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Intervention by Denise Caruso Read Intervention by Denise Caruso, Executive Director of the Hybrid Vigor Silver Award Winner, 2007 Independent Publisher Book Awards; Best Business Books 2007, Strategy+Business Magazine

UNCERTAINTY IS NOT A FACTOR IN
SYNTHETIC BIOLOGY — IT’S THE FACTOR

by ~ November 20, 2008.
Permalink | Filed under: 21st Century Risk, Hybrid Vigor, Planetary Life, Policy and Decisions.

Earlier this week, I got a phone call from Steve Aldrich and Jim Newcomb, respectively CEO and director of research for Bio Economic Research Associates, a private research and advisory firm.

They’d read my paper on risk and synthetic biology and thought my characterization of their report on synthetic biology, “Genome Synthesis and Design Futures: Implications for the U.S. Economy,” was unfair.

The larger issue that our disagreement is based on — that is, how to pay proper fealty to scientific uncertainty — is at the core of my discontent with how technology innovations are assessed for risk and benefit.

So I told them I would write about our disagreement here. This way, they have an opportunity to respond, and maybe we can get a discussion going on the subject.

Here is what I wrote:

Of the most concern in the context of risk and governance are the reports that uncritically support synthetic biology, as they encourage development and commercial release with little or no acknowledgment of the degree of scientific uncertainty that surrounds the endeavor. A 174-page report on synthetic biology published by Bio-Economic Research Associates in 2007 and funded by the Department of Energy (which itself has invested heavily in synthetic biology research), contained but a single, three-quarter-page discussion of the limitations of the engineering paradigm as applied to living systems. Giving such short shrift to a topic that is still under deep consideration in the broader scientific community lends an air of certainty to a highly uncertain endeavor. Such under-representation has real significance from the perspective of investment and economic risk, as well as from that of health and the environment.

[Italics added by me; they aren’t in the paper.]

Aldrich and Newcomb said it was “flatly unfair” to say their report doesn’t touch those issues, and objected to the implication that they were “apologists” for the paradigm of synthetic biology.

They mention the report’s final chapter, “Scenarios for the Future,” about how the synthetic biology future might play out. One of the “major uncertainties” (a key scenario element) is posed as, “How quickly will biological engineering advance?” And they note that in one of these scenarios, “technical challenges impede applications” outside the lab.

But this is precisely my issue. The idea that “technical challenges” are the only issues synthetic biology faces today is flat wrong. The engineering paradigm that synthetic bio is based on — that genetic components are like electronic circuits, with independent, clearly defined functions — simply does not apply to living systems.

Geneticists have known for years that genes and other biological components — the same components bio-engineers are using to snap together their synthetic creations — do not operate independently, like electronic circuits. They have long observed that in addition to whatever their primary function might seem to be, these components appear to operate in some kind of a network, that they interact and overlap with each other in ways that are not yet understood at all.

(The ENCODE study was most recent public acknowledgment of this fact.)

Yet the field of synthetic biology is pretending as though this gaping chasm of knowledge — a chasm that pretty much negates its entire raison d’etre — has no impact whatever upon the viability of its work. I’ve never known a synthetic biologist to proactively address the issue. If confronted with it directly, the most I’ve heard is the equivalent of, “Yes, it’s complicated. But we’ll figure it out.”

At the same time, investors are sinking hundreds of millions of dollars into developing products based on a fundamentally flawed scientific premise masquerading as a technology with predictable, “engineered” outcomes.

OK, back to Aldrich and Newcomb. In fact, I do not think they are apologists for synthetic biology. As far as I know they have no direct investments or interests in any synthetic biology companies. And they explicitly state at the beginning of the report that they did not intend to address issues of safety, unintended consequences, or ethical, legal and social questions.

Still, there is an inside the tent, it’s-a-done-deal orientation to the report that is discomfiting under such highly uncertain circumstances.

With its sections on “Enabling Technology,” “Economic Dimensions of the Biological Engineering Revolution,” and discussions of “Applications of Genome Synthesis and Design” that specifically target the energy, chemical and vaccine industries — and whether it means to or not — the report presents a de facto case that synthetic biology is already a viable investment.

And while it concurs that there may be some technical speed bumps, it simply does not acknowledge the deep, fundamental scientific uncertainties about the very premise on which synthetic biology is based.

From my perspective, this lack of acknowledgment is misleading to investors and anyone else who is trying to understand what a synthetic biology future might mean.

So, all of that to say:  Respectfully, I stand by my story.

But as I started out saying, I do think that the much bigger, critical issue here is about uncertainty itself, and that concern goes beyond any individual report or technology, particularly as private investment is driving science-based innovations to market much more quickly than ever before.

