Pehr A. B. Harbury
Rational drug design and combinatorial chemistry are the Felix and Oscar of biochemistry. The first aims to design new compounds from scratch–the other scoops them up after a throw of the chemical dice. But these opposites are no odd couple in Pehr Harburys hands. Harbury specializes in the finicky, Felix-like business of designing proteins on a computer, modeling them down to the level of individual atomic bonds. The goal is to create proteins that can catalyze chemical reactions that are not naturally found in living organisms. If successful, “designer enzymes” could revolutionize synthetic organic chemistry and provide new tools for drug discovery.
Like Oscar, the lab’s second line of research loves a gamble. Harbury is coming up with ways to produce better drugs via “molecular evolution.” This variant of the combinatorial chemistry theme is a trial-and-error method that mimics how the body’s immune system fends off invading pathogens by mixing and matching molecules until it hits on just the right antibody. According to Harbury, this two-pronged approach is a good bet to adapt life’s mechanisms in ways that serve both science and medicine.
The ubiquity of plastic in today’s consumer culture is annoying, but bioengineer Kristi Anseth wants to see plastic really get under your skin.Anseth develops new types of photopolymers,plastics that go from soft to hard when struck by ultraviolet light.Similar materials are used by dentists to plug cavities,but Anseth has invented novel photopolymers that actually wear away over time—a feature that promises much for orthopedic repairs. The idea, says Anseth,“is to have the polymer material degrade predictably and on schedule with the body’s own bone healing.”
Anseth’s polymers are now being tested in mending serious fractures and patching holes left by bone cancer. With precise control over the speed at which the polymers dissolve,Anseth envisions implants that might also release timed doses of bone-healing growth factors.
Tissue engineering is up next.Anseth is working to combine photopolymers with lab-grown cartilage to create a living implant that can mend worn-out joints. It is a more difficult problem than patching bone,according to Anseth,because “cartilage does not
have the capacity to heal itself the way bone does.” Collaborators at Massachusetts General Hospital in Boston are testing Anseth’s technique in animal models. Anseth’s ability to wring the most out of materials is evidence of a “superior creative genius” according to Robert Langer, an MIT professor and the father of modern biomaterials.
So far, says a recent Natureeditorial, molecular biology has produced only a “cartoon representation” of life’s myriad molecular pathways. And although “superb papers have been written for the purpose of adding a single arrow to an existing cartoon,” Nature’s editors concluded that the agenda for the next century is to add numbers to each arrow, and then equations to connect the arrows—only then will we learn to control specific processes when they go awry, as in cancer.
In a study hailed as a “benchmark for all future papers in the area,” Adam Arkin created a computer model connecting the arrows of the genetic circuit that controls when a bacteriophage virus decides to begin reproducing. Biologists had advanced several reasonable theories, but Arkin and his Stanford advisor Harley McAdams proved that the virus decision is in fact determined largely by chance chemical events.
A rising star in Lawrence Berkeley’s physical biosciences division, Arkin wants to go way beyond viruses, creating computer simulations that explain how genetic “switches” are thrown during human development to orchestrate the formation of our bodies. To get there, Arkin is developing a generalized modelling program known as Bio/Spice, named after software used by engineers to analyze electrical circuits. Arkin’s work foreshadows the biology of the next decades, when researchers begin to understand and control the cell’s own circuitry.
Without James Collins, stochastic resonance might have ended up science trivia–now it may give a big boost to patients. Stochastic resonance is a paradox in signal detection: Adding noise to a signal can sometimes make it easier to perceive. Collins had the outside-the-box idea that electrical noise could make mechanical signals easier for people to sense. It does: He found that people feel otherwise undetectable pricks in the presence of low-level electrical noise, opening the way to sensory prosthetics for touch-impaired diabetics, stroke patients and the elderly.
What’s more, Collins has taken similar approaches down to the
biomolecular level, showing how electric fields can cause controlled increases of protein production in laboratory bacteria. According to former BU colleague Charlie Cantor, now chief scientist at Sequenom, a San Diego biotech company, this physics-based approach to biology is totally new. Collins, says Cantor, “is applying nonlinear dynamics principles and methods to build molecular control systems to change the properties of living cells. This kind of work has the potential to revolutionize areas like gene therapy.”
Sandro de Souza
Genome research is big science–and it costs big bucks, which is why it’s centered in the United States, Europe and Japan. But thanks to scientists like Sandro de Souza, developing nations, such as his native Brazil, are not entirely out of the game. De Souza’s specialty is bioinformatics: computer-driven gene research that’s relatively cheap to get into, and where there’s great science to be done. As a postdoc in Nobelist Walter Gilbert’s Harvard lab, de Souza helped solve a crucial mystery in the evolutionary history of genes, a breakthrough Gilbert attributes to de Souza’s “technical abilities and profoundly creative insights.”
