An In Vivo Nanofactory: The Medicine of the Future

FOCUS GROUP DESCRIPTION

Background

Science fiction writers have conjured up bacterial colonies as future large-scale factories of engineered nanomaterials or nanomachines, which could then be assembled or self-assemble into macroscale objects useful to society. The convergence of nanotechnology with biotechnology has the potential to enable engineered biological processes to catalyze, ‘grow,’ and assemble complex engineered objects (Ref. 1). One step forward in this future vision is to use engineered biological (bio-mimetic) processes to create a desired step in such an assembly process, such as to create a nano chemical factory to synthesize three amino acids in a row, to synthesize a drug, or to perform a function such as closing a shutter or generating voltage across particular nanocontacts.

Science has made progress along these lines: cells are remarkably efficient at catalyzing a wide range of chemical reactions (Ref 2), such as fermentation, respiration, and photosynthesis, using a variety of electron donors and acceptors. Recently, researchers have been able to program cells in rudimentary ways to perform tasks not evolved in nature (Ref 3). For several years, researchers have been able to couple natural biomachines with engineered materials to create a hybrid nanomachine (for one example, see Ref 4). In addition, researchers have been able to; use RNA reactions inher-



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The National Academies Keck Futures Initiative Designing Nanostructures at the Interface Between Biomedical and Physical Systems: Conference Focus Group Summaries An In Vivo Nanofactory: The Medicine of the Future FOCUS GROUP DESCRIPTION Background Science fiction writers have conjured up bacterial colonies as future large-scale factories of engineered nanomaterials or nanomachines, which could then be assembled or self-assemble into macroscale objects useful to society. The convergence of nanotechnology with biotechnology has the potential to enable engineered biological processes to catalyze, ‘grow,’ and assemble complex engineered objects (Ref. 1). One step forward in this future vision is to use engineered biological (bio-mimetic) processes to create a desired step in such an assembly process, such as to create a nano chemical factory to synthesize three amino acids in a row, to synthesize a drug, or to perform a function such as closing a shutter or generating voltage across particular nanocontacts. Science has made progress along these lines: cells are remarkably efficient at catalyzing a wide range of chemical reactions (Ref 2), such as fermentation, respiration, and photosynthesis, using a variety of electron donors and acceptors. Recently, researchers have been able to program cells in rudimentary ways to perform tasks not evolved in nature (Ref 3). For several years, researchers have been able to couple natural biomachines with engineered materials to create a hybrid nanomachine (for one example, see Ref 4). In addition, researchers have been able to; use RNA reactions inher-

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The National Academies Keck Futures Initiative Designing Nanostructures at the Interface Between Biomedical and Physical Systems: Conference Focus Group Summaries ent to biomineralization pathways to catalyze mineralization reactions in-vitro (Ref. 5), use DNA or viruses to assemble nanocrystalline arrays (Ref. 6), and use biological pathways to create new engineered materials (Ref. 7). Researchers are also beginning to harness nature’s self-assembly processes (Ref. 8). The Problem Your task is to create a scientific plan for using biological or biomimetic mechanisms to create one or more steps in a bio-nanoscale assembly process that could be scaled up to synthesize useful products in volume. First, the group should decide what the ultimate product is, such as, for example: Create an engineered method of effective remediation of contaminated ground water, where the nanoproduct can learn what the dangerous contaminants are, grow the machinery to neutralize them, and then afterwards disassemble into environmentally friendly materials; Create an engineered method for creation of ‘smart’ clothes that will sense the environment and automatically adjust their breathability, UV blocking ability, water repellency, toughness, cooling and heating or germicidal abilities; or, Feel free to create your own grand challenge. Next, pick one or several limiting steps in the manufacture of such a product and come up with a scientific plan to potentially accomplish them, including what scientific knowledge or engineering prowess we currently lack, and thus would need to learn in order to accomplish this task. For example, in choice a) or b) above, how would one go about creating swimming devices or fibers that ‘sense’ the environment around them? What should be sensed? Once the environment is measured, what mechanisms, including feedback and control, would be relevant to react to that information? How does one deal with stochastic processes on the nanoscale? Finally, use the group’s ingenuity to propose a plan for the manufacture in large volume of your product or sub-product, using biomimetic principles. As always, the group should discuss the ethical considerations in the manufacture of your products. How would one perform the manufacture as safely as possible? What controls should be put in place?

