Hunting For A Deadly Genetic Misprint
Anne Calof ’78 stalks the genetic mutation responsible for the devastating disorder that claimed her daughter.
Inside the office of Dr. Anne Calof in the Biological Sciences building on the campus of UC Irvine, you would not be blamed for wondering how she keeps anything straight. On the desk, alongside a 27-inch iMac, a second monitor, and a wide-screen titanium Apple laptop, there is a pile of papers that, in display, would not seem out of place on the floor of a teenager’s bedroom. Behind those papers, on a bookshelf markedly devoid of books, are more papers, piled, heap-like, willy- nilly. (The books are high up above the cabinets, half-collapsed in a haphazard line.) With the blinds drawn, the office is workaday and plain; behind where Calof sits, a framed Ansel Adams poster leans, floor level, against a wall, nudged between a file cabinet and the window ledge. It is the only decoration.
And perhaps this is the essential detail: there is almost no decoration. Only papers. Books. Equipment. Tools of her research, for which she won (along with her husband and collaborator, Dr. Arthur Lander) the 2016 RARE Champion of Hope in Science award. An award given to honor her pioneering work in identifying the genetic signature of a devastating disease; an award given to scientists dedicated to doggedly pursuing questions about rare genetic diseases; an award which honors a career as focused and systematic as this office isn’t.
“It’s just that I’m organizationally challenged,” she says, brushing off the comparison. She looks straight forward as she talks, and leans into the desk, unfazed and undistracted by the environment around her. “My lab doesn’t look like this.”
Her energy is a breed of nervous—but not an anxious or insecure nervous. Rather, she seems to vibrate with intensity, the way the engine of a car might as it pushes itself up a steep hill. And Dr. Anne Calof—mother of a high school–aged daughter, professor of anatomy & neurobiology and developmental & cell biology, researcher in UCI’s Center for Complex Biological Systems, professor of histology for first year medical students, and author and coauthor of a list of significant papers about a rare and little understood genetic syndrome known as Cornelia de Lange syndrome (CdLS)—has shaken her way up quite a few hills.
A hospital bed is not necessarily the place a biological researcher would expect to reorient her career. Especially a career focused on basic research (“questions pursued for their own merits,” as she described it in a 2000 essay for Current Biology). Especially if it is the scientist herself in that hospital bed.
Yet that’s how it happened for Calof.
In 1999, she and her husband were working at UCI, and she was midway through a prominent career pursuing research into growth factor signaling and stem cell regulation—trying to understand the basic biological machinery that manages growth control within the nervous system—when she and her husband learned that they were expecting their first child.
Excitement, however, soon turned to concern, when it was discovered that the baby, while seemingly healthy in all detectable ways, was growing far too slowly. Early ultrasounds showed evidence of symmetrical growth retardation—everything was growing, but not fast enough—and no tests existed to determine the cause or effect. Such slow development likely meant something worrisome, but exactly what, no one seemed to know.
Meanwhile, Calof began to experience prenatal hypertension and was put on bed rest. A decision was made to extract a sample for testing, but at only 11 weeks, the sample had to come directly from the placental tissue, in a procedure called chorionic villus sampling.
“I sat there with the neonatologist and for a while I was watching the screen,” she says of the ordeal. “But you can’t have any anesthesia. You’ve got this honking big needle and the baby, the embryo, is this big,” she pinches her fingers together until they’re a little more than an inch apart. “I told the doctor, ‘I’m gonna close my eyes too so I don’t get too upset.’ ‘Yeah,’ he said. ‘I’m going to do the same.’” At this, she laughs, softly, holding eye contact and looking a bit relieved. “My husband was watching. He’s an MD and even he had to turn away. I looked over at him and he was blue—I was worried he would pass out.”
The test, however, was successful—in a way: certain chromosome abnormalities (like Down syndrome) and genetic disorders (like cystic fibrosis) were ruled out. But nothing was ruled in.
Then, two months before her baby was due, Calof began to experience preeclampsia. She spent a month in the hospital, where her child—Isabel—was soon born a month early via emergency caesarean section. That day, February 28, 2000, Isabel was whisked away for a full day of surgery: abnormalities in her gastrointestinal system required immediate attention—and she was still under three pounds in weight.
“She’d been born with what they call an annular pancreas. It means her pancreas was forming a ring around her stomach. It explained, in a way, her low birth weight. But even after hours and hours of surgery, no one knew what was causing it.” At that time, the majority of genetic syndromes were diagnosed through a rudimentary process: by sight. A geneticist working at the UCI Medical Center Neonatal Intensive Care Unit, Dr. Maureen Bocian, used to make rounds through the NICU looking at all the babies in case diagnosis of a genetic disorder was needed.
