One of the world's leading researchers in the new scientific revolution of nanotechnology, Ted Sargent is also an abundantly talented writer. In The Dance of Molecules, he demystifies the complex world of nanotechnology—the science and engineering of building new materials and devices from the molecule up—and offers a fascinating vision of what this innovative science may accomplish in the twenty-first century.
In a fresh and engaging style, Sargent explores the potential for nanotechnology in three crucial areas: health, environment, and information. He shows how nanotechnologists are revolutionizing the way illnesses such as cancer are diagnosed. Today we catch cancer at the tumor stage, seven years after it begins. Sargent reveals how nanotechnologists are seeking to see the disease when it's one cell, not a billion. Each day, the sun bathes the earth in ten thousand times more energy than we need; Sargent shows how nanotechnologists are working to capture even the small fraction that could let us meet our energy needs cleanly and sustainably. Nanotechnologists also envision a light-based Internet a hundred times faster than today's. Nanotechnology is radically improving our lives, and The Dance of Molecules equips readers to understand exactly how.
Sargent's reflections on nanotechnology fuse the scientific, the practical, and the personal. He ventures from molecules to mice to men, has fantasies of building Greta Garbo from the atom up, dreams in colors visible and invisible, and invokes tomato poetry. Along the way, he touches on an amazing variety of subjects, including scientific collaboration, demographic trends, and geopolitics. The Dance of Molecules is an intelligent and important book that you won't want to put down.
Visit the author's website at tedsargent.com
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Diagnose
Cancer occurs at the nanometer scale. It is a mistake in a molecule, an error in the DNA that programs our destiny. Slip-ups the size of nanometers have huge human consequences.
Inside we are abuzz with molecular mechanics. Whirring motors suck away sugar’s stored energy. Transporter molecules drag heavy loads along nanometer-narrow girders spanning the insides of our cells. Dangerous bacteria seek to colonize our bodies and we produce molecules to resist invasion. As with David and Goliath, our 10-nanometer molecules use their smarts to outwit attackers ten times their size. Romance happens too. That two molecules were destined to be together, bound to one another, cannot be determined at a demure distance by checking out each other’s incomes, aptitudes, and family histories. Instead, the cell is a vast orgy, molecules trying one another on for size with surprising promiscuity. Molecules fit into one another, or don’t, depending on size, shape, and affinity.
Molecular keys fit uniquely into particular locks. When a key and a lock recognize one another, they unleash a whole sequence of life-critical activities: the feeding, reproduction, or death of a cell. Protein molecules begin as simple chains, but chains with folding instructions that, like origami, produce a striking variety of shapes when Nature carries out the instructions. The resulting complex structures mate only selectively. DNA contains the code describing the chain of molecules that will make up a protein, and through this it determines the shape and function of the resulting folded protein. The translation from DNA into protein is a word-for-word transformation: English to Pig Latin. Our DNA is a complete library that describes every protein we need. From it limitless copies can be made to produce the billions of identical protein keys of each type in daily use inside our cells.
Within this buzz of activity, something is bound to go wrong every once in a while. There can exist both innocent and consequential errors. The machines inside our cells that manufacture proteins from DNA instructions can make a mistake and it will matter little: a useless key floats around, fitting nowhere. A mistake in copying the contents of the DNA library while cells are replicating, however, will alter the set of proteins the cell will produce. If the cell cannot survive without the right protein, it will die. If the mutation changes how the protein, and through it the cell, works, but not catastrophically, then a fortuitously evolved form of life is created—or a new disease spawned.
To live means to make mistakes: being open to fortuitous variation means being vulnerable to danger. If we cannot avoid mistakes, then we would do well to learn to detect them early and act on this information promptly. The opportunity for early detection could transform how we deal with cancer. According to David Ahlquist, professor of medicine and director of the Colorectal Neoplasia Clinic at the Mayo Clinic in Minnesota, a healthy colon lining becomes a polyp and eventually cancer over a span of seven to ten years. Instead of waiting for a polyp or the cancerous tumor to become apparent as a tumor colony containing one billion cells, what if we could see cancer when it is a molecule, or perhaps a few cells? That people must inevitably die from cancer may turn out to have been a fallacy derived from our current place in history, as erroneous as similar thinking during earlier times of plague or tuberculosis, and we may then look back on our beliefs about medicine as primitive.