As a society, we have got to find a way to talk more honestly about and have a strategy to anticipate the impact of uncertainty on innovation. That’s the only way regulators will be able to safely bring new technologies like synthetic biology to market without endangering either investors or the public’s health and welfare.

This is the driving force behind much of the work and thinking that I’m doing now, and I’ll be posting more about it as time goes on.

3 Responses to UNCERTAINTY IS NOT A FACTOR IN
SYNTHETIC BIOLOGY — IT’S THE FACTOR

  1. Steve Aldrich

    Denise:

    I have enjoyed and admired your work as a journalist exploring deeper questions about the potential risks of new technologies, and thanks for taking our call the other day. I enjoyed the conversation.

    Just to followup, I believe your characterization of our report is just plain wrong. Here’s my evidence.

    In your blog posting you write,

    “And while it [Genome Synthesis and Design Futures] concurs that there may be some technical speed bumps, it simply does not acknowledge the deep, fundamental scientific uncertainties about the very premise on which synthetic biology is based. [my emphasis] From my perspective, this lack of acknowledgment is misleading to investors and anyone else who is trying to understand what a synthetic biology future might mean.”

    On page 40 and 41 of “Genome Synthesis and Design Futures” we write,

    “There are strong reasons to believe that the revolution in biological engineering that is now emerging will advance much faster than previous “technology revolutions,” including the high tech revolution. To begin with, the rapid advance of scientific insight and capabilities in this emerging field is powerfully reinforced by the convergence of developments in the interrelated fields of information technology and bioinformatics, genomics, proteomics, metabolomics, systems biology, and simulation and design software. Moreover, biological engineering is being jumpstarted by the transfer of learning from electrical engineering about how to make systems that are more adapted to combinatorial engineering.”

    “On the other hand, biological systems are formidably complex. The integrated circuit chip is a pinnacle of abstraction, specialization, and concentration. Many major functions associated with the semiconductor are external to it in space and time, including energy supply, tools for fabrication, materials flows, waste streams from production processes, and degradation or disposal. By comparison, biological systems are typically highly integrated, containing construction blueprints, tools for fabrication, complex self-sustaining cycles for energy, materials, and waste disposal, and, perhaps most significantly, the ability to change and renew themselves through evolution—all within a single integrated system.”

    “The extraordinary complexity of biological systems has been a formidable obstacle to comprehensive analysis and description of the function of even relatively simple biological organisms. It has been nearly 40 years since Francis Crick and Sydney Brenner, in 1967, called for “the complete solution of E. coli.”15 Discovered in 1885, the bacteria had been extensively studied by scientists since the 1940s in part because of the ease with which it could be cultured in laboratories. Crick and Brenner were calling for a comprehensive analysis and modeling of the genetic and biochemical functioning of the organism. The genome of E. coli, with 4,288 genes, was published in 1997, and has since been intensively studied. Yet an E. coli cell contains approximately 60 million molecules, and the task of comprehensively simulating every molecule in space and time remains beyond the grasp of current capabilities.”16

    “In order to simplify the task, several research teams have attempted to develop simplified or “minimal” strains of E. coli, based on reduced or “stripped down” genomes. For example, a research team led by Dr. Fredrick Blattner at the University of Wisconsin, Madison, developed a strain of E. coli with a genome that is 15% smaller than conventional laboratory strains. Using synthetic biology methods, the original genome was “rationally designed by making a series of precise deletions, which included the elimination of non-essential genes, recombinogenic or mobile DNA, and cryptic, virulent genes.”1 7 Drug and vaccine manufacturers are optimistic that the simplified E. coli could provide a better platform for drug and vaccine production. Anthony Green, a scientist at Puresyn, Inc., a Pennsylvania pharmaceutical manufacturer, says that the simplified organism developed by Blattner’s team is “like turning a 6-cylinder engine into a 4-cylinder, without sacrificing quality, but giving it better gas mileage.”18

    Blattner’s E. coli strain is patented and licensed by the University of Wisconsin to Blattner’s company, where it is being developed and marketed under the name “Clean Genome® E. coli.” Other research teams are working to develop even simpler versions of E. coli with as few as 1,000 genes, less than one-fourth of the original total. Notwithstanding this progress, some researchers, including Dr. Michael Ellison, a biologist at the University of Alberta who is engaged in one such effort , believe that even considering the ongoing advance of computing power, it will be 5–10 years before the most powerful computers might be able to simulate the operation of a simplified E. coli. 19

