Here is the first article in an occasional series on cloning that we'll continue throughout the year. Stay tuned for more on this crucial issue in future editions of KnowledgeNews.

There are scientists out there trying to bring the dead back to life. They're not mad, but they are dedicated, because they believe it will happen, sooner or later. It might not occur on a cold stone slab, there probably won't be lightning flashing between huge steel electrodes, and it definitely won't take place in a gothic German castle. But it will happen. Somewhere, scientists will revive the dead--and not just an individual, but an entire species.

Species have been going extinct since the beginnings of life. Although millions of creatures have lived and thrived on this planet for more than 3 billion years, more than 99 percent of them are gone. It's a natural part of evolution. Like death and taxes, extinction is practically a sure thing. It's also permanent. Once the last living member of a species succumbs, it's all over.

But in 1997, a team led by Ian Wilmut at the Rosland Research Institute in Scotland made headlines with the announcement that they had successfully cloned a female sheep, the now famous "Dolly." The breakthrough surprised many, and immediately started discussion about the future of cloning and its impact on the world. In the midst of this swirling debate, wheels began to spin in the minds of several scientists. If living animals could be cloned, they thought, why not extinct species?

Cloning 101

In spite of the excitement surrounding the Dolly experiment, scientists urged people not to get too worked up about the possibilities. The reason is that, in spite of this success, cloning is really hard. Cloners compare it to assembling a one-million-piece puzzle where all the pieces are the same color. Of course, nature makes genetic duplicates all the time. We refer to them as identical twins. But twins grow according to the DNA code from developmental cells--cells that are supposed to divide and grow into complete adult beings. Cloning attempts to get the DNA from adult cells to do the same thing.

Unlike developmental cells, adult cells have gone through a process called differentiation. This process allows them to specialize into the muscle, bone, skin, and many other types of cells that make up an entire animal. But this specialization also causes the cells to lose their ability to grow into other types. Skin cells can only make more skin cells, and muscle cells can only make more muscle cells. They just can't do anything else.

Cloners attempt to overcome this cellular specialization by using only the DNA from cells in specific locations of the body. In the case of Dolly, after countless earlier attempts had failed, scientists used DNA from female mammary glands. They chose these cells because the cells had entered a state called quiescence. Quiescent cells no longer replicate themselves, which would seem to make them poor candidates for clonal development. But actually, they're just what Dr. Frankenstein ordered. The DNA in the nucleus of these cells is in its least active state, and that makes it most suitable for transfer. Because it's not busy doing anything at the moment, it seems to be more amenable to becoming a clone.

The next step is to find a suitable host cell from another animal to put the quiescent DNA into. As with donor cells, scientists need to choose host cells from just the right location. With Dolly, they used female oocytes, the cells that go on to form the egg cells used in reproduction. Of course, most cells already have a perfectly good set of DNA residing in their nucleus. Cloners must remove all of this DNA before they can insert the new set. They use a tiny glass tube to carefully suck the old nucleus out and put the new one in, hoping all the while that the rest of the cell doesn't notice. Seen through a microscope, the maneuver looks like trying to pierce a soap bubble with a turkey baster without bursting it.

Even after successful implantation of a new nucleus, which doesn't happen very often, the vast majority of these cells fail to grow into healthy adult organisms. The host oocyte and the new nucleus with the donor DNA in it need to cooperate with each other. The DNA from the donor has all the information needed to grow the cell into a complete adult being, but it needs the host oocyte to give it a biochemical "incentive" to do so. Even though oocytes are reproductive cells, supposed to grow into complete adults eventually, this doesn't always work. Scientists aren't sure why exactly, but a variety of genetic conditions inside the nucleus as well as biochemical conditions inside the host cell need to be just right for proper growth to occur. If any one of these conditions is missing or off just a bit, the cell fails--and failure is indeed what happens most of the time.

If the cell does start to divide, growing into the tiny ball of cells that marks embryonic development, cloners face the next hurdle: getting an adoptive mother to accept the embryo. Success at this important stage requires the mother to have a specific set of hormonal conditions--conditions which must synchronize with those in the developing embryo for it to properly implant itself in the mother's uterus and grow. The timing has to be just right, and as anyone trying to get pregnant can tell you, it usually isn't.

The end result is a success rate of less than 1 percent. Even Dr. Frankenstein had a better average than that. But scientists are learning more about the conditions necessary for successful cloning, and refinements to the original Dolly experiments promise to make the success rate increase in coming years. Confidence is high enough now that most scientists believe that any animal could be cloned given enough time--any living animal, at least.

Clone This!

If cloning a living animal is like trying to assemble a one-million-piece puzzle where all the pieces are the same color, then cloning an extinct animal is like doing the same thing with most of the pieces missing. Once an animal dies, there are no living cells from which to gather a complete set of genes, and fragile DNA quickly degrades. Only in a few, very rare circumstances are conditions after death conducive to preserving even small amounts of DNA. Consequently, scientists say that the hardest challenge in cloning an extinct creature would be gathering enough of the elusive genetic stuff to make a complete genome.

The most common remains of extinct animals are in the form of skeletal fossils, but they are poor candidates for harvesting DNA. Millions of years of weathering and biological activity have long since scoured the bones of any soft tissue, to the point where even a few molecules of organic matter are hard to find. A well-preserved fossil may yield a few bits of recoverable DNA, but nowhere near enough to reconstruct a complete genome.

