When a genome, or every letter of every line of DNA, is written just so, science has learned that people can live long, strong, and healthy lives. If a letter or two or a thousand are written incorrectly, however, it is considered a “mutation,” or as today’s scientists typically refer to it, a “variant.” Sometimes absolutely nothing ever comes of these misprints. Other times, even one single miscopied, changed, or eliminated letter can mean the difference between health and sickness, life and death.
The double-helix revelation was astonishing, a revolutionary breakthrough in the scientific community. Suddenly we could “see” DNA. We could actually “see” our genes! Now that we could see them, like a ribosome, we could begin to read them. And read them we did. One hundred years after Mendel’s purple and white pea shoots, hundreds of scientists of all different races, genders, and nationalities worked together to unmask the human genome. In a worldwide project, they laid out in exhaustive detail all the roughly 20,500 genes that make up a human being. Some say it is the greatest scientific accomplishment of all time.
In 1994, while my father was spending time battling infection, ignoring Aunt Joanie, and looking for answers at Brigham and Women’s Hospital in Boston, the Human Genome Project was still seven long years away from publication. Genetics has always been a science of patient observation over time. Studying generations across plant lifetimes can sometimes be accomplished in a matter of months. In humans, the same studies can take years—lifetimes. Unfortunately, as anyone with a genetic illness will tell you, and what my father was trying to forget, was that “lifetimes” were exactly what he didn’t have.
Six
Soon after Aunt Joanie brought Uncle Nathan’s chart to the hospital, Dr. Christine “Kricket” Seidman, one of the world’s leading genetic researchers, came onto my father’s case. Dr. Landzberg, who had taken my father on as a houseguest during his early Boston visits, might have alerted her to my dad’s case, or a cousin who says her neighbor knew Dr. Seidman from medical school might have told her about him. Regardless, when I met her, I remember thinking that she didn’t seem like a doctor. She was far too easy to talk to, and much too pretty. She had sparkling blue eyes framed by short black hair, and she told us—no, insisted—that all of us call her “Kricket.” I’ve come around to calling her “Dr. Kricket.”
Dr. Kricket, a cardiologist by training, has spent most of her career looking at genetic conditions of the heart. Initially, she found my father’s case interesting because of the cardiac component—his sticky valve from childhood—but she was also drawn to my parents. She found their situation heartbreaking and admired their steadfastness in trying to figure things out.
Lucky for us, Dr. Kricket already had her own thriving genetics lab. There, she and her husband, microbiologist Jon Seidman, had spent impressive careers uncovering genetic links to a multitude of congenital heart disorders. They received wide acclaim for their breakthrough studies of familial hypertrophic cardiomyopathy (HCM), a condition best known for taking the lives of young athletes on sports fields. It predisposes sufferers to a thickening of the heart tissue, which can lead to sudden death. The Seidmans mapped that variant and then spent years studying it.
Very early on, it was clear that my father’s murmur, while somehow connected to some genetic piece of pie, was probably not central to his strange and harrowing illness. Because his illness did not seem to involve a cardiac component, he was not going to be a typical case for the Seidmans.
Nonetheless, Dr. Kricket made the decision to stay with our family for the duration. Her and her husband’s research lab specialized in figuring out the genetic reasons behind certain conditions. Once she had begun working on the case, she wouldn’t leave it, regardless of any odd, remote, or even erroneous paths it took her down.
* * *
Dr. Kricket and her team began their investigations of rare diseases by constructing a family narrative. She would compile stories and pictures as well as medical data to pull together a cohesive history to study. In that spirit, I decided to find out what I could about Dr. Kricket’s own family narrative.
She grew up the middle child in a family who didn’t produce doctors, but did produce a lot of illness. She noticed that the one person around her who wasn’t sick was always the doctor, so she decided she wanted to become one when she grew up.
