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Wednesday, March 5, 2008

MIT student invents knock-out punch for antibiotic resistance

MIT graduate student and synthetic biologist Timothy Lu has won the $30,000 Lemelson-MIT Student Prize for inventing processes to combat bacterial infections by enhancing the effectiveness of antibiotics.

Timothy Lu awarded $30,000 Lemelson-MIT Student Prize for inventiveness
MIT graduate student and synthetic biologist Timothy Lu is passionate about tackling problems that pose threats to human health. His current mission: to destroy antibiotic-resistant bacteria.

Today, the 27-year-old M.D. candidate and Ph.D. in the Harvard-MIT Division of Health Sciences and Technology received the prestigious $30,000 Lemelson-MIT Student Prize for inventing processes that promise to combat bacterial infections by enhancing the effectiveness of antibiotics at killing bacteria and helping to eradicate biofilm - bacterial layers that resist antimicrobial treatment and breed on surfaces, such as those of medical, industrial and food processing equipment.

Bacterial infections can lead to severe health issues. The Centers for Disease Control and Prevention estimates that the antibiotic-resistant bacterium MRSA, or methicillin-resistant Staphylococcus aureus, causes approximately 94,000 infections and contributes to 19,000 deaths annually in the United States, through contact that can occur in a variety of locations, including schools, hospitals and homes. Bacteria can also infect food, including spinach and beef, and damage industrial equipment.

Lu explained that fewer pharmaceutical companies are inventing new antibiotics due to long development times, high failure rates and large costs. According to the Tufts Center for the Study of Drug Development, the cost to develop a new drug is $930 million (based on the value of the dollar in 2006). These factors, coupled with a decline in the number of prescriptions authorized for antibiotics, constrain profits. "Antibiotic-resistant bacteria are also becoming more prevalent," Lu noted. "My inventions enable the rapid design and production of inexpensive antibacterial agents that can break through the defenses of antibiotic-resistant bacteria and bacterial biofilms."

Delivering a one-two punch
Working with his advisor, J.J. Collins, professor of biomedical engineering at Boston University, Lu developed two bacteriophage platforms to overcome antibiotic resistance. Bacteriophage are viruses that only infect bacteria, not human cells. They have been used since the early 20th century to treat bacterial infections; however, they fell out of favor in the United States due to the advent of antibiotics. Lu's work represents an exciting application of synthetic biology, which is an emerging field focused on the rational engineering of organisms to achieve novel functions.

Lu has engineered bacteriophage to boost antibiotic effectiveness. The bacteriophage carries DNA that codes for factors that target bacterial gene networks, which former treatments failed to reach, and destroys bacterial antibiotic resistance mechanisms. The weakened bacterial defenses enable antibiotics to perform better. Administered together, Lu's bacteriophage and antibiotics have the potential to eliminate nearly 30,000 times more bacteria than antibiotics alone, including cells that survive antibiotic-only treatment. This combination treatment also thwarts development of stronger antibiotic resistance, which can extend the lifetime of existing and future antibiotic drugs.

"While working at a hospital as part of a graduate course, I saw many patients who contracted new infections due to already-compromised immune systems or equipment that is extremely difficult to keep sterile," Lu recalled. "Being infected by difficult-to-eradicate bacteria is a traumatic experience for patients and a serious public health issue that needs attention. I thought that there had to be a solution for these infections."

Penetrating biofilms
Lu also applied his work with bacteriophage to create a new technique for reducing harmful biofilms, which are slimy layers of bacteria that develop on the surfaces of medical, industrial and food processing equipment and are difficult to penetrate and remove. Current treatment methods to penetrate biofilms can involve peptides or enzymes, which must be administered systemically and are costly. Medical devices infected by biofilms, such as replacement hip joints or pacemakers, often have to be removed surgically.

Lu invented enzymatically-active bacteriophage that directly target the infection site, where they can simultaneously penetrate the biofilm's protective slime layer and kill the bacteria underneath. "Think of it as a Trojan Horse," he explained. "First you sneak into the bacteria and use it to overproduce enzymes precisely where they are needed most in order to overwhelm and break up the biofilm slime. Once the slime is disrupted, the bacteriophage then move in and kill the bacteria."

