Synthetic Biology – Big promises backed by bad theory

Synthetic biology is the newest purported cure-all technology for remedying our social, environmental, and public health ills. As many prominent synthetic biologists proclaimed in 2007, the world “face[s] daunting problems of climate change, energy, health, and water resources. Synthetic biology offers solutions to these issues…Fifty years from now, synthetic biology will be as pervasive and transformative as is electronics today.”

Bold claims aside, the basic assumption behind synthetic biology—that organismal complexity can be remolded with predictable outcomes using simplistic engineering tools and standardized parts—may divert scientific research and funding away from programs more beneficial to the advancement of science and the public good. In addition, the undeniable power of the technology to alter living systems also contains potential for harm.

Synthetic biology is a collection of techniques and agendas (both research and business) that includes:

Genome-driven cell engineering: the substitution of chemically synthesized DNA or DNA analogues for their natural counterparts in order to change cell behavior and/or produce novel products;DNA-based device construction: the construction of DNA sequences that encode protein or RNA molecules that assemble into complex entities with previously defined or novel functions; andProtocell creation: attempts to define and construct basic living systems from minimal sets of molecules.ii

The field’s implicit and sometimes explicit view of cells and multicellular organisms is that they are devices that implement sets of defined tasks or functions, or if they are not inherently so, they can be engineered to fit this description.iii To quote the synthetic biologist Drew Endy, the goal is “to help make biology easy to engineer.”iv Synthetic biologists view the world through the metaphor of “biology-as-machine,” and as such believe that DNA is the “code” that, once inserted into a “chassis” tells the cellular “computer” how to function.

Genome-driven cell engineering deliberately ignores many of the features of cells and organisms that have emerged from the broad area of systems biology (see below), including recognition of nonlinear responses to small internal or external variations, causality at multiple spatial and temporal scales, many-to-many mapping between genotypes and phenotypes, and the emerging field of epigenomics, which looks at how DNA interacts with its cellular and external environment.

A systematic understanding of the genotype-phenotype relationship is scorned in favor of industrialized natural selection. One highly touted strategy involves mass production of billions of variant E. coli genomes followed by screening for favorable phenotypes.v

Device Construction

DNA-based device construction propounds an alternative, marginally less simplistic view of biological systems, asserted with equal assurance to the genetic program idea though clearly inconsistent with it. This method seeks to produce biochemical-genetic circuits that constitute “standard biological parts” or “BioBricks,”vi molecular Lego blocks that can be put together to build new life forms with desired properties.

The field’s Registry of Standard Biological Parts exemplifies the difficulties of implementing this program in the face of complexities of even the simplest living organisms. Whereas the Registry promises “a collection of genetic parts that can be mixed and matched to build synthetic biology devices and systems,”vii presenters at a synthetic biology meeting in July 2010 concluded that, of the 13,413 items then listed in the Registry, 11,084 did not perform as advertised.viii

DNA-based device construction nonetheless capitalizes on and has contributed to the burgeoning field of systems biology, which works not only with genes, but also the physics and chemical dynamics of interacting gene products and cells on multiple spatial and temporal scales.ix Our best understanding of how these systems work comes from mathematical and computational models.

Even so, the results from these models seem to indicate that “partition[ing] of a network into small modules…could in some cases be misleading, as the behavior of these modules is affected to a large extent by the rest of the network in which they are embedded.”x In fact, simple genetic networks with minuscule changes can give rise to qualitatively different or even opposite effects.xi Furthermore, many proteins change their structure and function depending on the context.xii

The major conceptual deficiency of synthetic biology, however, arises from its side-stepping of the evolutionary history of all present-day organisms (e.g., those that genome-driven cell engineering seeks to reprogram and DNA-based device construction hopes to embellish). This pertains even to much work in the scientifically most fundamental branch of the field, protocell creation, which seeks to construct the minimal units of life.

When the original, ancient protocells arose more than 3 billion years ago from nonliving components, they most likely contained no DNA, RNA, protein, or membrane-forming lipid (i.e., water-insoluble) molecules; different molecules provided the material substratum for ancient life.xiii,xiv Protocells made from modern biomolecules, however “basic” they may appear, provide little insight into life’s origins.

When it comes to the more practically and commercially driven branches of the field described in this article, there is little acknowledgment that genomes of present-day cells are overwritten and revised records of the billions of years of evolution since DNA became the primary genetic material. Fundamental cellular mechanisms are therefore impossible to decipher by simply reading (or writing) any modern organism’s DNA sequence.

