Kavli Futures Symposium Report
"The Merging of Bio and Nano: Toward Cyborg Cells"
Symposium Held June 11-15, 2007, Ilulissat, Greenland
Introduction
Synthetic biology and nanotechnology are two of today’s most powerful and versatile emerging technologies. With their common focus on events at a similar size scale – from a few to a few hundred nanometers – they also offer the potential for synergies that might achieve far more than either technology standing alone. Initiated and organized by Cees Dekker and Paul McEuen, who are affiliated with the Kavli Institute for Nanoscience at Delft and the Kavli Institute at Cornell for Nanoscience, respectively, this meeting was convened to explore such possibilities. In particular, it would ask whether a convergence of synthetic biology and nanotechnology might soon supply new forms of life: living cells that are either partially or wholly synthetic. How close are we to this goal? What are the major obstacles? What might we do with such entities? And what are the dangers and the ethical dilemmas?
Starting with these questions, the discussion extended to broader issues in science, technology and society. Among the topics raised were the problem of defining life, the potential benefits of nanotechnology to cell biology and other life sciences, and the technological challenges that lie ahead in fields such as energy and medicine.
The meeting ended with the drafting of a declaration – the Ilulissat Statement, attached as Appendix III. The Statement sums up the participant’s views on what needs to be done to bring about a convergence of nanotechnology and synthetic biology with maximum benefit to humanity and the planet.
Key terms
Nanotechnology, as used in this report, refers to the attempts to control and manipulate matter on scales ranging from a few nanometres – the size of individual large molecules – to several hundred nanometers, which approaches the size of small whole cells. The biological applications of nanotechnology were of particular interest to the Ilulissat conference. Some that have already been developed include the use of nanoparticles as fluorescent labels for fundamental studies in molecular and cell biology, and the nano-manipulation techniques for studying the properties of individual biomolecules. Scientists look to biology to provide more ideas and components that would lead to new nanotechnological devices and functions.
Synthetic biology is the synthesis of complex, biologically based (or inspired) systems that display functions that do not exist in nature. It applies knowledge from fields such as genetic engineering, protein engineering, metabolic engineering, DNA synthesis and systems biology to enable the design of biological systems (e.g. cells or cell components) in a rational and systematic way. Its potential applications range widely across scientific and engineering disciplines, from medicine. It might, for instance, lead to the engineering of organisms to supply new drugs, or to more efficient production of ethanol and hydrogen.
Themes of the meeting
Basic challenges in cell biology
To create synthetic biological systems, it is necessary first to understand fully how natural systems work. One needs to know how each enzyme, organelle and module in a cell works, and how these activities are coordinated in the whole organism. As conference participants noted, science is still far from reaching that level of knowledge. They saw the need for new techniques to probe and visualize cell processes over a range of length and time scales. Other questions identified at Ilullisat included:
• How important are thermal noise, fluctuations and stochastic variation in the way components function? (In engineering such things are commonly seen as problems; in biology, it may be that they are exploited to good effect.)
• How does one describe chemical reactivity when it takes place not in a dilute, homogenous solution but in an environment that is well organized on many scales?
• To what extent can biological processes be understood by looking at single molecules, and when is it necessary to consider the statistical behavior of populations, including the possibility of collective effects?
• How do nanometer-scale molecules build structures much larger than themselves? How are information flows managed to enable that?
• How reducible is biology? How much can its processes by explained by general principles of physics? As one participant put it, are the rules of the cell “local,” or are cells entirely governed by global principles analogous to those that govern thermodynamic equilibrium or the stable steady states of dynamical systems?
One point of debate was the question of how much fundamental understanding is needed in order to make practical advances. Some participants argued that it was necessary to have a good grasp of how individual biological components work before trying to understand their collective behaviour. Others said this was not necessary. As one of them said, “We should be capable of making cells before we understand them” (just as engineers were able to make suspension bridges without a theory of quantum gravity).
Exploring evolution
The meeting examined the role of evolution as one key to understanding the design of organisms. One line of inquiry dealt with the concept of a “fitness landscape,” an abstract, multi-dimensional space that encompasses the possible characteristics of on organism. It was suggested that micro- and nanofabrication technologies might enable researchers to create structures that house microorganisms in designed fitness landscapes where the stresses and the exchanges between populations are controlled. With such devices coupled to automated systems for genomic analysis of the cell populations, experiments could be conducted on evolution in real time. As one participant noted, such experiments run for several years might provide detailed hard data on evolutionary questions that are difficult to study in the wild.
