How does an infinitesimal speck of cytoplasm and DNA become a living, breathing human being? Join one OMRF researcher as she offers a peek inside this remarkable process—through the story of her own pregnancy.
The sound of the surf lingered in her mind. Pushing open her front door, Courtney Griffin could still feel the sand between her toes. The young cardiovascular biologist had spent the last week at the beach with her scientist husband, Tim, enjoying a respite from the long hours they each worked as post-doctoral fellows in research laboratories—she at the University of North Carolina and he at Duke University.
But Courtney hadn’t made it more than a few steps into her home before she saw the message light on the phone blinking.
I hope it’s not the lab, she thought as she pushed play.
This is Dr. Schlegel’s office. The results of your triple-screen test are in. We’d like to schedule an ultrasound as soon as possible. Please call our office to make an appointment.
Beep. Memories of the past few lazy days at the beach vanished as Courtney reached to replay the recording. She looked down and put a hand on her growing baby bump.
You’re still moving around, she silently told the little person in her belly who seemed to grow more restless and active with each passing day.
The first 18 weeks had sailed along without any major issues, and now—what? She didn’t feel any different. But the message had mentioned her triple-screen test. This routine screening procedure measures a protein present in neural tube defects or Down syndrome. She knew that an unfavorable result could mean devastating news. Whoa, whoa, whoa, she thought. Don’t get ahead of yourself. This is just a preliminary result that doesn’t mean anything by itself. The ultrasound will tell us the real story.
Before the ultrasound, Courtney and Tim met with a genetic counselor to go over the results of her triple-screen test. The pair sat nervously as the counselor went over the numbers. As a scientist working in a laboratory that studied developmental genetics—how DNA influences the process of growth—Courtney knew far more than the average person about what should and shouldn’t happen during pregnancy. And when she saw the numbers from her test, she recognized that they were off the charts: triple, sometimes even quadruple, the normal levels.
These results could suggest a serious health issue, said the counselor. Or multiples. We could be looking at triplets.
Triplets? At once, Courtney felt both hope and a new wave of anxiety. Images of three cribs, hundreds of bottles and thousands of diapers swirled in her head. Braces in triplicate. A trio of surly teenagers. Triple tuition costs.
Far worse than the potential financial burden, though, was the thought that their little one—or ones—might have serious health issues. But how could it be? Courtney wondered. I’ve done everything right. I eat healthy food. I always take my prenatal vitamins.
Her mind raced as the ultrasound tech set up the equipment. Courtney stared at the ceiling, gripping Tim’s hand. The chill of the gel on her stomach got her attention. While the technician guided the sensor back and forth across her belly, Courtney tried to make sense of the grainy images on the gray screen in front of her.
In a moment, the reassuring whoosh, whoosh, whoosh of amplified fetal heartbeats echoed through the room. Everything looks good, said the technician. Normal. Never had such a seemingly mundane word meant so much to the couple. Then the technician began to count. One. Two. Two!
The genetic counselor’s hunch had been right. Sort of. Courtney was carrying twins.
By the time Dr. Courtney Griffin learned that she would give birth to twins, thousands of crucial steps had taken place in their embryonic development. While the Griffin children had not yet grown to even an inch in length, much of who they would become over the next 80 years or so had already been mapped out. To understand why, it helps to know a little about chromosomes.
Chromosomes serve as the mechanism for passing parents’ traits to their offspring. Each chromosome contains about 1,000 genes made up of strands of DNA wound tightly around proteins. The DNA serves as a sort of blueprint that holds all of our genetic information, the individual genes that determine height, eye color, gender and every other detail that makes us who we are.
Most human cells carry 46 chromosomes—23 pairs. But reproductive cells are the exception to this rule: Sperm and egg cells carry only one copy of each chromosome.
At the moment of conception, a sperm carrying 23 of the father’s chromosomes joins with the mother’s egg, which also contains a single copy of each of her 23 chromosomes. The sperm and egg unite to create an embryo with 23 new and unique chromosomes, each a blend of those contributed by the parents. That single cell then launches a series of divisions—a staggering trillion or more by the time the process is complete—that eventually result in a human baby.
