Human ovum (egg). The zona pellucida is a thick clear girdle surrounded by the cells of the corona radiata (radiant crown). Via Wikimedia Commons.
It was September of 2006. Due to certain events taking place on a certain evening after a certain bottle (or two) of wine, my body was transformed into a human incubator. While I will not describe the events leading up to that very moment, I will dissect the way in which we propagate our species through a magnificent process called fertilization.
During the fertilization play, there are two stars: the sperm cell and the egg cell. The sperm cell hails from a male and is the end product of a series of developmental stages occurring in the testes. The egg cell (or ovum), which is produced by a female, is the largest cell in the human body and becomes a fertilizable entity as a result of the ovulatory process. But to truly understand what is happening at the moment of fertilization, it is important to know more about the cells from which all human life is derived.
Act I: Of sperm and eggs
A sperm cell is described as having a “head” section and a “tail” section. The head, which is shaped like a flattened oval, contains most of the cellular components, including DNA. The head also contains an important structure called an acrosome, which is basically a sac containing enzymes that will help the sperm fuse with an egg (more about the acrosome below). The role of the tail portion of sperm is to act as a propeller, allowing these cells to “swim.” At the top of the tail, near where it meets the head, are a ton of tiny structures called mitochondria. These kidney-shaped components are the powerhouses of all cells, and they generate the energy required for the sperm tail to move the sperm toward its target: the egg.
The egg is a spherical cell containing the usual components, including DNA and mitochondria. However, it differs from other human cells thanks to the presence of a protective shell called the zona pellucida. The egg cell also contains millions of tiny sacs, termed cortical granules, that serve a similar function to the acrosome in sperm cells (more on the granules below).
Act II: A sperm cell’s journey to the center of the universefemale reproductive system
Given the cyclical nature of the female menstrual cycle, the window for fertilization during each cycle is finite. However, the precise number of days per month a women is fertile remains unclear. On the low end, the window of opportunity lasts for an estimated two days, based on the survival time of the sperm and egg. On the high end, the World Health Organization estimates a fertility window of 10 days. Somewhere in the middle lies a study published in the New England Journal of Medicine, which suggests that six is the magic number of days.
Assuming the fertility window is open, getting pregnant depends on a sperm cell making it to where the egg is located. Achieving that goal is not an easy feat. To help overcome the odds, we have evolved a number of biological tactics. For instance, the volume of a typical male human ejaculate is about a half-teaspoon or more and is estimated to contain about 300 million sperm cells. To become fully active, sperm cells require modification. The acidic environment of the vagina helps with that modification, allowing sperm to gain what is called hyperactive motility, in which its whip-like tail motors it along toward the egg.
Once active, sperm cells begin their long journey through the female reproductive system. To help guide the way, the cells around the female egg emit a chemical substance that attracts sperm cells. The orientation toward these chemicals is called chemotaxis and helps the sperm cells swim in the right direction (after all, they don’t have eyes). Furthermore, sperm get a little extra boost by the contraction of the muscles lining the female reproductive tract, which aid in pushing the little guys along. But, despite all of these efforts, sperm cell death rates are quite high, and only about 200 sperm cells actually make it to the oviduct (also called the fallopian tube), where the egg awaits.
Act III: Egg marks the spot
With the target in sight, the sperm cells make a beeline for the egg. However, for successful fertilization, only a single sperm cell can fuse with the egg. If an egg fuses with more than one sperm, the outcome can be anything from a failure of fertilization to the development of an embryo and fetus, known as a partial hydatidiform mole, that has a complete extra set of chromosomes and will not survive. Luckily, the egg has ways to help ensure only one sperm fuses with it.
When it reaches the egg, the sperm cell attaches to the surface of the zona pellucida, a protective shell for the egg. For the sperm to fuse with the egg, it must first break through this shell. Enter the sperm cell’s acrosome, which acts as an enzymatic drill. This “drilling,” in combination with the propeller movement of the sperm’s tail, helps to create a hole so that the sperm cell can access the juicy bits of the egg.