Nanotechnology can help in this quest for early diagnosis—before cancer spreads, before Alzheimer’s takes hold. Aided by chips that merge computer technologies with cells and genes and proteins, researchers are beginning to inspect cells one by one. With the aid of nanotechnology, medicine may protect its patients earlier: instead of looking only for massive tumors, we are gaining the ability to inspect each cell and thwart the malicious before they run amok.
Lighting Up Cancer Cells
In conventional medicine today, we use imaging techniques such as computed tomography (CT) and magnetic resonance imaging (MRI) to look for suspicious structures, tumors the size of a small grape. When it reaches this size, the tumor already contains one billion cells; these cells have undergone at least thirty generations of reproduction, giving them ample opportunity to spread throughout the patient.
In the summer of 2004, Professor Shuming Nie and his team at Georgia Institute of Technology used nanotechnology to look at individual flags on the surface of cells, and to light up only those cells that betray cancer. They reported that cancer might in the future be detected when it reaches only 10 to 100 cancer cells—a factor of ten away from diagnosing cancer in the first malignant cell, and thousands to millions of times more sensitive than detecting tumor masses once they have already developed to the size detectable by a CT or MRI. Nie built nanometer-sized beacons that shone brightly, announcing their whereabouts. He then put highly selective molecules on the beacons’ surfaces—Velcro that would stick only to cancer cells. By injecting his beacons into mice and looking to see whether his beacons had stuck, Nie could tell where cancer was developing.
Nie poured many elements of molecular design into his beacons. These needed to be small enough to course freely through the bloodstream, a requirement that prompted him to build probes that were about 10 nanometers in diameter. Each 10-nanometer beacon was itself multilayered: gobstoppers, nano matryoshka dolls. The outermost doll would be the bait, making the probes attractive to cancer cells alone, enticing them to decorate themselves lavishly in the gaudy garb of the flashy beacon: gold to a rapper, white socks and Birkenstocks to an academic. At the heart of the probe was the light-producing beacon itself, a sphere of semiconductor 5 nanometers in diameter, such a small speck of matter as to be called a quantum dot. The color of light it produced, and the purity of this color, would be of profound importance. A characteristic hue would allow it to be seen against the undistinguished glow emanating from all flesh illuminated by a laser. Nie would engineer his quantum dots to produce as pure a tone as possible, and thus stand out against their background.
In Newton's world of classical physics, the atoms that go into making a piece of material determine fully the color of light it will produce. It’s chemistry alone, and not the size of the particle, that matters. In the quantum world, however, the rules are different. When nanometer-sized objects are to be built, both the atomic constituents and the physical size and shape of a particle are important. The electrons that orbit atoms were declared by modern physics a century ago to be wafting waves of probability. Like guitar strings, we may tune electrons’ lengths and frequencies by changing their length. By controlling the size of his quantum dots—his beacons—Nie engineered particles that produced light with a distinctive orange-red hue. In this way he created contrast, allowing the nanoparticles’ bright orange splash to be readily discerned against the indistinct background of the mouse’s own glow.
Nie then set about attaching designer-molecular Velcro to the outer surfaces of his beacons. The outermost layer, the one seen by the mouse’s cells, would be made out of proteins, molecules engineered to stick only to particular cells: those showing signs of cancer. Previous researchers had already found the molecular key that fit particularly well into locks on the surface of human prostate cancer cells. Nie would decorate his beacons with this specially designed fluffy Velcro chosen to stick to the cancer cells. The beacons would announce only the cancer cells to be detected.
