Build a Synthetic Self-Replicator

FOCUS GROUP DESCRIPTION

Background

Long a fascination of science fiction writers and space exploration visionaries, nanomachines that can replicate themselves are already here: we have an existence proof on Earth in complex living systems, such as one-celled (and even more complex many-celled) organisms. Other “bionanomachines”—viruses—are able to reproduce themselves through the use of cell machinery external to themselves. Creating synthetic self-replicators would greatly scale up production of nanomachines from the atomic and molecular scale to the macroworld, as the process of self-replication allows for exponential growth. Your task is to propose a scientific plan for the design and creation of a simplified synthetic self-replicating nanomachine, using a replication method either completely self-contained, as in a cell, or requiring the use of external machinery, such as by a virus.

The Problem

All cells on earth appear to be built according to the same molecular plan, using evolved molecular self-replication:



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The National Academies Keck Futures Initiative Designing Nanostructures at the Interface Between Biomedical and Physical Systems: Conference Focus Group Summaries Build a Synthetic Self-Replicator FOCUS GROUP DESCRIPTION Background Long a fascination of science fiction writers and space exploration visionaries, nanomachines that can replicate themselves are already here: we have an existence proof on Earth in complex living systems, such as one-celled (and even more complex many-celled) organisms. Other “bionanomachines”—viruses—are able to reproduce themselves through the use of cell machinery external to themselves. Creating synthetic self-replicators would greatly scale up production of nanomachines from the atomic and molecular scale to the macroworld, as the process of self-replication allows for exponential growth. Your task is to propose a scientific plan for the design and creation of a simplified synthetic self-replicating nanomachine, using a replication method either completely self-contained, as in a cell, or requiring the use of external machinery, such as by a virus. The Problem All cells on earth appear to be built according to the same molecular plan, using evolved molecular self-replication:

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The National Academies Keck Futures Initiative Designing Nanostructures at the Interface Between Biomedical and Physical Systems: Conference Focus Group Summaries Ribosomes are molecular assemblers working from stored information. DNA is the information storage medium, directing the assembly of other parts. DNA polymerase duplicates the information storage medium. Thousands of enzymes convert available raw materials to building blocks required for the assembler and duplicator. The cell provides the following required infrastructure: The lipid cell membrane serves to define the body of the cell. The membrane signaling and transport proteins serve to allow for communication, energy, and raw material transport to and from the external environment. Complex machinery exists to allow for reproduction by binary fission. Various enzymes exist for regulation and error correction of cell processes. Current estimates (Ref 1) of the minimal number of DNA genes needed to create a living organism modeled after the modern cell machinery above are in the range of 250-350; however, this design is limited by the process of evolution. Can we design a more efficient and simpler self-replicator? For example, it is believed (Ref 2) that primordial life was based on RNA, and there are attempts to create RNA ribozymes in the lab (Refs 1, 2) as well as a major advance in understanding of ancient RNA processes that still exist in modern organisms (Ref 3). Another possibility would be to create stable alternatives to DNA and RNA, such as synthetic short peptide chains that can be more robust (Ref 1) for information storage and control. Yet another possibility is to create self-replicating DNA objects using synthetic DNA structures as engineering materials akin to viruses, requiring access to external machinery for replication (Ref 4). Current cell machinery is limited to water environments and thus a limited temperature range, in which thermal statistical motion and a diffusion-to-capture paradigm occurs for most functional tasks. Larger and more specialized tasks are carried out by machine-phase assemblies. Could we design self-replicators that evolve and grow in environments without water? DNA, RNA, and most proteins have limited lifetimes in cells due

