For many years, scientists thought that women were born with a limited number of oocytes (eggs) in the ovary, estimating around three thousands oocytes. This number declines by time until the age of fifty to a point of exhaustion, resulting in menopause. It is known that female flies, birds, and fish can generate new oocytes during their adult life, which has been thought to not happen in mammals like mice. Studies by Jonathan L. Tilly and colleagues at Massachusetts General Hospital and Harvard Medical School brought evidence that new oocytes could also form during the life of an adult mouse [1].

The findings in mice imply that humans might also possess similar characteristics. This increases the possibility and brings hopes of having a baby even at older ages along with treatments in the future, just like in the miraculous story of Prophet Abraham and Sarah as narrated both in the Qur'an (ad-Dhariyat 51:24-30) and the Bible (Genesis 21:7), showing us one aspect of the possibility and ultimate limits of knowledge and technology that humans can attain one day so that these miracles can become true, though to some extent, with the advancement of medicine.

Bone borne eggs

An interesting study showed an unexpected source of oocytes in the bone. Study by Tilly's group at the Harvard Medical School in 2004 showed that cells in the bone marrow of mice could be a source of oocytes that are developing in the ovaries [1, 2]. Their first observation was the expression of genes related to egg cells in the bone marrow samples of mice. To test the possibility of bone marrow cells as a source of new oocytes, they chemically generated infertile mice. Treating mice with two chemotherapy drugs called cyclophosphamide and busulfan causes infertility. Once they treated the mice with these drugs, the mice had extensive damage in their ovaries along with an end in new oocyte production in their follicles. Ovarian follicles are spherical aggregations in the ovaries which periodically produce oocytes. Remarkably, when they transplanted bone marrow from female donors, they found a number of oocyte containing follicles (about several hundred). Interestingly, the appearance of those oocytes were rapid and thought to be due to circulating oocytes originating from the bone marrow and developing as they travel through the blood stream. Although they don't have the evidence that those cells could be fertilized, findings could lead to fundamental changes in the current understanding of the female reproductive system.

Tilly and colleagues also report that bone marrow and blood transplants could also induce the development of oocytes in a genetically infertile mice model (which has a mutation in ATM gene) [3]. This mutant mice lack follicles and developing oocytes and are unable to produce mature germ cells (egg producing cells). Their study shows that bone marrow or blood transplant from healthy donors induces production of oocytes in this mice model. They conclude from those studies that bone marrow could be a source of germ cells to the ovaries throughout adult life. Their findings are somewhat supported by the clinical studies on cancer patients who were expected to be infertile but they could have babies after bone marrow transplant.

Another study on the circulating cells for female fertility used parabiotic (the union of two mice through an exchange of blood) mice model. This study by Eggan and colleagues tested the capacity of circulating bone marrow cells to generate ovulated oocytes and could not show any contribution of bone marrow cells to ovulated oocytes [4]. Blood or bone borne oocytes are highly debatable but bone marrow cells, at least, might have a role in enhancing women's fertility. This might lead to the treatment of infertility. In addition, it might bring new opportunities for those dreaming of having a baby even at a late stage, but requires much additional research to be realized.

Lab & bone borne sperms

Sperm formation is known to continue throughout adulthood. It involves various steps of cellular differentiations. Maturation of sperms in the body takes more than a month in most mammals. Trials to mimic this complex process in petri dishes failed to demonstrate the production of normal, fertile sperms.

Scientists had dreamed of growing sperms in petri dishes for years. Recently, researchers in Japan developed a technique that allowed production of fertile mammalian sperms in a petri dish [5]. Attempts to make such mature sperms usually failed due to meiosis, a specific type of cell division that halves the number of chromosomes. Meiosis is very essential step for sperm cells to get ready to fuse with an egg. Ogawa and colleagues demonstrated that meiosis of sperm cells lay in a simple change to standard petri conditions. They tried various petri conditions but they ended up with a special serum free medium that is commonly used for growth of embryonic stem cells. Several weeks later, they observed formation of mature sperm cells and even half of them had flagella, a tail-like structure that sperm cells use to swim. Injection of those sperms into egg was also able to produce offspring. In addition, when they used frozen testis tissues of newborn mice, they could grow sperms as well. This discovery in reproductive biology is likely to be beneficial not only for people having infertility problems associated with sperm maturation but also children that undergo cancer therapy which destroys fertility. It is known that chemotherapy impairs fertility. Adults could freeze their sperm before such treatment, but young boys can't. This new discovery offers such patients hope. In addition, this finding opens new avenues for protection of endangered animals that might die before reaching sexual maturity. It is a matter of time for the same technique to be applied to humans and other species.