Cell division, though, is far more complicated than simply cutting cells in half. The process begins with each of 46 chromosomes duplicating themselves, creating 46 identical pairs. Then, like soldiers standing back-to-back in formation, the 46 pairs line up, each facing the opposite direction from its twin. All the pairs must be in line, or the process halts.
Once the final pair aligns, a sort of biological knife cuts the pairs in two, and the chromosomes pull themselves to opposite sides of the cell. This split sends one complete copy of a cell’s genetic information to each side. Then the cell crimps down the middle and splits. The result: Two cells, each containing exact copies of all the chromosomes that came before it. The process then repeats itself. Over and over and over.
“Cell division requires intricate precision, because there are hundreds, maybe thousands, of steps to the process, and they have to occur in the proper order,” says Dr. Gary Gorbsky, who heads OMRF’s Cell Cycle and Cancer Biology Research Program and has spent more than three decades studying the process of cell division. “If there’s even one laggard chromosome, there’s a checkpoint system that stops the whole thing from going forward until that one makes it into the alignment. It’s a very precise, high-fidelity system. It has to know exactly when to turn things on and off.”
Still, with thousands of cells dividing at once, mistakes can occur. Every chromosome contains about 1,000 genes, each a sequence of deoxyribonucleic acid—DNA—that determines a particular trait. If just one of those chromosomes lines up incorrectly, says Gorbsky, “you’ve essentially changed the function of all 1,000 genes.” These genetic mistakes may result in disease, which can be passed on to future generations.
The cell division process goes awry when the embryo ends up with the wrong number of chromosomes. “A missing chromosome is the leading cause of spontaneous miscarriage,” Gorbsky says. More than half of first-trimester miscarriages result from chromosomal issues in the fetus, many times before the mother is even aware of the pregnancy.”
But chromosomal errors don’t always result in the death of the fetus. When the embryo receives an extra copy of chromosome 21, for example, the result is Down syndrome. “There are so many ways this process can go wrong,” Gorbsky says. “But that’s the amazing thing about human biology: it is almost always self-correcting. Most of the time the system works exactly as it should.”
Within five days of fertilization, that first single cell will have grown into a ball of about 16 undifferentiated cells. At this point, the cells are still considered “stem cells,” meaning that they possess the ability to become any type of cell in the body—heart, lung, bone or anything else needed to build a human. “Cells in the very early stages of development really aren’t obligated to becoming any certain sort of cell,” says Dr. Lorin Olson, whose lab at OMRF focuses its research on the study of stem cells.
But as they mature, the stem cells begin emitting and receiving signals to and from other cells. How and when does this signaling start? “That’s what everyone wants to know,” Olson says. “We know it happens, but scientists have yet to identify the trigger that sets the process in motion.”
The signals travel back and forth, cell to cell, encouraging them to migrate to specific areas of the embryo. In response, in a process known as gastrulation, the stem cells break away from their initial locations and begin grouping themselves into modules or clusters that will become various body parts. At this point, says Olson, the die is cast. “The stem cells are fully committed to becoming a certain type of cell. There’s no going back.”
The cells that move to the outer layer of the cell bundle, called the ectoderm, will become skin cells. Others migrate to the bundle’s center, or endoderm, to form internal organs like the heart, intestines or liver. Between the two layers, cells create the mesoderm, a middle layer that becomes bone and muscle. Although the cells have now assumed a unique identity (and, thus, are no longer stem cells), division continues. Only now, the division is much more specialized, resulting in the growth of specific cell types, and organs, skin and muscles.
The first major organ to form is the heart, which starts taking shape about a month into the pregnancy. “When an embryo is very tiny, all the oxygen and food can kind of diffuse in from mom,” says Dr. Courtney Griffin, who joined OMRF in 2008 to study blood vessel growth as part of OMRF’s Cardiovascular Biology Research Program. (She and Tim, also an OMRF scientist, are now parents to two healthy ten-year-olds, but we’ll get to that soon enough.) “As the embryo grows, the diffusion of oxygen and nutrients can’t get into the inner parts. That’s why the heart and circulatory system have to form early, because the cells won’t survive without that consistent nourishment.”