Now de Souza is home, where he says he is turning bioinformatics into “an opportunity to do front-edge science” in his native country. He works for the São Paulo arm of the Ludwig Institute for Cancer Research, a global research institution that’s partnered with local government to launch a gene discovery project. Heading up the bioinformatics branch, de Souza will play a key role in unearthing genes associated with stomach and breast cancers–tumors especially prevalent in São Paulo, where cancer is the leading cause of death. De Souza will organize the genes into a database accessible to scientists worldwide, including collaborators at the National University of Singapore’s Bioinformatics Center, where de Souza is also a faculty member.
Microelectromechanical systems, or MEMS, are millimeter-scale machines etched from silicon. These Lilliputian devices are opening up whole new frontiers in areas from communications to energy production (see “May the Micro-force Be With You,” TR September/October 1999). Tejal Desai aims to see MEMS conquer another field: bioengineering. Desai is using micromachining to create tiny implants that can carry needed cells into ailing bodies, all the while protecting them from attacks by the immune system. In one project, she prototyped a biocapsule for diabetics designed to deliver pancreatic cells to boost insulin production.
“She’s rapidly becoming one of the most established researchers in the biomedical applications of nanotechnology and bio-MEMS,” says Mauro Ferrari, director of Ohio State’s Biomedical Engineering Center. At just 26,Desai became the first professor hired into the University of Illinois newly created department of bioengineering, whose director Richard Magin says, “If I could clone Tejal, I would.” Luckily, Desai is already working to clone herself: She’s deeply involved with organizations that encourage girls and minorities to study math and science.
Like many inventors-to-be, Daniel DiLorenzo was fascinated with electricity and moving parts at an early age. By fifth grade, he’d assembled his first electrical circuit. As a high school senior he built a four-legged robot, and by the time he graduated from college he’d designed a digital control system to make the robot walk.
Despite his aptitude for hardware, DiLorenzo always wanted to be a doctor. So he set out to become a physician-inventor, and in June earned both a PhD in mechanical engineering from MIT and an MD in a joint Harvard-MIT program. Innovations like a patented method to control brain swelling during surgery and a project that used muscle-stimulating electrodes to enable a spinal-cord injury patient to walk 20 meters in the lab earned DiLorenzo this year’s $30,000 Lemelson-MIT Student Prize for Invention.
DiLorenzo started his residency at the University of Utah Medical School this fall, and is set on becoming an expert in functional neurosurgery. DiLorenzo is likely to play a key role in this emerging discipline, which looks to combine electronic brain implants and nerve stimulation to restore motion to the paralyzed and lost senses to the blind and deaf.
John Dobak is as persistent as frost on a January windowpane.
Working in the dermatology clinic during his med school residency, Dobak was trying to freeze a wart off a patient using cryosurgery—the destruction of tissue by the application of extreme cold—when he tipped over the day’s supply of liquid nitrogen. After resorting to a simple, plug-in electric scalpel, Dobak started wondering why there weren’t any equally cheap and efficient devices for cryosurgery. He never let the question drop.
Operating from home,and funded by his VISA card, Dobak designed and patented a “closed-cycle” cryogenic device that wouldn’t leak chilled liquids. After hitting a dead-end marketplace in dermatology and initially rebuffed by the technological challenges of cardiac surgery, Dobak eventually launched his first company, Cryogen, to make a new instrument for gynecologic cryotherapy.
The simple,compact cryo-device the firm developed has won design awards for its ease of use, and is now being tested for treating excessive menstruation by freezing the cells that line the uterus. The approach may prove safer and cheaper than alternatives such as hysterectomy. This year Dobak started Innercool Therapies, which is working on a Dobak- designed catheter that slows damage from strokes by chilling blood on its way to the brain. With eight patents issued, and another eight pending, Dobak’s inventions have so far garnered a cool $42 million from venture capitalists.
The eye is one of Nature’s great engineering feats–a delicate combination of optics, mechanics and electronics. For biomedical engineer Patrick Jensen, healing sick or blinded eyes is an opportunity to display similar virtuosity.
As co-director of the MADLab, the Microsurgery Advanced Design Lab at Johns Hopkins University’s Wilmer Eye Institute, Jensen works to join electromechanics, optics and software in order to extend the limits of the surgeon’s perception and dexterity. One example: force-feedback robotic systems that speed up operations and make them safer by enabling surgeons to “feel” the fragile retina as they repair it. Jensen’s lab is a key player in a 10-year,National Science Foundation-sponsored collaboration with MIT and Carnegie Mellon on computer-enhanced surgery.
