In 1989, an international group of scientists had discovered the cystic fibrosis gene, a breakthrough that marked not only an incredible milestone in the study of reproductive genetics, but catapulted the field into an era of rapid growth.
Taking off alongside the field was Deborah Driscoll, a witness to the discovery after six years of reproductive genetic work at Penn, who says she couldn’t have entered the field at a more exciting time.
“I still remember the day the gene was identified. I was on maternity leave, and I had just finished my genetics fellowship. We were just starting to use molecular technology to identify disease genes,” says Driscoll, who has devoted much of her time at Penn to identifying a genetic basis for DiGeorge syndrome. “We were using very basic techniques in 1989, but the field started moving very rapidly as technology advanced, and with the commitment to the Human Genome Project, it was a very exciting time, and it was very rewarding.”
In retrospect, Driscoll—an obstetrician, gynecologist, and medical geneticist—launched a career at Penn shaping a field that she says, in turn, was made for her. She’s been at the University since 1983, when she entered her residency and subsequent fellowship at the Hospital of the University of Pennsylvania (HUP).
“Penn is one of the most collegial places. There’s almost nothing you can’t do here,” Driscoll says. “Every time I thought of something else I wanted to do, a new research idea, launch a new clinical program, develop a new course for medical students, everyone said, ‘Great, let’s do it,’—and that’s the attitude at Penn.”
Her contributions to obstetrics, gynecology, and prenatal genetics at Penn have been both significant and wide-ranging—from her research and clinical work with DiGeorge/velocardiofacial and polycystic ovary syndromes, to helping families at risk for having children with inherited conditions, to her work as the chair of the Department of Obstetrics and Gynecology and in the classroom as the Luigi Mastroianni, Jr. Professor of Obstetrics and Gynecology.
Driscoll welcomed the Current to her HUP office to discuss the state of prenatal genetic testing, the value of working from bench to bedside, the future of “designer babies,” and almost everything else she’s packed into her 30-year Penn career.
Q: As chair of Penn’s Department of Obstetrics and Gynecology, could you talk about the department’s Division of Reproductive Genetics and the services it offers?
A: We are unique in that we have a Department of Obstetrics and Gynecology that has a separate Division of Reproductive Genetics. We have a team of genetic counselors, and we have three obstetrician geneticists: Dr. Lorraine Dugoff, Dr. Michael Mennuti, and myself. We work very closely with our colleagues in maternal fetal medicine and in genetics at the Children’s Hospital of Philadelphia. We offer genetic counseling, and genetic screening tests, such as screenings for Tay-Sachs disease and cystic fibrosis. Our goal is to assess whether an individual or a couple is at risk for having a child with an inherited condition or chromosome abnormality such as Down syndrome, and we review what screening and testing options are available. We also perform amniocentesis and chorionic villus sampling: These are diagnostic tests that allow us to actually use the material that we remove—the amniotic fluid or the villi—to either perform a molecular test to see if the fetus has inherited a gene mutation, or we can do a karyotype to see if there’s a chromosome abnormality. Today there’s even more sophisticated testing available such as microarrays to detect small submicroscopic chromosomal deletions or duplications that would be missed on a routine karyotype. The field is changing rapidly because now we have the ability to offer patients noninvasive screening tests to identify pregnancies at risk for Down syndrome. As a result, the number of women that are opting to have invasive diagnostic testing such as an amniocentesis has significantly declined in the past decade.
Q: In your opinion, what factors have caused the field to proliferate?
A: The completion of the Human Genome Project, where they were able to identify the 20,000 or more genes that are in our genome, and the rapid advances in technology have greatly impacted our ability to detect genetic disorders in utero. Also, the technology has changed. Our ability to use DNA sequencing, for example, and the fact that we now realize that there’s fetal DNA that is circulating in the maternal serum allows us to offer women a blood test as early as 10 weeks in a pregnancy to screen for Down syndrome.
Q: How do you discuss complex concepts such as DNA sequencing with your patients?
A: There’s a genetic code—an alphabet for DNA consisting of four nucleotides or letters—and so basically, sequencing is reading that code. When I talk to patients, I typically will tell them a gene is like a sentence, like a set of instructions, and for that gene to work properly, we have to be able to read every word in the sentence. And if there’s a misspelled word—the equivalent of a mutation—or a word is missing or duplicated, then we can’t read the sentence, and the gene doesn’t work. It is very simplistic, but it helps our patients begin to understand the complexities of genetics. We don’t just want to give them a diagnosis—we want our patients to have a basic understanding of the types of tests that are available and what the test results mean for them and their families.