This breach of the zona pellucida and fusion of the sperm and egg sets off a rapid cascade of events to block other sperm cells from penetrating the egg’s protective shell. The first response is a shift in the charge of the egg’s cell membrane from negative to positive. This change in charge creates a sort of electrical force field, repelling other sperm cells.
Though this response is lightning fast, it is a temporary measure. A more permanent solution involves the cortical granuleswithin the egg. These tiny sacs release their contents, causing the zona pellucida to harden like the setting of concrete. In effect, the egg–sperm fusion induces the egg to construct a virtually impenetrable wall. Left outside in the cold, the other, unsuccessful sperm cells die within 48 hours.
Now that the sperm–egg fusion has gone down, the egg start the maturation required for embryo-fetal development. The fertilized egg, now called a zygote, begins its journey into the womb and immediately begins round after round of cell division, over a few weeks resulting in a multicellular organism with a heart, lungs, brain, blood, bones, muscles, and hair. It’s an amazing phenomenon that I’m honored to have experienced (although I didn’t know I was until several weeks later).
The Afterword: A note on genetics
A normal human cell that is not a sperm or an egg will contain 23 pairs of chromosomes, for a total of 46 chromosomes. Any deviation from this number of chromosomes will lead to developmental misfires that in most cases results in a non-viable embryo. However, in some instances, a deviation from 46 chromosomes allows for fetal development and birth. The most well-known example is Trisomy 21(having three copies of the 21st chromosome per cell instead of two), also called Down’s Syndrome.
The egg and sperm cells are unlike any other cell in our body. They’re special enough to have a special name, gametes, and they each contain one set of chromosomes, or 23 chromosomes. Because they have half the typical number per cell, when the egg and sperm cell fuse, the resulting zygote contains the typical chromosome number of 46. Now you know how we get half of our genes from our father (who made the sperm cell) and half from our mother (who made the egg cell). Did I just put in your head an image of your parents having sex? It’s the birds and the bees, folks—it applies to everyone!
All text and art except as otherwise noted: Jeanne Garbarino, Double X Science Editor
World Health Organization. “A prospective multicentre trial of the ovulation method of natural family planning. III. Characteristics of the menstrual cycle and of the fertile phase,” Fertil Steril(1983);40:773-778
Allen J. Wilcox, et al. “Timing of Sexual Intercourse in Relation to Ovulation — Effects on the Probability of Conception, Survival of the Pregnancy, and Sex of the Baby,” New England Journal of Medicine, (1995); 333:1517-1521
Poland ML, Moghisse KS, Giblin PT, Ager JW,Olson JM. “Variation of semen measures within normal men,” Fertil Steril (1985);44:396-400
Alberts B, Johnson A, Lewis J, et al. “Fertilization,” Molecular Biology of the Cell. 4th edition. New York: Garland Science; 2002.
In the course of writing a paper on women and STEM, I came across articles in the Journal of Sex Research, as one does. [The "related papers" button on PubMed is one of the best ways ever to let a whole day get away from you.] Given that I have just moved to a new area and may dip toes into the dating pool, and I’m a scientist, of course I had to investigate the latest research on dating, sex, and loooooove.
My daughter, patiently waiting to get her own balloon jetpack. Photo credit: Phil Blake
Why can’t you understand that my daughter wants a damn jetpack?
Last weekend, I took my daughters to a birthday party that featured a magician/balloon artist. He was really fantastic with the kids, and kept their attention for close to 1 hour (ONE HOUR!!!). At the end of his magic show, he began to furiously twist and tie balloons into these amazing shapes, promoting energetic and imaginative play. Of these shapes was his own, very intricate invention: a jetpack.
When he completed the first jetpack, I watched as the eyes of my five-year-old daughter, who happens to be a very sporty kid, light up with wonder. She looked at me and smiled, indicating through her facial expression alone that she wanted the same balloon toy. But, alas, when it was her turn for a balloon, her requests were met with opposition. Here was the conversation:
Magician: How about a great butterfly balloon?
Daughter: No thanks, I’d like a jetpack please.