Unlike researchers who invent new technology and then go looking for applications, says Matthew Glucksberg, who heads the Northwestern University bioengineering lab where Jensen did graduate studies, “Patrick’s real strength as a technologist is that he sees the physiological problem.” Jensen also knows what it takes to see new inventions into clinical use; the MADLab works closely with commercial partners and has licensed 30 products.
Male contraception (i.e., the lack thereof) has been a hot topic in recent years. The research Bruce Lahn does might help bring that elusive commodity closer to reality. Lahn’s expertise is human genetics. For his PhD thesis under David Page at the Whitehead Institute, he took on the gargantuan task of cataloging the genes of the human Y chromosome, which distinguishes males from females. In the process he increased the number of known Y genes from 8 to 20. But that achievement was just a warm-up.
As a postdoctoral researcher, Lahn reconstructed a detailed evolutionary history of the Y chromosome and dug into functional studies of the newly found genes. He demonstrated that the Y chromosome carries a wealth of genes implicated in male fertility, a discovery that could open the way for new infertility treatments, perhaps even a male birth control pill that would work by deactivating key genes. Lahn’s undertakings have wowed colleagues, one of whom says that it’s his ability to invent clever experimental techniques that lets Lahn single handedly generate “as much data as a medium-sized laboratory.” Expect Lahn to take on even bigger projects; he’s just arrived at the University of Chicago to set up his own lab for the first time.
Christopher Lee calls it the “great anticlimax” of the Human Genome Project. “We’ve generated massive amounts of data. If we could only figure out what it means!” As a leading designer of bioinformatics software, Lee is doing as much as anyone to help biologists mine the mountains of data for clues to how genes work and their role in disease. Among Lee’s creations is GeneMine, a program that scours big Internet databases, compiling and analyzing information to identify the most functionally important of the thousands of human genes. Many of the world’s largest drug firms have bought a commercial version of the program, which is sold by Molecular Applications Group in Palo Alto, Calif., a company Lee co-founded in 1993 and one of the most successful players in the growing bioinformatics industry.
Lee’s latest effort focuses on “single nucleotide polymorphisms,” or SNPs, tiny genetic differences between people. He’s trying to zero in on the specific SNPs that account for physical traits and for individuals differing response to drugs. Hunting SNPs in the 6 billion bits of DNA in the human genome is no trivial task, but Lee’s enterprising lab recently built a supercomputer out of 150 400MHz Pentium II chips to speed analysis by an order of magnitude. “We are trying to make the most intense meeting of data and theory possible,” says Lee.
Ouch! And ouch again! As many as five times a day, diabetics endure needle sticks, sampling their blood to ensure their blood sugar remains within healthy limits. Samir Mitragotri envisions a day when measuring glucose levels is bloodless–and ouchless.
The Bombay native invented a way to use low-frequency ultrasound to make skin super-permeable (a process known as sonophoresis), then suck out interstitial fluid with a vacuum. This fluid, which bathes the space between cells, also gives a measure of glucose concentration, and Mitragotri co-founded a company, Sontra Medical of Cambridge, Mass., that’s raised $7 million to commercialize the idea. With 16 million diabetics in the United States the need and the market are both considerable.
Sonophoresis can also be used to pump drugs across the skin, but it was only when Mitragotri showed how low-frequency waves make the process 1,000 times more efficient that it became possible to consider transdermal delivery of big protein molecules such as insulin. Combining ultrasound diagnostics and drug delivery, Mitragotri says, could lead to a closed loop, wristwatch-sized device that automatically monitors and adjusts glucose levels. That would make diabetics lives not only pain-free, but carefree as well.
Credit David Mott with helping send MedImmune to the top tier of today’s biotechnology companies. In 1992,Mott left a job as a Wall Street investment banker to oversee business development at MedImmune. But the enterprising Gaithersburg, Md., company hit hard times when a flawed drug study prompted the Food and Drug Administration to nix approval for RespiGam, a first-of-its-kind treatment to prevent respiratory infections in newborns.
Investors drove MedImmune’s stock to an all-time low of $2 per share. Then Mott stepped in, assuming responsibility to get the drug back on track.
RespiGam won approval in January 1996.By then Mott had risen to become president and chief operating officer, leading the young company’s successful market launch of its first product. Growing sales have driven the firm’s stock price over $100.
