Designing microbes to make fuels and drugs.
Organisms that live in exotic environments have evolved unique traits in order to survive. Michelle Chang, an assistant professor of chemistry, hijacks the chemical reactions that confer those traits, combining them in novel ways. By inserting borrowed genes into easy-to-grow microbes such as E. coli, she creates organisms with new abilities.
In one project, she is creating a system that takes lignin, a tough polymer abundant in agricultural waste, and breaks it into molecules that can be converted into biofuels. Chang is also developing a way to incorporate fluorine into organic molecules. Many modern drugs–Lipitor, for instance–require at least one fluorine atom per molecule to perform their functions. But fluorine is difficult to add to molecules using traditional chemistry.
While her projects have important practical applications, Chang hopes that her work will lead to basic tools for engineering organisms that can perform all kinds of reactions that are too difficult, expensive, or dangerous with traditional chemistry. Read Chang’s insights on why biomass could improve biofuel production.
PROBLEM: Of the thousands of drugs used to treat disease, most are small molecules–organic compounds that bind with proteins and influence their activity. But researchers must screen many compounds to find potential drugs, and the large number of chemical reactions needed to synthesize any one compound makes the process slow and painstaking.
SOLUTION: Martin Burke, an assistant professor of chemistry, has figured out a way to simply and quickly generate diverse arrays of small molecules by repeatedly using a single reaction to join different organic components. He begins by turning a wide variety of organic molecules into standardized building blocks, each of which has a boronic acid on one end and a halide, such as bromide, on the other. In a test tube, the two ends react to link molecules with a carbon-carbon bond. Burke’s key advance is a way to reversibly obstruct the boronic-acid end, so that chemists can sequentially couple different molecules.
Burke is partnering with a major chemical company to release a set of premade building blocks. Ultimately, he hopes that the ability to quickly create large collections of compounds will help him find highly complex small molecules that can imitate the structure of proteins that malfunction in diseases such as cystic fibrosis. Such “molecular prosthetics” could provide new treatments for a whole array of diseases, saving lives.
Probing chemical reactions in the body.
Christopher Chang wants to revolutionize cellular imaging by changing the way biologists tag the molecules they want to see. Most tags fluoresce continuously, and each one binds to a target molecule of a specific shape. Chang, however, is developing probes that fluoresce only when they react chemically with their targets. This will allow scientists to observe the generation, accumulation, and release of molecules involved in passing signals within and between cells.
For example, one of Chang’s tags glows green when it reacts with hydrogen peroxide–a chemical found throughout the brain, where its function is largely unknown. The brighter the color, the more hydrogen peroxide a cell is taking up. Chang has used this tag to study neurons from the hippocampus, a brain area vital for learning and memory. His research shows that the chemical, known mostly for causing cell damage, also plays an important role in neural signaling.
Portable nuclear magnetic resonance.
Combined with specially engineered magnetic nanoparticles, nuclear magnetic resonance (NMR) is a potentially fast and easy way to spot cancer, bacteria, and viruses in blood samples. But current NMR systems use large and expensive magnets, making them impractical for, say, widespread cancer screening and other routine diagnostic tests. So Donhee Ham, an associate professor of the natural sciences, built a system that is only slightly bigger than a cell phone and weighs less than two kilograms–yet is 60 times as sensitive as existing 120-kilogram tabletop systems that could cost 70 times as much. The key is a silicon radio-frequency chip that compensates for the low-quality signal caused by using a smaller magnet. The system has been tested in collaboration with Massachusetts General Hospital, and companies have expressed interest in incorporating Ham’s technology into diagnostic instruments.
Turning adult cells into stem cells.
In 2006, scientists demonstrated that inserting four embryonic genes into mouse skin cells induced a small fraction of them to look and behave like embryonic stem cells. The technique promised to eliminate the need to destroy embryos to generate stem cells. But the first cells made this way were not completely “reprogrammed.”
Konrad Hochedlinger, an assistant professor of medicine, found a simple way to improve the technique. Working with mouse cells, he initiated the reprogramming process by means of the same four genes that previous scientists had used. But he used a different gene to identify the cells that had been successfully reprogrammed; cells in which that gene is active turn out to look and act more like embryonic stem cells than those made previously. The technique offers a way around the controversies that have slowed embryonic-stem-cell research, which has the potential to help scientists understand certain diseases and, eventually, replace diseased or damaged tissue.