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The National Academies Keck Futures Initiative Designing Nanostructures at the Interface Between Biomedical and Physical Systems: Conference Focus Group Summaries Initial References 1. Goodsell, D, Bionanotechnology—Lessons from Nature. Wiley-Liss (Hoboken, 2004) ISBN 0-471-41719-X. 2. Newman, D., Microbial Mineral Respiration. The Bridge, winter 2003. National Academy of Engineering, 33(4):9-13. http://www.nae.edu/TheBridge. 3. Kobayashi et al., Programmable Cells: Interfacing Natural and Engineered Gene Networks. Proceedings of the National Academy of Sciences, June 1, 2004. 101(22): 8414-8419. 4. Soong et al., Powering an Inorganic Nanodevice with a Biomolecular Motor. Science, 2000. 290:1555-1558. 5. Gugliotti et al., RNA–Mediated Metal-Metal bond Formation in the Synthesis of Hexagonal Palladium Nanoparticles. Science, 2004. 304(5672):850-852. 6. Ordering of Quantum Dots Using Genetically Engineered Viruses, Science, 2002, 296(5569): 892–895; Selection of Peptides with Semiconductor Binding Specificity for Directed Nanocrystal Assembly, Nature 2000, 405(6787):665–668; Taton, T. A.; Mucic, R. C.; Mirkin, C. A.; Letsinger, R. L. The DNA-Mediated Formation of Supramolecular Mono- and Multilayered Nanoparticle Structures, J. Am. Chem. Soc., 2000, 122:6305-6306. 7. First Steps in Harnessing the Potential of Biomineralization as a Route to High-Performance Composite Materials, Acta Metal. Mater., 1998, 46(3):733-736; http://www.materialstoday.com/pdfs_6_11/policy.pdf. 8. Bowden, N. B., Weck, M., Choi, I.S. and Whitesides, G.M., Molecule-mimetic Chemistry and Meso-scale Self-assembly, Accounts of Chemical Research, 2001. 34:231-238. FOCUS GROUP SUMMARY Summary written by: Kiryn Haslinger, Graduate Student, Department of Chemistry, New York University Focus group members: Placid Ferreira, Director, Center for Nanoscale Chemical-Electrical-Mechanical Manufacturing Systems, University of Illinois at Urbana-Champaign Richard Groff, Postdoctoral Research Engineer, Department of Electrical Engineering and Computer Science, University of California, Berkeley Kiryn Haslinger, Graduate Student, Department of Chemistry, New York University

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The National Academies Keck Futures Initiative Designing Nanostructures at the Interface Between Biomedical and Physical Systems: Conference Focus Group Summaries Michael Koonce, Research Scientist, Department of Molecular Medicine, Wadsworth Center Philip LeDuc, Assistant Professor, Department of Mechanical and Biomedical Engineering, Carnegie Mellon University Woo Lee, Professor and Director, Department of Chemical, Biomedical and Materials Engineering, Stevens Institute of Technology Christopher Love, Post Doctoral Fellow, Department of Pathology, Harvard Medical School Andy McCammon, J. E. Mayer Professor of Theoretical Chemistry, Department of Theoretical Chemistry, University of California, San Diego Nancy Monteiro-Riviere, Professor, Center for Chemical Toxicology Research and Pharmacokinetics, North Carolina State University Vincent Rotello, Professor, Department of Chemistry, University of Massachusetts Gary W. Rubloff, Professor, Department of Materials Science and Engineering, University of Maryland Robert Westervelt, Director, Nanoscale Science and Engineering Center, Harvard University Michael Wong, Assistant Professor, Department of Chemical Engineering, Rice University Minami Yoda, Associate Professor, School of Mechanical Engineering, Georgia Institute of Technology Summary Tiny solutions for big problems When great minds in modern science convene to identify and solve the big problems facing the world, it is impossible for them to disregard flaws in human health. Disease comes in many forms, but consistently confers pain and suffering on individuals. Some of the greatest challenges in science and engineering today involve understanding diseases at a fundamental level and developing innovative solutions for battling them. This grand challenge was the inspiration for a group of 13 researchers—biologists, chemists, physicists, and engineers; the best in their respective fields—to propose the construction of a biological nanofactory that could be broadly applied to prevent or remedy diseases ranging from mental retardation to prostate cancer. The nanofactory was a solution to a problem posed to these researchers