Magician: I think you should get a butterfly.
Daughter: I’d prefer a jetpack.
Magician: But you’re a girl. Girls get butterflies.
Daughter (giving me a desperate look): But I really want a jetpack!
Realizing that my daughter was becoming unnecessarily upset, especially given the fact that there were 3 boys already engaging in play with their totally awesome jetpacks, myself and the hostess mother intervened. We kindly reiterated my daughter’s requests for a jetpack. And, so she was given a jetpack.
Later that evening, my daughter asked me why the magician insisted that she get a butterfly balloon when she explicitly asked for a jetpack. Not wanting to reveal the realities of gender stereotype at that very point in time, I simply stated that sometimes we (a gender neutral “we”) might have to repeat ourselves so that others understand what we want. Then she asked, “but why are butterflies only for girls?”
I was able to more or less able smooth it over with her, but it was clear to me that a very archaic reality was still in play, and my daughters were about to inherit it. While I have nothing against typically female role-playing or dolls or princesses, I do not like when they are assumed to be the preferred activities. I also do not like the idea that some toys, based on years of “market research,” are designed to basically pigeonhole girls into a June Cleaveresque state of being, especially without alternative play options.
The five LEGO Friends
For instance, LEGO has recently launched a “for-girls-only” campaign, exemplified by the new “Friends” LEGO kit. Slathered in pink and purple, this kit is designed around a narrative involving five friends and a pretend city named Heartlake. Like nearly all cities, Heartlake boasts a bakery, a beauty salon, a cafe, and a veterinarian’s office to take care of sick animals. However, unlike every city, Heartlake lacks things like a hospital, a fire department, a police station, and a local airport (thought they do have a flying club). In essence, this toy is facilitating pretend play that centers ONLY on domestication, which absolutely limits both experiences and expectations for girls playing with this toy. In essence, LEGO is assuming that all girls want the butterfly balloon instead of the jetpack.
Some might think, “jeeze, it’s just a toy!” and dismiss my objection to all that the Friends kit encompasses. And perhaps when the Friends kit is offered in addition to a variety of toy types – gender neutral, masculine, and feminine – it may not have a significant effect on the mindset of its young, impressionable owner. But what if that’s not the case?
Traditional LEGO bricks: For boys AND girls, goshdarnit!
LEGO has also gotten it wrong when it comes to the assumption that girls are not into the traditional LEGO blocks. In fact, just last night, my daughter (the very one who wanted a jetpack) saw a commercial for a LEGO City product – I forgot which one – and asked that we put it on her ever expanding Christmas list. Furthermore, both of my daughters are huge fans of the LEGO produced show on the Cartoon Network, Ninjago: Masters of Spinjitzu, which is based on the traditional LEGO figures and game. My oldest daughter is arguably very sporty and may be more inclined to like “boy” things, but my younger daughter is chock-full of sugar and spice and yada yada yada. She prefers to wear dresses, LOVES shoes, and demands to have her nails painted at all times. And she still gets down with regular LEGOs and monster trucks and basketball and karate (all her own choices). So why is LEGO shoving pastel bricks down girls’ throats?
Gender and play
Play is an important part of cognitive development. When children engage in play, they learn through discovery, become familiar with their own limitations, gain a better understanding of spatial relationships, become introduced to cause and effect, and, most relevant to this discussion, play exposes children to societal and cultural norms, as well as family values. Placing limits on play can affect how a child sees him or herself in the world, which can impact both career and lifestyle choices.
Research (and experience) has shown that the toys kids choose are shaped by societal expectations; however, these expectations are often dictated by marketing teams and their assumptions of what they think their customers want to see, perpetuating a toy culture that has changed little since the 1950s. Furthermore, parents may impose toys that are gender “appropriate,” or even punish play that does not align with traditional gender expectations. But what toys do kids actually want to play with?
