PerspectivesAre you interested in submitting a Perspective Article? Be sure to read The Science Advisory Board's Editorial Guides for Perspective Articles. Click here. A Fantastic Voyage: From the Realm of the Tiny Come the Tools for Human Regeneration by Shirley Ann Jackson, Ph.D. Regenerating the human body -- cells, tissues, whole organs -- using genetic and nanoscale materials and techniques is happening in spaces smaller than the head of a pin, in tissues ten thousand times tinier than the diameter of a single human hair, on a time scale measured by atomic clocks. It is the revolution of atom-by-atom constructions, self-assembling molecular machines, and devices with fundamentally new properties and new functions. This is the dawning of the age of nano-biotechnology. I propose to take you on a fantastic voyage through nano-land -- its history, its applications, its promise. The field of nanobiotechnology is about five years old. It is defined by science's growing ability to work at the molecular level, atom by atom, combining biological materials and the rules of physics, chemistry and genetics to create tiny synthetic structures. The end result of nanobiotechnology -- technology operating on the 10 to the negative 9 meter scale -- a billionth of a meter -- is to create an invisible, highly functional world of electronic circuits, nano-sized microchips, molecular 'switches,' even tissue analogs for growing skin, bones, muscle, and other organs of the body. All accomplished in ways that allow these structures to assemble themselves, atom by atom.1 We can think of this nano-frontier as the intersection of materials science, bioengineering, and molecular biology. It includes the investigation of how living embryonic cells and genetic materials, including DNA -- the very essence of life -- behave and interact while encountering an unfamiliar nanoworld of synthetic materials on a submicron scale. For example, a plastic petri dish, a polished metal surface, a polymer, or a crystal of silicon and mica. When implanted or coated with biological material...cell contents...gels...these ceramic surfaces can act like molecular moonscapes, jagged and strange in detail and pattern, forcing new configurations of atoms. When cells are taken out of the body and interact with these surfaces, the cells and their molecular components often behave differently -- sometimes randomly, sometimes in controlled nano-scale alignments. In many cases, the cells react to the opposite cues from what they usually receive inside the human body, in their normal "environment."2 Ironically, these strange patterns of interaction promise one day to help us create nanoscale, bio-mimetic machines and devices -- part protein, part ceramic -- tiny sensors, reservoirs, and actuators that will help regenerate human tissues in a way that has never been done before. Already, scientists are building "nanobots," as we call them, self-assembling, hybrid bio-electrical-mechanical robots. So tiny are these devices that they will be implanted inside our bodies and work invisibly. They will be tinier than red blood cells. They will be composed of molecular motors, gears, propellers and fluid reservoirs that deliver drugs to specific targets at exact times of the day or night; sensors that can pick up the first changes in pre-malignant cells; nanoscale composites of bone and ceramic that build bridges across damaged tissue. Even virus-sized biomolecular motors composed of DNA strands. These strands have "sticky ends" that can self-assemble into geometric objects for medical use. Already, researchers at Cornell University have been able to create tiny nickel nanopropellers that spin at eight revolutions per second -- exactly eight -- in response to synthesis and hydrolysis of ATP...adenosine triphosphate...an essential component of human muscle energy and movement.3 Ultimately, these nanobots will be used to do things like swarm an injury site, sensing, diagnosing and activating therapeutic systems. Nanobots will be sentinels, discharging gases or vital fluids, collecting and transmitting vital data back to a "macrodoctor" -- human or computer. These fantastic descriptions are not science fiction. They are functional reality in laboratories today -- virtually all are being developed and tested in research centers right now. Indeed, within five to fifteen years, if progress continues at the current rate, nanobiotechnology will result in treatments that will become a regular part of an astonishing medical arsenal. History First It might be said that the coming of "nano-ness" began with remarkably accurate predictions of the atomic movements made by two Greek philosophers -- Leucippus and Democritus. These gentlemen lived about 550 years before Christ. To my knowledge, they had no electron or scanning tunneling microscopes with which to perform nanoscale experiments. Yet they believed -- they guessed -- that the very stuff of matter was composed of tiny, complete units -- plena -- or primary magnitudes, as they called them. These plena -- atoms as we call them today -- were infinite in number and in various shapes, but were not divisible. In fact, these Greeks believed...and I quote...that "worlds are formed when atoms fall into the void and become entangled with one another." Democritus further proposed the view that the differences in material bodies