Energy generation and conversion
Researchers are attempting to make fuels from biomass by using microorganisms to break down the complex, polymeric components of plant cells. However, plants have evolved a battery of defences against this process. Cellulose, the main component of plant cell walls, is already difficult for many organisms to digest, and the resinous ‘cement’ of plant cells, lignin, is even more resistant to degradation. The scientists at Ilulissat discussed the possible use of synthetic biology to overcome this problem by engineering metabolic pathways for digestion of lignocellulosic material. They heard a description of recent work on the engineering of Clostridium bacteria, combining the cellulose-busting properties of C. cellulolyticum (which makes glucose) with the ethanol/butanol-synthesizing capabilities of C. acetobutylicum (which cannot use cellulose. They also considered the possibility of engineering plants for easier digestion by removing lignin-making genes, and of extending the reach of synthetic biology to the production of fuels other than conventional biofuels (e.g. ethanol). They expressed interest, for instance, in exploiting the hydrogen-generating machinery of some organisms to make a zero-carbon fuel.
Cell-based chemical synthesis
The effort to make chemical fuels by re-engineering microorganisms is part of a more general strategy to use synthetic biology for chemical synthesis. The Ilulissat scientists discussed a number of initiatives in this area, including:
• Research to engineer microbes such as yeast for making the anti-malarial drug artemisinin. This is a natural product, found in an Asian shrub, but it is present in such small amounts that the cost of extracting it is prohibitive. A team led by Jay Keasling, (one of the Ilulissat participants, has made yeast that can generate artemisinic acid, the immediate precursor to artemisinin. It was suggested that the synthesis of drugs might best performed by “minimal organisms” designed from scratch to meet the stringent requirements of the process.
• The use of live organisms as miniature in vivo drug factories or doctors. (One example is a microbe that has been developed at the University of California at San Francisco to seek out tumor cells and inject them with a lethal drug). Addressing safety questions, one thread of the discussion focused on the use of bacterial viruses (phage) rather than human viruses or bacteria, since these should not be pathogenic or provoke an immune response.
• Using viruses to to synthesize new materials. A group led by Ilulissat participant Andrea Belcher has developed methods for coating virus particles with surface proteins that recognize and bind to specific inorganic materials, such as those used for semiconductors. This technique seeks to apply the selectivity and nanoscale precision of biological synthesis to the construction of new materials and devices. Other possibilities were raised for viral engineering, such as the use of viruses to transport encoded genetic “assembly instructions” for engineering new organisms, or the creation of viral templates with well defined sizes and shapes for the synthesis of inorganic nanostructures.
Personalized medicine
Ilulissat conferees discussed how nanotechnology might help match drugs to the patients who would benefit from them the most, with the least risk. One approach, being developed by Ilulissat participant Scott Fraser, is to use microscopic optical resonators (devices that respond to specific light-wave frequencies) to detect mRNA or protein molecules that indicate a patient’s sensitivity to particular drugs. It was suggested that such devices might reduce the culling of promising drug candidates that work safely and well, but only for people with a certain genetic profile.
Design of synthetic biology “parts” and platforms
In electronic and mechanical engineering, it is routine to design circuits and functions without the need to worry about the details of components. Will a similar standardization and abstraction emerge in biology, greatly simplifying the task of designing synthetic biological systems?
Ilulissat participants approached this topic from a number of angles. One was to consider the question of how design methods are themselves designed: Should they be based on ‘rational’ first principles, or should they should use an evolutionary approach to search the possible (and generally immense) design space? There was some consensus that the current understanding of biological systems is inadequate to make completely bottom-up design feasible, so that evolutionary methods will probably be indispensable to some degree. It was noted, however, that evolutionary designs can be very hard to reverse-engineer to figure out how or why they work.
Another line of inquiry concerned the nature of the system “platform” being designed. When a microorganism is redesigned to perform a non-natural functions, it can be embedded in a living or non-living system. One example of the latter, from the research or Ilulissat participant Ehud Shapiro, is “smart drugs” packaged in “logical envelopes” – analogous to computers – that receive information from their environment and process it to deduce an appropriate response. As for living platforms, the conferees examined the idea of a “minimal organism,” with the bare minimum of genes needed to retain viability. They discussed one candidate, explored at the Venter Institute, that might be pared down into a minimal organism. This is the bacteria Mycoplasma genitalium, which has just 485 protein-coding genes.