    Not surprisingly, opinions among scientists working in synthetic biology are diverse and formative with respect to the question of how hard it will be to achieve the goals of synthetic biology. Francis Arnold, Professor of Chemical Engineering and Biochemistry at California Institute of Technology and a member of the scientific advisory board for Amyris Biotechnologies, told the New York Times “There is no such thing as a standard component, because even a standard component works differently depending on the environment. The expectation that you can type in a sequence and predict what a circuit will do is far from reality and always will be.”20 A few months later, speaking at Synthetic Biology 2.0, a conference of leading scientists in the field held at the University of California, Berkeley, Arnold restated her views, at least in part, acknowledging the work of the synthetic biology community to pioneer the development of standardized parts. Still, there remains a tension between the perspectives of biologists like Arnold, whose orientations and approaches are more systems-based, and engineers such as Endy and Knight, whose approach aligns more closely with the parts-oriented combinatorial methods of software and electrical engineering.

    Synthetic biology practitioners such as Berkeley’s Jay Keasling, whose lab developed the metabolic pathway for the production of artemisinic acid in yeast cells, work at the interface between the world of abstract design and the often frustratingly complex world of cellular biology. According to Keasling, the cost of collecting parts from Nature or from the MIT Biobricks collection is relatively low; the real cost is tinkering with the parts so that they actually work together.21 In Keasling’s experience, none of the parts works “as advertised,” and there is no “manual” to consult to understand them better.

    Still, Keasling’s team was able to successfully reengineer the artemisinic acid pathway originally devised in E. coli to adapt it to yeast cells within less than 18 months. Amyris Technologies, a start-up company that Keasling helped to found, is hopeful that the experience gained from engineering the artemisinin pathway will pave the way for the development of other chemical pathways among the large class of natural chemicals to which artemisinin belongs, known as isoprenoids.

    On balance, while there are reasons for optimism that biological engineering could evolve quickly over the next decade, the future remains clouded with uncertainty. One key factor will be the degree to which systems composed of interoperable biological parts can actually be assembled without encountering complex interactive effects and feedbacks among the components.” [my emphasis]

    Those who carefully read our report – which is freely available through our website http://www.bio-era.net — should make note of our careful efforts to set up this question in Chapters 2 and 3. Also note the call-out boxes on “Modular by Nature”, page 43, and the “Limitations of the Engineering Paradigm as Applied to Living Systems” page 45, for additional examples of the authors raising the issue of the appropriateness of the engineering paradigm posited by synthetic biologists. Other references are sprinkled throughout the book.

    While we certainly did raise the question from several different perspectives, we never assumed we knew the answer. Some — perhaps you Denise — may know the answer, but we do not, and we had the good sense to openly admit that, and make that admission both transparent and central to our considerations regarding the future. Our approach was to offer the most honest and even-handed analysis of the alternative answers we could muster, based on the best available and carefully footnoted evidence we could find at the time. (It’s worth noting that the report was published almost two years ago now.) That is the job we signed up to do – and that’s what we did.

    What is unfair (and offensive, frankly) is your repeated statement that our report “simply does not acknowledge the deep, fundamental scientific uncertainties about the very premise on which synthetic biology is based. “

    As I have shown above, simply reading the report proves that statement to be false. We explicitly treat the question of whether the engineering paradigm animating synthetic biology proves workable or not as a major uncertainty in the scenarios of Section 5. And we set up that decision carefully, throughout the earlier chapters. If we were giving “investors in synthetic biology” advice, (which we certainly were not intending to do through the report), they would surely have been terrified by our scenarios – and could hardly claim that we failed to alert them to the risks of the paradigm failing in multiple ways. That would assume of course, that they had read the full report – and not just scanned the table of contents.

    Denise, I don’t think you owe the authors any apologies because of your opinions, which are your own, and to which you are entirely entitled. But I do think one’s in order about your misstatement of the facts. The statement of yours cited at the top of this entry is simply false.

    Steve Aldrich
    President
    Bio Economic Research Associates

    P.S. Jim Newcomb’s title is Managing Director of Research — not Director. He is the person who oversaw and managed the creation and authorship of the report. He is also a full and equal partner in bio-era. My title is President & CEO because somebody has to impress our vendors.

  2. Denise Caruso

    Thanks, Steve. I read the report pretty thoroughly, but I will try and find the time to go through it again before I respond to this.

    And for those who are interested in reading the report for yourselves, you can download the PDF, after providing Bio-ERA with some information, at http://www.bio-era.net/research/GenomePurchaseForm.html.

  3. Christopher Brown

    Even though there is much we as people do not understand about the effects of genetic engineering on an organism, I feel that a pharmaceutical-style approach would be better than an electrical engineering-style approach, that is, we should understand basic function of genes, splice them together, and see the results in large numbers, as opposed to the idea that we must completely understand the effect of what we are doing before doing it.

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