Risk Assessment

While the science behind synthetic biology rests on questionable theory, its potential to alter living systems may cause real harm. Unfortunately these risks have yet to be properly studied. According to an article on avoiding a “synthetic biology disaster” published in Nature, “no one yet understands the risks that synthetic organisms pose to the environment, what kinds of information are needed to support rigorous assessments, or who should collect such data.”xv

A study conducted by the Woodrow Wilson International Center for Scholars found that of the $430 million spent by the U.S. government on synthetic biology between 2005 and 2010, no projects were dedicated to environmental risk assessments, either from the accidental or intentional release of synthetic organisms into the environment.xvi

The U.S. Presidential Commission for the Study of Bioethical Issues stated in its 2010 report on synthetic biology that “responsible science should reject the technological imperative: the mere fact that something new can be done does not mean that it ought to be done. The history of science here and abroad is sadly full of examples of intellectual freedom exercised without responsibility that resulted in appalling affronts to vulnerable populations, the environment, and the ideals of the profession of science itself.”xvii

Rejection of this technological imperative and recognition of synthetic biology’s inherent limitations and risks requires the use of precaution moving forward.

The recently published Principles for the Oversight of Synthetic Biology,xviii endorsed by 113 civil society organizations from around the world, has called for a moratorium on the release and commercial use of synthetic organisms until government bodies, with full participation of the public, have:

Developed a research agenda guided by the public interest;Ensured that alternative approaches to synthetic biology applications have fully been considered;Conducted full and inclusive assessments of the implications of this technology, including but not limited to devising a comprehensive means of assessing the human health, environmental, and socio-economic impacts of synthetic biology and preventing harms where they are present; and,Developed national and international oversight and security mechanisms equipped to keep pace with the risks as synthetic biology technologies develop.

Until such time, it is ill-advised to move ahead with synthetic biology anywhere outside the laboratory.

For a different take on synthetic biology, click here.

Eric Hoffman ([email protected]) is food & technology campaigner for Friends of the Earth. Stuart Newman, Ph.D., is professor of cell biology and anatomy at New York Medical College.

Citations:
i. The Ilulissat Statement. June 2007. <http://www.research.cornell.edu/KIC/images/pdfs/ ilulissat_statement.pdf>.
ii. O’Malley, M.A., A. Powell, J.F. Davies, and J. Calvert. 2008. Knowledge-making distinctions in synthetic biology. Bioessays 30 (1): 57_65.
iii. Ball, P. 2004. Synthetic Biology: Starting from scratch. Nature 431 (7009): 624-626. See quote of Tom Knight, a senior computer scientist in the MIT School of Engineering and an originator of the BioBrick notion as stating, “an alternative to understanding complexity is to get rid of it.”
iv. See: http://openwetware.org/wiki/Endy:Research#Synthetic_Biology
v. Bohannon, J. “The Life Hacker.” Science 333, no. 6047 (2011): 1236-7.
vi. A trademarked coinage of the BioBricks Foundation: http://biobricks.org/
vii. See: http://partsregistry.org/Main_Page
viii. Kean, S. 2011. A lab of their own. Science 333 (6047): 1240_1241.
ix. Newman, S.A. 2003. The fall and rise of systems biology. Genewatch. 16 (4): 8_12.
x. Isalan, M., C. Lemerle, K. Michalodimitrakis, C. Horn, P. Beltrao, E. Raineri, M. Garriga-Canut, and L. Serrano. 2008. Evolvability and hierarchy in rewired bacterial gene networks. Nature 452 (7189): 840_845.
xi. Isalan, M. 2009. Gene networks and liar paradoxes. Bioessays 31 (10): 1110_1115.
xii. Uversky, V.N. 2011. Multitude of binding modes attainable by intrinsically disordered proteins: A portrait gallery of disorder-based complexes. Chemical Society Reviews 40 (3): 1623_1634.
xiii. Budin, I. and J.W. Szostak. 2010. Expanding roles for diverse physical phenomena during the origin of life. Annual Review of Biophysics 39: 245_263.
xiv. Deamer, D. and A.L. Weber. 2010. Bioenergetics and life’s origins. Cold Spring Harbor Perspectives in Biology 2 (2): a004929.
xv. Dana, Genya V., Todd Kuiken, David Rejeski, and Allison A. Snow. “Four Steps to Avoid a Synthetic-biology Disaster.” Nature 483 (2012): 29
xvi. Trends in Synthetic Biology Research Funding in the United States and Europe. Woodrow Wilson International Center for Scholars’ Synthetic Biology Project, June 2010.http://www.synbioproject.org/process/assets/files/6420/final_synbio_funding_web2.pdf.
xvii. Presidential Commission for the Study of Bioethical Issues. 2010. New Directions: The Ethics of Synthetic Biology and Emerging Technologies, December 2010, Washington, D.C.
xviii. “Global Coalition Calls for Oversight of Synthetic Biology.” Friends of the Earth U.S., 13 Mar. 2012. Web. </news/blog/2012-03-global-coalition-calls-oversight-synthetic-biology>. Full report found at: http://bit.ly/GQC7zQ