Computer Program Solves Flu Problem

By essentially decoding the flu virus, this software could create vaccines that are life-savers for millions.

THE GIST

A computer program could generate the best possible influenza vaccine.

Current methods of vaccination -- injections and nasal sprays -- have their drawbacks in terms of safety and effectiveness.

The resulting vaccine should generate strong immunity with very little risk of infection.

A new computer program is decoding influenza and could unravel other viruses as well. The research could save millions of people around the world from death by not only influenza, but eventually other diseases as well.

Scientists from Stony Brook University in New York have developed a computer program that solves a genetic version of the "traveling salesmen problem." Using the program, the researchers can create a live but greatly weakened vaccine that should provide greater protection against more strains of the flu.

"Live vaccines are better to provoke an immune response; they act like a real virus," said Steffen Mueller, a scientist at Stony Brook University in New York and co-author of a recent Nature Biotechnology paper. "But there is always a chance that the virus could revert back to its wild form and infect a person. With our new method, that seems impossible."

There are essentially two ways to vaccinate against influenza. The first method relies on injecting large doses of a dead virus. The second method involves spraying a live, but crippled, virus through the nose.

The first method is safe but not always effective. The injection occasionally doesn't immunize and requires large amounts of dead viruses, which means fewer people can be immunized.

Using a live virus provides more protection against the flu and uses far less of the virus, which means more people can be vaccinated. But there is a drawback: Since the virus is still alive, it can mutate back to its wild, virulent form. That doesn't happen very often, said Mueller, but on very rare occasions a vaccination could create an infection.

Mueller's new method would make infection-via-vaccination far more unlikely. Today's live viruses only change two of the eight genetic sequences in the virus (the H and the N of H1N1). Mueller takes a different approach looking at all eight genetic sequences.

Viruses encode genetic information using four nucleotides, commonly abbreviated A, U, C and G. Each group of nucleotides is called a codon. Each codon represents one kind of amino acid, which forms proteins. Those proteins assemble new viruses that infect other cells -- and other people.

Over billions of years, viruses have become exceedingly efficient at creating copies of themselves, which is why they can spread so quickly through a population. Mueller aims to constrain that ability by scattering genetic "speed bumps," as he calls them, through every codon in the genetic code of the virus.

Not all codons are created equal. Some codons are easy to turn into amino acids. Others are more difficult.

Viruses have maximized the number of efficient codons and minimized the number of inefficient codons. Mueller will replace the efficient codons with inefficient ones. Although the final proteins that confer immunity will look exactly the same, they will take much longer to produce. Slowing protein assembly, and in turn virus replication, will save lives.

Here's how it works. First, Mueller and his colleagues sequence the viral genome they predict will infect people during the upcoming flu season. Then they run that code through a new computer program that finds the efficient codons, and replaces them with inefficient codons.

This is not as easy as simply replacing one codon with another. There are many codons to choose from that code for one amino acid. Changing one codon affects how easily the codons on other side are expressed.

It's a genetic version of the traveling salesmen problem, said Mueller. In the traditional version of the problem, a traveling salesmen has to visit several clients and needs to find the fastest, most efficient way to visit everyone.

Instead of finding the quickest path to clients, Mueller and his colleagues found the most difficult path to viral replication.

Once the problem has been solved, Mueller pays another company to sequence the new inefficient genetic sequences. He then injects the new sequence into a virus, infects a cell and harvests the resulting viruses for use as a vaccine.

The new technique has two main uses, said Marc Lipsitch, a scientist at Harvard University's School of Public Health.

The program could be a better way to protect against some viruses, such as polio or influenza. The new software could also be used against other viruses that we can't currently attenuate, such as the notoriously flexible human immunodeficiency virus (HIV), something that Mueller's group is currently working on.

The computer program is a good one, said Lipsitch, but whether it works or not "is an open question until someone demonstrates (the vaccine's) effectiveness in humans."

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