In 2003, researchers at the University of Nebraska conducted a study to, in part, identify the impact that stereotyped toys have on play in young children. There were 30 children who participated in this study, ranging in age from 18-47 months. They were observed for 30 minutes in a room full of toys, with each toy defined as being traditionally masculine, feminine, or gender neutral. Interestingly, when assessing the toy preferences of the children, boys tended to play with toys that were either masculine or gender neutral, whereas girls played with toys that were largely gender neutral. These findings were consistent with previous studies showing that girls tend to play with toys that are not traditionally gendered (i.e. blocks, crayons, puzzles, bears, etc).
Cherney, et al, 2003
Why is there a disconnect between the natural tendencies of toy choice among female children and what marketing executives deem as appropriate toys for girls? While fantasy play based on domestic scenarios does have its place during normal development, restricting children to certain types of gendered toys can promote a stereotypical mindset that extends into adulthood, possibly adding to the gender inequity seen in the workplace. Furthermore, assigning and marketing toys to a specific gender may also contribute to the gendering of household duties and/or recreational activities (i.e. only boys can play hockey or only girls do laundry).
This is obviously problematic for females, especially given the disproportionately low number of women executives and STEM professionals (just to name a few). However, a conclusion from this study that I hadn’t even considered is the idea that overly feminized toys are not good for boys.
How “girls only” is disadvantageous to boys
When looking at “masculine” versus “feminine” play, one would see that there is some non-overlap when it comes to learned skills. For instance, “masculine” play often translates into being able to build something imaginative (like a spaceship or other cool technology) whereas “feminine” toys tend to encourage fantasy play surrounding taking care of the home (like putting the baby to sleep or ironing clothes).
Both types of learning experiences are useful in today’s world, especially given that more women enter the work force and there is growing trend to more or less split household duties. So when a kid is being offered toys that encourage play that has both masculine and feminine qualities, there is enhanced development of a variety of skills that ultimately translate into real, modern world scenarios.
However, the issue lies in the willingness to provide and play with strongly cross-gender-stereotyped toys. Because of the number of toys having this quality, there is a huge gender divide when it comes to play, and boys are much less likely to cross gender lines, especially when toys are overtly “girly” (see figure above). This is most often because of parents and caregivers who discourage play with “girl” toys, usually citing things like “they will make fun of you.” Toys heavily marketed to match the stereotypical likes of girls, such as the Friends LEGO kit, clearly excludes boys from engaging in play that develops domestic skills (in addition to pigeonholing girls into thinking that girls can only do domestic things).
Just yesterday, I came across an article on CNN discussing this issue, and it contained anecdotes similar to the one I described above. The author described how a little girl was scoffed for having a Star-Wars thermos as well as how a little boy was told (by another little girl) that he could not have the mermaid doll he wanted. My arguments thus far have been centered on developing a variety of skills through play, but I’d also like to add that limiting self-expression could be disastrous for the future wellbeing of an individual.
There is some progress being made with regard to how toys are being presented in stores. For instance, the same article described the new Toy Kingdom at Harrod’s, which does not conform to the traditionally separated “boy” and “girl” sections. Instead, it has “worlds,” such as The Big Top(with circus acts and fairies) or Odyssey(with space crafts and gadgets). This type of organization allows any child, regardless of gender, to engage in play that facilitates imagination and cognition.
Hey Toys’R Us, are you listening?
Please don’t misinterpret this as being anti-pink, anti-princess, or anti-feminine. I embrace my own femininity with vigor and pride. I like to wear dresses and makeup and get my hair did. Give me a pair of Manolo Blahniks and I will wear the shit out of them. But I will do so while elbow deep in a biochemical analysis of intracellular cholesterol transport.
My point is that if you are going to make a toy more appealing to girls by painting it pink, don’t forget to include facets that allow girls to be comfortable with their femininity while providing an experience that promotes empowerment and an unlimited imagination. Furthermore, don’t exclude boys from getting an experience that helps them acquire skills that are applicable (and desirable) in the modern world. As it stands right now, toys like the Friends LEGO kit does neither of these and I believe that they major fails, both of the Double X and the XY variety.