The quantum dots and the sticky proteins were so different from one another that Nie had to find a way to bind them together securely. He first wrapped his nanoparticles in a dense foliage of molecules pointing outward from the surface of the semiconductor particle—using nanometer hairs to make a furry quantum ball. One end of each molecule was designed to adhere strongly to the dot, the other to keep the dots well separated from one another. These spacers would keep the quantum dots from clumping together and losing the distinctiveness of their light-emitting properties, a behavior that arose from their precisely tailored size. The molecules with which they capped the surface of their dots created an insulating lifejacket, helping to keep the quantum dot afloat—dissolved in the bloodstream—and to preserve safe within the quantum dot the energy that would be injected to make it produce light. The brightness of the quantum dot probes—and thus the detectability of cancer in as few cells as possible—depended on the design and robustness of these capping molecules. To tell dim dots from tissue’s native light-emitting properties would be like trying to distinguish a cream-of-peach color against an eggshell-hued backdrop.
Next in Nie’s design was to stick on the double-sided tape that would allow him to decorate his beacons in cancer-cell-recognizing molecules. For these he used polymers—molecular chains composed of many links. Making this layer of molecules as sticky as possible required the researchers to design many anchor points for the specific-binding protein layer that was to follow. More docking stations meant more specificity: his beacons would stick to cancer cells and nothing but, and the culprits alone would glow brightly.
With the final protein layer added, Nie set about proving that his strategy worked. He first showed that, in a Petri dish, his quantum dot probes stuck only to human prostate cancer cells. By taking a known key and attaching it to the surface of his beacons, he had not compromised the specificity and strength of the previously designed tumor cancer-seeking molecules. Curving the fluffy half of designer Velcro around his dots left the molecules sticky and picky.
Nie then introduced the probes into the mice, using a syringe to inject his mixture into the tail vein. He illuminated the mice to power up the quantum dots, giving his nanoparticles the energy needed to produce their characteristic glow. He looked at his subjects using a camera and a filter that passed only the colors specific to his quantum dots.
It worked: they detected the cancer cells. A bright orange light shone out from the sick mice, and its glow emanated from the point where they had injected human prostate cancer cells. If it can be translated into human patients, Nie’s experiment could mean early diagnosis of cancer without surgery or tumor imaging. If surgery is necessary, Nie’s method could mean “live,” continuous, cancer-specific imaging throughout the operation, allowing the removal of the now brightly glowing tumor.
Nie set the stage for further improvements on his technique. He had chosen a particularly self-revealing form of cancer: human prostate cancer gives itself away by waving a single, distinctive pirate flag on the surface of affected cells. Not all cancers do. Many, though, do display a distinctive combination of signs, and Nie’s experiment will allow researchers to look for such combinations. He designed his beacons to allow a few different markers to be attached, and he made his beacons color-tunable so that he could follow the whereabouts of multiple probes. Multi-marker probes could one day open cancer’s more abstruse combination locks.
When many different markers have to be followed, the number of beacons that we need to distinguish will grow beyond the set of colors in our palette. Nie has also made optical nanobarcodes, a collection of complex, multicolored, multi-quantum-dot optical labels. In this way he expanded the library of codes from 10 to 100,000. With these, 100,000 different types of cancer-cell markers on the surface of cells could be hunted down at once. Imagine screening for prostate, liver, bone, breast, and lung cancers in a single test—and imagine doing it at an annual checkup so that cancer never had seven years to rampage through our bodies.
Though Nie has made remarkable progress, early disease detection using quantum dots still faces important challenges. His beacons, made using the semiconductor cadmium selenide, can be toxic to cells, especially when they are illuminated using intense light. On the positive side, Nie’s polymer protection layer keeps the semiconductor surface isolated from the bloodstream. But it is not yet known exactly where the beacons end up inside the patient. Ideally, well-protected dots will be cleared from the body through the kidneys. The issue of possible toxicity, however, needs to be addressed head-on before quantum dots can be contemplated for human use. This will be a major hurdle to clear, first to satisfy researchers that quantum dots are safe, and then to gain doctors’ and patients’ confidence.
The broader importance of the work may not, however, depend on proving quantum dots to be nontoxic. Zooming out, Nie’s research revealed that a shining beacon can illuminate cancer cells inside the body, and the hunt is on for even better beacons and improved Velcro. But even once a safe, efficient beacon is found, seeing cancer in mice does not prove that we can see it in humans. Our organs lie hidden beneath deep layers of tissue that visible light will barely penetrate. Light from a few quantum dots circulating in blood will already be subtle, and a layer of absorbing tissue between them and the camera will make resolving tumors deep within impossible.
