Safety/Learn More/RCSB Transcript
Transcript of video "Responsible Conduct in Synthetic Biology"
Hello! My name is Terry Johnson, I'm a bioengineering lecturer here at UC Berkeley. Today I'd like to talk about responsible conduct in synthetic biology. Now, why does synthetic biology require its own consideration of responsible conduct?
Let's consider: what innovations challenge traditional models of biosafety? Gene sequencing is becoming less expensive and faster, meaning that there's a tremendous amount, and an increasing amount, of genetic information. This genetic information is disseminated on the Internet, meaning that it's available both to researchers and the public. Gene synthesis technologies are also becoming faster and less expensive, and capable of producing larger and larger segments of genetic material. So information can more easily become actual genetic material. Lastly, the proliferation of BioCAD tools mean that users without the traditional amount of training will be capable of producing genetic material, genetic devices, and potentially participate in synthetic biology.
So, what must a synthetic biologist consider as the field progresses? Well, first of all, information propagates quickly. What you publish will rapidly be available to a large number of people. Second, that information can readily be made physical. Given a DNA sequence, it's increasingly inexpensive to make actual DNA. Lastly, emergent behaviors of complex, multi-gene systems are not obvious. One part of a genetic device may affect the function of another part of the device, or of the host organism itself.
To be a responsible member of the synthetic biology community, we need to: share information responsibly; share materials responsibly; design and build responsibly; and communicate with peers, agencies, and the public responsibly.
What about the sharing of biological materials? Here, we can be guided by the international gene synthesis consortium, or IGSC. This is a group of companies involved in gene synthesis. They've come up with the following guidelines: screen orders; screen customers; keep records; and report inappropriate orders.
So, before sharing biological material, ask yourself the following: One, is the material safe, with minimal potential for dual use? Two, does the request come from a lab certified to work responsibly with the material? If, for example, you were asked for a Risk Group 2 organism, you would want to be sure that the lab making the request was capable of working at Biosafety Level 2. If "yes" to both, mail in accordance with your institution's policies and record the transfer. If "no" to either, consider whether the request should be denied (or reported to local or federal law enforcement).
The responsible design of genetic devices can be quite complex. You need to ask yourself: Does your device involve any clearly hazardous or select agents? Are you using sequences from Risk Group 2, 3, or 4 organisms? You must also ask yourself, are there context-specific risks? And, what is your containment strategy?
What do we mean by context-specific risks? Well, we have to consider the context of a genetic device, the parts working together, and the fact that it's present in an organism. Let's take a look at an example. This is what's called a payload delivery device. Effectively, a bacteria is capable of generating a payload, invading a cell, sensing when it's in a vacuole, escaping by breaking the cell apart, which releases a vacuole lysis system and the payload. The vacuole is lysed and the payload ends up in the cytosol. Here is a diagram for the complete payload delivery device, which consists of several sub-devices: an invasion device, a self lysis device, a vacuole lysis device, and a payload, which in this case is a collection of fluorescent proteins. The first step in considering risk is to determine from what Risk Group organisms the various parts of the device come from. If we were to do that, we would note that the invasin and the vacuole lysis device proteins both come from Risk Group 2 organisms. Risk Group classification of your various sequences is only the beginning. One also needs to note their expected function and how they would work together. Invasin, for example, is a virulence factor. It's associated with disease. But the presence of invasin alone is not enough to make a bacteria pathogenic. Consider the device as a whole. Though it is designed to deliver a harmless payload of fluorescent proteins, it involves multiple sequences from Risk Group 2 organisms and involves virulence factors. As such, an organism with this device installed in it should probably be treated as Risk Group 2 at a minimum.
Let's take a look at another example. Let's say I have Mycobacterium tuberculosis, a Risk Group 3 organism. If I were to take the sequence for GAPDH from this organism, and place it in front of a constitutive promoter, I would have a device that involves a sequence from Risk Group 3. What would I expect this device to do? Well, it should produce the protein GAPDH, a well-characterized protein not associated with pathogenesis. In this case, an otherwise harmless organism equipped with this device is likely to be relatively safe, though the presence of a Risk Group 3 sequence suggests it deserves some extra scrutiny. On the other hand, if I were to do the exact same thing with a less well characterized gene from Mycobacterium tuberculosis, I would be unclear on what its function would be. Even if it had not yet been identified as a virulence factor, perhaps it is involved in virulence in a way that's not yet known. When you're dealing with less well characterized systems, it's always important to be cautious.
Evaluating context-specific risks can be challenging. Here are some things to consider: Is your organism hazardous? A harmless device inside of a pathogenic organism is likely to be harmful. Does your device use existing virulence factors? These are associated with, for example, immunosuppression, immuno-invasion, or colonization of a host. Does your device mimic the activity of a virulence factor? Say, if you were to use protein design to produce a novel protein that behaves similarly to an existing virulence factor. Does your device enable the dissemination of genetic material? Can a mutation of your device result in a dangerous organism? It is useful to subject your design to hypothetical failures and consider the consequences. Ask yourself, if any piece of a genetic device failed to function, what would happen? Finally, does your device present any novel risks? As the designer, you have both the expertise and the responsibility to consider potential risks that have not previously been considered. One way to analyze risk is with a risk matrix. On one axis you have the impact of an adverse event, and on the other you have its likelihood. So, for example, if you were to have a negligible impact that were remote or unlikely, that would be green and in those cases, it would probably be acceptable. On the other hand, if you had a minor impact that was likely or very likely, that would be yellow, suggesting that you may want to go back to the drawing board and attempt to mitigate the risk by changing your design. A severe impact that was likely or very likely would be red, completely unacceptable. This is not the only way to evaluate risk, but it's one that you might find useful.
Containment strategies aim to prevent the escape of an organism from its intended environment. For example, the use of dependent organisms. These could be organisms that are incapable of a necessary synthesis, like DH10b or del(DapD), or incapable of necessary transport, like del(TonB). These organisms require supplements, without which they will be unable to survive or proliferate. You can also use safeguard devices as a containment strategy. These would include induced lethality devices, or kill switches; gene flow barriers to prevent the dissemination of genetic material; and many others that are in development.
Lastly, let's consider the importance of communication. As a member of the synthetic biology community, it's your responsibility to publish and present your results to other members of that community. But you must also be a conscientious representative of the field to policymakers and members of the press. Lastly, engage with others, helping to inspire the next generation of synthetic biologists.
In summary, be aware of: the challenges to traditional models of biosafety, and the best practices for sharing genetic information and materials. Likewise, consider: how to evaluate and minimize risk in your projects, and your responsibilities as a member of the synthetic biology community.