June 3, 1997

Steen Malte Willadsen: Iconoclastic Genius of Cloning


WINDERMERE, Fla. -- There is a persistent rumor about Dr. Steen Malte Willadsen that rings so true to those who know him that it has taken on a life of its own. The story is that several years ago, without bothering to tell anyone, without troubling to write it up for publication, Willadsen cloned an adult cow.

Absolutely false, Willadsen said. But this 53-year-old Danish-born embryologist, described by others in the field as a genius and an iconoclast, has become bigger than life, almost a mad scientist, to hear some tell it, from whom anything is possible.

He was the first to clone an animal from embryo cells, taking cell nuclei, which contain the genetic blueprint for the animal, from an embryo and adding them to sheep eggs whose own nuclei he had removed. In this way, he produced lambs that were genetically identical to each other and to the original embryos. He did the same with cows.

Before that, he had made chimeras -- animals that were half sheep and half goat, and even half sheep and half cow. Rumors of Willadsen's unpublished work on embryo cloning prompted Dr. Ian Wilmut, the scientist who cloned an adult sheep, to decide that such a feat was possible even though the conventional wisdom said that once a cell has specialized, its genes cannot be reset to the state they were in when a sperm first fertilized an egg. And Willadsen's current projects, involving human eggs, appear to be pushing the envelope again.

Few have come away from encounters with Willadsen unscathed. "His personality is not one you'd find in anyone else," said Dr. Andrew Watson, an assistant professor of obstetrics and gynecology at the University of Western Ontario who worked with Willadsen in Canada several years ago. He also has a way of dominating a conversation. Every time it seems that he has completed a thought, he booms out, "But," and charges on.

"He does not follow any path but his own," Watson added. "He really sets the trends."

In an age when scientists so often seem to follow clear trajectories that lead them from college to graduate school, to postdoctoral fellow, to assistant professorship to professor at a university, Willadsen has always been an exception. He went from veterinarian in rural Denmark to research fellow in England, to cloning cattle embryos in Texas and then in western Canada, to a sort of freelance innovator in Florida.

In a speech last year upon his acceptance of the Embryo Transfer Pioneer Award of the European Embryo Transfer Association, Willadsen explained that one thing he had always dreaded was "the shot pheasant syndrome," which, he said, "is the most common postdoctoral ailment of career scientists." He explained: "though still airborne with wings flapping, the bird is already dead." His aim, he said, was "not just to become a scientist, but to engage in great, absorbing endeavors while maintaining a high degree of freedom, and avoiding tedium and coercion."

In an interview at his pink stucco home near Orlando, Fla., he put it more starkly. For him, he said, "the role of experimental science is to break the so-called laws of nature."

Willadsen grew up on a farm near Copenhagen, reared by his divorced mother and her family. His mother, he said, paid no attention to his schoolwork. He said he and his wife, Carole, a Scottish embryologist, spent more time in one month overseeing the schoolwork of their two children than his parents did in his entire career.

"When I went to school, I didn't even think about whether I liked it," Dr. Willadsen said. But he was adept.

"I was very good at anything I wanted to be good at," he said, observing, as he did several times in a long interview, that he was surprising himself with his brashness.

He became a veterinarian, but that lasted only a year and a half. He remembers the day when he decided he had had enough. At the time, veterinarians were responsible for all meat inspection in Danish slaughterhouses.

That day, assigned once again to slaughterhouse duty, Willadsen watched the pig carcasses come swinging down the line and looked over at the veterinarian working next to him. "His job was to remove the kidneys, liver, lungs, trachea and tongue from the dead pigs, all together," Willadsen said. "It was like watching an alien, the way he tore them out. I could see that he was not a happy man. I decided then and there that I would not get into a routine like that."

He went back to Copenhagen to work on a Ph.D., doing research on maturing cows' eggs in the laboratory. Once he got his Ph.D., Willadsen decided that there was not much he could do with it in Denmark. "At that time, the British Agricultural Research Council's unit in reproductive physiology in Cambridge was the mecca of embryo transfer in farm animals," he said. "I wanted to go there."

In 1973, he arrived and immersed himself in a frenzy of work. He began by perfecting the then-primitive methods for freezing embryos, working first with sheep, and then cows.

"At the peak, I probably had 400 sheep," he said. He even kept a few orphan lambs in his room for bottle feeding. In the morning, he would do surgery, removing eggs from the sheep. In the afternoon, he would work in the laboratory. In the evening, he would do more surgery, he would inject the sheep with hormones and he would walk around with a ram that had been trained to approach ewes in estrus, indicating which ones were ready to mate, but not mounting them.

