Dairy farmers would be delighted if cows could only have girl calves. The same goes for goats and sheep: The more female offspring the better, because these animals are husbanded chiefly for their milk. Males for dairy farmers are sheer loss; it costs more to raise them to the sellable point than farmers can get for their meat. Now, though, scientists at Tel Aviv University have invented a technique to help mammals have almost exclusively female — or male — offspring.
True, they only did this in mice, but are confident the method could be migrated to cattle, swine, goats, sheep, chickens and other animals. Not that farmers necessarily prefer the lady swine, since pig milk isn’t a thing. Also, male pigs fatten faster. But in chickens, the female is widely preferred to the male. They lay eggs, the males don’t and are madly aggressive. Cockfighting goes back around 8,000 years, but how many fighting cocks does a farm need?
The technique to genetically engineer rodents in order to have only female pups was published in EMBO Reports and isn’t applicable to human couples. At least not easily. “You’d need crazy people with control over a whole population,” explains Prof. Udi Qimron. He means total control, where a tyrant could do as he likes with them. “Say he wants only soldiers and the females are not something he wants. He could do that. It would take 20 years,” Qimron tells Haaretz.
In nature, animals produce roughly half male and half female offspring. But there are exceptions. In most snakes and lizards, sex is determined by sex chromosomes at the time of fertilization, as happens with us. But in crocodiles and most turtles, sex depends on ambient temperature after the eggs are fertilized.
Nor does it take much. “Small changes in temperature can cause dramatic changes in the sex ratio,” Prof. J.J.Bull wrote in the Quarterly Review of Biology in 1980. The same goes for many a plant, fish, crustacean and more: temperature is key to gender development in the unborn. (And yes, global warming is causing concern about sex bias in certain species, such as the painted turtle.)
There are some techniques to skew the natural statistics in mammals and chickens, but not significantly. For instance, centrifuging sperm cells separates them by weight, Qimron says: Since the male Y chromosome is a puny little thing and the X chromosome isn’t, female sperm cells are heavier than male sperm cells and a vigorous swirl in the centrifuge will separate X-sperm from Y-sperm - imperfectly, though. You won’t get 100% all females or all males. All the methods developed so far are complicated, very expensive and imperfect.
The solution, absent alternatives, is that farmers kill unwanted newborn male livestock — and the less said about how they do it, the better.
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The breakthrough how-to technique to breed only a specific sex was created by Qimron with Ido Yosef and Motti Gerlic, assisted by Liat Edry-Botzer, Rea Globus, Inbar Shlomovitz and Prof. Ariel Munitz, all at Tel Aviv University’s Sackler Faculty of Medicine.
In mammals, the eggs are all female, containing one X chromosome. The offspring sex is determined by the sperm cell, which has either an X-girl chromosome or Y-boy chromosome inside.
Qimron then explains an extremely complicated genetic engineering procedure with the help of a metaphor straight from Batman: Imagine placing a bombshell on Y chromosomes that explodes upon fertilization of an egg. Pow! All male embryos would blow up and only the females would come to term. Mission accomplished.
One snag is that the species would go extinct, Qimron explains. One has to have some males to perpetuate the species. But it is extremely difficult to engineer an organism to have only females except when we’d like a male to ensue.
The Tel Aviv team’s solution was to split the functions of bomb and fuse, to continue the metaphor: Engineer the male to have a fuse in the Y chromosomes of his sperm; engineer the female to have a bomb in her eggs’ X chromosomes. Then mix the two.
If their offspring is XY (male = bomb + fuse), it blows up (in reality, the embryo simply doesn’t develop properly, or at all.)
If the offspring is female (XX = bomb but no fuse), it survives. Ta-da! And the surviving female chick or goat or whatever will have little bombs in her little X chromosomes.
What about the survival of the species? No problem: To get male offspring, breed the engineered male with booby-trapped sperm with a wild-type female. Their chicks or pups will be 50-50 male-female and the males will not only survive but have the engineered fuses in their sperm.
To move beyond comic metaphors to the real world, the “bomb” is an enzyme called Cas9 that cuts DNA. The fuse on the instruction on RNA molecules tells the Cas9 enzyme where to cut.
The engineered instructions on the RNA molecules tell Cas9 to cut genes that are crucial to embryonic development — that is the bomb. And the embryo fails to develop.
So, the researchers crossed two genetically engineered mice. The murine mothers had engineered Cas9 protein that did nothing unless guided by special “guide-RNAs” that were encoded on the engineered father mouse’s Y chromosomes.
Upon fertilization, the father’s guide-RNAs and the Cas9 protein from mother combined in the male mice embryos, which didn’t develop, but not in the females, which did develop.
“This cross thus halts embryonic development of males without affecting the development of females,” says Qimron. Producing males only involves a small switch in technique.
The technique isn’t perfect: there’s a failure rate of about 5 percent, Qimron tells Haaretz. Why? “We don’t know but suspect, based on circumstantial evidence, that the DNA cut, the ‘bombshell,’ isn’t big enough. We cut only three genes and maybe we need to cut, say, two more.”
Asked about the affordability of the future technique, the professor points out that the existing techniques are both costly and inhumane. Improvement, expansion and commercialization of this engineering method could save a great deal of money, and a great many lives.