea to use DNA as a language to program living organisms instead of computers is the driving force behind GenoCAD,” explains Peccoud. “Using design strategies in grammatical models of DNA sequences, GenoCAD offers simple point-and-click actions to guide users through the process of designing new sequences consisting of dozens of functional blocks in literally a matter of minutes. After the design is complete, the sequence can be downloaded through GenoCAD for synthesis or further analysis.”
In 2009, the National Science Foundation awarded a three-year, $1.4 million grant to Peccoud to further develop GenoCAD, and Virginia Tech Intellectual Properties Inc. has licensed the source code for the program to the International Society for Computational Biology, facilitating open-source development by the synthetic biology community. The group is working to use GenoCAD for the development of a genetic detection device using the concept of co-design, which is common in engineering projects. The society is collaborating with the MITRE Corporation, a not-for-profit organization that provides systems engineering, research, development, and information technology support to the government, to adapt co-design methodologies for synthetic biology. As a test case, ISCB has developed an environmental sensing device that detects the presence of three chemicals and returns an output if at least two of the three chemicals are present.
According to Peccoud, “The concept of this test case is applicable to many areas, including the detection of chemical warfare agents. Genetically engineered cells have the capabilities to make effective environmental sensing applications. They can sniff out small concentrations of chemicals in their environment and provide a response to signal that a threat has been detected. We designed the device to be able to detect combinations of substances because many times chemicals that are normally harmless can become harmful when combined with another substance.”
Matthew Lux, a student in Virginia Tech’s genetics, bioinformatics, and computational biology Ph.D. program and a graduate research assistant in Peccoud’s research group, has been closely involved with efforts to develop the detection device. Lux has received a scholarship from the U.S. Department of Defense’s Science, Mathematics, and Research for Transformation Scholarship for Service Program. His sponsoring facility is the Edgewood Chemical Biological Center, the U.S. Army’s principal research and development center for chemical and biological defense technology, engineering, and field operations, located in Aberdeen Proving Ground, Md. Lux, Peccoud, and the rest of the synthetic biology team at VBI have worked to develop similar partnerships with various government entities involving its work.
Advancement and the need for standards
Peccoud has been invited to participate in several workshops organized by various branches of the federal government and other organizations for the evaluation of opportunities and the potential risks of synthetic biology for the nation’s defense and security. He chaired a session at the meeting, “Minimizing the Risks of Synthetic DNA: Scientists’ Views on the U.S. Government’s Guidance on Synthetic Genomics,” which was organized by the American Association for the Advancement of Science to bring together representatives from different sectors of the research community to discuss the draft guidance developed by the federal government for synthetic DNA vendors. In June 2010, Peccoud organized a visit from representatives from the Federal Bureau of Investigation’s Weapons of Mass Destruction Directorate to conduct a series of roundtable exercises involving biosecurity issues and the roles of academic institutions and law enforcement. These sessions were one example of outreach activities designed by the FBI to promote research safety and security at academic institutions, as well as build and strengthen collaborations while promoting scientific research and education.
Peccoud is also working with undergraduate students who are implementing, via software, the federal guidelines for synthetic biology. This work will help refine federal guidance while assisting gene synthesis companies and their customers in detecting the possible use of manufactured DNA as harmful agents for bioterrorism (see ‘Students compete to safeguard synthetic biology use’). In addition, the synthetic biology group at VBI closely monitors the use of GenoCAD for suspicious activity.
Peccoud and his team are as committed to advancing the field of synthetic biology as they are to supporting and protecting the standards of the evolving field. With a focus on identifying useful applications for GenoCAD, the team is exploring possibilities of vaccine development by focusing on the vesicular stomatitis virus (VSV), an RNA virus with a broad spectrum of hosts that has been identified as a good vector for therapeutic applications.
“Vaccine development is an exciting and promising application of synthetic biology, which could revolutionize the human vaccination process,” says Peccoud. “Our goal in working with VSV is to deliver a ‘plug and play’ platform for a DNA vaccine that would require a very short manufacturing cycle as compared to traditional vaccinations and be fairly inexpensive to produce.”