“Isabel was covered in gauze after her surgery,” Calof recounts, “but the minute most of the gauze and tubes were removed from her face, Maureen looked at her and said: ‘She has CdLS.’”
Calof lay in bed and her husband sat next to her. They were stunned, and they were frightened. As it became clear that their daughter wasn’t going to leave the NICU, rather than turn inward they turned to their work.
At this point in the story, even almost two decades on, tears come to Calof’s eyes. She lets them fall down her nose quietly, wiping them away with one hand without fanfare or shame. “That was a bad month,” she says and lets out a sigh. “But both my husband and I are people that want to fix things.”
“Arthur immediately got on the phone, right there next to me, and started to make calls.” He got in touch with Dr. Laird Jackson—the “grand old man of CdLS research”—and Jackson sent them a list of other scientists, doctors, foundations, and labs asking questions about CdLS. Isabel lived only 30 days, but by the end of the experience, Anne and her husband had opened up an entirely new avenue of research and collaboration. Even before she was out of bed, she had already started working toward a new, groundbreaking understanding of CdLS.
Anne Calof was born in Northern California, but with a father in the Air Force, she had lived in California, Japan, New Mexico, and Texas by the time she was 16.
She attended St. John’s College in Santa Fe as a young college freshman, attracted to its intensive Great Books program. It only sustained her for two years, though it did put a book in her hand that changed the course of her life: On the Origin of Species by Charles Darwin. It was a pivotal text for her. “I just completely connected with that book. Completely got into it.”
“It was systems biology: thinking through the performance objectives of a system—that’s sort of the way On the Origin of Species takes off. It’s trying to deal with a big problem, and Darwin’s observations lead him to think through that problem. It was pretty revolutionary. At the time I didn’t see it in those terms, necessarily, but I was pulled in.”
After dropping out of St. John’s, she moved to Austin, Texas, and got a job working for a motorcycle magazine called Cycle News while she got herself ready for the next thing. She spent a year at University College, Cardiff, as an occasional student, and in the meantime secured admission to both Stanford and Reed. She chose Reed. “It was something about the personal attention that attracted me. It was really important, working that way with professors. I mean, coming from St. John’s, Reed was big. Reed was kind of a big world—a six-fold expansion. It seemed enormous to me.”
At Reed, Calof lived what she describes as a “play hard, work hard” lifestyle. She stayed in a big house with a multitude of housemates, and befriended fellow Reedies studying in all disciplines and living a range of alternative lifestyles. There was a lot of compilation tape making, planning for and recovering from house parties, playing cards, and listening to Stevie Wonder and Mozart.
“I really had a good time. I made a lot of friends. I stay in touch with a lot of people from that time. I mean, it was the era of all-night parties—the ’70s. But if I hadn’t gone to Reed, I wouldn’t have met such a wide range of people, or learned to listen to Mozart, or met people tuned into interesting things, and by proxy, been tuned into them myself. ”
She also stayed tuned in to On the Origin of Species.
In her first year at Reed, she took a class in the psychology department with Prof. Dell Rhodes [psychology 1975–2006]. Prof. Rhodes, newly arrived at Reed at the time, was fresh from a postdoc at UCLA, where she’d worked in “big science” (large-scale research projects funded by government agencies). This style of focus impressed Calof, and Rhodes quickly became one of her most important mentors. She decided to major in psychology as well as biology.
Rhodes directed her to the Neurological Sciences Institute in Northwest Portland, which at the time sponsored Reed students seeking to do off-campus research. There, Calof met Dr. William J. Roberts (“Bill”), and they hit it off. He agreed to coadvise her on a project that Rhodes would direct, and to host the research component; they would use his electrophysiology lab, preparing and running the study that would become her thesis: “Adaptation of Cutaneous Sensory Neurons to Autonomic Nervous System Stimulation.”
Where Bill facilitated her research, Rhodes, and the Reed psychology department, inspired it. “Dell really pushed me forward by connecting me to the NSI, but also by giving me access to opportunities to present my work, both at Reed and elsewhere. That gave me confidence in what I was doing, in my own thinking and my findings. I was interested in graduate school by about my second conversation with Dell.”
After Reed, she followed her passion to graduate studies at UC San Francisco. And it was at UCSF that she met her future husband, Arthur Lander, and from there they both launched themselves into the kind of careers in “basic science” that found them, eventually, with appointments at UCI: he, as the Donald Bren Professor of Developmental and Cell Biology in the School of Biological Sciences, and she as a professor of anatomy & neurobiology in the School of Medicine.
“It was because of Dell and Bill that I got interested in neurobiology, which, in those days, was called physiological psychology. From there I got interested in molecular and developmental neurobiology, which is what they brought me out here to do. That’s what I was doing when Isabel—” She pauses here and takes a deep breath. “When I got pregnant with Isabel.”