The heart derives from two primitive heart tubes. The tubes fuse together, bending and twisting to form a simple version of the heart. About halfway through this process, around week 6 of the pregnancy, the heart starts to beat. At 65 contractions or so a minute, it circulates blood cells throughout the embryo, which is not yet as big as a grain of rice.
Over the next six weeks, the remainder of the first trimester of pregnancy, the fetus (as it becomes known at week 8) will grow at an astronomical rate. It will stretch from less than a quarter-inch to four inches long. All of its major organs and body systems will fully form, as will its arms, hands, fingers, feet and toes.
“With all of the growth and development taking place, fetuses are at their most vulnerable during the first trimester,” says Dr. Stephen Prescott, a vascular biologist and OMRF’s president. During this crucial phase of pregnancy, Prescott says, a mother needs to be particularly vigilant about protecting the child growing inside them. “Especially at this stage, exposure to drugs, alcohol, tobacco, radiation, certain toxic substances or even viruses like German measles can cause major damage and birth defects.”
Still, the end of this phase signals an important milestone. “Because a baby’s most critical development has taken place,” says Prescott, “the chance of miscarriage drops considerably after the first trimester.”
Courtney Griffin peered at the ultrasound screen, straining to make out the two tiny figures growing inside of her. The technician slid the sensor back and forth across her belly, searching for better angles to look at each fetus. She adjusted some settings on the machine, performing a series of measurements and capturing still images from various different perspectives. Do you want to know the sex? she asked.
Courtney looked at Tim and nodded. Yes.
The technician smiled. You’re having two girls.
Joy washed over Tim and Courtney. Twin girls! And everything looks normal! Yet Courtney was not just an expectant mother—she was a biomedical researcher. Within moments, she began to think about her pregnancy like, well, a scientist. So I’m having twins. How, exactly, did that happen?
She rushed back to the lab. Working in the field of developmental genetics, she knew plenty about the processes driving embryonic development. But now she wanted to learn all she could about her own pregnancy. And she quickly discovered that twins had bred their own sub-genre of scientific literature.
Twins occur in about 1 in 50 pregnancies. Non-identical or fraternal twins, the more common form, are a product of the ovaries mistakenly releasing two—rather than one—egg for fertilization. Different sperm cells fertilize each egg, which is why fraternal twins don’t look exactly alike, and often aren’t even the same gender. Studies have found a genetic component to fraternal twinning, so it can run in families. Factors such as advanced maternal age and in vitro fertilization can also lead to higher rates of fraternal twins. Yet neither of these issues was present in Courtney’s pregnancy.
The ultrasound had revealed that the Griffin twins shared a single placenta. This almost certainly meant that the twins were identical. Unlike fraternal twins, identicals begin as a single fertilized egg. At some point in the first week or so after fertilization, that egg splits into two separate eggs during cell division. Although people commonly believe that identical twins run in families, researchers have yet to find any evidence that genetics play a role. Indeed, as far as scientists can tell, it’s simply a random phenomenon.
Researchers, though, have figured out that the earlier the egg splits into two, the more independently the eggs will develop in the uterus. For Courtney, the ultrasound showed that from a single placenta ran a pair of umbilical cords, one to each fetus. Those cords delivered nourishment to the growing babies, each of whom resided in her own amniotic sac. That meant the egg had likely split four to six days after fertilization—too late to develop separate placentas to feed each embryo, but early enough still to form distinct, fluid-filled membranes to protect each of the Griffins’ soon-to-be-daughters. This, Courtney discovered, is a very good thing.
Had the egg split any later, the twins likely would have shared not only a placenta but also a single amniotic sac. In such close quarters, the umbilical cords can easily become entangled. If that happens, the pregnancy comes to a sudden and devastating end.