Judith E. Owen Blakemore and Renee E. Centers, Characteristics of Boys’ and Girls’ Toys, Sex Roles, Vol. 53, Nos. 9/10, November 2005 [PDF, paywall]
Gerianne M. Alexander, Ph.D., An Evolutionary Perspective of Sex-Typed Toy Preferences: Pink, Blue, and the Brain, Archives of Sexual Behavior, Vol. 32, No. 1, , pp. 7–14, February 2003 [PDF, paywall]
Isabelle D. Cherney, Lisa Kelly-Vance, Katrina Gill Glover, Amy Ruane, and Brigette Oliver Ryalls, The Effects of Stereotyped Toys and Gender on Play Assessment in Children Aged 18-47 Months, Educational Psychology: An International Journal of Experimental Educational Psychology, 23:1, 95-106, 2003
Carol J. Auster and Claire S. Mansbach, The Gender Marketing of Toys: An Analysis of Color and Type of Toy on the Disney Store Website, Sex Roles, 2012 [abstract link]
Isabelle D. Cherney and Kamala London, Gender-linked Differences in the Toys, Television Shows, Computer Games, and Outdoor Activities of 5- to 13-year-old Children, Sex Roles, 2006 [PDF]
Isabelle D. Cherney and Bridget Oliver Ryalls, Gender-linked differences in the incidental memory of children and adults, J Exp Child Psychol, 1999 Apr;72(4):305-28 [abstract link]
You may have had the experience: A medication you and a friend both take causes terrible side effects in you, but your friend experiences none. (The running joke in our house is, if a drug has a side-effect, we’ve had it.) How does that happen, and why would a drug that’s meant to, say, stabilize insulin levels, produce terrible gastrointestinal side effects, too? A combination of techy-tech scientific approaches might help answer those questions for you — and lead to some solutions.
It’s no secret I love lab technology. I’m a technophile. A geek. I call my web site “Biotechnically Speaking.” So when I saw this paper in the September issue of Nature Biotechnology, well, I just had to write about it.
The paper is entitled, “Multiplexed mass cytometry profiling of cellular states perturbed by small-molecule regulators.” If you read that and your eyes glazed over, don’t worry –- the article is way more interesting than its title.
Those trees on the right are called SPADE trees. They map cellular responses to different stimuli in a collection of human blood cells. Credit: (c) 2012 Nature America [Nat Biotechnol, 30:858--67, 2012]
Here’s the basic idea: The current methods drug developers use to screen potential drug compounds –- typically a blend of high-throughput imaging and biochemical assays – aren’t perfect. If they were, drugs wouldn’t fail late in development. Stanford immunologist Garry Nolan and his team, led by postdoc Bernd Bodenmiller (who now runs his own lab in Zurich), figured part of that problem stems from the fact that most early drug testing is done on immortalized cell lines, rather than “normal” human cells. Furthermore, the tests that are run on those cells aren’t as comprehensive as they could be, meaning potential collateral effects of the compounds might be missed. Nolan wanted to show that flow cytometry, a cell-analysis technique frequently used in immunology labs, can help reduce that failure rate by measuring drug impacts more holistically.
Nolan is a flow cytometry master. As he told me in 2010, he’s been using the technique for more than three decades, and even used a machine now housed in the Smithsonian.
In flow cytometry, researchers treat cells with reagents called antibodies, which are immune system proteins that recognize and bind to specific proteins on cell surfaces. Each type of cell has a unique collection of these proteins, and by studying those collections, it is possible to differentiate and count the different populations.
Suppose researchers wanted to know how many T cells of a specific type were present in a patient’s blood. They might treat those cells with antibodies that recognize a protein known as CD3 to pick those out. By adding additional antibodies, they can then select different T-cell subpopulations, such as CD4-positive helper T cells and CD8-positive cytotoxic T cells, both of which help you mount immune responses.