are caused by the atoms' individual shapes; their inclination, or direction of turning; and their exact arrangements.4 This rational and deterministic view of the universe stressed the size of atomic units and their weights -- and gave us the first inklings of combinatorial chemistry and molecular movements. How amazing -- no instruments save the human mind. How incredible. How human. Flash forward to A.D. 1959: Nobel-prize winning physicist Richard Feynman delivers a talk in which he outlines the possibility that scientists one day will be able to maneuver matter atom by atom without violating the laws of physics. Exactly thirty years later, in 1989, scientists at IBM do just that: At the Almaden Research Center in San Jose, scientists are able to pin down and manipulate exactly thirty-five atoms of the element Xenon. Despite all the obstacles presented by Heisenberg's uncertainty principle, by thermal vibration, radiation, and the like -- the atoms are attached to a nano-sized surface until they spell out the letters "I B M." Thirty-five atoms, three letters. A perfect logo...and the beginning of a new era of nanoscience.5 Since that time the field has exploded in different directions. At first nanotechnology focused on inorganic "materials sciences" -- the art of making novel molecular machines, computers, and lithographic etching equipment, including photonic, electrical, and storage devices. In the early 1980s, scientists were developing the instruments to enable us to "see" and manipulate the jagged edges of the nanoworld. For example, Gerd Binning, a fellow at IBM in Switzerland, collaborated with Heinrich Rohrer to build a "scanning tunneling microscope" -- STM -- a device that enabled a metal probe to come within 'two atoms' of a sample material under study. STMs painted vivid nano-snapshots of the surface of inorganic materials such as metals and semiconductors, showing they were not flat, as previously thought, but as bumpy as the mountains of Mars. From these early glimpses Binning and his team were able to develop nanoscopic brushes with tiny tips, each attached to its own cantilever. The cantilevers moved up and down and made dents in a Plexiglas-like polymer, creating a player piano effect. By moving the brushes over the dents again, the information could be 'read back' at rates of up to 100 megabits per second. The result: a 'millipede" storage system able to record more than 400 gigabits of data in a square inch. That amounts to a 50-fold increase from IBM's densest commercial drive, a 70-millimeter platter packing in 26 gigabits.6 And, that was just the beginning. Soon microelectronics engineers were looking at ways of coaxing molecular materials to 'self-assemble,' or put themselves together in precise, novel combinations. Moreover, the ultimate goal was to let these molecular machines 'self-replicate' so that they could grow to a macroscale, manipulating and physically transforming common materials into an end product -- for example, blood or beef or a new kidney. All of this was possible, said Dr. Kim Eric Drexler, an MIT molecular nanotechnologist (Yes, he actually got a Ph.D. in that field) who pioneered many of this country's original designs for nanoscale machines. In 1992 Dr. Drexler gave formal testimony before then-Senator Albert Gore's Senate Subcommittee on Science, Technology and Space. At that time the Senator correctly identified the phrase 'molecular nanotechnology' as a 'brand-new approach to fabrication, to manufacturing' and to control of the basic building blocks of life -- including human biology. Senator Gore also described the nanoscale approach as resting on the 'principle that your first building block is the molecule itself." Drexler then confirmed that the basic scientific research breakthroughs were already in place to build invisible nanobots and nano-scale gears, assemblers and devices -- one molecule at a time. He went on to describe and run a film showing his mechanical designs for what he described as "planetary gears" -- that is, perfect, nanoscale gear systems composed of 3,557 individual atoms -- no more, no less. All these atoms were precisely aligned to produce rotation on an inner shaft (the "sun gear") and a smaller outer shaft (the "planet gears"). Now, in the macro-world, such gear designs would be used for aircraft assembly, propeller hubs, and automobile drive trains. But in Drexler's world, these little devices would be part of a molecular factory producing novel end products in a mechanical way. For example, using our special microscopes we would see molecular manipulator arms -- "assemblers" -- grabbing molecules physically and forcing them into the right positions. We would have nanosized conveyor belts and rollers, sorting mills, vacuum pumps, gears, sprockets, springs, and ball bearings. These machines could be used not only for new manufacturing and lithographic techniques -- etching microchips, for example -- but also for designing prosthetic devices and drugs. However, unlike a purely biological process -- think of a cow transforming the oxygen, carbon, and nitrogen atoms of amino acids into milk -- the molecular machines could grab and configure individual atoms into new arrangements mechanically.7 Far-fetched? In nanotechnology's view, atoms are atoms: they don't care how their bonds are established, as long as they happen. The