Designing microfluidic chips to study cells.
Hang Lu has a flair for adapting to new environments. At 16, she moved from China to Colorado, where she excelled academically. As a postdoc, she applied her expertise in building bioMEMs – tiny devices that manipulate cells and microorganisms – to devising innovative experiments in neurobiology. Lu has designed minute mazes to test how microscopic worms learn using smell, and she constructed microscale gas gradients to help identify the sensory pathways that the worms use to detect oxygen levels. Now an assistant professor of chemical and biomolecular engineering, Lu hopes her continued worm work will yield clues to the workings of the human brain.
Silencing the genes that cause cancer.
Amassing detailed information about which human genes play a role in cancer and what their roles are is central to many efforts to fight the disease. One of the most promising new approaches to the identification of cancer-causing genes is called RNA interference, a method for suppressing genes to learn their functions. But RNAi is costly, and silences genes for only a few days at a time – not long enough for researchers to study slow-developing diseases. Thijn Brummelkamp has developed an inexpensive way to make the effect last, silencing a single gene indefinitely. Brummelkamps work “will lead to new treatments” for cancer, says MIT biologist and Nobel laureate Phillip Sharp.
Discovering how genes are regulated.
Figuring out how genes coordinate the complex phenomena of life involves more than deciphering a DNA sequence. Proteins called transcription factors control genes by attaching to DNA; discovering where each of these proteins binds is critical to understanding how genes regulate working cells. Martha Bulyk has taken the gene chip technology originally developed to measure gene activity and adapted it to determine the DNA binding preferences of proteins. The technology replaces painstaking assays with efficient screens, which could aid research on diseases that are affected by mutations in transcription factors or in their binding sites, such as hypertension, cancer, and diabetes.
Delivering more medicine from microbes.
Each year, billions of dollars worth of drugs, from insulin for diabetics to the stroke drug tPA, are made in huge vats full of microbes engineered to produce human proteins. The process is both inefficient and enormously expensive. Matthew DeLisa, an assistant professor of chemical and biomolecular engineering, was the first scientist to use a twin arginine translocation (Tat) pathway to produce human proteins. This should mean cleaner proteins and longer-lived cultures. DeLisa is also modifying bacteria to improve each step in protein production. His focus, he says, is “the engineering of biological machines to tackle problems that nature itself cant do.” Until recently, the biotech industry focused on changing the growth environment for bacteria to boost protein productivity, but DeLisa is supercharging production by going inside the cell itself. For example, hes replacing key parts of the bacterias protein-making machinery with components from higher organisms to produce finely tuned miniature drug factories.
Using cloning to study degenerative diseases.
While earning his PhD, Kevin Eggan helped make Rudolf Jaenischs lab at the Whitehead Institute for Biomedical Research a preeminent cloning lab. Eggan became “arguably the most skillful mouse cloner in this country,” says Jaenisch. Eggan used those skills to clone mice from neurons, proving that animals could be cloned from even the most specialized cells in the body – a feat that many scientists considered impossible. Eggan also helped explain how cloning “reprograms” the genetic material from an adult mouse cell, identifying the changes that take place to reset the nucleus to the beginning of development.
Eggan, now an assistant professor of molecular and cellular biology, plans to create human stem cell lines from patients with neurodegenerative disorders such as Parkinsons and Lou Gehrigs diseases, in order to study disease development and search for new drugs. He has also begun studying nuclear reprogramming in human cells in the hope of finding a way to create patient-specific embryonic stem cells without using human eggs.
Discovering drugs that defy convention.
Paul Hergenrother is a chemist who takes on huge, unsolved medical problems: antibiotic resistance, cancer, and neurodegenerative disease. His small-molecule compounds bind tightly to unconventional disease-related targets, deactivating them. For example, Hergenrother found compounds that eliminate plasmids, the DNA rings that deadly bacteria use to spread antibiotic resistance. That pioneering project led him to a general method for finding drugs that target a particular type of RNA – messenger RNA – as a way to silence disease-causing genes, something standard drugs cant do. Hergenrothers “ten-year vision” could lead to treatments for Alzheimers and Parkinsons.
