Happy International Donor Conception Awareness Day!
The purpose of this day is to “shed a light on families made in different ways due to medical infertility [(40-50% of which is due to male infertility of various kinds)]1, chromosomal impairments, childhood or young adult cancer, and various other reasons” and to reduce the “shame and secrecy” surrounding donor conception2. Indeed, at least half a million women used donor insemination between 1995 and 2017 in the United States alone3, and the total number is likely much higher given the secrecy around use of donor insemination since its first use in humans in the late 1700’s4.
To support this educational mission, we decided to highlight the work of Dr. Oliver Rando in our department. Dr. Rando studies how the life experiences of a biological father can influence their offspring. Even though we often think about inheritance as working through the sequences in our DNA (deoxyribonucleic acid that is tightly coiled in the nucleus of a cell), information can be passed along in other ways as well. Eggs and sperm both contain additional genetic information in the form of RNA (ribonucleic acid that can float around in the nucleus or cytoplasm of a cell) that are important in helping to kick-start development of a new embryo. For example, Dr. Rando and many other scientists have discovered that the diet and exercise habits of male mice result in changes in the recipe of RNA’s inside sperm. These changes can then impact the development of the resultant embryo that forms after fertilization and are even linked to diseases in the adult offspring5.
But how do sperm get loaded up with all these RNA’s? Do sperm make the RNA’s themselves like most cells in the body, or do they come from somewhere else?
Some of Dr. Rando’s work focuses on these exact questions. It turns out, sperm may not make all these RNA’s by themselves. As lean, mean, fertilizing machines, they don’t have the space or the energy to make lots of RNA. RNA’s are instead gifted to them by the cells around them as they mature in the male reproductive system.
A whole mouse epididymis imaged by the Rando Lab.
Before we dive into some of Dr. Rando’s findings, let’s quickly orient ourselves regarding the sperm production process: As a refresher, “sperm” is the name for the haploid (only contains one copy of every gene, compared to the usual two copies) male germ cell. These germ cells contribute half of the genetic information (DNA) during the cellular process of sexual reproduction to form a new embryo. Sperm are constantly being made – the average post-puberty and fully fertile biologically male human can make over 1,000 new sperm per second6. These sperm are “born” from germline stem cells residing in the testes. These immature sperm then flow out of the testes and get pushed through an organ called the epididymis on their way to the vas deferens (their eventual escape route to the urethra). The mysterious epididymis is the focus of some of Dr. Rando’s research. This ~1.5inch long organ made up of several feet of twisting tubes is where sperm mature and acquire the ability to swim and fertilize eggs.
Despite its important role in the biological male reproductive tract, Dr. Rando heralds the epididymis as “the least-studied organ in the whole body.” For a long time, scientists didn’t know exactly what the epididymis was doing in sperm production. In fact, scientists thought the epididymis was just a storage compartment for sperm as they made their way through the male reproductive tract. It turns out, the 10-15 days sperm spend in the tightly-packed twisting turning tubes of the epididymis are critical for sperm to reach functional maturity. It also turns out that the epididymis plays an active role in shaping the unique mixture of RNAs found in mature sperm7.
Dr. Rando’s lab has been one of the few groups to take a deep dive into the structure and function of the epididymis to try to figure out exactly how it helps sperm mature. Dr. Rando and his team took an extreme close-up look at each individual cell making up the epididymis to ask, “Who are these cells, really? And what are each of them doing?” This study confirmed work from other labs and made some new discoveries about the kinds of cells that make up the epididymis and the roles they might be playing in sperm maturation. Excitingly, Dr. Rando found that, even though many cells look the same all along the considerable length of the epididymis (if you untangle the convoluted tubes of the average human male epididymis, it could stretch to be 20ft long)8, these cells have distinct identities and functions that define different regions of the epididymis9. Scientists think these gradients of cell function and identity found along the length of the epididymis help sperm undergo a series of different important changes during their maturation.
Dr. Rando also helped discover the role of the epididymis in completely changing the RNAs that sperm carry. In the epididymis, these RNA gifts are wrapped up in little tiny bubbles that are secreted by the cells making up the tubes of the epididymis (called epididymosomes), which have different contents depending on where along the length of the epididymis they were made10. The uptake of these RNA-filled bubble-shaped epididymosomes turns out to be critical for sperm to help regulate healthy embryonic development once they’ve fertilized an egg. And as we mentioned before, these sperm RNA’s are one of the ways the life experiences of the biological father can affect the developing embryo.
An illustration of epididymis morphology showing longitudinal and cross-sectional depictions of the tissue. The epididymis hugs the top of the testis and is full of tightly-packed tubes (grey). A look into the lumens of these tubes (yellow) reveals sperm getting pushed through the tubes (light yellow with dark yellow nucleus). Zooming in on the sperm shows different species of small RNA that are being modified as sperm pass through the epididymis. Illustration by Dr. Leonora Martínez Núñez.
Dr. Rando and his team are working hard to further our understanding of the way sperm RNA’s transfer information about the life of the biological father to the offspring. Once we understand more about this process, medical doctors and scientists might be able to find ways to prevent the transfer of harmful information through RNA. For example, if we knew how the RNA made by the epididymis changes in biological males fed a high fat diet, scientists might be able to find a way to neutralize the harmful effects of that RNA and prevent the offspring from having metabolic diseases.
An illustration of the delivery of sperm RNA (green) during oocyte (egg, light yellow) fertilization. The sperm (dark yellow) membrane fuses with the oocyte membrane leading to a mixing of cytoplasms, thus delivering the RNA from the sperm to the oocyte. Illustration by Dr. Leonora Martínez Núñez.
Learning about Dr. Rando’s work is a perfect way to celebrate International Donor Conception Awareness Day, as the emerging layers and complications of inheritance studied here in the BMB department mirror the layers and complications faced by families built using this technology. To learn more about the challenges faced by families built by Donor Conception, check out this website. To learn more about Dr. Rando’s mission to decode the epididymis, check out this website.