Cells of the immune system Source: http://stemcells.nih.gov/info/scireport/chapter6.asp
In a basic flow cytometry experiment, each antibody is labeled with a unique fluorescent dye –- the antibody targeting CD3 might be red, say, and the CD4 antibody, green. The cells stream past a laser, one by one. The laser (or lasers –- there can be as many as seven) excites the dye molecules decorating the cell surface, causing them to fluoresce. Detectors capture that light and give a count of how many total cells were measured and the types of cells. The result is a kind of catalog of the cell population. For immune cells, for example, that could be the number of T cells, B cells (which, among other things, help you “remember” previous invaders), and macrophages (the big cells that chomp up invaders and infected cells). By comparing the cellular catalogs that result under different conditions, researchers gain insight into development, disease, and the impact of drugs, among other things.
But here’s the problem: Fluorescent dyes aren’t lasers, producing light of exactly one particular color. They absorb and emit light over a range of colors, called a spectrum. And those spectra can overlap, such that when a researcher thinks she’s counting CD4 T cells, she may actually be counting some macrophages. That overlap leads to all sorts of experimental optimization issues. An exceptionally talented flow cytometrist can assemble panels of perhaps 12 or so dyes, but it might take months to get everything just right.
That’s where the mass cytometry comes in. Commercialized by DVS Sciences, mass cytometry is essentially the love-chid of flow cytometry and mass spectrometry, combining the one-cell-at-a-time analysis of the former with the atomic precision of the latter. Mass spectrometry identifies molecules based on the ratio of their mass to their charge. In DVS’ CyTOF mass cytometer, a flowing stream of cells is analyzed not by shining a laser on them, but by nuking them in superhot plasma. The nuking reduces the cell to its atomic components, which the CyTOF then measures.
Specifically, the CyTOF looks for heavy atoms called lanthanides, elements found in the first of the two bottom rows of the periodic table, like gadolinium, neodymium, and europium. These elements never naturally occur in biological systems and so make useful cellular labels. More to the point, the mass spectrometer is specific enough that these signals basically don’t overlap. The instrument will never confuse gadolinium for neodymium, for instance. Researchers simply tag their antibodies with lanthanides rather than fluorophores, and voila! Instant antibody panel, no (or little) optimization required.
Periodic Table of Cupcakes, with lanthanides in hot pink frosting. Source: http://www.buzzfeed.com/jpmoore/the-periodic-table-of-cupcakes
Now back to the paper. Nolan (who sits on DVS Sciences’ Scientific Advisory Board) and Bodenmiller wanted to see if mass cytometry could provide the sort of high-density, high-throughput cellular profiling that is required for drug development. The team took blood cells from eight donors, treated them with more than two dozen different drugs over a range of concentrations, added a dozen stimuli to which blood cells can be exposed in the body, and essentially asked, for each of the pathways we want to study, in each kind of cell in these patients’ blood, what did the drug do?
To figure that out, they used a panel of 31 lanthanides –- 10 to sort out the cell types they were looking at in each sample, 14 to monitor cellular signaling pathways, and 7 to identify each sample.
I love that last part, about identifying the samples. The numbers in this experiment are kind of staggering: 12 stimuli x 8 doses x 14 cell types x 14 intracellular markers per drug, times 27 drugs, is more than half-a-million pieces of data. To make life easier on themselves, the researchers pooled samples 96 at a time in individual tubes, adding a “barcode” to uniquely identify each one. That barcode (called a “mass-tag cellular barcode,” or MCB) is essentially a 7-bit binary number made of lanthanides rather than ones and zeroes: one sample would have none of the 7 reserved markers (0000000); one sample would have one marker (0000001); another would have another (0000010); and so on. Seven lanthanides produce 128 possible combinations, so it’s no sweat to pool 96. They simply mix those samples in a single tube and let the computer sort everything out later.
This graphic summarizes a boatload of data on cell signaling pathways impacted by different drugs. Credit: (c) 2012 Nature America [Nat Biotechnol, 30:858--67, 2012]
When all was said and done, the team was able to draw some conclusions about drug specificity, person-to-person variation, cell signaling, and more. Basically, and not surprisingly, some of the drugs they looked at are less specific than originally thought -– that is, they affect their intended targets, but other pathways as well. That goes a long way towards explaining side effects. But more to the point, they proved that their approach may be used to drive drug-screening experiments.