Making artificial cells and new life forms
Research on Mycoplasma also figured prominently in another area of discussion, about the possibilities of creating artificial cells or organisms. The participants generally agreed that anything warranting the genuine description of ‘artificial life’ is going to come first from a top-down strategy rather than bottom-up: by reconstituting existing cells rather than making them from scratch. As an example of this, they heard about the Venter Institute’s latest work with Mycoplasma “genome transplants,” a process in which one species of the bacteria receives an entirely new genome from a different species. The recipient cells are then able to “boot up” with the new genome and show phenotypic behavior characteristic of the donor species.
The conferees also learned more about the work of Ilulissat participant Petra Schwille, who is synthesizing microenvironments – liquid droplets – that contain the molecules needed to encode and transcribe genetic information. These are created in a microfluidic system, and might ultimately contain elements such as membrane channels and surface recognition groups to allow binding to real cells or assembly into artificial “tissues.”
Complexity and computation
Even the simplest living organisms are enormously complex. One major challenge of synthetic biology is to know just how much of that complexity really needs to be reproduced to create artificial life. Ilulissat participants discussed at least two approaches to this issue. One, embodied in the work of conference participant Bob Hazen and his Harvard colleague Jack Szostak, is to identify how much of the information in a complex system is directed towards attaining its functionality. This method might enable one to estimate the minimum amount of information /complexity required to achieve a given function – or conversely, what functionality can and can’t be obtained from a given complex system.
Another aspect of complexity -- robustness – is the subject of research by Ilulissat participant Hiroaki Kitano. Conferees learned about his attempts to characterize gene networks in terms of the contributions that each of the components makes to the overall robustness (against, in this case, over-expression of genes).
Social and policy concerns
As the Ilulissat participants noted in their concluding statement (see Appendix III), the coming convergence of nanotechnology and synthetic biology has the potential to produce enormous benefits by helping to the “daunting problems of climate change, energy, health, and water resources." It also carries risks, and these were a signficant topic of discussion at the conference. As one participant pointed out, the rapid progress in synthetic biology has lowered the cost of doing harm as well as doing good: The price of an amount of DNA equivalent to the genome of the Ebola virus is about the same as a Volkswagen car, while in three years it will cost about as much as a laptop computer, and in 5-7 years, about that of an iPod.
In their concluding Statement, the scientists at Ilullisat expressed a hope for “protective measures against accidents and abuses of synthetic biology," as well as "a system of best practices … to foster positive uses of the technology and suppress negative ones." One participant proposed setting up an organized professional body that is able to deal with questions of ethics and responsibilities in this area. These issues now are considered largely by isolated groups or individuals on an ad hoc basis.
Intellectual property protection was also a key concern for the Ilulissat group. One of the scientists argued that excessive patenting in the pharmaceutical industry has had an inhibitory effect on biotechnology. For the production of pharmaceuticals from engineered organisms, and probably for synthetic biology in general, he proposed that the patenting be carried out at the high levels (whole organisms, for instance), not at the level of individual components.
Summary
The Ilulissat meeting was organized to stimulate discussions, not come up with definitive answers. But the discussions did sound common themes such as these:
• Nanotechnology and synthetic biology have plenty to offer one another. At this stage, nano is primarily a fertile source of new techniques for probing the biomolecular world. But it might ultimately provide new parts and suggest design principles. Molecular biology is already a source of inspiration and components for nanoscience, and may in the future offer ways of organizing matter and information flows in a hierarchical manner over many length scales.
• There is still much that we do not know about how cells work, in terms of the logic, the spatial and temporal organization, the design principles, or even the details of how many individual molecular components function.
• As a consequence, the idea of de novo design of an ‘artificial living cell’ is probably not practical.
• By the same token, we still have much to learn about evolution: about what determines the behavior and history of groups of organisms, and how evolution has shaped organismal design.
• The nature of the environment and context is crucial to any discussion about what constitutes life.
• There are roles for both rational and evolutionary approaches to design of complex systems, although it is hard to generalize about their relative roles.
• Energy and medicine will be two of the key drivers toward a convergence of nanotechnology and synthetic biology. The creation of new materials is also an important (and often related) objective.
For the official presentation of the conferees’ views on the future of synthetic biology and nanotechnology, see “The Ilulissat Statement,” Appendix III.
Appendix I
Appendix II
Appendix III
Appendix IV
Appendix V