Merrill Lynch biotech analyst Eric Hecht says, “David is probably the most adept young executive I’ve ever met, and moves the ball from A to B better and faster and with more energy than anyone.”
Thanks to driven leaders like Mott, MedImmune’s other research programs, including a vaccine against urinary tract infections, stand a better chance of making it to market.
Cancer is out-of-control growth, caused when a cell’s molecular brakes wear out, or its gas pedal gets stuck. Fixing cancer means getting under the hood, and Nikola Pavletich is fast becoming one of the field’s pre-eminent grease monkeys.
Pavletich uses X-ray crystallography to map the three-dimensional shape of the molecular components that control cell growth. It’s exacting work that’s usually done far from the limelight of the latest miracle cure. But Pavletich’s depiction of the structure of the tumor-supressing protein p53 in its molecular embrace of DNA landed his work in a Newsweek cover story. The reason? p53 plays a role in half of all cancers, and Pavletich’s pictures of the protein in action showed how it can malfunction. The work is a first step toward new drugs that prevent cancers, rather than just killing tumors with devastating side effects to patients. Pavletich’s technical skill is matched by a growing reputation for bold science. “Nikola is absolutely fearless in his choice of projects,” says Carl Pabo, an MIT biology professor and Pavletich’s postdoctoral advisor
In pharmaceutical companies around the globe, chemists labor for untold hours tweaking newly discovered drugs so that they will enter the bloodstream and reach their targets more effectively. Mark Prausnitz takes a different approach: “I’m choosing to manipulate the body, and have it let the medicine in.” As a grad student, Prausnitz showed for the first time how short electric pulses could move large quantities of drugs across the skin,a phenomenon known as electroporation. That approach could help in treating tumors and autoimmune diseases.
Since joining the Georgia Institute of Technology’s chemical engineering department, Prausnitz and colleague Mark Allen invented a 10-millimeter-square array of silicon needles (each 150 microns long) that make microscopic holes in the skin and can painlessly pump drugs into the body. The device could offer the convenience of skin patches, but administer a much wider variety of drugs. A startup company, Redeon of Cambridge, Mass., is working to commercialize the invention.
Carmichael Roberts greatest invention is himself. A scientist with entrepreneurial dreams, colleagues say Roberts has poured unmatched energy into his transition from lab bench to boardroom. After carrying out world-class glycobiology research for his PhD at Duke, Roberts co-founded NPG Research, a nonprofit institute that’s landed funds from biotechnology companies and the National Institutes of Health to turn his science into lifesaving drugs. Soon, it was on to an apprenticeship in the for-profit realm when he joined Union Carbide, a chemical firm trying to break into new life-science businesses. After breezing through an eighteen-month training program in four months, Roberts started sizzling up the ranks. But entrepreneurship beckoned, and he headed to Boston where he’s getting an MBA from MIT’s Sloan School of Business.
Roberts didn’t wait long before launching his first venture. His startup company, Surface Logix, which he co-founded this year with Harvard nanotechnology guru George Whitesides (see “Nanotech: Art ofthe Possible,” TRNovember/December 1998), is looking to commercialize a chemical approach to microfabrication. Handing over the promising technology to Roberts doesn’t worry Whitesides, who says, “Every one of Carmichael’s instincts is what I expect from an entrepreneur with 15 years more experience.” Beyond his scientific and business skills, Whitesides says it is Roberts’ outstanding human qualities–enthusiasm, humor, courage and caring–that guarantee his success organizing and motivating others to move innovations into the marketplace.
Everybody knows that, in fashion, it’s accessories that really make the outfit work. Sometimes that’s true in biochemistry, too.
For instance: a protein’s functionality often hinges on the addition of a carbohydrate molecule. Consisting of chains of oxygen, hydrogen and carbon atoms, carbohydrates play a key role in everything from healing wounds to heart disease. Yet their chemistry remains somewhat mysterious, partly because they’re tough to make in the lab. Biochemist Peter Seeberger has set out to change all that.
A transplant from Nuremberg, Germany, Seeberger has already dreamed up new ways to string carbohydrates together from their simple sugar building blocks, and also spearheaded the assembly of the most complex carbohydrate ever made by man. Seeberger’s work, says University of Colorado chemist Marvin Caruthers, sets the stage for an automated carbohydrate-making device that could “profoundly influence biochemistry and medicine.” In Seeberger’s lab newly synthesized carbohydrates are already being exploited to probe how cells transmit signals, as well as how immune-system cells recognize HIV and parasites. Those insights could lead to new ways of targeting gene therapies against pathogens, and potent new cancer vaccines. Whether those specifics materialize or not, expect Seeberger to be a leader in discovering how those tricky cellular outfits really go together.