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The National Academies Keck Futures Initiative Designing Nanostructures at the Interface Between Biomedical and Physical Systems: Conference Focus Group Summaries at the Second Annual National Academies Keck Futures Initiative Conference, “Designing Nanostructures at the Interface between Biomedical and Physical Systems.” Charged with “building a factory to synthesize products,” utilizing biological systems as starting materials, the group pooled their broad and varied areas of expertise to design a prototype for an artificial pseudo-cell that will have the ability to manufacture and deliver a biological product to an appropriate region of the body to correct an existing biological condition. Such a nanofactory would be therapeutic in a number of diseases including diabetes, thyroid disorder, and cancer. A nano-“mobile defense force” Before delving into the specific aspects of disease chemistry, the group used their engineering prowess to describe a prototype for their powerful nanofactory, a weapons factory a billion times smaller than a single bullet, that could single-handedly wage war against human disease. A sketch of the nanofactory highlights six basic components. These key features are comparable to those required in a more conventional factory. Just as pharmaceutical or car manufacturers must carefully select their location site to market their product to consumers, the nanofactory must have a mechanism for targeting the region for which it will manufacture its products. A delivery sensor—manifested as a cell-specific antibody or another recognition molecule—can be chemically attracted to the body tissue that would benefit from the factory’s product. A second, and somewhat self-evident, requirement of the factory is its walls. A car company will construct a building that will be suitable for the conditions necessary for its purpose; and the nanofactory, likewise, needs a compartment that can contain its inner workings. It must thus be like a human cell, which is compartmentalized inside a vesicle. The pseudo-cell’s walls can be built out of a variety of materials that will suit its purpose of containing the inner workings without being rejected by the body. Both a lipid bi-layer and a polymer structure would serve to sequester the chemical assembly line. while allowing the flow of water through its pores to survive the strict osmotic regulations that the human body requires. Next, there must be a front door, or input gate for the raw materials—chemical precursors, cofactors, and energy molecules—to flow in. In the most sophisticated incarnation of the nanofacotry, the door will be locked and will only open when the product the factory creates is needed in the

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The National Academies Keck Futures Initiative Designing Nanostructures at the Interface Between Biomedical and Physical Systems: Conference Focus Group Summaries body. The key to opening the door will be a sensor that will detect chemical levels near the factory site. Once the door is open, reactants, cofactors, and energy molecules can flow into the factory where they will move through an assembly line of enzymes each with a specific job to modify the raw materials into the desired product. The enzymatic assembly would be specific to the metabolic pathways necessary to produce the output of each nanofactory. After the product is created it must exit the factory to be distributed where it is needed. An output gate can also be regulated with a key that will detect the presence of product inside the cell and open only when there is material to exit. Finally, there must be damage control. What if the factory malfunctions or the patient reacts badly to its insertion? As it cannot be withdrawn, it must have a self-destruct mechanism that could be initiated by an external electric or magnetic field—something like an MRI—that would trigger the factory walls to decompose so that its inner workings could diffuse safely through the body. A model for moderating PKU The features described here must undergo significant engineering analysis to determine the best solutions to remedy or prevent a particular disease. A simple prototype can be built to provide an important proof-of-principle that the strategy will work. A prototype nanofactory can be built to contain phenylalanine hydroxylase (PAH), the naturally occurring enzyme that is absent in sufferers of phenylketonuria (PKU) who experience severe mental retardation because the phenylalanine they consume in their diet cannot be properly converted to tyrosine. This disorder results from a common genetic mutation that affects 1 in 10,000 individuals. There is no cure; and the only remedy is a simple dietary measure that urges individuals genetically predisposed to PKU to avoid eating foods high in phenylalanine or its precursors, such as diet soda due to the product aspartame. An anti-PKU nanofactory would include only one enzyme, PAH, in a simple assembly line that would convert phenylalanine, entering through the input gate, into tyrosine, which would exit through the output gate and diffuse through the patient’s blood, remedying the natural deficiency. The factory could be dissolved in a solution and administered through injection. It would be targeted to the liver, where PAH is normally produced, via