She got into Harvard for undergrad and followed a traditional premedical course load, which meant starting with an introduction-to-biology class her freshman year. Jon Seidman, also premed, took the same class. Soon the two were in love. Kricket came from a traditional family and understood that if she was going to move somewhere with a man, she was going to do it married. When Jon had an opportunity to perform doctoral work at the University of Wisconsin, they decided to tie the knot.
By 1984, they were working together and became two of the first scientists to successfully clone a piece of heart tissue. Dr. Kricket completed her residency at Johns Hopkins, where she turned her focus to research. Mentored by Victor McKusick, known as the father of medical genetics, she lent her drive and genius to the Human Genome Project. Twenty-five years later, she called on her mentor one more time. He was now in his eighties but still practicing on a limited basis. At that point, Dr. Kricket had met a patient at Brigham and Women’s Hospital. He was a forty-seven-year-old man who seemed to have been born with a congenital heart defect and was now riddled with wayward lymphatic fluid throughout his body.
After she took on my father’s case in the mid-1990s, Dr. Kricket’s primary job was to figure out what other genetic illnesses showed similar symptoms. Her goal was to find a family or group of families with physical presentations that mirrored my father’s. This was the part of the plan I liked the best. Once we found that group, we would pool our collective knowledge, build a community, maybe start a support group, and have fund-raising bake sales, dance-a-thons, and ice-bucket challenges.
* * *
I was thrilled when I heard that Dr. McKusick was going to work on our case. In the world of genetics, he was something of a celebrity. A cardiologist by training, he’d chosen to study the heart because he loved the musicality of heartbeats. A hereditary heart condition called Marfan’s syndrome led him toward a developing field that later became known as medical genetics, as the head of Johns Hopkins brand-new Division of Medical Genetics in 1957. In 1969, he was one of the first to propose a human genome map, which many believe led directly to the Human Genome Project—first published in 2001. It wasn’t until 1983 that the first genetic illness was “mapped,” pinpointing an exact genetic variant inside the complex proteins of DNA coding.
I recently read a popular book by a journalist named Rebecca Skloot called The Immortal Life of Henrietta Lacks that principally focused on the history of immortalized cells. Immortalizing cells has been an enormous boon to genetic medicine and research. It protects, purifies, and safeguards specific cells for research, sometimes long after the host has died. More specifically, immortalizing cells allows researchers to keep a single cell alive in a frozen environment for as long as it is required for study. Doctors were soon capable of cloning cells an infinite number of times.
Henrietta Lacks was diagnosed with cervical cancer in 1951. Unbeknownst to her or her family, doctors harvested some of her cancer cells and preserved them. Because cervical cancer cells are already structurally heartier than other cancer cells, Lacks was a good candidate for an experiment to see whether or not her cells could withstand the then-crude conditions to become immortal, a complex process of heating, cloning, and freezing them. It worked. For the first time, cells replicated through cell division outside of Lacks’s own body. Eventually, Lacks became the first person to have her very own living cells outlive her. If you consider that Henrietta Lacks died in 1951, her still-living cells have outlived her by more than sixty-five years.
Called HeLa cells (the first two letters of her first and last name), Lacks’s cells have helped the scientific community to accomplish wonders,
like discovering successful cancer treatments and studying how a body might survive space travel. Lacks’s contribution to science, however, remains a controversial one. First, neither she nor her family gave consent before her cells were harvested. Largely, this is a reality for all of us when we enter a hospital. Our tissues can be discarded or utilized at the hospital’s discretion. That’s why you rarely hear about people taking home a souvenir appendix. Second, many people ultimately made a lot of money on the results of research conducted using HeLa cells, while the Lacks family languished in relative poverty in urban Baltimore.
For better or worse, HeLa cells served as an early and vital tool for Dr. McKusick in his ongoing development of medical genetics. Skloot writes about Dr. McKusick in her book. Today, medical genetics, by way of immortalized cells, is directly responsible for many of the innovative medical weapons that will one day cure cancer and fix many of our worst genetic anomalies. DNA lives in cells, so the same gene in the same cell can keep on living, even after the host of that cell has died.