It took Isabel’s birth—and her abrupt death—to change that. And to change not only her research interests, but her perspective on the role of scientific research in the world, and in her world, more profoundly.
CdLS is a multisystem birth defects syndrome that affects one in 10,000 children. For those individuals born with CdLS, symptoms can be quite severe and usually have a profound impact on quality of life. According to the CdLS Foundation—a research, family support, education, and advocacy group (which Calof has worked with extensively, currently serving on the Clinical Advisory Board and the Scientific Advisory Committee for the international foundation)—people with CdLS can experience a wide range of severe medical issues including gastroesophageal reflux disease, heart defects, seizures, feeding difficulties, vision problems, and hearing problems. Likewise, it’s not uncommon for those with the syndrome to present with limb differences, as well as cognitive and behavioral issues and growth delays.
When Calof and her husband began to work on CdLS, they joined a small team of researchers who had solid knowledge of the characteristics of the syndrome—one being the classic array of facial features that Dr. Bocian had noticed that day—and some guidance on how to help those with the disorder live with it, but little understanding of its genetic basis. Through Dr. Jackson, they found their way to a doctor at the Children’s Hospital of Philadelphia working to map the genetic mutation responsible for CdLS, Dr. Ian Krantz.
With Krantz, they spent four years mapping CdLS. They donated Isabel’s blood to the project, as well as countless hours of mentoring, conversation, guidance, and debate. Finally, Krantz and his associates, along with Calof, her husband, and one of her postdocs, published the findings in Nature Genetics in 2004: they had identified the gene, named it NIPBL (Nipped-B-like gene), and found evidence that it could influence a wide range of fetal and adult tissue present in those with CdLS. It was a breakthrough for CdLS—but so was it also for an understanding of how far-ranging gene effects can be in syndromes like CdLS, and how thoroughly influential in organ system development a single genetic “typo” can be.
For Calof, it was just the beginning. With the knowledge created in their initial CdLS gene mapping study, she and her colleagues, students, and graduate assistants continued to seek a deeper understanding of the disease. In her lab at UCI, she and her collaborators created mouse and zebrafish CdLS models by using molecular genetic tools to create NIPBL-deficient animals. She and her collaborators have spent over a decade analyzing the models to better understand the genomic, molecular, and cellular effects of NIPBL deficiency, (the most common cause of CdLS) on fetal development. Since that initial paper, they have published findings related to the NIPBL’s effect on gene expression and synergistic gene action in growth control, adipose tissue development, congenital heart disease, gastrointestinal development, limb defects, limb development, and more. These are all highly impactful findings for those living with CdLS and those who will be born with it in the future. But so are they also for those undertaking corollary studies related to other genetic syndromes.
Today, her research continues to follow the path inspired by Isabel’s birth, diagnosis, and short life: she maintains a focus on understanding CdLS through a modeling and systems biology approach, a renewed focus on developmental genetics and growth control in the nervous system, and a brand new focus she’s never embarked upon before: therapeutics. “It’s humbling,” she says, shrugging. “It’s really hard. I have a newfound respect for people who perform good translational research to develop new drug treatments. It’s extremely difficult to determine efficacy.”
In her 2000 Current Biology article, “Long Odds,” Calof wrote about the shift triggered by Isabel’s diagnosis: “I used to think that basic research was somehow better than applied research, but now I’ve changed my mind,” she wrote. “Now it seems entirely worthwhile to focus one’s scientific curiosity on problems whose solutions will have a direct impact on our lives and the lives of our children.”
She echoes that sentiment today. Outside her office, she makes a beeline for her car—an ancient, faded Honda Civic. “This is my nemesis,” she says patting the driver-side door. “I’m surrounded by people who drive big SUVs, but this thing punches. It really does.”
She opens the door and looks back at the biological sciences building she’s just left. In 10 days she’ll be heading to Taiwan for a summer of research and child raising. “You know that award I got last year?” she says, suddenly reenergized, refocused on what she’s spent the last hour discussing. “Well, it came out of the blue; I don’t know what happened. But when I was there, accepting the award, this woman came up to me and she said, ‘Are you Anne Calof?’ I nodded. She said, ‘I flew here from New York to meet you. I have a son who has CdLS, and I wanted to talk to you and I wasn’t sure if you’d be willing.’ I was blown away. Of course I was willing! So we spoke, and we were able to hook her up with the foundation, with doctors. Look, to me, that is the true achievement. People are always patting you on the back for the time you put in. But that somebody actually read what I’d written, and thought that I could help them, and came to me, and I was able to give them some useful information? Most scientists don’t get that privilege. It’s huge.”
She laughs, opens the car door and turns the ignition. As the old car makes its way onto the road and up a nearby hill, it begins to shake just a bit. But, knowing that Calof is driving, there is no doubt that it will get where it’s going.
Tags: Alumni, Health/Wellness