"As a physician who has treated patients with resistant bacterial infections, I am well aware of the devastating effect they have on morbidity and mortality," added Collin M. Stultz, associate professor of biomedical engineering in the Harvard-MIT Division of Health Sciences and Technology, and one of Lu's recommenders for the award. "Tim has developed a series of methods that can be used to treat such problematic infections."

In tests, Lu's platform proved greater than 99.997 percent effective at destroying biofilms - a significant improvement over current treatment options. "The ultimate goal is to develop a sustainable source of antibacterial therapies that are effective and easy to produce at low cost, and will last us through the 21st century," said Lu.

According to Lu, his engineered enzymatically-active bacteriophage could be initially applied in food processing settings to kill food-borne bacteria, such as Escherichia coli (E. coli) that contaminate spinach and cause severe illness when ingested. In line with these hopes, there is evidence that U.S. regulatory authorities are warming up to the therapeutic use of bacteriophage. For example, in 2006, the U.S. Food and Drug Administration approved the first U.S. treatment for Listeria contamination of processed meats using natural bacteriophage.

Lu added that enzymatically-active bacteriophage could also benefit industry by being used to treat infected pipes and reduce corrosion.

Inherited inventiveness
Born in Stanford, California, and raised in Yorktown Heights, New York, and Taiwan, Lu credits his inventiveness to his father, Nicky, an engineer and entrepreneur who helped develop modern semiconductor memories with IBM and the integrated circuits industry in Taiwan. Lu recalls spending time at his father's office during his formative years, where he reviewed plans and designs for new integrated circuits.

"I inherited my interest in invention and entrepreneurship from my father," Lu said. "It was very inspiring to see the amount of effort my father and his team put into their work and their joy and elation when they achieved success."

"Tim is one of the young stars in the emerging field of synthetic biology" said his advisor Collins. "I am confident he will develop into a leading clinical investigator and innovator."

"Tim demonstrates the type of ambitious and inventive thinking the $30,000 Lemelson-MIT Student Prize was established to recognize," said Josh Schuler, executive director of the Lemelson-MIT Program, which provides the annual award. "What is truly impressive about Tim's approaches is the breadth of his applications. Not only does his work have potential in healthcare, but also in protecting the general public through safer food processing and prevention of industrial biofouling. Harmful bacteria everywhere should be afraid."

Second Year of National Student Prize Expansion
On February 28, the winners of the second annual $30,000 Lemelson-Illinois Student Prize and Lemelson-Rensselaer Student Prize will be announced at the University of Illinois at Urbana-Champaign and Rensselaer Polytechnic Institute, respectively. Details about each winner will be posted on and

About the $30,000 Lemelson-MIT Student Prize
The $30,000 Lemelson-MIT Student Prize is awarded annually to an MIT senior or graduate student who has created or improved a product or process, applied a technology in a new way, redesigned a system, or demonstrated remarkable inventiveness in other ways. A distinguished panel of MIT alumni and associates including scientists, technologists, engineers and entrepreneurs chooses the winner.

About the Lemelson-MIT Program
The Lemelson-MIT Program recognizes outstanding inventors, encourages sustainable new solutions to real-world problems, and enables and inspires young people to pursue creative lives and careers through invention.

Jerome H. Lemelson, one of U.S. history's most prolific inventors, and his wife Dorothy founded the Lemelson-MIT Program at the Massachusetts Institute of Technology in 1994. It is funded by the Lemelson Foundation, a philanthropy that celebrates and supports inventors and entrepreneurs in order to strengthen social and economic life in the U.S. and developing countries.

Shedding a bright light on village needs

Villagers in Ha Teboho, in the southern African nation of Lesotho, gather to learn about a new concentrating solar generator and hot water system installed by MIT students.

Bethel High School is a rural school in the tiny landlocked nation of Lesotho, which is entirely surrounded by South Africa. The school draws students from many surrounding villages, and they live in dormitories during the school year. Though the winter temperatures often drop well below freezing, students in the dormitories only rarely have access to hot water, and the only power in the school comes from a diesel generator which runs for about four hours a day to power a small computer lab, thanks to diesel fuel provided by the state.

The girls' dorm, however, now has an extra amenity, thanks to work that some MIT students carried out during an 11-month stay last year. Amy Mueller and Matt Orosz, both graduate students in the Department of Civil and Environmental Engineering, designed and installed a concentrating solar array that provides the girls with plenty of hot water.