Today, scientists immortalize all kinds of human tissues, which is important for people like Dr. Kricket who are studying families with genetic conditions. Specimens for her tiny study of my father slowly began to fill up a freezer in a single corner of her sprawling lab. After all, when she figured out what my father was suffering from, she’d want to be able to share those specimens, whether or not she was in time to save his life.
* * *
Only so many illnesses exist in the world. In 2007, the World Health Organization (WHO) identified 12,420 human diseases. However, in 2004, GenBank—a DNA-sequencing bank and online forum—had already categorized 22,000 disease categories based on DNA makeup alone. Today, the WHO reports around 10,000 named monogenetic (single gene) disorders. Given the rapid growth of genomic medicine, and the formidable ease and low cost of genome mapping, that number is certain to grow. Scientists will continue to find genetic nuances among illnesses once forced into a single box.
For example, “cancers” are now being broken down by genetic makeup so that they may be treated uniquely. Unlike my family’s gene variant, passed from parent to child via egg or sperm, cancer mutates one cell at a time until the number of cancer cells begins overwhelming the body’s systems. A growing field of medicine called “genomics” studies the genome of both the cancer and the patient. This vital step in cancer treatment is changing the way medicine is practiced. Instead of looking to statistics culled from a pool of outdated data, doctors can narrow their scope down to a specific type of cancer and look to those treatments that have the best possible outcomes. Who knows? One day the blanket term “cancer” might even become obsolete as genetic distinctions highlight various cancers’ profound differences.
But in the mid-1990s, when my dad was sick, the medical community only knew about roughly 741 genes linked to genetic disease. Other diseases that were believed to be genetic had not yet been linked to specific genetic anomalies, and those that had been linked numbered only in the dozens. The possibility that Dr. Kricket was looking at a whole new disease bordered on the nearly impossible. It just didn’t happen, at least not in plain sight, not the way this illness was behaving and playing out among three generations. However, no other populations seemed to share, or ever have shared, my father’s symptoms.
Discovering a new disease is always unusual and surprising. Genetic diseases do not pass from host to host by way of germs like the measles or the flu. A genetic condition must either occur in a person who can live with it until he or she reaches an age when they can pass it to offspring, like Huntington’s disease, or it has to lie dormant, recessive in healthy parents, until it finds a match that will produce a child with the condition. Both conditions illustrate how genetic diseases that impact children continue to pass among generations by “carriers.” Carriers are people who do not experience the detrimental symptoms of a genetic condition, but still carry the gene in half of the chromosomes in their cells. They have a 50 percent chance of passing that particular gene to their offspring. Like Mendel’s second-generation purple-pea-shoot plants, that gene for white flowers was there; it was simply dormant and not being expressed.
Genetic diseases with an adult onset like my family’s are very rare, but they are the ones that predispose—usually guarantee—that people will develop grave symptoms later in life, as my father did. In the case of my family gene, based on the three cases we knew of, it seemed that the disease affected its victims only during or after their fertile years.
Humanity probably never knew about some genetic diseases. Perhaps the detrimental genetic anomaly simply naturally selected out of existence, or died out because it affected a single life, a baby or a child, who didn’t survive long enough to reproduce. But if Dr. Kricket figured out that my father was truly alone in this, if my father was only the third person in three generations to have a unique genetic condition, then what she was looking at was a private mutation—a mutation impacting a group of related individuals that, over time, could expand into something called a “founder population.” This is a group of distantly related people exhibiting the symptoms of a heretofore unknown mutation—a “founder mutation.”
The founder mutation of Tay-Sachs disease, a rare, brutal child-killing illness most common among Ashkenazi Jewish populations, originated thirty to fifty generations ago, dating all the way back to the eighth or ninth century. Cystic fibrosis, a respiratory condition that affects hundreds of thousands of people of mostly European descent, is even older, originating in Europe fifty-two thousand years ago, or 2,625 generations. Sickle cell anemia, a debilitating blood disorder of principal significance in sub-Saharan Africa and among African-Americans, is comparatively new, but still affects more than ninety thousand children per year. The disease is believed to go back to a single common ancestor who lived a mere five thousand years ago.