Defining and advancing systems biology.
As a graduate student, Trey Ideker published a paper that helped define the discipline of systems biology. His research goals today reflect those of the entire field: to integrate the myriad data that researchers can collect about a cell into coherent computer models. As an assistant professor of bioengineering, Ideker is not only improving these models but employing them in biological discovery. For instance, he is looking for protein networks uniquely present in pathogenic organisms; these could make good drug targets. He hopes that, ultimately, systems-derived models will let researchers simulate how potential drugs will affect the body – long before the compounds are tested in humans.
Making materials to treat brain damage.
Nerve cell transplants offer tremendous promise for patients who are suffering the effects of stroke, or from Parkinsons disease or other neurodegenerative illnesses. But experiments in rodents showed that about 95 percent of cells transplanted into the brain die before they can help the recipient. Melissa Mahoney is working to develop hydrogel materials that can house the cells, protecting them and supplying them with proteins that encourage their growth. In collaboration with scientists at the University of Colorado at Denvers Health Sciences Center, Mahoney, an assistant professor of chemical engineering, plans to test these cell-loaded gels in rats within the next year.
Developing devices for wound closure and early heart-attack intervention.
In addition to working about 80 hours a week as a surgical resident at the University of California, Los Angeles, Medical Center, Daniel Riskin is building companies to develop and market new medical devices. “Physicians have an obligation to innovate,” says Riskin.
While training to be a doctor at Boston University and Tufts University, Riskin dabbled in technology development, writing software to help physicians manage their practices and researching different designs for surgical clips with a medical-device company. But he wanted to do more – to come up with his own inventions and bring them into widespread use. Thus he enrolled, partway through his residency, at MITs Sloan School of Management. While studying for his MBA, he kept up his operating-room skills by working at private surgical practices on evenings and weekends.
After graduating from Sloan, Riskin was named the first fellow in Stanford Universitys new surgical-innovation program. At Stanford, he and his collaborators developed an elastic, adhesive, polymer-based patch that they hope will provide a less painful alternative to staples or stitches as a way to close up wounds and surgical incisions. He is now forming a company to commercialize the patch, which he expects will also reduce scarring.
Riskin also helps doctors with few business skills or little experience to become innovators themselves.
Last year, Riskin, along with Michael Laposata, director of clinical laboratories at Massachusetts General Hospital in Boston, started a company, MedPacks, to develop portable diagnostic tests and medications that patients could use at home – before getting to the emergency room – if they thought they were having heart attacks. Such early treatment could lower the risk of death or complications by as much as 50 percent. “If were going to do anything innovative,” says Laposata, “were going to need more Dans.”
Delivering drugs to cancer cells.
As a masters student in India, Shiladitya Sengupta developed an anti-inflammatory gel thats now sold in India under the brand name Nimulid. During his doctoral studies at the University of Cambridge, he revealed how a protein that causes liver regeneration promotes blood vessel growth, and cofounded Dynamic Biosystems to turn the discovery into treatments for chronic wounds such as pressure sores. But a childs toy – several small balloons encapsulated in a bigger one – inspired what may be his greatest innovation: a nanoscale device to treat cancer. Senguptas drug delivery device, developed during his postdoc at MIT, consists of a lipid sphere about 200 nanometers wide surrounding smaller, biodegradable polymer spheres. These nanocells home in on cancers based on the unique characteristics of tumor blood vessels. The outer shells then dissolve, releasing a drug that destroys the vessels. As the cancer cells starve for oxygen, they secrete enzymes that break up the inner spheres, dispensing a standard chemotherapy agent. The nanocells have the potential both to treat tumors more effectively than existing regimes and to reduce side effects. The nanocells have proved effective in mouse models of melanoma and lung cancer. Because Sengupta designed them using polymers and drugs already approved for human use, doctors can quickly move them into clinical trials. Now an assistant professor at Harvard Medical School and Brigham and Womens Hospital, Sengupta is extending the concept to treat other diseases.