HARVARD GAZETTE ARCHIVES
Sperm cells made in laboratory can fertilize eggs
From sperm cell in petri dish to embryo
By William J. Cromie
Harvard News Office
Scientists know that stem cells from embryos have the potential to develop into brain, bone, or any other type cell, but getting them to actually do this in a laboratory is a different thing. Now, for the first time, researchers have crossed this bridge by coaxing uncommitted stem cells to grow into sperm cells in a petri dish.
They then injected the sperm into eggs, and the resulting embryos grew to the point where they would normally be implanted into a womb. The experiment was done with mouse stem cells, but mice, genetically speaking, are so close to men, few scientists doubt that the same experiment can be done in humans.
The breakthrough, made by researchers at the Whitehead Institute for Biomedical Research and Harvard University, was reported today in the Dec. 11 issue of the journal Nature.
"This is the first time that sperm cells made in a petri dish from embryonic stem cells have resulted in the creation of an embryo," says George Daley, a Harvard Medical School biologist who led the experiments. (Egg cells were developed from mouse embryonic stem cells earlier this year by another group of scientists.) "Such experiments are being done solely for the purpose of studying how genes regulate the transformation of stem cells into germ cells, one of the basic mysteries of life."
However, Daley quickly admits that this work has implications for genetically modifying animals, for treating human infertility, and, perhaps, for other medical purposes. His team has already begun the next task, implanting an embryo grown from laboratory-devised sperm cells into a surrogate mother to see if it develops into a healthy mouse pup.
Probing male infertility
Niels Geijsen, a Harvard Medical School biologist who is the lead author of the Nature report, is cautious about applying the new method to humans. "Transferring the technique from mice to humans may not be that simple," he notes. "Human embryonic stem cells are quite different from those of mice." But if it works, he admits, it could well lead to new treatments for fertility.
Most male infertility, Geijsen says, is due to not having enough sperm cells. If further studies can reveal how to stimulate sperm development, then in vitro fertilization might no longer be necessary. "Now, we have a situation where eggs must be harvested from women and then fertilized in a test tube," he points out. "The procedure does not have a high success rate and it's emotionally trying. You have a situation where you're treating the partner rather than the patient."
Geijsen also suggests that the technique might play a role in cancer treatment. Normal cells remember which one of their two sets of chromosomes comes from the mother and which from the father. When their genes produce growth factors, they use only one set of chromosomes, not both. But tumor cells lose that memory and a double dose of growth proteins may trigger uncontrolled growth. If enough was known about how genes regulate the signals involved at the level of stem cells, the knowledge might lead to treatments that better control cellular memory.
As far as using the technique to customize humans in a test tube, Geijsen points out that this is illegal. "Using such technology to create genetically modified animals, like mice and cows, is definitely an option," he admits. "However, it is illegal to tinker with the gametes [eggs and sperm] of humans. At present, you cannot do it even to treat a genetic disease.
"As far as controlling gender," Geijsen continues, "This would not be the technique of choice. Better ways already exist."
Kevin Eggan, a Harvard biologist who participated in the experiments, notes that the size of a sperm head carrying a Y, or male, chromosome is slightly lighter than one that carries an X, or female, chromosome. Cell-sorting techniques exist that can take advantage of the difference, and skew the odds in favor of either a boy or girl.
The good, the bad, and the infertile
Eggan visualizes a sequence wherein an infertile man could create a fertile sperm line. He would begin by donating skin or another type of cell, which could be injected into a female egg to create a cloned embryo with his genes. The new technique might be used to extract embryonic stem cells that, depending on the reason for fertility, could be morphed into sperm cells. The latter might then be injected into his wife's egg cells to produce an embryo that could be transferred to her womb. If all went right, the infertile man would father a child with his own genes.
Eggan calls this "an extreme and controversial way around fertility." He emphasizes that such a procedure will not be tried at Harvard to treat infertility. "Eventually, what we hope to do is learn enough about the differentiation of human embryonic stem cells into sperm and egg cells to devise less extreme treatments for inherited infertility," Eggan says. "The wonderful thing about this technique is that it can produce enough germ cells to easily study the problems. Under natural conditions humans do not make enough germ cells for us to efficiently isolate them for examination. If we can find the genetic signals that regulate the production of sperm and eggs, then perhaps we could provide alternatives to in vitro fertilization."
As far as illegally modifying human stem cells to customize embryos - to select for sex, intelligence, size, etc. - Eggan sees that as fraught with danger. "It's irresponsible and unethical to modify genes that will be passed on to succeeding generations," he insists. "Although the intent to fix infertility is good, the unknown implications of these, or other engineered genetic changes, could be bad for the future. All scientists and ethicists agree on this."
Eggan sees good in using the new technology to help people such as Lance Armstrong, the world champion cyclist who survived testicular cancer. Such survivors are often made infertile by radiation, drugs, or surgery, not by genetic inheritance. In such cases, making a new embryonic stem line by cloning might be a viable option. The same is true for women who lose their reproductive ability as a result of treatment for ovarian cancer.Eggan is quick to point out that reproduction without sex and genetic tinkering are not likely to become widely used, if test-tube sperm making is extended to humans. "Right now these new techniques for assisted reproduction are very controversial and uncomfortable, even painful," he notes. "Sex is fun; it will always be the preferred method for reproduction."