Another target for the would-be Frankenstein lies in amber, the hardened and fossilized resin of ancient tree sap. Many chunks of amber have been found with well-preserved animals, mostly insects, trapped inside. The amber coating protects the animal's carcass from the ravages of nature over time. But in spite of what the celluloid scientists in Jurassic Park might have done, amber is not a perfect preservative, and only limited amounts of DNA have ever been successfully extracted from amber-encased animals.

One potential DNA source that scientists are exploring is based on a secret that restaurateurs have known for years: that ice makes a nice preservative. At the end of the most recent Ice Age (about 10,000 years ago), a few arctic animals were frozen in large blocks of ice, preserved in death until thawed out by modern explorers. The most notable of these animals, and the most compelling to the imagination, is the woolly mammoth. A relative of modern elephants, the last mammoths went extinct more than 4,000 years ago, victims of the Earth's warming climate and the spread of early humans. Well-preserved mammoth specimens have been recovered from the ancient glaciers of northern Russia. Complete with remains of skin, hair, and possibly even internal organs, these mammoth carcasses could be better preserved than last week's tuna casserole.

In 2000, an international team of scientists attempted to recover a 23,000-year-old specimen from the Taimyr Peninsula in Siberia. After the remains were carefully carved out of the ice and taken back to the lab, the extracted mammoth DNA was found to be heavily damaged by ultraviolet radiation and the freezing and thawing of the ice. In spite of the sophisticated methods used to recover the tissue samples, only small fragments of DNA were recovered. Scientists now doubt that a complete genome could be put together anytime soon, if ever.

That leaves one last option: alcohol. Scientists have been using alcohol and similar compounds to preserve specimens for centuries. It sterilizes the tissues placed inside, preventing bacteria and other organisms from consuming them and slowing down decay. It is in such a jar of alcohol that perhaps the best hope for raising the dead exists.

Pickled Tiger, Ethical Pickle

In the 1930s, the Hobart Zoo in Tasmania housed a variety of animals. Like many zoos around the world, Hobart's star attractions were its predators. But compared to the lions, bears, and other exotic mammals brought in from the far corners of the world, Tasmania's local predator was decidedly unimpressive. Zoo visitors would take a few moments to watch the dull brown animal's quiet and nervous pacing and then move on.

What visitors to Hobart's zoo had seen was the Tasmanian tiger (Thylacinus cynocephalus). A predator native to Australia, New Guinea, and Tasmania, its common name was misleading. It didn't look much like a tiger, except for the bold stripes on its back. At five feet in length, it looked more like a large dog or wolf, but it wasn't one of those either. It was a marsupial, more closely related to the koala or kangaroo than to any big cat or wolf. Shy and secretive, these "tigers" wandered the forests and grasslands, hunting and scavenging for wallabies and other animals.

Driven off Australia and New Guinea by the introduction of wild dogs thousands of years earlier, Tasmania became the shy hunter's last refuge. But after sheep farmers settled Tasmania in the 1800s, its days were numbered. Once the tiger decided sheep made a pretty good snack, farmers vilified the predator as a menace and put a bounty on its head. For 75 years, the tigers were trapped and shot in large numbers. Slow moving and unused to dealing with humans, they were easily killed or captured. Those that were brought to zoos didn't last very long, and in spite of efforts to breed them, they never reproduced in captivity.

So it was on September 9, 1936, that the last Tasmanian tiger on display at Hobart died alone in its cage. Almost before anyone realized it, the Tasmanian tiger had gone extinct. Ironically, the zoo itself closed its doors the following year, and all that remained of the strange predator were pictures, a few skeletons and pelts, and the preserved specimen of a pup floating in alcohol on a shelf at the Australian Museum.

With the successful cloning of Dolly, the directors of the Australian Museum knew they had an incredible opportunity floating in that jar. Thousands or even millions of years had passed since other extinct species walked the Earth, but the Tasmanian tiger had been gone for just a little more than six decades. The question was whether or not the DNA had remained intact enough in the alcohol to be converted into a complete, viable set.

Scientists intend to find out. To see whether they can render the tiger's complete genetic code, they are relying on a technique called polymerase chain reaction (PCR), which uses DNA's natural ability to replicate itself to make many copies. By replicating enough of the many small pieces of DNA they find, scientists hope to piece together the puzzle and come up with the tiger's complete genome. Early results have been positive, as scientists have successfully replicated DNA. Now the researchers believe that no technological barriers prevent them from accomplishing their goal--only countless hours of hard work.

Whether or not the scientists can successfully clone the pickled tiger they possess, it's doubtful that tigers will ever again walk the forests of Tasmania. One clone is still just one clone, and since you obviously need one of each sex to reproduce, creating a viable population remains impossible. But for many, that is not the point. Just accomplishing the difficult task would be its own reward. For others, though, the implications give pause. Whether recent or ancient, extinction is nature's way of removing that which no longer belongs. Like Frankenstein, the cloners might be focused too hard on creating life, and not enough on what happens next.

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This issue of KnowledgeNews is brought to you by Mary Shelley's Frankenstein, the original need-to-know tale of scientific creation gone awry.