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The National Academies Keck Futures Initiative Designing Nanostructures at the Interface Between Biomedical and Physical Systems: Conference Focus Group Summaries to degradation by nucleases and denaturization (Ref 5). Is it possible to create more robust and longer lived replicators? What are the trade-offs? The measured mutation rate in bacterial cells is 1 nucleotide in 109 nucleotide polymerization events. What level and kinds of transcription and replication error rate and error correction processes are needed to sustain self-replicating nanomachines? (Ref 6) Although transcription errors can be fatal, some types of transcription errors, along with gene duplication and complex gene networks, can help an organism evolve in a changing environment (Ref 7). Self-replicating nanomachines would have many positive uses for society, but their possible existence in the near future also raises many concerns of “gray goo” either inadvertently or purposefully being unleashed on the environment with unforeseen possible grave consequences. What kind of ethical controls should be put in place over their creation and use? Initial References 1. Goodsell, D, Bionanotechnology—Lessons from Nature. Wiley-Liss—Chapter on Self-Replication (Hoboken, 2004 ) ISBN 0-471-41719-X. 2. Zimmer, C., What Came Before DNA?. Discover June 2004. 25(6):34-41. 3. Novina, C., Sharp, P., The RNAi Revolution. Nature, 8 July 2004. 430:61-164. Cech, T., RNA finds a Simpler Way. Nature, 18 March 2004. 428:263-264. 4. Seeman, N., Nanotechnology and the Double Helix. Scientific American, 6 June 2004. 290: 65-75. Also see Viruses: Structure, Function and Uses, pp. 191-204 of Ref 6. 5. Henry, C., High Hopes for RNA Interference. Chemical and Engineering News, Dec. 22, 2003. 81(51):32-36. 6. Lodish, Berk, Zipursky, Matsudaira, Baltimore, Darnell, Nuclear Control of Cellular Activity, Molecular Cell Biology (Chapters 9-14). W. H. Freeman and Co. (New York, NY 2000). 7. Bergman, A., Siegal, M., Evolutionary capacitance as a general feature of complex gene networks. Nature, July 2003. 424:549-552. Also for a discussion of ageing mechanisms in Eukaryotic cells, damage due to ATP and oxidants, DNA mutation and repair mechanisms see Dying Before Their Time—Studies of prematurely old mice hint that DNA mutations underlie aging, J. Travis, Science News, July 10, 2004 166:26-28. FOCUS GROUP SUMMARY Summary written by: Kevin Bullis, Graduate Student, Science Writing Program, Massachusetts Institute of Technology

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The National Academies Keck Futures Initiative Designing Nanostructures at the Interface Between Biomedical and Physical Systems: Conference Focus Group Summaries Focus group members: Ronald Breslow, Professor, Department of Chemistry, Columbia University Kevin Bullis, Graduate Student, Science Writing Program, Massachusetts Institute of Technology Peter Burke, Assistant Professor, Department of Biomedical Engineering, University of California, Irvine Sharon Glotzer, Associate Professor, Department of Chemical Engineering, University of Michigan Jan Liphardt, Assistant Professor, Department of Physics, University of California, Berkeley Maria Pelligrini, Program Director, W. M. Keck Foundation Alan Porter, Evaluation Coordinating Consultant, The National Academies Keck Futures Initiative, Georgia Institute of Technology Suzie Pun, Assistant Professor, Department of Bioengineering, University of Washington Meera Sitharam, Associate Professor, Department of Computer and Information Science and Engineering, University of Florida Erik Winfree, Assistant Professor, Computer Science and Computation Neural Systems, California Institute of Technology Bernard Yurke, Optical Physics Research Department, Bell Labs Summary Focus Group 2 met to discuss how scientists might develop synthetic self-replicators, devices that can make copies of themselves. These devices could have many valuable applications. Substances made of microscopic self-replicators could heal themselves by producing replacements for damaged parts. For example, molecular scale self-replicators could combine to form self-maintaining paint or spacecraft skins that can repair damage caused by space debris. In addition to replacing damaged parts, self-replicators can scale up production exponentially, as each new product is at the same time a new factory for more products. This could be a solution for accurately and inexpensively producing useful quantities of novel nanoscale materials. While technological applications have caught the attention of many, including science fiction writers, researchers are also excited about potential non-technological payoffs for research into self-replicators. Building

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The National Academies Keck Futures Initiative Designing Nanostructures at the Interface Between Biomedical and Physical Systems: Conference Focus Group Summaries our own self-replicators could give us insight into the origins and mechanisms of existing self-replicators, ranging from bacteria to balboa trees, all of life, in fact, including ourselves. Life serves as proof that self-replication is in fact possible. Other, non-living self-replicators also exist. Because a range of self-replicators exist in the world, the members of the focus group had to first define the parameters for designing a model self-replicating system. The group discussed several types of existing self-replicators. First, several examples of simple replicators were named. Fire, in the right environment, produces more fire. Crystal seeding leads to more crystal. Autocatalytic reactions produce chemicals that in turn increase the reaction. For example, if hit with a source of energy, like gamma rays, formaldehyde makes glycoaldehyde. Once glycoaldehyde is present, it can couple with formaldehyde and break it apart, making two glycoaldehyde molecules where there had been one. These in turn can convert more formaldehyde to glycoaldehyde. As long as formaldehyde is available, this reaction causes more of itself to occur. Viruses fall into another category of self-replicators. They are more complex than fire, but to make copies of themselves they have to depend upon the machinery inside biological cells. One of the things that make viruses interesting is that, like life, they carry instructions for copying themselves. They inject either DNA or RNA into a cell, where cellular machinery follows the directions and produces more viruses. The last category of self-replicators the group considered was biological cells. In part because many in the group hoped to use the pursuit of a synthetic self-replicator to throw light on the origins of life, the group decided to specify a self-replicator much like a cell. Like fire and crystals, its self-replicator would make copies of itself. Like viruses, it would contain instructions for self-replication. It would be like a cell in many ways. First, unlike viruses, the replicator would include the machinery for carrying out the instructions. Also, it would take simple environmental materials, as cells use amino acids, and create something more complex, such as a cell’s proteins. The group wanted to make clear it was not looking for a self-replicator that made copies of itself by, for example, breaking off parts of a more complex material in the environment. In addition to these basic requirements, the group hoped its self-replicator would have other things in common with a cell. The instructions in a cell can be changed, and as a result the cell can produce different kinds of products and perform various functions. Muscle cells can contract. Nerve

