First live births from artificial sperm

By Mark Henderson, Science Editor of The Times

Seven mouse pups, six of which survived to adulthood, were born in a laboratory in Germany after scientists fertilised eggs with sperm that had been grown from embryonic stem (ES) cells.

The births provide the strongest evidence yet that it will eventually be possible to use ES cells to treat infertile men who make no sperm of their own.

Stem cell grafts could repair malfunctioning testes, or artificial sperm could be grown outside the body for IVF, while therapeutic cloning would ensure that the ES cells used carried the patient’s own genes.

Other experiments have suggested that artificial eggs can be made in the same way, though no offspring have yet been born.

In the longer term, it may even prove possible to produce sperm from female stem cells, and eggs from male ones, allowing homosexual couples to have children that bear the genes of both parents.

This would also enable a single man or woman to provide both the sperm and eggs needed to create an embryo, so that a person could essentially mate with himself or herself.

The creation of “male eggs” and “female sperm”, however, still faces difficult technical barriers, as embryos need genetic material from both a mother and a father to develop normally.

The immediate benefit of the new research will be to deepen understanding of how mature sperm are formed, potentially improving treatments for male infertility.
One promising idea is to remove tissue from the testes, culture immature sperm in the laboratory and then transfer them back to the patient to restore his fertility.
The study, which was published today in the journal Developmental Cell, was led by Professor Karim Nayernia, who has recently joined the Newcastle-Durham Institute for Stem Cell Biology and Regenerative Medicine from Georg-August University in Göttingen, Germany.

His team first created male mouse embryos, which were allowed to develop for a few days until they became small balls of cells known as blastocysts.

The cells were then stained with two marker dyes, one to identify spermatogonial stem cells (SSCs), which will go on to form sperm, and the other that would show up more mature sperm as they developed.

The SSCs were removed and cultured in the laboratory, after which the second dye was used to pick out the ones that had formed sperm. These were then injected into mouse eggs, and the resulting embryos were placed in the wombs of surrogate mothers.

Fertilisation was very inefficient: hundreds of mouse eggs were injected, but only about 50 developed as far as two-cell embryos, while only seven were carried to term. One of the pups died in infancy, and all were dead within five months, compared to a normal lifespan of about two years.

The limited success suggests much more work is needed before artificial sperm can be tried in humans, but it proves the principle that they can lead to live births.
“This is a problem we will have to solve before human trials, but it is a very important result from a biological viewpoint,” Professor Nayernia said. “We have a model for studying how life begins.

“This research is particularly important in helping us to understand more about spermatogenesis, the biological process in which sperm is produced. We must know this if we are to get to the root of infertility.

“If we know more about how spermatogonial stem cells turn into sperm cells, this knowledge could be translated into treatments for men whose sperm is dysfunctional, although this is several years down the line.

"For example, we could isolate a patient’s spermatagonial cells using a simple testicular biopsy, encourage them in the laboratory into becoming functional sperm and transplant them back into the patient.”

In the more distant future, he said cloning by nuclear transfer could be used to create ES cells that carry an infertile patient’s DNA, which could then be transformed into sperm. “If the problems are solved, then we could think about humans, and see if with nuclear transfer we could establish ES cells from a patient and bring them to be sperm.”

Another research team, at the University of Sheffield, has already established that it is possible to grow human sperm from ES cells, though no attempt has been made to use them to fertilise eggs.

Other groups in the United States and Japan have also shown that mouse eggs can be made from stem cells and fertilised, though no pups have been born.
Professor Harry Moore, who led the Sheffield research, welcomed the new study, though he cautioned that much more work was needed before human therapies can be tested. “This is important work which builds on a number of discoveries showing that embryonic stem cells can generate sperm and eggs in the lab,” he said.

“This latest finding is exciting, as it is the first indication that immature sperm cells produced in this way have the full potential to create an individual. This opens up many important possibilities for research related to genetics, cancer and cell reprogramming.

“The latest findings also highlight that these processes in the test tube are far from perfect as the mice that were born by this process were abnormal. We therefore have to be very cautious about using such techniques in therapies to treat men or women who are infertile due to a lack of germ stem cells until all safety aspects are resolved. This may take many years.”

Medical ethicists said the work raises important questions that need to be considered before human trials begin. “Sperm and eggs play a unique role in our understanding of kinship and parenthood, and being able to create these cells in the laboratory will pose a serious conceptual challenge for our society,” said Anna Smajdor of Imperial College, London.

“Who is the father of offspring born from laboratory sperm? A collection of stem cells in a petri dish? The embryo from which the cells were derived...? The answers to these questions are not clear, but they go to the foundations of our sense of identity.

“But there is still a long way to go before these techniques are likely to be used in human beings. Many of the mice born from this ‘artificial sperm’ died prematurely, and displayed abnormal growth patterns, so it is clear that much more work is needed before laboratory-manufactured sperm is available for us. In the meantime, it is essential that we stay ahead of the game by addressing the ethical issues involved and constructing appropriate regulatory frameworks.