Reconstructing tissue architectures from scratch.
How do organs such as the lungs or kidneys generate the intricate, treelike internal anatomy essential to their function? To find out, Celeste Nelson developed a lab technique for growing structures from simple shapes like the ones from which organs begin developing in the embryo. Nelson knew, for example, that lungs begin as an inverted Y. By experimenting with different shapes, such as a T instead of a Y, she discovered that the exact form of these initial structures plays a pivotal role in how the tissue’s sophisticated architecture develops. Different starting shapes produce different patterns and concentrations of signaling molecules. The molecules cause growing branches to repel each other. Subsequent mechanical stresses in the branches determine where new branches will begin to develop and, in turn, produce their own signaling molecules. Other researchers had previously theorized that geometry matters in tissue development. But Nelson’s technique–adapted from a process originally used to make computer chips–allowed her to prove it for the first time, and to spell out the mechanism involved.
Nelson, now an assistant professor of chemical engineering at Princeton, has worked with her group to identify several genes that need to be present and functional for branching tissue to develop properly, and they are trying to figure out how those genes work together to orchestrate the process. She hopes that understanding how branching normally happens will reveal ways to intervene when it goes awry. Recent work has shown, for example, that the signals that spur branching–which are typically silent once development is complete–are reawakened in some tumors. In addition, her techniques for building three-dimensional tissue structures could ultimately be used to help engineer replacement organs.
Reprogramming cells to cure diseases.
Mere months after Kyoto University researchers announced in 2007 that they had discovered how to turn skin cells into induced pluripotent stem cells (iPS cells), Jacob Hanna used these new types of cells to cure mice of sickle-cell anemia, in which a genetic defect causes bone marrow to make defective red blood cells. Hanna, a fellow at the Whitehead Institute, took skin cells from a diseased mouse and reprogrammed them create iPS cells, which behave like embryonic stem cells, readily turning into any cell type in the body. He then corrected the sickle-cell genetic defect and prodded the iPS cells to develop into the type of marrow stem cell that manufactures a mouse’s blood cells. These healthy cells were transplanted back into the mouse, whose immune system accepted them as the animal’s own tissue. The treated mouse began producing healthy red blood cells on its own.
Hanna’s work was a turning point for iPS research, says George Daley, director of the Stem Cell Transplantation Program at Boston’s Children’s Hospital and a professor at Harvard Medical School: “It was a beautiful demonstration of a mouse model of a human disease, and really demonstrated the potential of iPS cells.”
Before iPS cells can be used to treat diseases such as sickle-cell anemia in humans, a lot of work has to be done to make sure they won’t cause adverse side effects and to improve the efficiency of deriving them from skin cells. Hanna is now developing simulations to understand what happens when cells are reprogrammed, and he’s searching for new types of human stem cells that could be easier to turn into adult cells.
Portable devices for monitoring brain activity.
The study of sleep has been a cumbersome affair. Test subjects must spend the night on a laboratory bed, hooked to machines by over a dozen leads. The next day, a technician scores the machines’ output by hand, categorizing each 30-second interval by stage of the sleep cycle.
Philip Low, seeking a better way, created an algorithm that can classify sleep stages using data from just a single EEG lead. In 2007 he founded NeuroVigil, a startup based in La Jolla, CA, that manufactures a sleep-monitoring device based on the technology.
The device is small enough to be worn on a headband, so subjects can sleep at home rather than at a clinic. To make life even easier for subjects, the company is developing a version of the device that gathers data and beams it to a subject’s cell phone, which can then send it wirelessly to NeuroVigil for analysis.
Pharmaceutical companies use the device to watch for brain-related side effects when testing therapies for disorders of the central nervous system. NeuroVigil has used these trials to amass a database of readings from patients with particular diseases. Low hopes that by mining this database, he will discover EEG signatures in the data that might warn of conditions like Alzheimer’s, schizophrenia, or Parkinson’s before symptoms appear.
Engineering viruses to destroy biofilms.
At Harvard Medical School, many of Timothy Lu’s patients were being attacked by carpets of microbial goo. They had “really bad infections,” Lu says. “Patients with cystic fibrosis, people getting infections in their catheters. All caused by biofilms.”