Summers were a time when Willadsen tried wild and daring experiments. "I was checking fences," he said, looking for holes in the scientific fabric, ways to break through what others considered dogma.

Willadsen made embryo twins by splitting embryos in two. Working with Carole Fehilly, who later became his wife, he also made chimeras -- animals which have a mosaic of cells of two different sets of DNA. He and his future wife did this by mixing cells from different embryos and even mixing cells from embryos of different species, like a sheep and goat, or a sheep and cow. Their sheep-goat chimera was published on the cover of Nature in February 1984, to enormous publicity.

The chimeras grew to adulthood and some were fertile. But when Willadsen left England in 1985, he lost track of them. He suspects that, as with most of the animals he created, they were eventually killed. The research station, he said, "was not an animal shelter."

But Willadsen does remember the fate of one sheep-cow. He had mated the animal with a ram, and she was due to deliver in two months. Willadsen, however, was about to depart. So, he said, he killed his animal to see the fate of the fetuses -- they were healthy, and sheep -- and then ate her at his farewell party. The animal, he said, "didn't taste very good, but that was because she was a sheep rather than a lamb."

Willadsen, however, considers the chimeras a minor part of his work, which has always been focused on animal breeding. The traditional approach is to inbreed animals that were selected for certain traits and then mate those inbred animals, which tend to be feeble or runts, with healthy animals from the general population, thereby merging genetic selection with hybrid vigor.

But when the hybrids are mated, the valuable traits from the inbred animals tend to be diluted or lost. Hence, cloning. It would allow breeders to multiply the valuable animals, including hybrids, without the vagaries of the genetic lottery. They could take cells from selected embryos and clone them, making multiple copies of a single creature. Elite cattle embryos cost $5,000 to $15,000 each, so breeders saw gold in an ability to clone.

In 1986, Willadsen published a paper in Nature announcing the first successful cloning of cells from sheep embryos. By that time, he had already begun cloning cow embryos and he moved to Texas, where a new company, Granada Genetics, wanted him to set them up in the cattle-cloning business.

A year later, Willadsen left Granada and moved to Alberta, Canada, where another newly formed company, Alta Genetics, wanted him to do the same thing. The company's main investors promised that if Willadsen and his embryo transfer team could create 100 pregnancies with cloned embryo cells in their first year, they would invest another million dollars in the company. Willadsen exceeded that goal.

Watson worked with Willadsen at Alta Genetics, recalling how Willadsen would bring in Shakespeare's sonnets for his junior scientists to read. He had decided, Watson said, "that we were not well-rounded enough." Watson and Willadsen also played their clarinets in the afternoons, working on Mozart's concerto.

In the meantime, as early as 1982, when he first started cloning, and also in Canada, when he was churning out embryos, Willadsen did some experiments that were on the edge. He cloned from more developmentally advanced embryo cells, those that had already begun to specialize. Many had thought that could not be done, that once a cell started to specialize, its DNA could not be brought back to its primordial state.

But Willadsen says he successfully cloned cells from embryos that had 60 to 120 cells, in contrast to most work, which used 8-cell embryos. He never published these results, but when Wilmut heard rumors of this work, it made him think that the old dogma that cloning of differentiated cells would fail could not be true. And that led him to the research that resulted in the birth of the sheep named Dolly, the first animal cloned from an adult cell.

Now Willadsen is working on studies with mouse and human eggs, developing ways to freeze them. His part-time work, at an in vitro fertilization clinic, the Institute for Reproductive Medicine and Science of St. Barnabas Hospital in Livingston, N.J., involves human eggs that failed to develop and would otherwise have been discarded.

Asked if he thought that some day humans would be cloned, Willadsen said yes. In fact, he said, they may have been accidentally cloned already. Infertility specialists can now fertilize eggs by injecting them with sperm, even immature sperm taken directly from a man's testicles. The immature sperm have no tails and, in fact, look just like other cells that may be mixed in with them. They have just one set of chromosomes, like mature sperm or mature eggs. But, Willadsen said, other cells in the same sample can have two sets of chromosomes, as do most other cells in the human body. If the embryologist inadvertently injects a nonsperm cell into an egg, and if the egg, as sometimes happens, spontaneously sheds its own nucleus, the procedure would be transformed into cloning of the father.

"The likelihood of a baby resulting is small, but, in the light of the Dolly experience, not nil," Willadsen said. And, he added, although it is unlikely that men have inadvertently been cloned in this way, such cloning "is not unlikely to occur in the future."

Willadsen said he also suspected that humans would be intentionally cloned some day. But, he said, if that happens, doctors will avoid controversy by using some other term for what they are doing. "It probably will not be called cloning," he said.



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