My father’s disease remained uncategorized, but as Dr. Kricket was learning, it bore striking similarities to stories she was told about his grandmother and uncle’s diseases. She couldn’t make a definitive claim about whether or not my father’s illness was genetic, and what it might mean if it was, but she was prepared to find out. First, she needed tests, she needed blood, she needed to preserve some of his cells, and above all else, she needed stories, and lab work from all the members of our family.
* * *
Dr. Kricket contacted everyone she could find who was related to my great-grandmother Mae. She recommended testing or offered to fly them in to Boston, one by one. She put family members up in hotels and gave us spending money for food. One weekend in 1995, I drove from Tufts, where I was a sophomore, to Logan Airport to pick up my sister and our cousin Danny.
On that trip, Dr. Kricket took our vitals and focused on our hearts. She was going on a hunch based on my father’s childhood heart surgery, lifelong heart murmur, and little else. The tech listened to our heartbeats closely. The gel on my chest was cold and sometimes the angle of the ultrasound wand dug into the soft spots between my ribs. After a few minutes of carefully tweaking the echocardiogram, which provides images of the heart, she turned up the sound. It wasn’t immediately obvious. I mostly heard whirring noises, but Dr. Kricket was nodding. She pointed to a cluster of colors beside me on the monitor. Then I could hear it and even see it: a tiny but distinct little whoosh of air in the middle of my heart thump, which according to Dr. Kricket was caused by turbulence as blood exited my heart to the vessels. Buh-sh-bum. Buh-sh-bum. A murmur. Hilary had it too.
Danny, my aunt Kathy’s son, didn’t have it. We high-fived him.
The two lists divided, as cousins, aunts, uncles, great-aunts, and uncles all flew in or went to their own family doctors for a checkup. Some, like Danny and his mom—my father’s little sister—didn’t have the murmur. My dad’s younger brother, Norman, who lived in California, had visited a lab at the University of Southern California with explicit instructions from Dr. Kricket. His doctors didn’t detect a murmur either, nor was there
a murmur in the hearts of his children.
Hilary and I were placed on the other list, the one composed of those in whom Dr. Kricket had found murmurs. In all, out of forty-one of Mae’s direct descendants—five children, eleven grandchildren, and twenty-five great-grandchildren, including Mae and her son Nathan—thirteen of us had the heart murmur that provided Dr. Kricket her very first clue.
She put out a call looking for similar cases in the medical community. She contacted descendants of Mae’s two brothers, and any other distant relatives she could find. She pored over literature. She consulted with Victor McKusick. But she found nothing.
Seven
As my father lay swollen and dying, and as Aunt Joanie stood clutching the chart of her dead husband, Nathan, I remember asking my grandmother Shirley again what she remembered about the death of her mother. Great-Grandma Mae’s death was shrouded in mystery.
In the past, my grandmother had shrugged her shoulders and answered, “I don’t know.” This time, as she sat near the hospital bed of her very ill son, she replied bleakly, “What do you think? She filled with water.”
But the story Dr. Kricket collected from my grandmother and her siblings was decidedly better drawn.
Mamie Bloom stood an inch over five feet tall. The oldest child in her family of three children and the only girl, she met a young rabbi through a friend. Rabbi Morris was Pittsfield’s first Orthodox rabbi. He had fought to make ends meet as a seventeen-year-old Russian immigrant. While he taught himself English and put himself through Yeshiva University in New York City, Rabbi Morris was the kind of poor that meant sometimes you just didn’t eat. His mother and siblings helped him when they could, but eventually his strong faith and an even stronger work ethic landed him his own congregation in the foothills of the Berkshire Mountains. He was young, tireless, and deeply religious. The second youngest of eight children, Rabbi Morris stood five feet four inches, with a handsome face and a stylish mustache. A fated fix-up by his older sister with an American-born girl with a large and ready smile who lived four hours away in Brooklyn changed his life.
The Family Gene Page 4