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Collins: Boston University University Professor Lecture

Biology By Design

Boston University Professor James J. Collins delivered the 64th annual University Lecture before an audience of more than 500 Boston University students, staff and faculty on October 21, 2008. The annual University Lecture honors faculty engaged in outstanding research.  

Synthesizing life. Creating life. Franken-microbes. Engineers run amok in molecular biology labs.

Headlines such as these are appearing with increasing frequency as synthetic biology emerges, scaring and exciting people. Here I hope to give a sense of what synthetic biology is, what it’s not, where it came from, and where it’s going.

Synthetic biology is bringing together engineers and biologists to design and construct biological circuits out of proteins, genes and other bits of DNA, and to use these circuits to rewire and reprogram organisms, primarily bacteria. These re-engineered organisms are going to change our lives in the coming years, leading to cheaper drugs, “green” means to fuel our cars and clean our environment, and targeted therapies to attack “superbugs” and diseases such as cancer.

Synthetic biology builds on decades-old work in genetic engineering. In the early 1970s, scientists realized they could use different enzymes to cut a gene out of one organism and insert it another. In this way, bacteria could be modified to produce clinically relevant proteins, such as human growth hormone and insulin.

But many engineers felt left out of the biotech revolution and didn’t consider genetic engineering real engineering. They thought of it more as the biological equivalent of replacing a red light bulb with a green one, an act not requiring any training in engineering but perhaps the efforts of 10 non-engineers.

This changed in the late 1990s as the Human Genome Project neared completion. With several organisms sequenced and the parts list of genetic components growing, the genomics community became increasingly interested in understanding how genes and proteins interact in cellular networks. These complex interactions underlie biological functions, and their breakdown often results in disease. Engineers are trained to deal with complexity, and several saw this as an opportunity to enter the genomics candy store.

But many who entered were quickly taken aback by how complicated real cellular networks are. Luckily, a few of them learned enough molecular biology to realize that instead of grappling with this inherent complexity, they could create small synthetic gene circuits in a cut-and-paste fashion, using the same enzymes from the early days of genetic engineering. In this way, engineers could make "wet" biological versions of electronic circuits, and rewire existing organisms just as they might tinker with a radio.

In 1999, Tim Gardner embraced this approach in one of the first demos of synthetic biology. Gardner, who then was a bioengineering graduate student in our lab at Boston University, recognized that biology is messy and maddeningly hard to do, so he decided to start with something simple. He sought to build a genetic version of a toggle switch or flip flop, a simple memory element at the heart of digital computers.

Gardner’s design consisted of a network of two interacting genes, gene A and gene B. The genes were arranged so that each tried to shut the other off. The network could exist indefinitely in one of two stable states – gene A on and gene B off, or gene B on and gene A off. The genetic switch, which worked in the bacterium E. coli, could be flipped between the states by delivering pulses of a chemical.

This work created a form of cellular memory, exciting many people to call for the design of biocomputers based on synthetic gene networks. While this is intriguing, it is unlikely we will soon have desktop computers labeled with "E. coli inside." In part, this is because the digital switches inside computers take tiny fractions of a second to flip, whereas genetic switches take many minutes if not hours. Imagine using your microbial microprocessor to surf the web to check on the weather forecast. Two days later after the webpage has downloaded, you may be surprised to learn it was supposed to rain the day before. This is an unworkable scenario for our hyper-active, hyper-caffeinated society.

However, if you consider biocomputing to be the programming of cells to perform novel functions, then this is already happening under the banner of synthetic biology. Along these lines, we recently engineered a gene network enabling bacterial cells to sense different levels of DNA damaging stimuli. This system can be easily modified to detect many different substances in the environment including heavy metals, opening up the possibility of using cell-based biosensors to identify lead paint on products or the location of mines in an abandoned mine field.

The idea of putting engineered microbes into the environment, however good their intended uses, worries some. To alleviate these concerns, our lab has been working to create genetic counters, networks that can count events such as cell divisions. These circuits enable us to program microbes so that they have a specified expiration date. That is, after the bacterial cells have been out in the environment for some time, they commit cellular suicide, self-destructing by design.

Efforts in synthetic biology will become increasingly sophisticated and applications-driven, enabling researchers to put together and download multiple biological circuits in a plug-and-play fashion. This represents a new mastery and level of control over living organisms, with all the potential good (and bad) this can bring. In the coming decade or two, we can expect to see designer bacteria that quickly degrade plastic, microbes that soak up oil spills and decontaminate Superfund sites, and injectable cells that detect, invade and attack tumors.