The system was built last year at MIT's D-Lab, with a lot of help from the D-Lab students. The project got some early funding by twice winning MIT's IDEAS competition and receiving grants from the MIT Public Service Center as well as from the World Bank. After initial testing here, just getting the components out to the remote site was quite an effort: the roadless community can only be reached by crossing a wide river on small boats, Mueller explains.

Nearby, in the tiny village of Ha Teboho, another concentrating solar heater that Orosz and Mueller installed near the communal village well also provides hot water on demand. "We can easily boil lots of water even during freezing weather," Mueller says. But that's just the beginning of their ambitious project.

The two students, along with others at MIT and local co-workers in Lesotho, have formed an organization called Solar Turbine Group International. Their original plan was for the systems to provide electrical power using Rankine-cycle heat-powered engines, with hot water just an extra bonus. But in their work in the field they encountered numerous mechanical problems with the engine, and they decided to return to MIT to work out the bugs under more controlled laboratory conditions.

"The arrays performed satisfactorily, but the engines did not," says Orosz. To fix the problems, "we figured we could make headway faster in this environment than over there."

In a return visit to Lesotho this summer, they plan to add a more robust version of the generator to the large trough-shaped mirror systems, enabling them to produce enough power to be used to recharge cell phones and batteries.

The initial systems are prototypes, designed to be relatively easy to build from inexpensive materials. The engine system, which essentially works like an air-conditioner in reverse, is built largely from off-the-shelf car parts that are readily available near the site and can easily be repaired by local mechanics.

After a bit more experience with actually setting up and operating the systems in the villages, the Solar Turbine Group's plan is for local workers who have been collaborating on the project to take over manufacturing and launch a locally based business to produce the units for installation throughout the country.

"We already built a machine shop there, and hired local technicians and engineers," Orosz says. "We've set up the seed of a company" that hopefully will become self-sustaining, he says, providing a useful product and generating local income.

The systems are designed to be competitive with existing solar photovoltaic systems or diesel generators for producing power, and provide the added bonus of hot water. Orosz hopes the systems will ultimately cost 10 to 15 percent less than the other systems for power alone.

"If the price is even in the ballpark of photovoltaics, we've won," says Mueller, "because you get lots of hot water as well."

In the World is a new column that explores the ways people from MIT are using technology--from the appropriately simple to the cutting edge--to help meet the needs of local people in places around the planet.

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Expert says big energy picture must balance security, sustainability, and supply

Expert says big energy picture must balance security, sustainability, and supply

The world has no choice but to build more energy-producing plants--and find new sources of energy--but the build out process will not happen overnight, a government expert recently told an MIT audience.

A worldwide boost in demand for energy, coupled with environmental concerns, will force a huge U.S. increase inthe number of nuclear power plants--but it will take more than two decades to come to fruition, according to Carl O. Bauer, director of the U.S. Department of Energy's National Energy Technology Laboratory (NETL).

Bauer's Feb. 26 colloquium, "Energy Supply and Demand, Economics and Greenhouse Gas Management: Are They Related?" was sponsored by the MIT Energy Initiative. The discussion focused on the intertwined aspects of security, sustainability, supply and the environment in relation to the world's energy production.

Bauer said blackouts in California, Texas and New England by 2016 are just some of the challenges facing decision makers as they tackle America's energy future.

"I happen to believe we're right on the cusp of a huge energy build out because we have no choice," Bauer said. But, he added, the lack of U.S. nuclear plant construction in recent decades has led engineers to turn to other fields, and construction companies to commit resources to building plants overseas.

In facing the U.S. energy challenge, decision makers, he said, must juggle three "co-dependent" entities: the economic sustainability of energy sources; energy supply and security; and the effect of solutions on the environment and climate change. But "too often we divorce the circles and make a decision in policy that we can't live with," he said.

Coal, natural gas and oil use will remain largely unchanged in the United States over the next two decades, projections show, while the use of renewables is likely to increase from 6 to 9 percent of the total. Nuclear is slated to remain constant at 8 percent because old plants will shut down and new plants can't come on line fast enough to make a big dent in usage patterns by 2030.

And while U.S. energy use is expected to increase by 25 percent in that time frame, worldwide energy demand is expected to leap 50 percent, further straining resources.