There are also reports suggesting the generation of male germ stem cells (sperm producing cells) from bone marrow [6, 7]. Mesenchymal stem cells, which are derived from the bone marrow, have shown to differentiate into male germ cells. Studies testing the effect of retinoic acid and testicular extracts showed to induce human bone marrow stem cells to differentiate into male germ cells as shown by male germ-cell specific marker expressions. Another approach tested the possibility that bone marrow-derived stem cells would differentiate into germ cells when transplanted into the mouse testis. Using GFP positive bone marrow cells transplantations, it has been demonstrated that bone marrow-derived stem cells can also be induced to differentiate into germ cells. Interestingly, there seems to be a connection between bones and fertility.

Bones and fertility

The Qur'an tells the story of Prophet Zachariah, peace be upon him, when he secretly prayed to God to ask for a successor. He said "My Lord! My bones have grown feeble and my head glistens with gray hair from old age..." (Maryam 19:4). His prayer was accepted and the angels came with the glad tidings of his son, John. He was surprised as to how he could have a son while his wife was barren and that he had already reached infirmity in old age. It has been said by scholars that weakness of bones here refers to weakness in engaging in sex due to old age and gray hairs as a sign of infertility. It is also worthy to mention another verse where the creation of human is described as happening from a lowly fluid that gushes forth the vertebra and rib bones: Let human, then, consider from what he has been created. He has been created from some of a lowly fluid gushing forth. It proceeds (as a result of incitement) between the (lumbar zone in the) vertebra and the ribs (At-Tariq 86:5−7). As commentator Ali Unal explains, these verses refer to both the mechanism of the ejection of the seminal fluid and where it is emitted [8], which is a relatively recent discovery in biology. Remarkably, the Qur'an mentions two major bones where this fluid is emerging. Our current knowledge in medicine do not say anything about the role of ribs in reproduction or fertility but both the Islamic and Judeo-Christian traditions mention the creation of Eve from Adam's ribs, peace be upon him. Could this refer to the relation between bones and fertility? God knows best. Lastly, it is of importance to note that one of the symptoms of menopause is the loss of bone mass. Isn't it amazing how mysterious events regarding bones and fertility are taking place beyond our control and knowledge?

Ali Fethi Toprak is a PhD candidate at University of Texas Southwestern Medical Center.

References

1. Johnson, J., et al., Germline stem cells and follicular renewal in the postnatal mammalian ovary. Nature, 2004. 428(6979): p. 145-50.

2. Vogel, G., Reproductive biology. Controversial study finds an unexpected source of oocytes. Science, 2005. 309(5735): p. 678-9.

3. Johnson, J., et al., Oocyte generation in adult mammalian ovaries by putative germ cells in bone marrow and peripheral blood. Cell, 2005. 122(2): p. 303-15.

4. Eggan, K., et al., Ovulated oocytes in adult mice derive from non-circulating germ cells. Nature, 2006. 441(7097): p. 1109-14.

5. Sato, T., et al., In vitro production of functional sperm in cultured neonatal mouse testes. Nature, 2011. 471(7339): p. 504-7.

6. Hua, J., et al., Derivation of male germ cell-like lineage from human fetal bone marrow stem cells. Reprod Biomed Online, 2009. 19(1): p. 99-105.

7. Lue, Y., et al., Fate of bone marrow stem cells transplanted into the testis: potential implication for men with testicular failure. Am J Pathol, 2007. 170(3): p. 899-908.

8. Unal, A., The Qur'an with Annotated Interpretation in Modern English. Vol. Qur'an 86:5−7, 51;24−30 and 19:4. 2009.

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