For weeks, Courtney consumed information about twins. She also learned plenty by joining a local Mothers of Multiples group. Of course, these hardened veterans of raising twins (and triplets) spent less time discussing the genetics of multiples than the more practical aspects of preparing for them. They gave her advice that just about every expectant mother hears. Get the nursery ready now, they told her. Learn how to use the car seats before the babies arrive. But they also told her about companies that would provide free cases of formula or coupons for disposable diapers. Just tell them you’re having twins. Membership in the “multiples club,” it seemed, also carried some unexpected benefits. Be ready. When the babies are born, you and your kids will be treated like rock stars.
Almost anything they might need, the Griffins found, they could find through multiples club channels. An extra crib? Check. Changing table? Double stroller? Done.
As the young couple adjusted to their new reality, they got used to saying it out loud. We’re having twins. Tim felt the babies kick for the first time. At their next ultrasound, he and Courtney watched as one twin sucked her umbilical cord while the other kept her thumb firmly planted in her mouth. The tech took some measurements. Twin A weighs 14 ounces. Twin B is 13 ounces.
The fetuses were growing rapidly and beginning to move and act like babies. It was, Courtney and Tim decided, time to name them. Goodbye, Twin A and Twin B. Hello, Olivia and Delancey Griffin.
The second and third trimesters represent a sort of paradox. On one hand, the period from 13 weeks of pregnancy until birth represents a time of unprecedented growth. Over that time, the fetus will stretch from roughly an inch-and-a-half long to 20 or so inches, and its weight will increase from an ounce or 2 to its birth weight of 5 to 10 pounds.
Yet, from a developmental biology perspective, the most exciting days have passed. “The first trimester is when you see the greatest transformation, going from a single cell to a fetus with fully formed organs, body systems and extremities,” says Dr. Gary Gorbsky. “The growth and development that take place in the second and third trimesters are, in many ways, simply the consequences of the processes that were set on track during the first 12 weeks of the pregnancy.”
In the second trimester, the skeleton forms into bones. The eyes, at first on the side of the head, migrate to the front of the skull. The ears drop, begin to stand out on the sides of the head, and then the baby begins to hear.
By the time of Courtney’s second ultrasound—at 22 weeks—Olivia and Delancey had become noticeably active. This phenomenon, known as “quickening,” comes about thanks to a functioning nervous system and developing muscles calling out for some exercise. The increasingly cramped quarters of the mother’s uterus serve as a sort of gymnastics training ground for the babies, as they wiggle and twist in a cocoon of amniotic fluid. The watery fluid provides a weightless environment, a sort of cushion to protect growing children. Fetuses breathe the liquid in and out, helping the lungs strengthen and develop properly.
Amniotic fluid also helps support the umbilical cord, which pumps food and oxygen into babies’ bodies. This direct delivery mechanism is one way a mother’s habits, from what she eats to what she breathes, can affect her unborn child. But this impact is not limited to mom; the past behaviors of the father and generations of ancestors on both sides of the family can affect the child’s health in unseen, unfelt and, until recently, undetected ways.
At OMRF, Dr. Courtney Griffin is studying this emerging field, known as epigenetics. “Behaviors such as diet, exercise and tobacco use create chemical markers that can cover the DNA,” explains Griffin. Although the DNA—each person’s essential genetic blueprint—remains unchanged, the chemical markers obscure certain portions of the blueprint, changing the way the body reads that plan.
“Once the epigenetic marks are there, they can stick like glue and pass on for generations,” says Griffin. Worst of all, they become heritable, carried by both males’ sperm and females’ eggs. So the choices young people make may not only affect children they’ve yet to conceive—they may also impact their children’s children and generations beyond.
For example, a recent study published in the journal Human Molecular Genetics discovered a distinct epigenetic “footprint” in smokers. Compared with people who’d never smoked, the smokers showed different patterns of epigenetic markers on 20 different regions of their DNA. When the researchers extended the analysis to a separate group of patients and mice that had been exposed to tobacco smoke, they narrowed down the epigenetic modifications to sites in four genes previously linked to cancer. The scientists suspect these changes will increase the activity of these genes and, hence, the smokers’ chances of developing cancer. At this point, it’s still too early to say whether the smokers’ children (and grandchildren) will show the same epigenetic footprint. But, Griffin says, “Already in laboratory animals, we’re seeing that these types of marks are passed from one generation to the next.”
