What do you make of molecules these days?
"Well, they're still the place where life gets really interesting, where nature encrypts the plans for all the processes that matter, and we're still learning how much we have to learn."
And how about your lab what do you make of molecules?
"Almost anything you want!"
This might be a typical conversation between scientists at Cornell these days as researchers with different approaches but complementary goals increasingly are working across campus, across the hall or across the lab bench from one another. The details they are discovering about how the basic bits of nature come together are enabling a remaking of the molecules of life. All of the basic studies of life at the most fundamental level are helping molecule-makers aid and abet nature, and even to outwit nature by attacking diseases.
An intriguing place to begin a cross-campus molecular mystery tour is the Riley-Robb Hall laboratory of Carlo Montemagno, associate professor of agricultural and biological engineering a workshop for the biologically inspired that contains elements of the fantastic. "Like microscale robots powered with muscle and fueled by light, by photons," he hints. "Or smart dust devices smaller than bacteria with a well-directed intelligent function to perform."
Smart dust, says Montemagno, is based on bacteriorhodopsin, the protein in heliobacter and certain other bacteria that allows them to be photosynthetic. NASA wants to use smart dust on Mars to look for likely sites where life albeit equally tiny might exist. Even smarter dust could have a diagnostic and therapeutic function, seeking out and treating pathogens in plants. Or people.
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| Adenosine triphosphate synthase (F0F1-ATPase) biological motors attached to the membrane of a mitochondria. Copyright © Montemagno Research Group/Cornell University, 2000 |
If you want to deal with living things on the molecular level, you want devices in a size and form that life's molecules can understand, Montemagno says, stating the nanobiotechnologist's creed that will be heard again and again across campus. "Our goal is to integrate micro- and nano-scale engineered devices with human cells, and we would like components to self-assemble on devices and become part of the devices. In molecular motors, we have a propeller that spins and makes the motor move and we're now testing integrated chemical switches to turn the motors on and off," Montemagno says.
Not only NASA is funding such schemes. The Defense Advanced Research Projects Administration and Office of Naval Research are both very interested in Cornell work developing myosin, the motor protein in muscles, to move a light shutter or an actuator in robotic sensors. Then there's the Department of Energy, the funder that keeps some of the more than two dozen researchers and students in Montemagno's group busy, developing light-fueled molecular-motor-powered machines. Also, the National Science Foundation is funding a project to use molecular motors to sort other molecules as well as a bigger, macro-scale effort to make insect-sized smart sensors.
All of this research is aimed at moving simple objects with molecular motors, those tiny but elegant ways that nature has developed to move other molecules around cells. It is easy to forget that until recently graduates knew more about General Motors' motors than molecular biologists did about the self-propelled miniatures.
Then Cornell graduate student Hongwei Yin started work with Anthony Bretscher, a professor of molecular biology and genetics, and she solved the mystery of how the mitotic spindle in newborn, dividing cells gets sufficiently oriented to transfer all those DNA molecules of genetic instructions from the mother to the daughter cell.
While the mitotic mechanics labored in the Biotechnology Building, biophysicist Michelle Wang was in Clark Hall, elucidating an even earlier role of molecular motors. The assistant professor of physics' molecular motors run along the DNA template each time an RNA copy is synthesized. Without RNA molecular motors there would be no replication of DNA and nothing for the mitotic spindle to deliver.
Next door in S.T. Olin Laboratory, molecule-maker Dotsevi Sogah is thinking about Lego®. The professor of chemistry and chemical biology is careful to write the name with a little trademark symbol, out of respect for the intriguing children's game of modules that inspired him to assemble diversely shaped molecules into forms that nature never knew.
The key to the Lego method is catenation the formation of chains of atoms Sogah explains, "and we're not limited to naturally occurring protein sequences. We can handle a variety of synthetic polymers. We build a functional material on a scaffold with catenation A plus B, A plus B, repeated as many times as necessary. That's catenation. That's the biomolecular Lego set modular method, and that's what is letting us achieve the ultimate goal of the synthetic polymer chemist: to precisely control polymer architecture and obtain materials with well-defined properties."
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| Dotsevi Sogah, left, professor of chemistry and chemical biology, and College of Arts and Sciences senior Adam Braunschweig review the structure of newly developed, bioinspired molecules in S.T. Olin Laboratory. A children's game of modules, Lego®, also inspires their research. Frank DiMeo/University Photography |
Sogah describes one bioinspired material he's working on artificial silk. "Natural spider silk has some excellent properties. Pound for pound, it's stronger than the strongest manmade material, Kevlar, and spider silk has properties of elasticity and resilience that Kevlar does not. First, we examine the natural materials to see what makes them work as well as they do. Then we try to reproduce the natural material as closely as possible, and look for ways to put the parts together on our Lego scaffold." Sogah also likes to merge the "soft" (or organic) materials with the "hard" (inorganic) ones, especially on the nanoscale (in structures a few billionths of a meter in size), in a domain where many of the old rules of chemistry and physics don't apply. Nanocomposites of plastic-plus-clay could reduce the flammability of materials in aircraft seats, or make a better timing belt for automobile engines. Operating on the nano level lets Sogah and Emmanuel Giannelis, a professor of materials science and engineering, independently make microspheres with improved porosity to deliver drugs to sensitive parts of the body, such as the brain.