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The National Academies Keck Futures Initiative Designing Nanostructures at the Interface Between Biomedical and Physical Systems: Conference Focus Group Summaries chemical receptors. Intelligent design may mitigate the need for such receptors. Since all mid-size objects put into the body tend to congregate in the liver, an appropriately sized nanofactory—about 100 nanometers in diameter—will be drawn to the right place without any sensors. The tyrosine product would exit into the patient’s blood stream, preventing a profound irreversible mental disease. This pared down factory, proposed by the group, may require input and output sensors to serve as door-keys, but a molecular understanding of the nature of the disorder must be mastered for their design. While this gap in knowledge is not a general scientific failure, it was, unfortunately, not available within the expertise in the group. It points to a larger gap, though, for the expansion of this technology for other diseases: the metabolic pathways and basic biochemistry of the problem must be understood before a factory can be built to fill in for the body’s malfunction. Miniaturized pharmaceuticals The design for the nanofactory laid out by the group can be modified for the production of hormones like thyroxine to manage thyroid disorder; growth factors, such as tumor necrosis factor-α (TNFα), to specifically target and kill cancerous tumors; and insulin precursors that could be produced and self regulated to relieve diabetes sufferers of daily injections. Nanofactories could also be used to withdraw unwanted materials from a biological environment—toxic chemicals resulting from a drug overdose or excess LDLs (low density lipoproteins), famous for their link to heart disease. Each of these conditions would require a complex multi-enzyme assembly line to produce the biomedically useful product. The nanofactory blueprints developed by the group have the potential to revolutionize individualized medicine. Instead of taking daily doses of drugs, which are mostly excreted before they are absorbed and can cause nasty side effects, injections of medicinal nanofactories have the potential to offer selective, regulated, time-sensitive therapy to produce and deliver the medicine your body needs exactly when and where your body needs it. While the factory blueprints can be drawn up without much further effort, as the biochemistry and engineering knowledge already exists, there are some gaps that must be bridged before the nanofactories can be mobilized to treat disease. The most difficult challenges to overcome will be disease specific, as the construction of the nanofactory will vary based on its desired function. Designing a vesicle to safely contain particular enzymes

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The National Academies Keck Futures Initiative Designing Nanostructures at the Interface Between Biomedical and Physical Systems: Conference Focus Group Summaries will, of course, vary with the nature of those enzymes. The size and durability of the cell may also change, depending on its ultimate desired lifetime. A PKU sufferer, for instance, would require injections throughout his life, so a very stable pseudo-cell would maximize the factory’s lifetime so that the patient would need to receive an injection only, say, once a month. Unknown unknowns Science fiction writers have conjured up images of nanomachines that can self-assemble into macroscale objects with powerful functions. Even on the nanoscale, a self-sustained and self-regulated factory inserted into a human body could potentially wreak biomedical havoc instead of providing therapeutic assistance to its host. Is such a concern menacing enough to impede research into their construction? On the other hand, therapeutic nanofactories could be considered to be “politically correct” stem-cells, as they can be created to provide distinct therapy to various parts of the body selectively, without dealing with the matter of using discarded embryos. In addition, while the mechanism of stem cells is not yet well understood, the nanofactories present an intelligent alternative because they will be able to regulate and correct metabolic processes in a planned and organized way. There are, as always, ethical concerns that must be considered along side the scientific details of the new technology. Overall, if further development of the in vivo nanofactory is approached with biochemical acumen and levelheaded caution, the gaps that exist in the current scientific wisdom can and should be resolved. The in vivo nanofactory holds a world of promise in treating a range of human diseases. Postscript: To further explore this topic, a focus group member recommends the following publication: Noireaux, V. and Libchaber, A., A vesicle bioreactor as a step toward an artificial cell assembly, PNAS, December 21, 2004, vol. 101, no. 51, 17669-17674. (Published online before print December 10, 2004).