BCM, Rice scientists map flu’s chemical key

BCM, Rice scientists map flu’s chemical key
Research on type B flu strain could yield clues about bird flu

BY JADE BOYD
Rice News Staff

Scientists from Baylor College of Medicine (BCM) and Rice University have developed a three-dimensional, molecular map that could yield clues about the genetic mutations that will allow bird flu to spread among humans.

JIANPENG MA

The research, which appears this week in the Proceedings of the National Academy of Science (PNAS) Online Early Edition, was conducted on a strain of the influenza B virus initially isolated from Hong Kong. Unlike strains of influenza A — which include bird flu, swine flu and others — influenza B affects humans only.

“The big question is, ‘What would it take for the bird flu to change and start killing us?'” said research co-author Jianpeng Ma, Rice associate professor in bioengineering, who holds a joint appointment at BCM. “Since flu B is a distant relative of flu A, the fewer common features among them would allow identifying the critical parts required for infecting humans.”

The research is based on more than six years of painstaking experiments by lead author Qinghua Wang, assistant professor of biochemistry and molecular biology at BCM. The experiments focused on a protein called hemagglutinin (HA), the chemical key that allows flu viruses to attach to target cells and infect them with viral DNA. There are 16 HA proteins, but only flu B and H1, H2 and H3 of flu A are found in human-transmissible strains. Scientists know H5, the HA key used by bird flu, is very similar to the chemical keys used by human strains of flu A. Like all proteins, the HA keys consist of a precise sequence of amino acids.

“In terms of sequence, there is only a 25 percent overlap between HA proteins for type A and type B,” Ma said. “But in terms of function, the two are remarkably similar.”

JIANPENG MA

Scientists from Baylor College of Medicine and Rice University have developed the first three-dimensional, molecular map of the protein that allows influenza B to infect healthy cells with viral DNA.

Wang said, “It would be better if there were more differences. The similarities suggest that only minor mutations are needed for bird flu to become transmissible to humans.”

Scientists know the precise 3D structure of several HA keys for flu A, but Wang and Ma’s work represents the first mapping of an HA key for flu B. Wang said it is not for lack of trying.

“People have been working on this problem for 30 years,” she said. “It is a very, very difficult problem.”

The structure was revealed with X-ray crystallography, a method in which scientists decipher the exact three-dimensional arrangement of atoms inside a crystal based upon the way the crystal scatters X-rays.

Getting proteins to form crystals is often one of the most difficult challenges in crystallography. Wang said it took years to develop a process capable of yielding the highly pure, concentrated liquid form of the HA protein that’s required to make crystals. To form the crystals, Wang and postdoctoral fellow Xia Tian created thousands of test jars of solution and placed a single droplet of concentrated protein on the underside of each jar lid. Most droplets never form crystals, but as the liquid in the droplets evaporates, a crystal of pure protein is occasionally left behind. However, it can take months, or even longer, for these crystals to form.

“I have kept some jars for a long time,” Wang said. “Random factors play a big role in determining whether a crystal forms, and since we never know which ones will yield crystals, we never want to give up on a sample too soon.”

Once Wang and Tian found a solid method for making useful crystals, X-rays were used to determine the precise structure of atoms in the crystals.  Currently, Ma and Wang are working out the precise molecular mutations that will be required for bird flu’s HA to change into a human transmissible form.

The research is supported by the National Institutes of Health and the Welch Foundation.