"Do we think the oil supply can grow by 50 percent? The challenge for increasing the oil supply is increasingly onerous, and many believe peaking will happen in this decade," Bauer said. We will become increasingly dependent on coal and natural gas, which have their own supply and production problems, he said.

A state-by-state North American Electric Reliability Corp. long-term reliability assessment questioned states' capacity to generate electricity for the hottest days of summer in coming years.

Besides possible peak-usage brownouts and blackouts, the shortfall could bump up electricity prices in states neighboring high-demand regions by 30 to 40 percent.

While alternatives such as wind look promising, even the country's windiest states--such as North Dakota and South Dakota--don't have enough consistently windy days to meet high demand. Nights--when demand is down for air conditioning--tend to be windiest.

Managing public electricity use--limiting use during peak times or setting allowances--could become a reality.

If so, Bauer predicted that Americans might be in for some unfamiliar discomfort.

"How much are we willing to sweat or shiver?" he said. "How much are we going to allow someone to manage our own use through a meter on our house to control the flow of electricity and shut us down if demand goes too high?"

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Team probes mysteries of oceanic bacteria

Wee creatures are key to Earth's environment

Microbes living in the oceans play a critical role in regulating Earth's environment, but very little is known about their activities and how they work together to help control natural cycles of water, carbon and energy.

A team of MIT researchers led by Professors Edward DeLong and Penny Chisholm is trying to change that.

Borrowing gene sequencing tools developed for sequencing the human genome, the researchers have devised a new method to analyze gene expression in complex microbial populations. The work could help scientists better understand how oceans respond to climate change.

"This project can help us get a better handle on the specific details of how microbes affect the flux of energy and matter on Earth, and how microbes respond to environmental change," said DeLong, a professor of biological engineering and civil and environmental engineering.

"The new approach also has other potential applications, for example, one can now realistically consider using indigenous microbes as in situ biosensors, as well as monitor the activities of human-associated microbial communities much more comprehensively," DeLong said.

Their technique, which has already yielded a few surprising discoveries, is reported in the March 3 issue of the Proceedings of the National Academy of Sciences.

The work was facilitated by the Center for Microbial Oceanography: Research and Education (C-MORE), a National Science Foundation Science and Technology Center established in 2006 to explore microbial ocean life, most of which is not well understood.

The traditional way to study bacteria is to grow them in Petri dishes in a laboratory, but that yields limited information, and not all strains are suited to life in the lab. "The cast of characters we can grow in the lab is a really small percentage of what's out there," said DeLong, who is research coordinator for C-MORE.

The MIT team gathers microbe samples from the waters off Hawaii, in a part of the ocean known as the North Pacific Gyre.

Each liter of ocean water they collect contains up to a billion bacterial cells. For several years, researchers have been sequencing the DNA found in those bacteria, creating large databases of prevalent marine microbial genes found in the environment.

However, those DNA sequences alone cannot reveal which genes the bacteria are actually using in their day-to-day activities, or when they are expressing them.

"It's a lot of information, and it's hard to know where to start," said DeLong. "How do you know which genes are actually important in any given environmental context?"

To figure out which genes are expressed, DeLong and colleagues sequenced the messenger RNA (mRNA) produced by the cells living in complex microbial communities. mRNA carries instructions to the protein-building machinery of the cell, so if there is a lot of mRNA corresponding to a particular gene, it means that gene is highly expressed.

The new technique requires the researchers to convert bacterial mRNA to eukaryotic (non-bacterial) DNA, which can be more easily amplified and sequenced. They then use sequencing technology that is fast enough to analyze hundreds of millions of DNA base pairs in a day.

Once the sequences of highly expressed mRNA are known, the researchers can compare them with DNA sequences in the database of bacterial genes and try to figure out which genes are key players and what their functions are.

The team found some surprising patterns of gene expression, DeLong said. For example, about half of the mRNA sequences found are not similar to any previously known bacterial genes.

Lead authors of the paper are Jorge Frias-Lopez, research scientist in MIT's Department of Civil and Environmental Engineering (CEE), and CEE graduate student Yanmei Shi. Maureen Coleman, graduate student in CEE, Gene Tyson, postdoctoral associate in CEE, and Stephan Schuster of Pennsylvania State University also authored the paper with Chisholm and DeLong.

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