Stem Cell Studies’ Bizarre Start
The words “embryonic stem cell” evoke miraculous images to many: of freshly grown nerves repairing severed spines or treating Parkinson’s or Alzheimer’s diseases, of pancreas cells created in dishes and used to cure kids of diabetes.
If and when such things will happen is unclear. Only three years have passed since biologists first isolated embryonic stem cell lines from humans. The cells, taken from embryos at a very early stage in development, retain the potential to become any kind of tissue in the body: bone, liver, skin, you name it.
Scientists, however, still have much to learn about coaxing cells down one developmental path or another.
The hoopla, promise and controversy surrounding stem cells are new, but the science behind the headlines has roots that stretch back to the 1950s, decades before the topic entered public consciousness.
“It didn’t just spring out like Athena from Zeus’ head, fully armed; it all had a very long intellectual and experimental history,” says Dr. Davor Solter, director of the Max Planck Institute of Immunobiology in Freiburg, Germany.
Without that history, today’s human embryonic stem cell science would simply not exist. From the first experiments and those that logically followed, scientists learned where and when super-versatile embryo cells can be found; how to extract them from embryos and coax them to thrive and divide in dishes; how to maintain their versatility; and how they might be coaxed to develop into different cell types.
The roots of the science are bizarre--a reminder that important discoveries can spring from strange places.
Two of the key players are a man working in a lab in Maine and a pale-colored mouse with a swelling in its groin.
Flashy cures were on neither participants’ mind.
In 1954, Leroy Stevens, a developmental biologist at the Jackson Laboratory in Bar Harbor, Maine, was busy testing whether cigarette paper might cause cancer.
The mouse was just one of many from a strain dubbed “129”--unremarkable in all ways but one.
Mouse and man came together when Stevens, who no longer talks to reporters, noticed a huge swelling on the animal’s scrotum. He decided to dissect the mass, and found it contained a weird mixture of bone, muscle, nerves, fat and cartilage.
The animal, it turned out, had a “teratocarcinoma”--a kind of cancer in which cell types develop willy-nilly into a grotesque, disorganized parody of an embryo.
Such tumors are strange indeed, recalls Solter, a long-time stem cell researcher and an adjunct scientist with the Jackson Lab.
“You would cut them and little bones would crunch,” he says. “You would see cartilage, and little black areas where the melanocytes were. There were twitching muscle cells. There were areas full of skin and hair.”
Humans teratocarcinomas, described as far back as ancient Egypt, are even stranger--sometimes containing teeth and fingers.
Normally, such cancers are very rare. But in Stevens’ mouse strain (after a bit of breeding), they cropped up in 1 mouse in 10--often enough to be studied.
Intrigue Increases With New Findings
And, as the data piled up through the years, the stranger and more intriguing these growths seemed.
* You could mince up a tumor from one mouse and place it under the skin or in the abdomen of another mouse, and you would get brand new growths.
Most were just jumbled mixes of different tissues, “almost like one took the basic tissues of an embryo and threw them in a bag, shook them up and poured them out,” said Gail Martin, professor of anatomy at UC San Francisco.
But some growths looked like they were actually trying to develop into embryos.
* Some of the tumors would grow and grow. Others wouldn’t: they would become a jumble of muscle and bone and nerve, then they would stop and just harmlessly sit there, unable to divide any more. The tumors that kept on growing bigger always contained little round cells that looked just like those from very early embryos.
* If you put these little round cancer cells into a mouse embryo, they wouldn’t behave like cancers at all. They would participate in the making of a totally normal mouse.
* The opposite was also true. You could take cells from a totally normal embryo, insert them under the skin of mice, and they would make teratocarcinomas.
Over the years, it occurred to Stevens and others that those strange, round cells were acting like cells of an embryo just a few days old. They could still become any part of a body--skin, a piece of leg, whatever. A single one of these cells could go on to make a tumor with a smorgasbord of tissues.
That was a stem cell.
No one studying these strange cells had the grand dreams that fill the airwaves today whenever embryonic stem cells are mentioned.
“We didn’t think about putting stem cells in the brain to form new brain tissue or anything like that,” says Dr. Barry Pierce, professor emeritus of the University of Colorado and a long-time colleague of Stevens.
But there was excitement over this curious cell. It would be great for studying how normal embryos developed, some said. It would be great for figuring out how cancers form.
Others like Pierce reckoned: Maybe you could cure cancers by getting malignant cells to turn into skin or muscle instead of spreading.
“It was a model of both cancer biology and developmental biology, and for a while we were selling it as the answer to everything in the world,” Solter says.
As it turned out, these little round cells didn’t end up providing cures for cancer or answers to all of developmental biology’s mysteries. But they left a legacy rich with promise.
First, scientists such as Martin learned to grow them and study them in labs.
That done, the scientists turned their attention to another target: growing real embryonic stem cells, cells that had never been a cancer in an animal but that came from the earliest of early mouse embryos. Pure lines that could live and divide and thrive in dishes.
Research Success Strikes Twice
In 1981, two groups reported success: Martin Evans, then of the University of Cambridge in England, and Martin at UC San Francisco. (Evans, who published a few months before Martin, shared this year’s prestigious Lasker award for basic medical research.)
To get her precious lines, Martin said, she first flushed a whole load of embryos from mice. Then she took the tiny, 31/2-day-old balls of cells and chemically treated them to find the few that were destined to become the fetus.
She placed her treated cells in dishes along with other, skin-like cells known as “feeder cells,” which ooze hormones essential for stem cells’ growth. She tended her dishes in incubators at a balmy 99 degrees Fahrenheit. And she waited.
A week later, she saw tiny colonies of cells growing among her fibrous feeder cells--real embryonic stem cells.
“There have been a couple moments in my career when I’ve been really excited, and one was the night I saw those stem cells growing,” Martin says.
Mouse embryonic stem cells have had a huge impact in basic, nonmedical research: they became essential ingredients in a powerful method that revolutionized the way scientists could figure out the function of genes.
And, eventually, scientists repeated with human embryonic tissue what had been done in mice. In 1998, scientists at the University of Wisconsin reported they had isolated human embryonic stem cell lines.
Given all that came before, “the development of human stem cells is really not surprising at all,” Pierce says.
Today, researchers are focused like never before on figuring out how embryonic stem cells move along different developmental paths and end up as different types of tissues.
Meanwhile, no one yet knows what wild, genetic mistake caused cells in Stevens’ mouse strain to divide and behave like cells of a very early embryo. But in a fitting legacy to Stevens, a former student of his--Joe Nadeau, of Case Western Reserve University--says he has narrowed down one of the genes involved to two possibilities, out of the 30,000 to 40,000 in the mouse genome.
“We should know the answer soon,” Nadeau says.