Matthew Shair makes and studies complex molecules at an extraordinary rate. His research is an engine driving important discoveries at Harvard’s new Institute for Chemistry and Cell Biology (ICCB), an interdisciplinary collaboration that teams chemists, biologists and medical school faculty with industry researchers. Shair’s molecule-making technique is called split-pool organic synthesis, an iterative process that requires highly skilled chemistry and yields vast numbers of distinct, manmade compounds that are as complex as anything found in nature.
Shair’s talent surfaced early. As a postdoc in the lab of ICCB director Stuart Schreiber, he spearheaded a project that generated more than two million compounds. Those molecules are a critical enabler of “chemical genetics,” a new paradigm for rapidly analyzing the functions of newly isolated genes. “Matthew is on his way to establishing a breakaway research program,” says Schreiber.Merck and other corporations contribute heavily to ICCB to see early results from this work. Their bets are not misplaced.
The microscope. The X-ray machine. PCR.Every once in a while, a technology comes along that transforms the way biologists see the world. The latest in this lineage is the DNA chip: a combination of chemistry, imaging equipment and genetics that allows scientists to peer into a cell and measure the activity of its genes, tens of thousands at a time. Within a few years of their debut, DNA chips have transformed genome research and sped up the search for new drugs. This process wouldn’t have happened as fast without the work of technologist/entrepreneurs such as Dari Shalon. In 1992, as a Stanford PhD student, Shalon co-invented a type of DNA chip–and immediately saw its commercial potential. Shalon beat competitors to the punch with a clever business plan in which his startup firm, named Synteni, did experiments on the cheap for customers rather than selling them big costly systems. The rest is history. Synteni was a smash hit, and was soon bought out by Palo Alto, Calif., gene giant Incyte Pharmaceuticals.
Recently, Shalon’s mix of scientific, technological and business acumen landed him the director’s post at Harvard’s Center for Genomics Research, a new multimillion dollar hub for multidisciplinary life sciences research. Shalon says he’s working to build “a strong intellectual community [that] integrates research in biology, chemistry, physics, engineering and medicine.” This eclectic enterprise, Shalon predicts, will be “a powerhouse” ininventing eye-opening new genomics technologies.
One ofthe driving concepts in biology these days is an idea insiders call “The Movie”: a depiction of a cell in which the action of all life’s molecules–genes, enzymes, nutrients and the like–can be seen in vivid detail, close up,and in real time. The movie doesn’t exist yet, but talented technologists including Jason Shear are working hard to bring it into focus. Combining a grab bag of advanced imaging technology and analytical methods, Shear is developing a system to record chemical communiqués between neurons as they happen–for instance measuring the neurotransmitter serotonin as it’s secreted across a living nerve cell junction, or synapse. The design will use robotically controlled silica needles, nanometers in diameter, to sample the chemicals present inside lab-grown neurons, then measure them with an ultrasensitive detection method called multiphoton excited fluorescence.
If Shear’s approach works, it will produce scenarios guaranteed to keep neurobiologists riveted. Shear hopes the denouement will be a better understanding of the chemical basis of learning. This work-in-progress isn’t Shear’s first clever invention; another scheme used nerve cells themselves as molecular detectors, and with colleague Eric Anslyn he’s developed a chemical-sensing “Electronic Tongue.”
Computer scientist Erik Winfree embodies the remarkable potential of the spot where biology and engineering meet. For his PhD project, Winfree zeroed in on the natural inclination of corresponding strands of DNA to zip themselves up into a double helix. Could such “self-assembly” reactions be harnessed to carry out basic computational processes? In work that extended existing theories of DNA-based computers, Winfree showed that the reactions should be able to carry out all the operations of a computer, doing anything from crunching prime numbers to playing chess. In Winfree’s world of biological computers, both the information “input” and the “output” come in the form of molecules. As a result, the same methods can be used to assemble nanostructures.
Imagine simple DNA elements prepared (“programmed,” ifyou will) to automatically assemble into a complex structure, like a jigsaw puzzle solving itself via chemical reactions. With New York University’s Ned Seeman, Winfree designed a self-assembly reaction to construct a two-dimensional DNA crystal. Winfree sees no reason to stop there. The DNA self-assembly approach could eventually lead to new ways of building more complex materials–even nanometer-sized electronic components–one molecule at a time.
David Baltimore, president of Caltech, where Winfree will join the faculty in 2000, calls Winfree “an unconventional thinker” whose work “will open up entire new areas of inquiry.”