There is a solution, however. Light in the infrared—not visible to us, but just as real and powerful as visible light—travels more readily through tissue. Cameras and filters are available in the infrared as they are in the visible. An MIT–Harvard Medical School team has shown that beacons that glow in the infrared can be used to see the lymph nodes of mice and pigs during surgery. The surgeons, guided by their infrared camera, fully removed the quantum-dot-labeled lymph nodes and satisfied themselves of the success of their operation before it was over. These infrared quantum dots had, however, lost their light-producing capacity too rapidly, dimming as optical beacons. My group at the University of Toronto recently announced that it is possible to build beacons in the infrared that keep their brightness in blood plasma over days and weeks. We built particles directly on a biomolecule, DNA taken from a calf, to protect the semiconductor particles within a molecular wrapper. The particles glowed brightly and stayed bright in blood at body temperature. By using the structure of DNA molecules to program the growth of nanoparticles of just the right size, we managed to produce light that would flow deeply into live tissue.
All of these breakthroughs need now to be brought together. Already each team has broken through traditional boundaries that artificially slice research into chemistry, physics, biology, and engineering. Now teams spanning basic science, engineering, and medicine need to translate basic discoveries, with the tools of engineering, into the operating theater.
A visit to the doctor might one day involve swallowing a pill containing color-coded Christmas tree lights that stick only to renegade cells within nascently cancerous prostates, esophagi, and brains. Surgeons could ensure that they had fully removed emergent tumors without needing to remove excess margins of surrounding tissue. With such early diagnosis, we can envisage a world in which we do not give cancer the time to run rampant.
Sorting through Cells: Molecular Spring Cleaning
Shuming Nie’s molecular beacons put nanometer-sized probes inside the patient. Reading these probes and extracting the results happens outside of the patient through the combination of lasers, cameras, and computers. To add to the set of diseases that can be diagnosed—new forms of cancer, or genetic diseases such as cystic fibrosis—new probes with new selectively sticky surfaces need to be developed.
Another approach is being pursued: put the lab inside the patient. Biochips, also known as the lab-on-a-chip, might one day enter into their subjects: colonize the patient rather than stand on the outside and observe, arms crossed. Just like the chips inside our computers, biochips can perform millions of precise experiments in the blink of an eye. Unlike silicon chips, biochips’ currency is not limited to a single form—the flow of electrons representing digital information. Instead they deal with cells and their insides; the machinery of proteins that make life happen; and the genetic code that is DNA, which contains the assembly instructions for the machinery of life. Biochips go beyond the Spartan, pure, inorganic world of perfect digital logic, augmenting it with the liquid innards of cells: wet, slippery, organic life slithering atop a rigorously logical chip—the marriage of Beauty and Brains.
Biochips allow us to merge the narrow but impressive performance of computation with the admirable elegance and variety of biology. The union provides us with new ways to understand what goes on within ourselves. Life is complex, and in ways not fully understood, in many realms of size: sub-nanometer atoms, many-nanometer proteins, long but narrow DNA molecules, micrometer-sized cells, colonies and organs and people from the sub-millimeter to the many meters. The relationships among these lengths form a hierarchy without which life as we know it would not function. If each layer did not build on the next, we would be less sophisticated than fungus, our sentience a truffle.
Quantum dots touch on one or two layers in the hierarchy—binding to proteins that reveal cancer, clumping into groups the size of tumors. Biochips could span a greater range, which in disease is important. The nanometer scale is undoubtedly important: What happened in our genes that led to cancer? How have proteins been affected? Questions on a bigger size scale are important as well. Could a 100-nanometer virus be engineered to combat selectively the guilty cells? How does a cell’s environment—including the society of surrounding cells—create pressure for negative behavior? Could the cell gone wrong reform its behavior if placed among the right crowd? Biochips could get us closer to looking at these interactions—and the cures to disease that they could provide.