Of course, despite the rapid development of its brain during the third and final trimester, which begins at 28 weeks, the fetus remains unaware of complex biological notions such as epigenetics. Yet by this time he or she can blink, close the eyes, turn the head, grasp firmly, and respond to sounds, light and touch. As the baby grows, movement often diminishes due to the tight space. In the final weeks of pregnancy, the baby drops down in the mother’s pelvis to prepare for delivery.
Today, many otherwise healthy pregnancies are deliberately ended early by induced labor or Caesarean delivery. Studies have shown that as many as one-third of elective deliveries now occur before 39 weeks. But research has shown that with each decreasing week of gestation below 39 weeks, there is an increased risk of complications like respiratory distress, jaundice, infection, low blood sugar and even death.
“If there are no medical complications, the healthiest outcome is delivery at 40 weeks,” says Dr. Stephen Prescott. But, he says, this is not to suggest that women should panic if natural labor occurs earlier. “When labor begins on its own, that’s a whole different story.”
In the summer, the North Carolina air takes on the consistency of stew, a hot gruel more suited for eating than breathing. I could not, thought Courtney Griffin, have picked a worse time and place to be pregnant. With twins.
A few weeks into her third trimester, Courtney’s lab moved. That meant lots of time on her feet, packing boxes and hauling scientific equipment and supplies. Her feet and ankles had blown up like marshmallows. With an added 40 pounds—and counting—each step felt like a needle jabbing into her hips.
Then came the contractions. This can’t be it! she thought when she first felt a marked tightening in her belly. I’m only at 31 weeks. But soon enough, the sensation subsided. A wave of relief washed over her. These must be Braxton-Hicks contractions. Courtney had read about these “false” contractions that could come several times a day in the final trimester. They began to come and go so frequently that she almost got used to them. This isn’t the real thing, she’d reassure herself each time. Still, there was always a chance. I’ve made it this far. Please just let me hang in there little bit longer.
At her 33-week appointment, Courtney’s doctor voiced concerns about her swollen feet and ankles. Plus, you’ve put on 10 pounds in the last two weeks. You’re retaining a lot of water. Let’s try some light bed rest for a week.
Courtney liked the sound of that. Heck, she was napping all the time anyway. A little R and R might be just what I need.
Even in bed, though, Courtney’s hips kept her in constant pain. Sitting was almost as uncomfortable as standing, and lying down wasn’t much better. An ultrasound showed that by 34 weeks, the babies each weighed about 4½ pounds. Olivia’s head was positioned low in Courtney’s pelvis, pushing on her hip. Which explained the pain.
Yet as uncomfortable as she was, Courtney knew that every day she could forestall delivery lessened the chance of complications. Twins usually arrive early. When an extra fetus occupies a space designed for one, the uterus swells, triggering early labor. With twins, that typically occurs at 36 weeks.
For Courtney, it happened on the first day of her 35th week. In the wee hours of July 12, 2003, she felt the telltale wetness. My water just broke. It didn’t happen quite like in the movies, where there’s an obvious gush. But there was no doubting it: The amniotic sac in which the twins had resided for the past eight months had ruptured. Labor had begun.
Just as pregnancy differs for every woman, so does labor. For Courtney, it took 10 hours for her body to push Olivia from her uterus. In another three minutes, Delancey arrived.
Moments later, Courtney cradled her two, healthy newborn daughters, one in each arm. No more worries about test results. Complications. High-risk pregnancies or birth defects. Trillions of cells had divided. Organs had formed. And out had come these living, breathing creatures.
The scientist in Courtney understood that this was no miracle. Sure, there had been a few detours along the way—hello, twins—yet in the end, everything had worked just as it should have. Still, as a new mother, she couldn’t help but feel awe. And joy. Now, she laughed to herself, all we have to do is raise them.