Some hype and others worry that this tinkering and re-engineering of organisms is equivalent to creating or synthesizing life, invoking the modern Frankenstein myth. It is not. Instead it is essentially a high-tech version of breeding, an activity which has been practiced for centuries. Only now instead of mixing and matching traits by mating organisms, we swap and tweak genetic material using a combination of engineering and biology. This is not equivalent to building an organism from scratch.

Frankly, we just don’t know enough biology to create or synthesize life. Many confuse information with insight, but more information and data do not always lead to deeper understanding, particularly when it comes to biology. While the Human Genome Project has expanded the parts list for cells, we don’t yet have the instruction manual worked out for putting these parts together to produce a living cell. Imagine trying to assemble an operational 747 jumbo jet simply from its parts list – it would be impossible. Although some of us working in synthetic biology have delusions of grandeur, our goals are much more modest.

Underlying these concerns about creating life is an unjustified hubris about our technological abilities. We can build rockets, computers and MP3 players, but these machines are nothing compared to the sheer brilliance of a single bacterium. It’s going to be a long time (if ever) before we are able to compete with this.

Nonetheless the notion of engineers invading molecular biology labs and rewiring microbes scares a lot of people. Many are worried that a synthetic biology project will accidentally lead to the creation of a voracious organism that will escape the lab and gobble up City Hall, or worse, Fenway Park.

These worries are reminiscent of those that arose in the 1970s in the early days of genetic engineering, and lead to the introduction of biosafety regulations and protocols to prevent mishaps in molecular biology labs. These regulations remain relevant and sufficient for synthetic biology in light of the baby steps we are taking and the fact that the organisms being worked on in synthetic biology labs are by design, neutered and weak. These microbes need five-star treatment to survive, and they would get beat up and die should they ever make it outside the comforts of a university lab.

Indeed, don’t worry about a vigilante, engineered microbe sneaking out of a synthetic biology lab and wreaking havoc. Worry instead about the nasty germs that are on the outside, those that have arisen naturally and resistant ones that have resulted from our misuse of antibiotics. Many panicky patients don’t want to hear that if they wait a few days their viral illness will go away. So doctors are giving out antibiotics as if they are sugar-pill placebos. Further we have patients who actually have bacterial infections and are not completing their antibiotic treatments. These tendencies are leading to stronger, persistent bacteria out in our communities.

This growing problem is made worse by the fact that resistant genes can be carried on plasmids, or rings of DNA, and these plasmids can be readily exchanged between different bacterial strains and species. This is nature’s form of synthetic biology, and it can result in modified organisms with powerful, dangerous properties. Of note, a new strain of MRSA out in the community has been found to harbor a plasmid containing multiple, antibiotic-resistant genes.

Unfortunately we do not have any drugs that can counteract these mobile genetic elements, and the antibiotic pipeline is almost dry. Pharmaceutical companies have largely abandoned antibiotics in favor of bigger money makers like lifestyle drugs and programs addressing chronic diseases. We need to come up with a blue pill that can kill off resistant bacteria and enhance someone’s sex life, which could also lead to some pretty odd TV ads during the Super Bowl.

Fortunately the synthetic biology community is beginning to address our need for novel, more effective antibiotics. For example, Tim Lu, an MIT graduate student working in our lab, recently engineered bacteriophages – viruses that infect bacteria – to attack resistant bugs, expanding our arsenal of anti-microbial weapons.

Having said all this, it is possible that as synthetic biology develops and gets more sophisticated in the coming decades, microbes with unexpected consequences or potency could be created. This risk will increase as we take on more challenging problems and attempt to construct larger, more complicated synthetic gene networks. It will be increasingly difficult to predict how re-engineered organisms will perform, and this will become more problematic as we try to make designer organisms robust enough to be used outside the lab.

Consider the case of trying to create bacteria that can quickly degrade plastic. What would happen if a powerful, fast-acting bug of this sort were created and got on your PC keyboard in the lab, or worse on your clothes and transferred to your car when you drove home. You might wake up the next morning to find only your leather seats in the driveway. To prevent such accidents, it would be prudent to consider conducting work of this nature in higher containment labs, even though the starting organism might be harmless, non-pathogenic bacteria.

Scenarios such as these may be several years away, but it is useful to begin thinking about them now. Luckily the synthetic biology community recognizes this need. In fact, workshops and conference sessions bringing together synthetic biologists, ethicists, legal scholars and environmentalists, to consider these important issues have already begun to take place.

We are only just beginning to feel the impact of synthetic biology, and its popularity is growing. So parents, don’t be surprised if your budding engineer asks for a DNA kit to go along with her Lego Mindstorms.

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