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A team of University of Ottawa researchers has solved the mystery of how our bodies adapt to low-oxygen environments, raising the prospect that life-threatening conditions such as cancer, stroke and heart disease could someday be successfully treated using a simple, antibiotic-like drug.
The team’s findings were published Sunday in Nature, the world’s leading scientific journal.
“It’s a tremendously important discovery in understanding how life without oxygen works,” said Dr. Stephen Lee, a professor in the university’s Department of Cellular and Molecular Medicine, whose laboratory did the groundbreaking research.
Scientists have known for decades that in the presence of oxygen, cells make proteins — the building blocks of life — using a process called protein synthesis. But how they do so in conditions of limited oxygen had remained a mystery.
“There’s a huge amount of research, hundreds of thousands of papers,” Lee said in an interview. “But still nobody has discovered how we make the basic building blocks of life in these conditions. That’s what we discovered.”
Lee’s team found there’s an oxygen-regulated switch in the protein synthesis machinery, a “very novel and unexpected way of synthesizing proteins,” Lee said. “It’s very different.”
The discovery explains, for the first time, how mountain climbers and highland Tibetans are able to adapt and function in environments that would kill or sicken most people.
“These are very basic processes of life,” Lee said. “It’s kind of strange that we discovered this in the 21st century. That tells you there are still basic processes that we just don’t know exist.”
The implications for cancer treatment, though still speculative, are potentially huge. Lee’s team discovered that cancer cells proliferate by using the same protein synthesis machinery the body employs to deal with low levels of oxygen.
Cancer cells “utilize that way of producing proteins without oxygen, even if oxygen is present,” Lee said. “They hijack that system and that drives their proliferation.”
If the cancer cells use the low-oxygen machinery to spread, he said, “we can develop an antibiotic against that protein synthesis machinery. It’s as easy as that. And it’s working very well.”
The comparison to antibiotics is apt, Lee said. Drugs such as penicillin and tetracycline kill bacteria by preventing them from synthesizing proteins. A future cancer drug would “work in a similar fashion,” Lee said, using the low-oxygen machinery to block protein synthesis in cancer cells.
That should make it “very easy to kill cancer cells,” he said. “We’re doing it right now in the lab. We just need to develop a drug now, which is not trivial, but it’s not that difficult, either.”
The sort of cancer treatment imagined by Lee would be a radical departure from the current approach, which relies on toxic doses of chemotherapy and radiation.
“The major dogma right now is that we have to attack cancer cells using very specific drugs that target very specific molecules,” Lee said.
“If we’re right, this is the first systemic difference between a normal and a cancer cell. Rather than targeting one precise molecule, we would just strip the cancer apart by preventing it from making the building blocks.”
Lee hadn’t originally planned to include the reference to cancer treatment in the Nature article “because we thought it was too speculative and Nature is a very conservative journal. But they really asked us to point the possibility out.
“They liked it. I like it. We have data that suggests we’re right. We just need to prove it more and convince some chemists to start working on it.”
The team’s research could also lead to the development of drugs to treat and protect people who have strokes or heart attacks.
Strokes and heart attacks cut off the supply of blood, damaging or killing brain cells or heart tissue. At such times, “our cells just don’t have enough time to adapt to low oxygen,” said Lee.
But as a result of the University of Ottawa team’s discoveries, drugs could be developed that would switch on the alternate protein synthesis machinery within seconds, allowing cells to survive with little oxygen. As well, Lee said preventive drugs could “definitely” be developed for high-risk patients to improve their chances of surviving a stroke or heart attack.
Similar drugs could also be used by mountain climbers and others who operate in low-oxygen environments to eliminate the need for weeks or months of acclimatization.
Lee said papers published about 18 months ago found that the high-altitude Tibetans have a genetic mutation that allows them to survive.
“The mutation they have is exactly in the gene that’s involved in my pathway,” he said. “That protein synthesis system is on all the time.
“It’s strange that out of the hundreds of thousands of genes that we have, the one nature selected for the highlanders to live up in the mountains is the one that makes the switch in our system from high oxygen to low oxygen. That’s incredibly interesting.”
Lee first twigged to the existence of an oxygen-regulated switch in 2006 while doing post-doctoral work at the National Cancer Institute in Washington after a former Ph.D. student of his did an experiment.
“We looked at that and said, “Oh-oh, we’re on to something here of big, big, massive proportions,” Lee said. He continued the research after relocating to the University of Ottawa and opening his own laboratory. “Nature published this because we took our time and we figured out the full pathway and really proved it.”
Lee’s team includes Dr. James Uniacke, a post-doctoral fellow who did most of the research, along with graduate students, technicians and others who worked under his supervision.
The team also collaborated with Dr. Martin Holcik, a research scientist at the Children’s Hospital of Eastern Ontario, and Dr. Arnim Pause, of McGill University’s Cancer Research Centre. Both are experts in protein synthesis and provided feedback and analysis of the University of Ottawa team’s research.