Lu, who is now an assistant professor at MIT, began researching how to destroy biofilms. But unlike those who had previously attacked the problem, he took advantage of the new tools of synthetic biology. He engineered a type of virus, known as a phage, to destroy biofilms and sabotage their defenses against antibiotics. His accomplishment could produce synthetic biology’s first big commercial success by attacking the biofilms that infest industrial equipment.
When bacteria settle on a surface, they spew out molecules that bind the entire population together and cover it in a protective shield. Bacteria in these biofilms are up to 500 times more resistant to antibiotics than free-floating microbes are. Normally, viruses have a hard time penetrating the dense layers of a biofilm. But Lu stumbled across an enzyme produced by oral bacteria that can break up biofilms. He inserted the gene for the enzyme into a phage called T7 so that when the virus infects a microbe, it makes as much of the enzyme as possible.
When the engineered T7 is unleashed on a biofilm, it invades the top layer of bacteria. These bacteria soon burst open, spilling out enzymes and new phages. Aided by the enzyme, the viruses then penetrate the next layer of bacteria, repeating the cycle until the biofilm is destroyed. Lu and his colleagues have also found other ways to turn phages into effective weapons against biofilms, such as creating versions that can shut down the genes that bacteria use to defend themselves against antibiotics.
Last year Lu cofounded Novophage (now called Ascendia Biotechnology) to develop commercial applications for the phages. The company is initially concentrating on biofilms that Lu says can corrode water pipes and block heat transfer in heating and cooling systems, decreasing energy efficiency by up to 80 percent. Conventional industrial attempts to deal with biofilms have involved scrubbing pipes, applying chemicals, or exposing the films to ultraviolet light, but these treatments are not very effective, can damage piping, and are toxic to humans and the environment. A small injection of phages into a water pipe, however, could clean an entire system, with the phages replicating themselves as they consume the biofilm.
Who better to determine which fledgling technologies should form the basis of new venture-backed biotech companies than someone who’s helped develop significant new neurotechnologies and has firsthand experience with launching a revolutionary startup? In 2001, Mikhail Shapiro, still a sophomore at Brown University, cofounded a company called Cyberkinetics to develop implantable devices that would allow quadriplegics to control external devices with their thoughts. Shapiro, then 20, ran the business side of the company and helped raise its first $20 million in venture funding, which led to groundbreaking clinical trials. “His knowledge of the business world even at that young age was frightening,” says cofounder John Donoghue, a professor of neuroscience and engineering at Brown, who was chief scientific officer of the startup. Though Cyberkinetics has since folded, the results of its pilot trials proved that this type of technology could work, and they brought new funding and interest to the field.
Shapiro then earned a PhD at MIT, where he developed a noninvasive imaging technology for observing chemical messengers in the brain. Since joining Third Rock Ventures in 2008, he has led the venture capital firm’s efforts to evaluate neurotechnologies such as optogenetics, a method of controlling the brain with light. So far he has helped found two more companies, with combined funding of $50 million. One is focused on a new pain drug and the other on using personalized medicine to fight cancer.
Inexpensive microfluidic chips for diagnostics.
Using cheap components and few moving parts, Samuel Sia, an assistant professor at Columbia University, has helped create a microfluidic chip that tests blood samples for multiple diseases and is practical for use in poor countries. The chips cost pennies instead of dollars to make, and the results are read with a small battery-powered device.
Inventing the technology was just one step: Sia has given equal emphasis to getting it used. He and his partners wanted to develop microfluidics for use in poor countries, but they realized they would have trouble finding funding for such a venture. So in 2004 they founded a company, Claros Diagnostics, to create a prostate-cancer monitor for use in the United States and Europe. They received $7.8 million in venture funding in 2007, and marketing approval was granted in Europe in June of this year (see To Market, p. 21). While Sia’s partners worked full time on that device, Sia modified the technology to create a test for sexually transmitted diseases, including HIV, syphilis, and hepatitis.
Intending the test for use in Africa, he then orchestrated a number of field trials in collaboration with Columbia’s school of public health and the Rwandan government. His efforts have progressed further than many other attempts to deploy new medical technologies in the developing world, but he still faces the hurdle of finding funding to commercialize the chip. “There are mechanisms to get money to develop new technology,” he says. “But getting funding to implement it [on a broad scale] is very difficult.”