Scientists a step closer to mimicking way human body creates sperm

Scientists have come a step closer to mimicking the natural process by which the body creates sperm from stem cells in work that could ultimately provide new treatments for infertility.

Speaking at the Progress Educational Trust annual conference in London this month, Azim Surani, director of germline and epigenetics research at the University of Cambridge’s Gurdon Institute, said he and colleagues had passed a significant milestone on the path to producing sperm in the laboratory. The team is thought to be the first to have reached the halfway point on the developmental path from human stem cells to immature sperm.

The study hints that one day it may be possible to manufacture sperm and eggs from stem cells or even adult skin cells.

Previously, scientists have used stem cells to create viable mouse sperm, that were then used to produce healthy pups. Other teams have also injected immature human germ cells into the testicles of mice to produce cells that superficially looked like sperm, but which did not have the ability to fertilise eggs.

“We can’t be absolutely sure that they are really sperm-like cells,” said Surani. “There are developmental timers in cells and so you have to let them develop according to their internal timing.”

There are particular safety concerns around the use of artificially created sperm and eggs, because any genetic flaws would be potentially passed on to all future generations.

Surani’s team is attempting to tightly track the lengthy developmental pathway that happens in the body as embryonic cells morph into immature sperm through a series of complex steps known as meiosis. During the first few weeks, cells destined to become sperm and eggs follow the same route, with the trajectories diverging at around eight weeks. In mice this happens after just 13 days.

“The challenge is that the timelines are very long in humans,” said Surani.

In a recent study, his team showed they could reach roughly the four week mark, but they are aiming to extend this to the crucial eight week milestone when sperm and eggs become distinct.

With this goal in mind, the team has developed miniature artificial testicles, called gonadal organoids, which comprise a blob of gonadal cells (also grown in the lab) suspended in gel. The mixture of cell types seems to be providing some of the right biochemical cues to propel the cells further down the path to becoming sperm.

The DNA in germ cells has to undergo a process known as “erasure” – the stripping away of chemical marks that were laid down on parental DNA through exposure to the environment. Most of these so-called epigenetic markers are wiped clean shortly after an egg is fertilised, limiting the degree to which the life experience of parents can influence the biology of their children. However, a second, more thorough, resetting occurs as the embryonic stem cells develop into eggs or sperm.

Surani’s recent study, which has been submitted to a journal for publication, demonstrated that the cells were undergoing this process in the dish.

“This process of erasure is much more comprehensive and global; you don’t see it anywhere else,” said Surani. “We’re starting to see that erasure process.”

Ensuring that lab-grown sperm and eggs replicate the subtleties of those produced in the body will be essential if they are to be used in clinical applications in the future, and could also offer clues as to what causes infertility in the first place.

“If this was ever going to be used in a clinical setting we have to be sure that it has gone through all the right stages – all of these steps are incredibly important,” said Surani. “You can make an egg that looks like an egg, but it might not be the right cell in molecular detail. You could get a lot of problems with that. You don’t want something that’s going to grow into some kind of abnormal structure.”

Allan Pacey, professor of andrology at the University of Sheffield, who was not involved in the work, agreed that replicating the precise genetic activity in a normal sperm would be the priority for any future clinical applications. “I’m trying to get away from the notion that it’s something that looks like a sperm, because that’s just the vehicle,” he said. “It’s about what’s in the head and the quality of the DNA. What it looks like is somewhat immaterial.”

Fertility clinics in Britain are currently banned from using artificial sperm or eggs to treat infertile couples. However, if scientists perfected the ability to produce germ cells in the lab – something Surani predicts is at least a decade away – regulators could face pressure to revise the law to reflect the new possibilities. For instance, two men could potentially have a baby that was genetically related to both of them by using skin cells from one to make an egg and cells from the other to make the sperm. Women with fertility problems could have eggs grown in the lab, rather than taking drugs to stimulate their ovaries.

Helen O’Neill, who directs the reproductive science and women’s health programme at UCL, said clinical applications were not on the immediate horizon. “Much of the ambition to recreate reproductive processes in the lab is to further our understanding of these processes,” she said. “It is surprising how little we understand about the fundamental dynamics of the beginnings of life.”

(THE GUARDIAN)