There are times when a new medical technology is thrust into the public spotlight because it seems like it might solve what we thought was unsolvable.
Not for the first time, this is being played out in the field of reproductive technology with in vitro gametogenesis, or IVG. It’s been hailed as revolutionary technology that will be life-altering for those with infertility. “Think of it as IVF 2.0,” NPR’s Rob Stein said in a recent story.
IVG refers to the laboratory production of sperm and eggs, which are collectively known as gametes, from just about any adult cell. Gametes are produced in ovaries or testes, and their production is as complex a biological process as one can ever study. To create them from stem cells that have the capacity to form any cell in the body, and in almost endless numbers, would be a remarkable feat to successfully achieve in a lab.
But I have spent more than three decades in reproductive medicine, which have given me a healthy dose of cynicism any time I hear of something that promises to upend IVF clinical practice.
IVG first came to prominence more than a decade ago, when two researchers in Japan turned mouse stem cells into egg cells, which gave rise to healthy offspring. Earlier this year, the same researchers announced they had produced fertilized embryos using stem cells from male mice, prompting a fresh flurry of media coverage and discussions about IVG and its potential to create egg cells from almost any cell in the body.
The field of IVG is primarily expanding because IVF is not a guaranteed solution to infertility, especially for women who are 35 years old or older and wish to conceive their own child. Egg aging is the most common form of infertility. While men can father children almost regardless of their age — albeit with increased birth risks — live births significantly decline from women beyond age 35 and are very rare by age 45.
IVG proponents argue that it offers older women (as well as those experiencing early menopause) the potential to have their own children later in life. Equally, it could help preserve fertility for women facing the destruction of their eggs due to cancer treatment.
Yet this very promising prospect is likely decades away from becoming a clinical reality. It’s been 11 years since the Japanese team published their research on mice, and translation to another species has yet to be announced (although there are some promising approaches with non-human primate data emerging). IVG is very much in the research phase of development and, like with other reproductive technologies such as embryo cloning, scrutiny over the ethical use, safety, efficacy and long-term health of future children are already being raised.
But what if there are other more achievable advancements that could provide a solution to the greatest challenge in fertility: how to pause, or even turn back, the biological clock?
When considering this issue, it’s worth examining why IVF doesn’t solve age-related infertility in women. At birth, a girl has hundreds of thousands of early egg cells within the ovaries. This pool of eggs is always decreasing; even before puberty, tens of thousands of these early egg cells are lost. Some of these eggs begin the path of maturation and form what we call follicles. But without the stimulation of hormones from the brain, these early follicles and their eggs simply disappear.
This changes at puberty. During each ovulatory cycle, a group of follicles (with an egg inside of each) are randomly selected and begin to grow. A tussle ensues between them to see which becomes the selected follicle that will ovulate. Once one follicle (or sometimes two in the case of twins) establishes a dominant position, the other follicles that started to grow will collapse and their eggs disappear. The process of egg and follicle growth is beautifully complex, and we are still unraveling all the pieces that make it work (and why sometimes it doesn’t).
As a woman ages, the number of follicles and eggs keeps diminishing, and the eggs are less resistant to other cellular stresses. This all leads to a greater propensity for errors in the number of chromosomes in these older eggs, which is why problems such as Down syndrome are more prevalent in older mothers. Eventually, there are too few eggs to even mount a regular ovulatory cycle, leading to menopause.
During IVF, the patient is prescribed a large amount of follicle-stimulating hormone. No “tussle” occurs, so many follicles grow to completion and are all ovulatory. IVF clinicians capture the eggs from all these follicles just before they ovulate, by using a second hormone to control the timing of ovulation. IVF doesn’t shrink the pool of eggs; rather, it rescues the eggs that would have disappeared once the one ovulatory follicle was established during a natural cycle.
IVF is a numbers game: The more eggs obtained, the more likely more than one embryo will be produced, although there are circumstances where too much stimulation is dangerous and reduces egg quality. Over the years of developing IVF, clinicians have optimized for the numbers of eggs collected and subsequent embryo quality. However, as the quality and number of eggs decrease in older women, there is little they can do to compensate. This is what makes IVG sound so alluring. Some people pitching it suggest it’s coming soon — in the recent NPR segment, Stein notes, “A California biotech startup called Conception says really soon. … They claim they’ll have human IVG eggs ready to fertilize within a year.”
But, as exciting as it is, IVG is a long way off, as one of the Japanese researchers told NPR. IVG has yet to be developed for human egg production, and even if the technology were fully developed, the demonstration trials to prove clinical safety for regulatory approvals will take years.
Which brings us back to finding an interim solution: the need to rejuvenate the eggs of older women. IVG may be the ultimate goal, but research is also being conducted that points to the possibility of in vitro oocyte rejuvenation (IVOR). Some of this research has already been applied clinically and focuses on how we can stimulate the “power stations” of the egg, the mitochondria.
Mitochondria are the energy generators of cells, and eggs from older women have fewer and less active mitochondria. The principle of IVOR is that if we rejuvenate the population of mitochondria, this would prevent chromosomal errors and improve embryo quality, effectively removing many of the issues that come with aging eggs. Put simply, IVOR is a way of turning the poor oocytes from older women into better quality oocytes. IVG aims to create many more new “young” oocytes from stem cells, but IVOR aims to fix the existing old oocytes, and therefore deals with the most common issue in infertility.
Thanks to advancements in research, we now have a greater understanding of what cells already exist in the ovaries. Within the ovary, there appears to be a small number of stem cells that have begun the pathway to become an oocyte, but have ceased their full differentiation. These cells, if harvested from an older woman’s ovary and expanded in number in the lab, may provide a source of not eggs, but of mitochondria of cells, which can then be used to aid the fertilization process through IVOR. A recent publication by a Japanese team headed by Yoshiharu Morimoto in the International Journal of Molecular Sciences details how they simultaneously injected sperm and this relatively new source of mitochondria into oocytes, resulting in 11 live births.
There is also the promise of rejuvenating compounds that activate the existing mitochondria within eggs from older women. This approach — which is a similar but alternative pathway to IVOR — could be either stand-alone or incorporated with mitochondrial injection, dependent on initial egg quality. Working with the woman’s existing mitochondria to boost her egg numbers and activity of this essential cell component is a workable solution that is on the verge of clinical practice. With the advancements already made on mitochondrial injection, I expect clinical development and adoption to accelerate over the next 10 years. This is a much more promising path to fertility for older women compared with IVG, which may be decades away.
Therefore, while waiting for IVG to mature to a clinically safe and reliable technology, we shouldn’t dismiss the opportunity that IVOR offers as a potential short-term solution to an unsolved problem. IVG is incredibly exciting, but IVOR is already within reach.
Jeremy Thompson is co-founder and chief scientific officer of Fertilis and a professor at the University of Adelaide.