New Chapter: Bionanotechnology So, a new chapter began. In the 1990s, chemists began experimenting intensively with biological processes that could be applied to nanotechnology -- hence a new field, bio-nanotechnology. Among those processes, researchers started to look at the ability of DNA and RNA to use a set of biological 'rules' to recognize molecules, and hence to link nucleotides together to generate proteins and even an expanded genetic alphabet.8 'Designer' DNA, in other words -- ways of extending DNA's combinatorial powers to create whole new substances not formed in the original genetic alphabet. Quickly, the idea of proteins as toolkits took hold -- for example, one can use fragments of DNA to create nanocircuits -- 'building materials' for tiny, extensible hybrid electro-biological-mechanical structures. In addition, researchers discovered that the physical and chemical characteristics of DNA can actually control the placement of particles and interparticle distance in two- and three-dimensional materials. For example, according to Chad Mirkin, a leading nanotechnology researcher at Northwestern University, "the ultimate goal is to control particle composition and crystallization of colloids. That is, to understand the optical, structural, and electrical properties of these nanostructures." This knowledge can be used in both biological and industrial applications -- to create new materials and processes in photocatalysis, nonlinear optics, separations, sensor design, and photonics.9 Beyond this, tiny DNA arrays on microchips are already being developed to detect specific DNA sequences, thus speeding up the decoding process. This will not only further our knowledge of the human genome, but will give scientists an opportunity to explore DNA's capacity to generate "artificial DNA" -- DNA combinations never found in nature. Understanding how the molecular recognition rules of DNA work, and how they might be employed on the nanoscale to assemble new base pairs, scientists can come up with novel structures. Their techniques will surpass current recombinant DNA techniques (e.g., gene splicing), literally changing out nucleotides to produce more versatile genetic systems that can be used for molecular switches, three dimensional circuits -- all less than one billionth of a meter in size.10 The power of DNA and proteins to generate novel structures may be the key to unlocking a whole new generation of hybrid organic and inorganic materials, including semiconductors and biocompatible tissues. For example, at the University of Texas, researcher Angela Belcher has been working on proteins that may be the keys to unlocking new semiconductor materials and more efficient forms of crystal growth. Abalone, for example, makes shells by generating a brick-like wall of nanoscale tiles -- about 3000 times tougher than the chalk found in ordinary rock. These proteins signal the abalone to grow new tiles when needed. So Belcher began combining literally billions of viruses in solutions, each carrying a different genetically modified protein, to see which "sticks" to the semiconductor, and hence may be able to redirect its growth. In two years of work she has collected a "toolbox" of proteins that can alter crystal growth in about 20 different inorganic materials.11 At Rensselaer Polytechnic Institute, Dr. Richard Siegel is examining how osteoblasts in bone cells adhere to delicate nanoceramic structures composed of aluminum oxide, calcium phosphate, and other substances. It turns out the human bone cells interact in a different way toward nanostructured materials than they do toward coarser structures -- and this is exciting: these hybrid structures -- nanocomposites of bone and ceramic -- may be more effective in growing new bone than biological substances alone.12 In fact, this regenerative research could form the backbone for new human backbone, even spinal cords. This is exciting -- regenerative medicine writ large -- hope for a new level of healing, and healing technology, in the years to come. The National Science Foundation Initiative But who will coordinate and support all these nanoscale investigations? We believe that government, universities, private industry, and health care professionals have a role. Collectively, our goal is to build a whole new infrastructure and set of clinical applications that will benefit human kind. Until a few years ago, most of the nanoscale research was focused on semiconductor materials, physics, and chemistry -- the inorganic aspects of nanotechnology. But now, the United States government has entered a new phase of biologically oriented research and preparedness. This is enormously important in these challenging, troubling times -- where fantastic new advances in science and medicine are being matched by the equally terrible specter of biological and chemical terrorism. It is my belief that our country is ripe for a commitment to new levels of research and humanitarian protection. And certainly, I am not alone in this belief. ###
### Adapted with permission from a presentation by Dr. Shirley Jackson, President of the Rensselaer Polytechnic Institute at the Second Annual Conference on Regenerative Medicine, Cloning and Stem Cell Biology, Washington, DC, December 2001. ### << Previous Next >> [ View All Perspectives ] |
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