Systems biologists study the relationships between nanometer-sized details and our own day-to-day experiences. How do genes and proteins result in coughs, orgasms, the spilling of coffee, the curvature of hips? If we could understand how human reality evolves out of the chemistry of molecules, then we might control our fate: engineer improved Greta Garbos, subjugate cancer, master depression, overcome or at least slow ageing. Or make our skin convert sunlight to sugar and our eyebrows consume dangerous greenhouse gases.
Experimental systems biologists fantasize about performing experiments that would help us understand how function arises from structure. Consider what we might wish to do to understand, with a narrow category of cells, how a number of signaling molecules influence the cell’s fate. How do different proteins program cells to relax, reproduce, or die? The answer will depend on the cell’s stage of life: whether it is in early childhood, adolescence, parenthood, middle age, or retirement. And the proteins will also influence the cell’s stage of life. This is an example of feedback—loops of causality that circle back on one another.
All of these variables necessitate an array of experiments. Huge numbers of cellular subjects must be recruited and interviewed about their most personal daily habits. Identical cells would be placed in a separate compartment for individual study. Each compartment would be furnished with a personal webcam to monitor the habits of each cell. Systems biologists demand to witness nanometric intrigue, resolving new plot twists every trillionth of a second. Their voyeurism knows no bounds: details of fluids excreted in replication titillate. Cells’ reproductive scatology beguiles. The cell’s fluid samples are not generous; each one contains a trillionth of a quart of liquid. It is reasonable to ask cells to donate one-thousandth of this quantity in the name of science. Nanotechnologists are successfully analyzing femtoliters of goo.
Biology is not chemistry alone—it is architecture and mechanical engineering as well. A community of cell biologists attributes tremendous importance to the role of tension and compression in the cell’s skin and skeleton. These give the cell structure and connect it to its neighbors. Cell biologists poke and prod their cells one by one using the tips of atomic-force microscopes, studying how cells behave when push comes to shove. The lab-on-chip community needs to make millions of such controlled stimulus–response interrogation rooms to witness the cell’s response to the good cop–bad cop routine.
The territory to be explored within each cell is vast indeed. Imagine a group of tiny scientists donning micrometer lab coats and wielding nanometer syringes, performing their batteries of tests systematically and reporting their findings to central headquarters. The research needs to be automated, and systematizing millions of repetitive tasks cries out for the power and performance of computers. Nanosystems biologists espouse putting nanolabs-on-a-chip to work around the clock to help them unlock systematically the remaining secrets of life.
Linking Life, Chips, and People
Labs-on-chips and nanometer probes link the logical and the biological—the computational and the sensational, and the dry and the moist. They open avenues to applying our most powerful human-made engines of analysis to the most intricate, fascinating system ever engineered: the organism. With the human genome sequenced, we have read the string of letters that make up the book of life, but we know only a little of what they mean. We are at the earliest stages of decoding life.
When we do understand in detail how and why we work, we will unquestionably be able to intervene. There are at least two dimensions to the ethical future of biology understood well from the bottom-up: what do we do with the information, and what do we do with our newfound power to effect change?
On the matter of information: If quantum dots, labs-on-chip, and whatever else nanotechnology gives us can monitor and sort cells based on disease, and report back—say, over the wireless Web—then to whom shall they report? To your physician, presumably. Your insurance company too, though, might like to know about your early-morning mutation.
If we can begin to intervene in our own biology, where will it end? If we could rescue cancer patients, prolong the duration and quality of their lives, then we would not hesitate to do whatever it took. What else would we be willing to do, especially since less morally unambiguous possibilities will likely come to us before the curing of complex, dreaded diseases? How short does a prospective new child need to be before we call social disadvantage a disability? Will genetically preprogrammed nasal aquilinity be downloadable off of the wireless Web? Today we interfere abundantly with the course of life, heroically and without reserve. Nanotechnology will further increase our power to change the course of life. Our new powers will come with new responsibilities—and for this we shall rely on our individual and collective will and ethics, two areas in which scientists can provide information as to our growing capabilities, but citizens will have to add their resolve.