Patching damaged hearts.
The heart has a limited capacity to generate new cells on its own, making it hard to heal after injury. Scientists have experimented with injecting stem cells into the heart, but they have found it difficult to predict how the cells will behave, and they’ve had little success in coaxing cells to make functional tissue. To better anticipate which cell types may help heal hearts, bioengineer Milica Radisic has used embryonic stem cells to create a small patch that mimics human heart tissue.
Radisic grew her first heart patches using cells from the hearts of newborn rats. But coaxing the cells to form functioning heart tissue proved challenging; established tissue-engineering techniques didn’t work. Radisic hit upon the idea of applying a small electric field to the cardiac cells, similar to the one formed as the heart develops in an embryo. This spurred the cells to connect in patterns that resembled those of actual heart tissue.
Radisic, an assistant professor of chemical engineering, is now using the same technique to grow heart patches derived from human embryonic stem cells. The patches respond to various stimuli as real heart muscle would, providing a way to more accurately test the potential of different cell lines and new drugs. Radisic is now adding various lines of stem cells to the engineered patches to see which–if any–multiply and form functioning heart tissue; her goal is to find cells that are useful in repairing muscle damaged by a heart attack or by high blood pressure. She also aims to help researchers find treatments for heart damage associated with diabetes by designing a patch that simulates the heart tissue of a person with that disease.
Preventing congestive heart failure.
Three years ago, surgical resident Bilal Shafi was in the thick of a heart transplant. The patient was a heart attack survivor whose heart function had silently continued to deteriorate, as it does in 30 percent of such cases. When that happens, the heart works harder, expanding to keep up its pumping ability and stretching its walls thin. Shafi had previously helped to install a permanent textile mesh around the patient’s heart, an experimental and extreme procedure meant to prevent further dilation and ultimate heart failure. But the patient grew sick enough to require a transplant. During the surgery, Shafi thought, “Why aren’t we treating this disease much earlier?”
So he became a fellow in the Stanford Biodesign Innovation program and, over the next three years, developed a biopolymer coating that wraps around the heart and prevents dilation. The coating, which starts out as a liquid, is injected through a catheter immediately following a heart attack. Then it gels, becoming flexible enough to expand with each heartbeat, yet firm enough to support the heart and allow it to heal. After six months, the polymer degrades and the body absorbs it. So far, Shafi has successfully tested it in mice and sheep. He recently returned to his surgical residency at the University of Pennsylvania and has launched a company, COR Innovations, to further develop the technology.
Joo Chuan Tong
My vision: Personalized vaccines.
In recent years, Asia has been the epicenter of many emerging and reëmerging diseases, including avian influenza, severe acute respiratory syndrome (SARS), malaria, and chikungunya. The 2003 SARS epidemic, which coincided with the start of my PhD at the National University of Singapore’s department of biochemistry, left a particular impression on me. Thus began my quest for more effective ways to create vaccines to combat such diseases.
Vaccination is a powerful tool. Each person’s immune system is unique, however, and vaccines do not take these individual differences into account. So although today’s vaccines protect the majority, some people fail to develop immunity, while others may have adverse reactions. At the same time, rapidly mutating bacteria and viruses evolve to evade immune protection. Every time a new strain emerges, a new vaccine must be created, as with the annual flu shot.
If we could map out the genetic profile of each individual’s immune system, efficiently create vaccines against the newest strains of a disease, and match the two, we would stand a far better chance of protecting people. At the Institute for Infocomm Research, I lead a team that is developing computer algorithms to help make this dream of personalized vaccines possible.
Our bodies rely on proteins called human leukocyte antigens (HLAs) to recognize foreign substances (i.e., antigens) from disease-causing microbes and marshal our immune systems against them. These same proteins process the antigens in vaccines, triggering resistance. But there are thousands of variants of the 11 HLA proteins, and each person inherits at most two of the possible variants for each one. Our algorithms take those genetic differences into account to help select antigens that are most effective in triggering an immune response.
We begin by creating 3-D models of the interactions between different HLA molecules and antigens. We then use those models to train machine-learning algorithms to identify antigens likely to bind to the largest variety of HLA molecules; those antigens have the best potential to be effective vaccines. Our goal is to create models of the 120 to 150 most common HLA variants, which should cover 95 percent of the global population. By matching possible antigens with the HLA variants most common in a population, vaccines may be tailored to specific groups or, with personal screening, even to individuals.