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Inducing suspended animation

Roth, Padilla discover 'Sleeper' of a clue to cell division in zebrafish
Dr. Pamela Padilla
Dr. Pamela Padilla inspects the device she uses to create an oxygen-free chamber for her suspended-animation studies on zebrafish embryos. Photo by Clay Eals

The survival last February of a 14-month- old Canadian toddler who nearly froze to death stunned doctors and the public alike. With her body temperature dipping to 61 degrees and without a heartbeat for two hours, Erika Nordby's recovery from biological limbo seemingly defies scientific or medical explanation.

But Dr. Mark Roth, investigator in the Basic Sciences Division, notes that a temporary halt to virtually all life processes can - and does - occur in many organisms.

Roth should know: He and postdoctoral fellow Dr. Pamela Padilla are the first to develop a method for inducing this state of so-called suspended animation in a vertebrate animal.

Roth and Padilla discovered that after 24 hours of oxygen deprivation - resulting in cessation of all observable metabolic activity, including heartbeat - zebrafish embryos can be restored to a normal program of development with no deleterious effects on their health or growth.

Their work, the first demonstration of this phenomenon in a model vertebrate highly amenable to laboratory analysis, promises to open new paths of research into understanding this remarkable condition.

The study was published in the June 19 Proceedings of the National Academy of Sciences.

On the fringe?

Roth is the first to admit that his project - reminiscent of the Woody Allen comedy "Sleeper" - may seem to some as "on the fringe" for research at a cancer research center. That is, until he points out that his studies on biological quiescence may shed light on two problems that perplex cancer biologists - the control of stem-cell division and how oxygen deprivation affects tumor cell growth.

"We typically think of cancer cells as growing out of control," said Roth, also an affiliate professor of biochemistry at the University of Washington. "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 sometumors don't respond to certain forms of therapy."

Many chemotherapeutic agents work by selectively killing actively dividing cells, meaning that any quiescent tumor cells are unaffected by treatment. Other cancer drugs have been developed that can target non-dividing cells.

Suspended animation can also be important for normal cells, Roth said.

Self-renewing cells

"Stem cells - like those that give rise to your skin - are self-renewing cells that 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 active cell division."

The phenomenon can be critical for the normal development of many animals.

"Numerous organisms have naturally occurring states of suspended animation," Roth said. "About 70 species of mammals 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 the lab resembles the reversible state of limbo seen in other organisms.

Roth and Padilla compared the developmental capability of zebrafish embryos that had been exposed to normal atmospheric conditions or were grown in anoxic 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 anoxia 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."

Two discrete points

Microscopic analysis and examination of the DNA content of the anoxic embryos revealed that their cells halt at two discrete points in the cell cycle - S phase, when DNA duplication occurs, and G2, the period just prior to cell division.

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 recover, you suffer from brain damage."

Some humans, for unexplained reasons, manage to survive extreme forms of stress like cold temperature and recover from a metabolic shutdown.

Roth admits that it is hard to predict whether suspended-animation 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," he said. "It could give us an ability to control life processes at the most basic, fundamental level."

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