In This Issue >>

Disease Forecasting

Cell Suicide by Melissa Hendricks, Page 2

Since these early findings on Bcl-2, Hardwick and other researchers have identified a raft of cell death genes and proteins. Ten to 20 percent of the human genome is somehow connected to programmed cell death, Hardwick says, adding, "That may even be a conservative estimate."

Ten to 20 percent of the human genome is somehow connected to programmed cell death. "That may even be a conservative estimate," says Marie Hardwick

These discoveries are providing tools for hundreds of research endeavors in medicine and biotechnology. A sampling of projects by investigators who have collaborated with Hardwick or sought her advice:

  • The cells under John Clayton's microscope come from the Asian tiger mosquito, which can transmit viruses that cause encephalitis but that do not harm the mosquito. Clayton hopes to develop a bio-friendly insecticide against these pests. The insecticide will contain a genetically engineered virus that carries a cell suicide gene that works in mosquito cells but not human cells. When the virus infects a mosquito, the gene will induce the mosquito's cells to commit suicide, thus obliterating this irritating source of disease.
  • In the case of male infertility, reduced levels of testosterone may induce the suicide of cells that would otherwise develop into sperm, says Barry Zirkin, PhD, professor of Biochemistry and Molecular Biology and head of the Division of Reproductive Biology at the Bloomberg School. Zirkin's research on this process may lead to new treatments for infertility, as well as to new forms of male contraception.
  • By exploiting cell death, researchers may have found a way to improve the potency of an experimental cervical cancer vaccine. The vaccine is designed to activate special immune cells called dendritic cells, explains ,T. C. Wu, professor of Pathology at the School of Medicine. But these cells normally have a short clock. By adding an anti-apoptosis gene to the vaccine, Wu has been able to extend the life of these cells and, animal studies show, improve the effectiveness of the vaccine.
  • Likewise, Hopkins chemical engineer Michael Betenbaugh has found a way to lengthen the lifespan of the cell "factories" that the biotechnology industry uses to churn out drugs and other products. By inserting anti-death genes into these cells, Betenbaugh demonstrated he can increase the yield of these factories by 20 to 30 percent.
  • Studies by Hardwick and School of Medicine neurologist Doug Kerr suggest that programmed cell death plays a role in a neurodegenerative disease called spinal muscular atrophy, or floppy baby syndrome. Babies with the disease have too few motor neurons, which makes them floppy and sometimes too weak to suck properly, explains Kerr, MD, PhD, who is also an assistant professor of Molecular Microbiology and Immunology at the Bloomberg School. The researchers hypothesize that the neurons are produced during development but then are destroyed when a malfunctioning protein triggers apoptosis.

If all disease involves programmed cell death, as Hardwick suggests, then one might imagine that blocking apoptosis would defy disease. Reality has proven more complicated.

"Initially, we had this exuberance about anti-apoptotic therapies," says Kerr. "It could be the miracle cure in degenerative diseases." However, it would not be that easy. Kerr once tried blocking apoptosis in cells that carry the mutation for spinal muscular atrophy. The cells lived longer than usual—but only a few days longer, and they were not healthy. "It was like preserving the undead," says Kerr. "The cells weren't really live or functioning."

Doug Kerr's hopes for a miracle cure for degenerative diseases faded when he blocked apoptosis in cells only to find "it was like preserving the undead"

Spinal muscular atrophy, says Kerr, is a complex disease that begins with a defective gene and ends with apoptosis. In between, numerous molecular events transpire, and blocking apoptosis will not fix every problem along this pathway. Kerr likens the process to a house being condemned. A deconstruction crew comes along and takes down the house piece by piece. The deconstruction, like apoptosis, gets rid of the ruined edifice. But that doesn't explain why the house—or cell—was condemned in the first place.

Kerr now says that a "multi-modal approach" will be required to treat spinal muscular atrophy: drugs that block the cell death pathway, as well as other medicines. Researchers in other diseases are coming to the same realization.

Exploiting cell death may offer more possibilities in cancer treatment, where researchers aim not to stop apoptosis but to turn on the cell death mechanism. Thousands of scientists are involved in this pursuit, says Charles Rudin, an oncologist at the School of Medicine. Rudin himself is testing tools that stimulate cell death in small-cell lung cancer.

Apoptosis is now an established subspecialty of biology, and talk of cell suicide no longer elicits raised eyebrows. Hardwick's colleagues say that she has played an important part in making that happen. "Marie Hardwick is a highly respected pioneer whose major contributions have revolved around highly innovative research on the regulation of cell death," says Doug Green, a biologist who studies apoptosis at the University of California at San Diego.

Still, Hardwick continues to push the envelope. Lately, she is exploring the notion that yeast, a single-cell organism, performs programmed cell death. "We believe that cell death is so ancient that all organisms, including bacteria, anything that is a cell, [has the tools to] perform programmed cell death," she says.

In experiments in Baker's yeast, she and Iva Ivanovska, PhD '05, currently a postdoctoral fellow at Harvard, recently demonstrated that a virus can induce cell suicide in yeast in a similar fashion to that observed in higher organisms, findings that appeared in the August 11 issue of The Journal of Cell Biology.

Small numbers of researchers are also studying apoptosis in yeast, but again, Hardwick's research broaches difficult questions. One of the main reservations is that the notion of cell suicide in yeast suggests a sort of altruism, a word that makes some biologists cringe when applied to something like yeast. How would suicide benefit a single-cell organism? You kill yourself, you're dead. End of story.

"The idea that single-cell organisms might undergo active cell death is viewed skeptically, but I think there is some acceptance of this idea," says Green. However, he says that "the jury is out" on whether the cell death in yeast qualifies as apoptosis.

Hardwick, on the other hand, says she has no doubt that what she sees in Baker's yeast is cell suicide.

No organism lives in isolation, she explains. Yeast reside among hundreds or thousands of other yeast. If one of those organisms becomes infected with a virus, the entire group is threatened. But if the infected yeast kills itself, it spares the population. "Single-cell organisms need programmed cell death not for the survival of that cell, but for the survival of the species," says Hardwick. "I think it's as old as the cell itself."

<< Previous Page

Support JHSPH

The Johns Hopkins Bloomberg School of Public Health strives every day to keep millions of people around the world safe from injury or illness.

Invest in
Public Health >>