Wooly mammoth's secrets traced through hemoglobin

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No one has yet fulfilled the fantasy of many a budding teenage scientist and cloned a woolly mammoth.

But using the DNA from well-preserved mammoths found in northern Siberia, an international team of researchers recently managed to replicate mammoth hemoglobin and study it, lending new insight into just how the extinct relative of elephants managed to survive in such extreme cold during the Ice Age.

"The resulting hemoglobin molecules are no different than going back in time and taking a blood sample from a real mammoth," said team leader Kevin Campbell, an associate professor of environmental and evolutionary physiology at the University of Manitoba in Winnipeg.

The findings were released Sunday in the journal Nature Genetics.

A critical part of the research -- recreating the hemoglobin itself -- was done by Chien Ho, a professor of biological science at Carnegie Mellon University and a world-renowned expert on blood substitutes and hemoglobin, which is the blood protein that delivers oxygen from the lungs to tissues in the body. His colleague, Tong-Jin Shen, a senior research scientist who works in Dr. Ho's lab, also helped with the project.

"I can say that I never thought when I first started this work 30 years ago that I would be working with mammoth hemoglobin," said Dr. Ho, who believes this research could also lead to potentially important breakthroughs in his specialty of coming up with blood substitutes for humans.

What Dr. Ho, Dr. Campbell and 12 other scientists -- spread over four continents -- found was that mammoth hemoglobin contained four amino acids that had evolved from its closest cousin, the Asian elephant, that allowed this protein to deliver oxygen efficiently to tissues in mammoths.

That by itself was not surprising. Other modern animals that live in cold climates, such as reindeer and musk ox, have a similar mutation in their hemoglobin that differs from, say, how human hemoglobin would deal with the cold. (Think about how we have to warm up our fingers on a cold day.)

But Dr. Campbell said in a phone interview that what surprised everyone involved was the novel way the mutations allowed mammoths to use different amino acid substitutions in the proteins to get hemoglobin to tissue in a cold climate.

"They solved this problem in a completely different way," he said. "The way they did it is not found in any other living animal."

For the mammoth, this meant that they could keep extremities cool and concentrate heat internally, minimizing heat loss. In addition, it meant that when food was scarce they could live on less of it since they didn't need as much heat (or calories) to move the oxygen to the tissues.

Daniel Fisher, a mammoth expert at the University of Michigan, who was not involved in the study, said the finding could be an important step in understanding the biological processes that allowed the mammoth to survive in the cold, dry climate it lived in.

"I would say it's a big step forward," said Dr. Fisher, who added that he and some fellow colleagues have also been working on some related studies that have yet to be released.

He said the finding also opens up questions about how other extinct animals from the mammoths' time adapted to the conditions, such as the woolly rhino, and what might be learned from those adaptations.

Dr. Campbell said he came up with the idea to try to do this a decade ago.

He had seen Discovery Channel show about the excavation of a mammoth and realized that with Dr. Ho's system of growing hemoglobin -- which he had been aware of for some time -- it might be possible to do the same thing.

"These thoughts intertwined and right then I wondered, why can't we get mammoth DNA and bring mammoth blood back to life?" he said.

In January 2006, Dr. Campbell, a longtime Pittsburgh Penguins fan, contacted Dr. Ho and came to Pittsburgh to meet with him and see if he was willing to help -- and to see a Pens game.

Dr. Ho was enthusiastic -- though dealing with extinct animals was a new field for him.

"But I was not surprised that we could do it because I thought we'd be able to express the mammoth's hemoglobin once we got the mammoth's DNA," Dr. Ho said.

The process Dr. Ho first perfected in 1993 for human blood involves taking a plasmid, a DNA molecule that can replicate chromosomal DNA, and inserting it into E. coli bacteria -- which acts as a manufacturing facility, of sorts -- to grow the protein, or hemoglobin.

In this case, the plasmid would have to be created by taking mammoth DNA and sequencing it with DNA from its closest cousin, the modern-day Asian elephant.

To do that, Dr. Campbell needed mammoth DNA (from Siberia) and then experts (from Australia) to sequence that with the genetic information from an Asian elephant's hemoglobin (from Canada) with additional help from scientists (in Japan) -- truly an international team.

"No single lab in the world could do what we wanted to do. No one person has the expertise," said Dr. Campbell. "Because it's so ridiculous what we wanted to do: To bring something back to life after 20,000 years and study it. But we did it."

Sean D. Hamill: shamill@post-gazette.com or 412-263-2579.


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