• Mice with just two ‘male’ genes father babies
As part of efforts to stop obesity and its attendant health consequences such as heart attacks, strokes, diabetes, hypertension, kidney failure, cancer, among other chronic diseases, a research group headed by ETH-Zurich professor Martin Fussenegger from the Department of Biosystems Science and Engineering in Basel, Switzerland has now developed an early warning system and treatment: an implantable genetic circuit mainly composed of human gene components.
On the one hand, it constantly monitors the circulating fat levels in the blood. On the other hand, it has a feedback function and forms a messenger substance in response to excessively high blood-fat levels that conveys a sense of satiety to the body.
In order to construct this highly complex regulatory circuit, the biotechnologists skillfully combined different genes that produce particular proteins and reaction steps. They implanted the construct in human cells, which they then inserted into tiny capsules.
The researchers studied obese mice that had been fed fatty food. After the capsules with the gene regulatory circuit had been implanted in the animals and intervened due to the excessive levels, the obese mice stopped eating and their bodyweight dropped noticeably as a result. As the blood-fat levels also returned to normal, the regulatory circuit stopped producing the satiety signal.
Also, in a technique called round spermatid injection, immature sperm cells are used to fertilise an egg. Researchers have used the method to produce live offspring fathered by mice that lack a full Y chromosome.
Researchers in the study published in Science have shown that just two genes from the Y chromosome - that genetic emblem of masculinity in most mammals - are all that is needed for a male mouse to sire healthy offspring using assisted reproduction. The same team had previously reported1 that male mice with only seven genes from their Y chromosomes could father healthy babies.
The study brings researchers one step closer to creating mice that can be fathers without any contribution from the Y chromosome at all. The findings also have implications for human infertility, because the work suggests that the assisted-reproduction technique used in the mice might be safer for human use than is currently thought.
Fussenegger said: “The mice lost weight although we kept giving them as much high-calorie food as they could eat.” The animals ate less because the implant signalised a feeling of satiety to them. Mice that received normal animal feed with a five-per-cent fat content did not lose any weight or reduce their intake of food, says the biotechnologist.
One major advantage of the new synthetic regulatory circuit is the fact that it is not only able to measure one sort of fat, but rather several saturated and un-saturated animal and vegetable fats that are ingested with food at once. However, this development cannot simply be transferred to humans. It will take many years to develop a suitable product.
Nonetheless, Fussenegger can certainly envisage that one day obese people with a body mass index of way over thirty could have such a gene network implanted to help them lose weight. Fussenegger sees the development as a possible alternative to surgical interventions such as liposuction or gastric bands. “The advantage of our implant would be that it could be used without such invasive interventions.”
Another merit: instead of intervening in the progression of a disease that is difficult to regulate, it has a preventive effect and exploits the natural human satiety mechanism.
This gene network is one of the most complex that Fussenegger and his team have constructed to date and was made possible thanks to the biotechnologist’s years of experience in the field. It is not the first time he and his team have succeeded in constructing such a complex feedback regulatory circuit: a number of years ago, they produced an implant that can also be used to combat gout via a feedback regulatory circuit.
Meanwhile, Jennifer Marshall Graves, a geneticist at the La Trobe Institute of Molecular Science in Melbourne, Australia, who was not involved in the Mice chromosome research said: “To me it is a further demonstration that there isn’t much left on the poor old Y chromosome that is essential. Who needs a Y?”
An embryo without a Y chromosome normally develops into a female, but biologists have long questioned whether the entire chromosome is necessary to produce a healthy male. A single gene from the Y chromosome, called Sry, is known to be sufficient to create an anatomically male mouse - albeit one that will be infertile because it will lack some of the genes involved in producing sperm - as researchers have shown by removing the Y chromosome and inserting Sry into other chromosomes.
More recently, researchers led by Monika Ward of the University of Hawaii in Honolulu have shown that with just two Y chromosome genes, Sry and Eif2s3y, male mice lacking a Y chromosome can at least produce sperm-cell precursors known as round spermatids (albeit not mature sperm).
In the latest study, published in Science this week, the team got these mice to reproduce, with some help. They injected the round spermatids into eggs in culture dishes in a technique called round spermatid injection (ROSI). Some of the eggs developed into embryos and were implanted into the wombs of female mice. From these transfers, nine per cent resulted in the birth of live mice, compared with 26% of transfers from mice with a full Y chromosome.
ROSI has been used as an assisted-reproduction technique to help infertile men whose testes cannot produce normal sperm, only spermatids. But fertility specialists consider it an experimental procedure because of fears that immature round spermatids would contribute to the birth of genetically defective offspring. In particular, there has been concern that genetic processes such as imprinting - the switching on and off of genes that occurs in sperm cells before they come into contact with the egg - is incomplete in spermatids.
The current study could help to alleviate those fears, says developmental geneticist Robin Lovell-Badge of the Medical Research Council’s National Institute for Medical Research in London. “The fact that normal offspring were obtained using ROSI with just Sry and Eif2s3y suggests that concerns about using ROSI in humans with respect to imprinting defects are probably unfounded,” he says. “This in itself is important,” both for men with defective Y chromosomes, and for those who are unable to make normal sperm for some other reason, he says.
However, it would probably be impossible to fertilize a human egg by using just these same two genes; researchers still have much work to do to define which genes from the human Y chromosome would be minimally essential to give rise to healthy offspring.
In the future, it may be possible to bypass the Y chromosome altogether, says Ward. She is working to find genes on other chromosomes that interact with Y chromosome genes; activating these partner genes might completely eliminate the need for the original Y chromosome genes, she says.