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The National Academies Keck Futures Initiative Designing Nanostructures at the Interface Between Biomedical and Physical Systems: Conference Focus Group Summaries cells can process and send signals. Likewise, an ideal synthetic self-replicator would be programmable so that it could serve multiple functions. The group decided its self-replicator could be different than a cell in one important way: it would not necessarily have to have a physical barrier like the cell’s membrane. The group’s self-replicator still would need to be distinct from its environment, if only to confirm that it is indeed making a copy of itself. Rather than using a physical barrier, however, this distinction could be made by defining the parts or functions of the self-replicator. By agreeing not to include a requirement for a cell membrane-like physical boundary, the group significantly reduced the complexity of the design task. At the same time, the group increased the requirement for researchers to control the environment for the self-replicator. In a cell, the membrane, including its embedded proteins, control what comes into the cell. By doing this it creates a special environment within the cell that allows the reactions necessary for the cell to function and eventually copy itself. For the group’s self-replicator, the researchers in effect take the place of the membrane, carefully preparing and maintaining the environment. They would keep out things that might damage the machine, and they would include an energy source and all the required raw materials. The need for this specified environment makes it much less likely that this self-replicator could survive and reproduce outside of the lab. In summary, the group defined as its goal a self-replicator that: produces a copy of itself carries information for replication is distinct from its environment uses raw materials that are simpler than the final product ideally would be programmable and multifunctional The group’s defined goal will not be easy to accomplish. As a first step, however, the group outlined a research direction building on current work with RNA. David Bartel of the Massachusetts Institute of Technology has developed an RNA-based RNA polymerase, that is, a form of RNA that can copy RNA. If this polymerase could make a copy of its own RNA sequence, it would be a self-replicator. For this to happen, key obstacles need to be overcome. For one thing, so far the polymerase is slow and as a result cannot copy long strands of RNA such as itself. Another main problem is the fact that once the RNA is

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The National Academies Keck Futures Initiative Designing Nanostructures at the Interface Between Biomedical and Physical Systems: Conference Focus Group Summaries copied and folds into a non-linear structure, like a helix, its parts are no longer available to be copied again. What is needed is another enzyme, a helicase, that will unfold the structure so it can be copied. In spite of these obstacles, working with RNA seems promising because, in addition to possibly fulfilling the group’s basic requirements, it might even lead to a device that can be programmed to perform a variety of functions. Nucleic acids have been used for a variety of surprising things. Researchers have made DNA that folds into an octahedron, opens and closes like a pair of tweezers, or walks on a substrate much as the protein molecular motor kinesin walks along microtubules. They have also used RNA for a variety of catalytic roles. Even more functions may be found if the so-called RNA world hypothesis is correct. According to Nobel Prize for Chemistry winner Sidney Altman, in the primitive earth RNA both stored genetic information and performed, “the full range of catalytic roles necessary in a very primitive self-replicating system.” If scientists are able to synthesize an RNA-based self-replicator, it may confirm this hypothesis and give us a better understanding of how life could have begun and evolved. The proposed self-replicator might work something like this: RNA polymerase would be added to a solution containing all the raw materials it needs, including fuel in the form of rNTP. The helicase would unfold some of them, making them available for copying by other, still folded, molecules of RNA polymerase. These copies would fold into new RNA polymerase molecules. These could be fed other strands of RNA that code for RNA-based structures like tweezers and catalysts, or more polymerase. After offering the RNA example, the group went on to suggest that non-biological heteropolymers might be used to make self-replicating machines that could survive within extreme environments like space, where the vacuum, cold, and radiation would keep biological self-replicators from functioning or even maintaining integrity. Such non-biological self-replicators would depend upon a supply of raw materials that do not occur naturally, suggesting that they would not be able to replicate outside of a carefully prepared environment. While the theoretical advantages of non-biological heteropolymers make them desirable, the group noted that building them would present an array of new obstacles. Public concerns about self-replicators have been heightened by books like Michael Crichton’s Prey. Although the replicators proposed by the group would likely have trouble surviving outside of narrow environments,

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The National Academies Keck Futures Initiative Designing Nanostructures at the Interface Between Biomedical and Physical Systems: Conference Focus Group Summaries the group proposed that attempts to make self-replicators should be accompanied by critical assessments of safety issues, including consideration of ways to recognize and respond to unforeseen problems. These assessments from the beginning should include discussions between scientists and nonscientists with the goal of self-regulation.