Nature is a constant inspiration for much of this interdisciplinary research. Take, for instance, the super-small directionally sensitive hearing aid that is based on the auditory organ of a tiny parasitic fly that homes in on the mating calls of crickets. Ron Hoy, professor of neurobiology and behavior and a specialist in bioacoustics, had been listening to bug noises for years when he discovered how a minuscule creature one that theoretically shouldn't know where sound comes from manages to cheat physics.
The fly's directional hearing organ was little more than a footnote in neurobiology until Norman Tien, assistant professor of electrical engineering, caught on. Now the Cornell collaboration of biologists and engineers is on the way to producing a better hearing aid.
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| The F1-ATPase powered motor will power tiny pharmacies inside living cells. Copyright © Montemagno Research Group/Cornell University, 2000 |
Attacking disease is a major goal of nanobiotechnologists, who dream of drugs being delivered straight to needy cells by smart micropharmacies. Where will this next generation of pharmaceuticals come from? Perhaps from Cornell's Baker Laboratory where Jon Clardy, professor of chemistry and chemical biology, practices the science and infinitesimal art of structure-based drug design atom by atom, molecule by molecule.
Just appointed to the National Cancer Institute's advisory unit, the NCI Board of Scientific Counselors, Clardy explains how knowing the exact, three-dimensional structure of an enzyme called DHODH (for dihydroorotate dehydrogenase) could lead to a treatment for malaria and possibly other parasitic diseases, and even cancer.
"DHODH catalyzes important reactions, including synthesis of nucleotides, the basic units of nucleic acid in DNA and RNA," Clardy says. "Nucleotides are difficult and energetically expensive to synthesize in the body, so we tend to recycle them through salvage pathways, but sometimes recycling is not sufficient and we need to make new nucleotides. T-cells in the immune system need to make new nucleotides and so do cancer cells and this tells us that DHODH could be the Achilles heel of nucleotide synthesis. If we could find the right inhibitor to block nucleotide synthesis, cancer cells couldn't grow."
Another organism that uses a form of DHODH to make its own nucleotides is the blood-borne malaria parasite Plasmodium falciparum. "It turns out that the malaria parasite is very dependent on the DHODH pathway it lives inside red blood cells, it feeds on them, they burst and that harms the capillaries and Plasmodium needs to synthesize its own nucleotides, in order to reproduce, because it can't get nucleotides from red blood cells," he says.
One of the most exciting places on campus for molecular research, says Clardy, gesturing southward across campus, is the X-ray crystallography labs of CHESS, the Cornell High Energy Synchrotron Source. There, intense X-rays, a by-product from the electron-positron beam ring of the Wilson Synchrotron Laboratory, are used to illuminate the atomic structure of almost any material, from flu viruses to geological samples.
It was at CHESS that a team, based both in the Department of Molecular Medicine at Cornell's College of Veterinary Medicine and in the Department of Chemistry and Chemical Biology, demonstrated for the first time the atom-by-atom structure of a molecular "switch" called Cdc42, and a regulator of the switch, a protein called GDI. These control an essential chemical pathway for both normal and cancerous cells. The achievement was deemed so significant that their diagram of molecules merited the cover of the journal Cell last February.
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| A complete F0F1-ATPase motor anchored to a lipid membrane. c. Montemagno Research Group/Cornell University, 2000 |
Richard Cerione, leader of Cornell's Cdc42 team and professor of molecular medicine, notes that more options are being found for therapeutic intervention because "the more molecules we learn about, the more we can interfere with." It was Cerione who "discovered" the human Cdc42 protein at Cornell in 1990. He and his collaborators postdoctoral researchers, graduate students, even undergraduates cloned and purified the protein then tried to turn it crystalline for the X-ray diffraction studies. "Making a crystal that will diffract X-rays properly is not a trivial task," Cerione said. The prettiest crystals are not necessarily the best at defracting. It can often take years."
The Cdc42 team was impelled by the knowledge that the cell-growth-regulating protein was "conserved" throughout evolution, appearing in organisms as primitive as yeast and continuing to function in human cells. Then they "went fishing," as Cerione modestly puts it, for another link in the cell-signaling reaction, the regulator of the Cdc42 regulator, and finally found GDI, which stands for guanine nucleotide-dissociation inhibitor. And they figured out how to make a crystal form of the two proteins together in complex, to discover exactly how they interact in normal and cancerous cell growth.
Sometimes as Cerione makes the Tower Road "commute" between his labs in veterinary medicine and in chemistry, he reflects on why Cornell is the perfect place to do his brand of biomedical research.
"We have the biologists, the physicists, the engineers, the computer programmers and the chemists who really know how to make molecules," Cerione said, "people in all areas who might not have thought they could make an impact on cancer and our understanding of how cells work."
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