Molecular Systems Biology | The Seven Stones

Contrasts: Craig Venter and NSABB on synthetic biology

 Craig Venter: On the verge of creating synthetic life

Two rather contrasting videos on synthetic biology this month. In the first videocast, released by TED, Craig Venter exposes his grand vision of synthetic genomics. He insists on the notion of ‘combinatorial genomics’, that will combine the power of large scale DNA synthesis (‘robots that can make a million chromosomes a day’) with a database of 20 million genes, ‘the design components of the future’. This approach, a pragmatic mixture of rational function-oriented design and empirical large-scale selection, is envisioned to prepare a modern ‘Cambrian explosion’ of new synthetic species. It is good to see Craig Venter laughing when announcing casually the ‘modest goal of replacing the entire petro-chemical industry’. In any case, Craig Venter appears to be more concerned that the technology may not develop sufficiently rapidly to match the urgency and scale of the major ecological and medical challenges faced by our planet than by potential threats represented by harmful biohacking and bioterror.

<img style=“float:right” alt=“webcast of the NSABB Meeting, Day 1” src=“” " width=“200” />The second video, admittedly less entertaining, is a recording of the recent deliberations of the National Science Advisory Board for Biosecurity (NSABB). In his presentation entitled ‘Assessing Biosecurity Concerns Related to Synthetic Biology’, David Relman presents some preliminary findings and recommendations of the Working Group on Synthetic Genomics (jump to 1hr:34min:37sec). It is interesting to see that no consensus definition of synthetic biology exists among the various practitioners of the field, who all use different blends of the typical bottom-up engineering approach assembling circuits from standard components and top-down strategy, based on the modifications of existing genomes. Beyond the lack of definition, the current ability to predict biological functions from sequence (eg virulence) remains very limited complicating the possibility of realistic risk assessment. Finally, the development of synthetic biology can be seen as an extension of the success of ‘kit-based’ molecular biology, which facilitates access of these technologies to groups outside the traditional Life Sciences communities and institutions, making the mission of oversight, outreach and eduction more challenging. David Relman also clearly emphasizes the importance of not discouraging the enthusiasm directed towards potentially beneficial research and applications by overzealous oversight and regulations.

The intersection between the two talks above was perhaps made when the question of virulence was raised (jump to 1hr:59min:35sec). The fraction of pathogenic agents is very small compared to the number of existing species, a point also made by Craig Venter, and the rate of appearance of new pathogens is low. The idea was then raised as whether it would be possible to roughly estimate the risk of creating synthetic pathogens by calculating the likelihood that the amount of natural recombination responsible for the emergence of new pathogens ‘in the wild’ could be matched by an equivalent amount of experimental recombination in the laboratory. In other words, is there any way to estimate the probability that new forms of virulence could emerge from the announced synthetic ‘Cambrian explosion’?


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    abc zyz said:

    You write an interesting piece about the contrasts between Venter and the technocrats at the National Science Advisory Board for Biosecurity meeting, neither I feel know what synthetic biology is, at least as it was founded over five years ago.

    Venter has his own particular view of what synthetic biology is and it is most definitely colored by his deep background in genomics. Anyone who comes from genomics and professes to be a synthetic biologist will naturally have an odd view of what synthetic biology is compared to the pioneers in the field. To get a real sense of what synthetic biology is, ask the young undergraduates from the iGEM teams, graduates and postdocs who are so excited by the opportunities for science and technology in this field. Unfortunately like all scientific revolutions, those who control the purse strings and who review grants for funding tend to be the old guard who will try to do one of two things, kill the field before it emerges, or as is happening here, subsume it and claim it their own.

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    Thomas said:

    Thanks for this comment, ‘abc zyz’. To be frank, it is not immediately apparent to me why a genomic view of synthetic biology should necessarily be considered as ‘odd’. If it provides a pragmatic approach to solve concrete problems, what is wrong with it?

    It is true that there are many different flavors to this field, and this was actually one of the main points made by David Relman in his talks at the NSABB: there is no consensus definition of what synthetic biology is. The question of ‘what is systems biology?’ is still not settled and it is not that surprising that the same question is now arising in synthetic biology.

    Personally, I tend to believe that the many variations on the theme of synthetic biology (‘combinatorial genomics-driven’, ‘standardized engineering-inspired’ or ‘molecular tinkering-based’, ‘bottom-up’, ‘top-down’, etc,…) are all valid in principle, as long as they advance science or lead to concrete applications. So, my take on this is that the field should be defined mainly by what it delivers and by its concrete achievements.

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    Drew Endy said:

    What is the fraction of all computer programs that are “pathogens” (i.e., computer viruses)? The fraction is very low. To focus on this fact would not be a good approach to computer security. Neither is it likely to be a good starting point for developing a strategy for biological security as it becomes easy to engineer biology.

