June 14, 2001 Last February, a toddler in Alberta, Canada, made headlines worldwide after she wandered outside and nearly froze to death. Although her heart stopped beating for two hours and her body temperature was 61 degrees when she was found lying face down in the snow, 14-month-old Erika Nordby made a complete, stunning recovery.
While such recovery from biological limbo seemingly defies scientific or medical explanation, researchers at Seattle's Fred Hutchinson Cancer Research Center have developed a method to induce a similar state of so-called suspended animation in the zebrafish, a relatively new model of vertebrate developmental biology.
Their work, the first demonstration of this phenomenon in a vertebrate model organism highly suitable to laboratory analysis, will be described tomorrow in the June 12 issue of the Proceedings of the National Academy of Sciences (Early Edition No. 24).
This discovery, by Mark Roth, Ph.D., a member of the Hutchinson Center's Basic Sciences Division, promises to open new paths of research into understanding the phenomenon of suspended animation. The achievement ultimately could lead to new ways to treat cancer and prevent ischemic injury from insufficient blood supply to organs and tissues.
Roth, in collaboration with postdoctoral research fellow Pam Padilla, Ph.D., discovered that after 24 hours of oxygen deprivation - resulting in cessation of all observable metabolic activity, including heartbeat - zebrafish embryos can resume a normal course of development with no harmful effects on their health or growth.
Roth's studies on biological limbo may shed light on two problems that perplex cancer biologists: the control of stem-cell division and how oxygen deprivation affects tumor growth.
"We typically think of cancer cells as growing out of control," said Roth, also an affiliate associate professor of biochemistry at the University of Washington School of Medicine. "But actually, within a tumor there are many types of abnormal cells, and only a subset are multiplying at any one time. The vast majority of cells in a tumor are in a state of low oxygen tension and are non-proliferating - which is the reason that some tumors don't respond to certain forms of radiation and chemotherapy." Most chemotherapeutic agents work by selectively killing actively dividing cells, meaning that many quiescent, or non-dividing, tumor cells are immune to treatment.
Suspended animation also has a role in the growth of normal cells, Roth said.
"Stem cells - like those that give rise to your skin - are self-renewing and have the capacity to reproduce at certain times in your life," he said. "Some of those cells might be dividing right now, while others withhold their proliferation potential until a later time. Lots of scientists are interested in how cells maintain this state of quiescence and then resume cell division." The phenomenon also is critical for the normal development of many animals.
"Numerous organisms have naturally occurring states of suspended animation," Roth said. "About 70 species of mammals alone do this as a way to increase reproductive fitness. For example, mice delay implantation of their embryos in the uterus while they are lactating. The embryos halt implantation - and any further development - until lactation stops."
Zebrafish in the wild haven't yet been observed to undergo suspended animation, but the metabolic shutdown that Roth induces in his laboratory resembles the reversible state of limbo that has been observed in nature in other organisms.
Roth and Padilla, the paper's co-author, compared the developmental capability of zebrafish embryos that had been exposed to normal atmospheric conditions to those grown in anoxic (oxygen-free) chambers. Absence of oxygen caused development to arrest and all observable metabolic activity to cease - including a shutdown of the heart, which normally beats 100 times per minute. The researchers found that embryos 25 hours post-fertilization or younger could survive without oxygen for 24 hours and resume normal development after re-exposure to standard levels of oxygen.
"We can't detect any abnormalities in these fish after they recover," Roth said. "They have grown to adulthood, mated and produced normal offspring."
Roth's next goal is to figure out the molecular pathways that permit this recovery and why some vertebrates can survive a lack of oxygen - or other forms of extreme stress - and why others can't. "In the case of heart disease, humans typically die of a failure to get enough oxygen to cells," he said. "Cells deprived of oxygen for too long, particularly brain cells, typically undergo apoptosis - a form of cell suicide. If that happens and you live, you suffer from brain damage."
Some humans, for unexplained reasons, do manage to survive extreme forms of stress, such as brutally cold temperatures for an extended amount of time, and manage to recover from a metabolic shutdown. "What makes some animals - and even some people, like the case of the frozen little girl in Canada - able to survive extreme stress? Wouldn't it be great to have some control over this process?"
While it may seem in the realm of science fiction right now, a potential application of this control would include helping people survive life-threatening injuries while in transit to a hospital emergency room. Bodies or organs held in a state of suspended animation could be repaired and suffer no long-term consequences from extreme stress such as oxygen deprivation.
Roth admits that it is hard to predict whether such strategies will work, but for now, he is caught up with trying to explain the mechanisms controlling this puzzling phenomenon.
"Understanding the mechanisms that control biological quiescence could have dramatic implications for medical care, as it could give us an ability to control life processes at the most basic, fundamental level," Roth said.
This work was supported in part by funding from the National Institutes of Health and the National Science Foundation. The Hutchinson Center has filed a patent application to cover this technology, which is available for licensing.
The Fred Hutchinson Cancer Research Center is an independent, nonprofit research institution dedicated to the development and advancement of biomedical technology to eliminate cancer and other potentially fatal diseases. Recognized internationally for its pioneering work in bone-marrow transplantation, the Center's four scientific divisions collaborate to form a unique environment for conducting basic and applied science. The Hutchinson Center is the only National Cancer Institute-designated comprehensive cancer center in the Pacific Northwest and is one of 37 nationwide. For more information, visit the Center's Web site at http://www.fhcrc.org.
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