OHSU team – For millions battling infertility, the effortless miracle of procreation is a punishing ordeal of tests, treatments and trials, often chipping away not just at their finances, but also their sense of self. Researching embryos and embryo-like models is therefore critical to peering into the earliest moments of human development to understand why conceptions fail. A recent experiment at an American lab in this direction has drawn much global attention.
Researchers at the Oregon Health & Science University (OHSU) announced a breakthrough in using skin cells to create eggs that can produce early human embryos. Their findings were published in Nature Communications. Although nascent and limited in scope, their research offers a fresh direction in dealing with infertility.
What they have created is proof of concept, demonstrating that the idea, even if not fully safe or ready yet, is feasible. According to the researchers, it could take at least 10 years before the method qualifies for initial clinical trials.
Why new eggs? Making a baby requires an egg and a sperm with each contributing half the required genetic material. Human cells have 46 chromosomes arranged in 23 pairs. Eggs and sperm — or female and male gametes — carry 23 chromosomes each so that the number of chromosomes remains 46 when they combine.
Infertility is caused by the lack of healthy eggs or sperm. Current treatments such as IVF (in-vitro fertilisation) often hit a wall when a person has no functional gametes.
The only resort in that case is donor eggs or sperm. The OHSU team wanted to find ways to create eggs or sperm directly from a patient’s own cells to make it possible for them to have genetically related children. How our cells divide Human cells divide in two ways.
Mitosis — the everyday kind that produces two identical cells from one parent cell — occurs in skin, muscle, organ and other body cells. It enables the human body to grow, repair tissues, and replace damaged or dead cells while keeping the same number of chromosomes in the new cells. Meiosis, which occurs only in the cells of ovaries and testes to produce gametes, halves the chromosome count, giving eggs and sperm only 23 each.
Genetic variations result from the mixing and swapping of genes during meiosis. This is a delicate process, where one wrong move can leave the cell with too many or too few chromosomes. Most embryos with this condition, called aneuploidy, cannot grow normally.
Inside the breakthrough While scientists have long tried to copy meiosis in the lab, the OHSU team pioneered a combination of mitosis and meiosis called ‘mitomeiosis’. They replaced the DNA in donor human eggs with that taken from regular skin cells. They then forced these cells to behave like natural eggs using special lab techniques that mimic what happens during natural egg formation.
“We achieved something that was thought to be impossible,” says senior author Shoukhrat Mitalipov, director of the OHSU Centre for Embryonic Cell and Gene Therapy. “Nature gave us two methods of cell division; we developed a third. ” In-vitro gametogenesis (IVG) is an important area of research in making eggs or sperm from stem cells in laboratory dishes instead of through natural reproduction.
As part of this, scientists sometimes try to turn special “starter cells”, called induced pluripotent stem cells, into sperm or egg cells. This process of turning stem cells into sperm or egg cells could be likened to baking a cake. One way would be to start from scratch: grow the wheat, grind it into flour, make sugar from sugarcane, raise chickens for eggs, and so on.
This transformation can take many months, even years. A faster way is to start baking right away by just procuring flour, sugar, and eggs from the store. The method used by the OHSU team sidestepped altogether, the long process of reprogramming stem cells, by directly using the nucleus of a skin cell.
Their method was based on the somatic cell nuclear transfer technique, used in Scotland in 1997 to make Dolly the sheep, the first cloned mammal, by placing a full set of DNA from one sheep inside an empty egg. In their research, the OHSU team was aiming to form an egg with only half the DNA, so that it could be joined with sperm from a second parent. Detailed genetic tracking during their research revealed that the reduction in chromosomes was random, unlike the normal crossover patterns seen during natural egg formation.
With an average of about half of the chromosomes successfully discarded, what resulted were eggs containing somatic (body cell) DNA as well as sperm DNA. The team produced 82 such modified eggs (oocytes) and fertilised them with sperm through the standard in-vitro fertilisation (IVF) process to yield embryos with both sets of chromosomes. The results Only 9% of the oocytes reached the blastocyst stage, the very early but crucial stage of embryo development that is usually reached 5–6 days after fertilisation.
By this time, the embryo develops enough to form an outer layer of cells that later becomes the placenta, an inner cell mass that becomes the baby, and a cavity filled with a fluid. This is the stage that the embryo would reach in natural conditions, growing inside the uterus, indicating better potential to grow. And it is at this stage that the embryo is considered mature enough to be transferred into the uterus and improve pregnancy rates.
In the OHSU research, most eggs stopped growing before reaching the blastocyst stage. When the team activated the process using chemical and electrical stimulation, some of the eggs moved past the earlier block and divided properly to form embryos.
Yet, many of them had chromosomal errors. Dr.
Mitalipov notes that even in natural reproduction, only about a third of the embryos develop into blastocysts. “Aneuploidy is pretty common in human eggs, especially as women age,” he says.
What comes next The researchers will now study how chromosomes connect and separate, so as to ensure that the eggs formed in the lab carry the correct number of chromosomes. “There are still a number of scientific challenges before IVG would be ready for clinical use,” co-author of the study, Paula Amato, professor of obstetrics and gynaecology at the OHSU School of Medicine says.
“We would need to address the aneuploidy issue, as well as recombination, and imprinting. And, likely, we would need to conduct multigenerational animal studies in a non-human primate model before clinical use. ” If and when the method devised by the OHSU team becomes reliable, it could enable not only older women but also cancer survivors, people born without functioning ovaries, and same-sex couples to have children with their own DNA.
According to Dr. Amato, the informed consent process then would be similar: risks, benefits and alternatives. “Obviously, as with any new reproductive technology, there will be uncertainties about long-term safety and potential multigenerational effects,” she says.
Ethical, legal concerns There are also other ramifications. An ethical debate surrounds the moral status of embryos and embryo-like structures: how potential medical benefits stack up against respect for early human life and concerns about instrumental use and destruction.
Legal challenge arises from the fact that most countries allow clinics to use only real eggs and sperm taken from ovaries and testes, which means that alternative approaches would require tedious changes to the law based on proven safety. Far-reaching promise The biggest takeaway however, is the proof that it is possible to force body cells to act like eggs and reduce their chromosome count, which marks a big step towards creating eggs or sperm in the lab.
The process is inefficient and unpredictable at this point, but its far-reaching promise makes it immensely exciting despite the many hurdles in its path. (Harsh Kabra is is an independent journalist and commentator. harshkabra@gmail.
com).