    The fact of the matter is that the risk of creating an engineered biological pathogen that will cause harm to humans, the environment, or both, is above zero. Thus, we don’t need to estimate the exact risk to 5 (or even 2) significant digits. Instead, we need to prepare for a future in which engineered biological pathogens will be produced and released. Importantly, we can practice today by getting much better at dealing with the problem of emerging infectious diseases. How long did it take us to detect SARS? How long did it take us to isolate the virus? How long did it take us to sequence the genome? How long did it take us to develop a vaccine? How can we get much faster at each of these steps?

    Both Craig and David are constrained by their roles within a biosecurity framework that forces them to instinctively defend ongoing advances in biology and biotechnology, or risk an imagined political and funding firestorm. Although these roles are not intellectually impressive, it is an important service given the current environment. The real problem is that we (i.e., everybody) do not have a strategy for biosecurity that addresses synthetic biology (I’ll come back to the definition of synthetic biology below). Instead, we have a reactive biosecurity framework that is dominated by the shadow of the 2001 anthrax attacks on the US Congress, and that has resulted in the US spending ~$50,000,000,000 (so far) for activities such as classified BSL4 facilities, including at least one facilitiy at the same site that the US located a past offensive biological weapons program (i.e., Ft. Detrick).

    Meanwhile, the recent and ongoing popularization of the term synthetic biology can be traced to the entry of many new, formally trained engineers into the field of biological engineering, starting ~10 years ago, and really picking up steam ~5 years ago (more on this below). In contrast to earlier engineers moving into biology, we “synthetic biologists” did not decide to use our engineering skills and tools to model natural biological systems, or discover (invent) the origins of life. Instead, we have set out to rebuild the living world starting from as it exists today, so that we can help understand it (“sure, why not?”), but primarily so that we can better deploy biology as a technology for constructive purposes. Our activities are genuinely new, both politically and practically. We are fighting many battles, from editors and reviewers who do not understand that “making something easier” is valid engineering research, and that not every paper needs to “discover new biology” (what is really amazing to me is that many journals with the words “biotechnology” or “engineering” in their names suffer from this phenotype too; it leads me to wish for something like a Proceedings of the National Academy of Engineering, to complement the PNAS), to research colleagues in other fields who either (i) act as if they are being left behind or are not being properly acknowledged (e.g., synthetic chemists), or (ii) wonder endlessly about definitions, having succeeded in perpetually muddying other fields of work (e.g., systems biology). What’s unsurprising but ultimately not acceptable is that many of these same people foment confusion and ambiguity about what is actually happening in synthetic biology.

    Thankfully, there are many excellent primary sources of material that ground the field of synthetic biology as it exists today, and that also address issues such as biosecurity. Have you read all of them? For example, here’s one that might be worth a look!

    2003 US Govt Study on Synthetic Biology

    Endy et al.

    doi: 1721.1/38455

    As a second example, “Engineered Communications for Microbial Robotics,” published by Weiss & Knight in 2000, describes the engineering of LuxR-based cell-cell signaling; unlike the other early references cited in Serrano’s recent editorial on “synthetic biology” published in this very journal (doi:10.1038/msb4100202) , Weiss’s work has actually been directly and dramatically extended by many others; note that ease of reuse is one of the underlying features that synthetic biology is all about!

    As a third example, search out the seminal paper “Cellular Gate Technology” published by Knight and Sussman in 1997; this paper describes building genetic ring oscillators and so on, foreshadowing Elowitz’s great work by several years.

    The definition and understanding of synthetic biology matter greatly (just in case you missed it, sĭn-thĕt’ĭk bī-ŏl’ə-jē: an area of research combining engineering and biology that seeks to make biology easy to engineer). The problems that might be solved via biological technologies are real and are becoming more serious, and the issues (e.g., biological security, to name just one of many) require deep thought and strategy in order to be addressed. Get with it!

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    Kyle said:

    (just a thought as I’m not well enough read in the field)

    I think it is too soon for Synthetic Biology to reach its own vision. A system’s components cannot be effectively designed to perform specific tasks unless there is an understanding of how the components interact (half of E. coli’s predicted genes haven’t even been named yet, and studies in E. coli reveal increasingly complicated regulatory mechanisms). Synthetic Biology’s self-realization may be a long way off and will require a great deal of basic biology research first.

    Venter’s combinatorial SB may be the best bet at the moment. If you don’t have enough information to (nearly) guarantee that your hypothesis is right, just test a million hypotheses. This method will become more popular if the efficiency of synthesis and sequencing is really growing exponentially. But I’m not sure why it wouldn’t just follow the same trend as combinatorial drug design.