Prof Hagai Levine’s 2017 paper reporting a drastic decline in male sperm counts has been referred to as the ‘spermageddon’ paper. Recent work by Prof. Levine has also reported that average male testosterone levels have halved over the last fifty years. Moreover, male infertility cases are particularly difficult to treat because around 40% of these cases have no known cause. What we are fighting right now is a twofold crisis: decline and a lack of knowledge. However, lab-grown sperm might help us understand more about male infertility and even help us find new treatments.
Immature Sperm Cells made in a laboratory
While making a fully mature sperm cell in lab settings remains out of reach for now, a team of researchers reported in the journal Cell Stem Cell that they have grown immature sperm cells by transforming a person’s blood cells and then incubated them in a tiny pouch grown on a mouse’s kidney.
Kotaro Sasaki, a developmental biologist also at the University of Pennsylvania, and his colleagues previously determined how to convert human induced pluripotent stem (iPS) cells into cells similar to embryonic cells that eventually give rise to eggs and sperm. To protect these immature cells and support their nutrition, the scientists mixed them with non-reproductive cells from the testicles of developing mice.
The cells did not progress beyond the early stage of sperm development seen in human fetuses; however, Sasaki was heading in the right direction. Now, Sasaki, Eoin Whelan, a reproductive biologist at the University of Pennsylvania in Philadelphia, and their colleagues have taken the process up a notch. The scientists transplanted their cell mixture into living mice, specifically in a region of the kidney well-suited to supporting tissue transplants.
The transplanted tissue self-organized into tubular structures akin to those in testicles, where sperm are produced inside the kidney pouch. Six months after the transplant, the human cells had developed into spermatogonia—a type of cell that are precursors to mature sperm. Gene activity in these immature sperm cells closely resembled normal human spermatogonia. However, the cells didn’t proliferate any further, and none went on to form mature sperm. Next, the team performed the experiments in macaque monkeys, but most human cells halted their development at this stage.
Maturity Blockers at Play
Sasaki believes that rather than a procedural drawback, the development of human spermatogonia stopped due to species differences. Sperm development is complex, requiring input from non-reproductive cells in the surrounding tissue and hormonal signals from distant organs, which the supporting mouse cells couldn’t provide. In other words, the factors might not be compatible in mice and humans.
There is a workaround that could help the cells develop into mature sperm. In this case, the developing spermatogonia can be incubated with human non-reproductive cells, which Amander Clark, a developmental biologist at the University of California, Los Angeles, thinks might be next in line for this innovation.
It is also important to confirm whether the spermatogonia are functional, which Sasaki hopes to test out in macaques. To really be able to say that a bona fide sperm has been developed, scientists need to make a baby.
Bioethical Barricades
The lab-grown cells stopped developing at an immature stage, but the latest development is a step in the right direction. To go from an immature sperm cell to a mature one in a dish, the team needs to overcome many hurdles, including ethical considerations. Potential clinical applications are controversial, particularly if lab-grown sperm or eggs are used to make babies. While some researchers are optimistic about synthetic sperm or egg cells as a treatment for specific cases of infertility, the practice raises concerns around producing ‘designer babies’.
Researchers also struggle to reconstruct the earliest days of sperm and egg development, as studying human fetal development is difficult. Sasaki considers the work in humans far behind compared to the success scientists enjoyed in mouse models. Researchers cannot also use lab-grown sperm to make babies without running into ethical roadblocks.
However, the obstacles do not represent a dead end for progress. Several private companies are working to produce lab-grown eggs and sperm. Last month, a Berkeley-based biotech firm called Conception reported that it had grown immature human eggs from stem cells in the lab. Paterna Biosciences in Salt Lake City, Utah, announced in May that it had grown mature sperm; however, they didn’t do it using iPS cells. Instead, Paterna began its process by using immature sperm cells collected from the testicles, without recapitulating the earliest stages of sperm development.
Sasaki believes that these claims are difficult to evaluate. “They don’t show any data,” he says. “If you want to make a big claim, you need huge evidence.”
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