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Monday, September 24, 2007

MIT model could improve some drugs' effectiveness

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24hoursnews-In this image, a fragment of the antibody Erbitux (cetuximab) binds to its target, a fragment of epidermal growth factor receptor (EGFR). The blue ribbon at the top is the backbone of the EGFR fragment, and the red and gray ribbons at the bottom are the backbone of the antibody fragment. The licorice sticks and the balls in the central portion represent protein side chains making close interactions between the antigen (EGFR) and the antibody, with the balls representing one of the mutations designed computationally.

MIT researchers have developed a computer modeling approach that could improve a class of drugs based on antibodies, molecules key to the immune system. The model can predict structural changes in an antibody that will improve its effectiveness.

The team has already used the model to create a new version of cetuximab, a drug commonly used to treat colorectal cancer, that binds to its target with 10 times greater affinity than the original molecule.

The work, which will appear Sept. 23 in an advance publication of Nature Biotechnology, results from a collaboration using both laboratory experiments and computer simulations, between MIT Professors Dane Wittrup and Bruce Tidor.

"New and better methods for improving antibody development represent critical technologies for medicine and biotechnology," says Wittrup, who holds appointments in MIT's Department of Biological Engineering and Department of Chemical Engineering. Tidor holds appointments in Biological Engineering and the Department of Electrical Engineering and Computer Science.

Antibodies, which are part of nature's own defense system against pathogens, are often used for diagnostics and therapeutics. Starting with a specific antibody, the MIT model looks at many possible amino-acid substitutions that could occur in the antibody. It then calculates which substitutions would result in a structure that would form a stronger interaction with the target.

"Combining information about protein (antibody) structure with calculations that address the underlying atomic interactions allows us to make rational choices about which changes should be made to a protein to improve its function," said Shaun Lippow, lead author of the Nature Biotechnology paper.

"Protein modeling can reduce the cost of developing antibody-based drugs," Lippow added, "as well as enable the design of additional protein-based products such as enzymes for the conversion of biomass to fuel." Lippow conducted the research as part of his thesis work in chemical engineering at MIT, and is now a member of the protein engineering group at Codon Devices in Cambridge, Mass.

"Making drugs out of huge, complicated molecules like antibodies is incredibly hard," said Janna Wehrle, who oversees computational biology grants at the National Institute of General Medical Sciences, which partially supported the research. "Dr. Tidor's new computational method can predict which changes in an antibody will make it work better, allowing chemists to focus their efforts on the most promising candidates. This is a perfect example of how modern computing can be harnessed to speed up the development of new drugs."

Traditionally, researchers have developed antibody-based drugs using an evolutionary approach. They remove antibodies from mice and further evolve them in the laboratory, screening for improved efficacy. This can lead to improved binding affinities but the process is time-consuming, and it restricts the control that researchers have over the design of antibodies.

In contrast, the MIT computational approach can quickly calculate a huge number of possible antibody variants and conformations, and predict the molecules' binding affinity for their targets based on the interactions that occur between atoms.

Using the new approach, researchers can predict the effectiveness of mutations that might never arise by natural evolution.

"The work demonstrates that by building on the physics underlying biological molecules, you can engineer improvements in a very precise way," said Tidor.

The team also used the model with an anti-lysozyme antibody called D44.1, and they were able to achieve a 140-fold improvement in its binding affinity. The authors expect the model will be useful with other antibodies as well.

The research was funded by the National Science Foundation and the National Institutes of Health.

Wittrup and Tidor also co-teach a class focusing on connecting fundamental molecular and cellular events to biological function through the use of mathematical models and computer simulations

Technorati :

Man on Mars by 2037

(24hoursnews )

This NASA handout obtained 01 August 2007 of an artist's concept depicts NASA's Phoenix Mars Lander a moment before its 2008 touchdown on the arctic plains of Mars. NASA aims to put a man on Mars by 2037, the administrator of the US space agency indicated here Monday.

NASA aims to put a man on Mars by 2037, the administrator of the US space agency indicated here Monday.

This year marks the half-century of the space age ushered in by the October 1957 launch of the Sputnik-1 by the then Soviet Union, NASA administrator Michael Griffin noted.

In 2057, the centenary of the space era, "we should be celebrating 20 years of man on Mars," Griffin told an international astronautics congress in this southern Indian city where he outlined NASA's future goals.

The international space station being built in orbit and targeted for completion by 2010 would provide a "toehold in space" from where humanity can travel first to the moon and then to Mars, Griffin said.

"We are looking at the moon and Mars to build a civilisation for tomorrow and after that," Griffin added in his remarks at a conference session attended by heads of the world's space agencies.

President George W. Bush in 2004 announced an ambitious plan for the US to return to the moon by 2020 and use it as a stepping stone for manned missions to Mars and beyond.

NASA's Phoenix spacecraft is scheduled to land on the northern plains of Mars next year to determine if the Red Planet could support life.

The agency's Mars rovers Opportunity and Spirit resumed their three-year-old mission this month after surviving giant dust storms that nearly destroyed the twin robots.

The rovers were placed in hibernation mode in July to save power because the dust storms were covering their solar panels, impeding their ability to absorb energy from the sun.

And on September 15, 10 gerbils took off from the Russian-run Baikonur space centre in Kazakhstan for a 12-day voyage to test the possible effects of a human mission to Mars.

Missions to the moon and Mars, amid a renewal of global interest in space exploration, are at the top of the agenda for the 2,000 space scientists, astronauts, satellite manufacturers and launchers who gathered in Hyderabad.

NASA is due to start sending a series of robotic missions to the moon starting next year to prepare for future spaceflights and do research on the effects of extended space travel on human beings.

From India

India is planning to conduct 60 space missions over the next five years to achieve multiple objectives in navigation, positioning, advanced communications, space transportation, earth observation and space science, Minister of State in the prime minister's office (PMO) Prithviraj Chavan said here Monday.

Inaugurating the 58th International Astronautical Congress (IAC), Chavan said the ambitious Indian space programme would unfold huge opportunities for commercial and scientific cooperation among the space-faring nations the world over.