Rice physicist Huey Huang is on a quest to understand death —or at least a little piece of it. Huang has spent the past 15 years studying the properties of cell membranes in an effort to unravel a mystery about cell suicide, a mystery that starts with a tiny hole.
The hole is important because it’s a trigger. It kicks off a process known as apoptosis, or cell suicide, and scientists want to understand apoptosis because of the role it plays—or fails to play—in cancer. In healthy bodies, defective cells are marked for an orderly death by apoptosis. These cells commit suicide and even have the courtesy to package their remains for convenient recycling. Why this happens is a mystery. How cancer cells avoid apoptosis is perhaps a bigger mystery, and one reason scientists want to crack the code on apoptosis is to find better ways to fight cancer.Thanks to a breakthrough in Huang’s lab late last year, scientists now understand a key feature of apoptosis: They know the shape of the hole, or pore, that triggers it. Apoptosis is triggered when a hole is punched through a membrane that walls off the mitochondria inside a cell. The mitochondria are the cell’s internal power centers, the place where the cell produces the energy necessary to live.In cells marked for suicide, a protein called Bax gets a signal, and starts punching holes in the outer wall of the mitochondria. Molecules leak out of these pores, bind with proteins and kick off a process that ends with “executioner” proteins systematically dismantling the entire cell. But knowing that Bax forms pores and understanding how it forms pores are two different things.
In 1996, Huang and his graduate students proposed a new idea about the way proteins might form pores in membranes. They suggested that certain proteins, including Bax, react with the bilayered membrane in such a way as to cause it to curve, forming a rounded hole like the one in a doughnut. Huang, students and longtime colleague Lin Yang of Brookhaven National Laboratory, took hundreds of X-ray diffraction images of pores formed by pieces of Bax. They confirmed the toroidal, or doughnut-shaped, hole, settling the debate about how Bax forms holes in membranes.Huang said the group is now turning its attention to a more difficult investigation—working with the entire Bax protein to find out what causes it to start making holes in the first place. Huang’s is the only research group in the world that’s focused solely on studying “protein- induced structure in lipid bilayers.” And as such, the group has pioneered many of its own techniques for investigation. One ingenious example of this is the group’s bromine marker technique. Bromine atoms give off a unique diffraction signal when they’re exposed to X-rays, and Huang, Yang and colleagues helped infer the shape of the toroidal pore last year based on the way bromine atoms were distributed through their samples.