Q: You’ve spent a good part of your professional career advancing the medical field’s understanding of DiGeorge syndrome and chromosome abnormalities. What exactly is DiGeorge syndrome, and what is its relationship to the deletion of a small part of chromosome 22, known as the 22q11.2 deletion?
A: DiGeorge syndrome was first described by Dr. Angelo DiGeorge at St. Christopher’s Hospital for Children here in Philadelphia. He recognized that there were children who were born with immune deficiencies, low calcium levels, and heart defects. Over the course of the last 20 years, a team of physicians at Children’s Hospital of Philadelphia led by my colleagues Dr. Elaine Zackai and Donna McDonald-McGinn has been studying these children, and we now realize that in fact, these children have many more problems. They can have cleft palate, learning and speech difficulties, feeding difficulties —almost every system can be affected. The features are highly variable, and in some cases, adults often went undiagnosed until giving birth to a more severely affected child. In the 1980s, there were a few reports of children born with DiGeorge syndrome that had a chromosome abnormality, a translocation that involved chromosome 22. This observation provided us with a clue to where to begin to look for the genes responsible for this syndrome. Using basic molecular techniques, my colleagues Dr. Beverly Emanuel and Dr. Marcia Budarf and I identified a region on chromosome 22 that was deleted in these children that you could not have detected using routine cytogenetic techniques that were available at that time. Once we defined the region, we were able to design a probe that could be used to test children that presented with clinical features seen in children with DiGeorge syndrome, as well as pregnancies at risk. And we learned that it was a very common problem—it occurred in one in 4,000 births.
Q: You’ve worked with DiGeorge syndrome at clinical and research levels. How do those experiences play off of each other?
A: I think it’s an example of the concept of bench to bedside. We saw children in the clinic, and we went to the laboratory to try to find what was causing DiGeorge syndrome. Once we identified the cause, then we could go back to the clinic and use this information for diagnostic purposes. We could also study children with similar findings, and that’s when we were able to expand the phenotype and really understand what it meant to have that deletion. We began to understand that about 10 percent [of these deletions] are inherited, transmitted from a parent to child, and that the majority occur only in that child. So we were able to provide parents with a more accurate estimation of their recurrence risk. They could share this information with their relatives. And then we went back to the lab and started to study the variation in these families to try to understand what other factors influence the severity. We also identified a small subset of patients who didn’t have this standard 22q11.2 deletion, but actually had different deletions, smaller deletions—in fact, even deletions on other chromosomes. And we were able to go back to the lab and identify all of the genes in the region and see if some of those genes were responsible for a particular feature. Is there a gene that just causes heart defects? Or is there a gene that is responsible for behavioral or learning difficulties? So it’s a continuous circle from bench to bedside, and that’s how we learn and were able to connect all of these projects. And it took a team—a team of geneticists and specialists in cardiology, GI, immunologists, general pediatricians, genetic counselors, psychiatrists, learning specialists— all working together to care for these children to learn specifically about the types of problems these children can have, and look for ways that we can meet their needs.
Q: Some people have said that advances in genetic testing raise certain moral issues, such as the potential for parents to handpick their children’s characteristics while in the womb. As a physician and a researcher, to what level do you and your colleagues take notice of these moral issues? Do they ever affect the way you conduct your work?
A: So first of all, the decision to have genetic screening is a very personal decision. We offer patients genetic testing, but we also recognize and accept that there are many patients who aren’t interested in testing and don’t want to know if their child has a chromosome abnormality like Down syndrome. But for those couples who do, testing is a good option. Sometimes we use testing just to prepare for the birth of a child who may need special care, who perhaps needs to be delivered where the pediatric cardiologist can care for them after delivery. But there are couples that also use testing and screening to decide whether they want to have a family or whether they want to continue a pregnancy. One of the big breakthroughs was our ability to offer preimplantation genetic testing, so that if a couple or an individual is a carrier for an inherited condition, and we can test for the gene mutation, then we could test the embryo after in vitro fertilization and select which embryos to transfer back to the mother. For many couples, this is preferable to having to wait until 12 to 16 weeks of pregnancy for a diagnostic test, and then consider a termination of the fetus that has inherited a gene mutation. Pre-implantation genetic diagnoses have become much more popular today. Genetic testing is not being used for ‘designer’ babies, but rather to increase the odds of having a healthy baby. There are companies that do offer genetic screening and directly market to consumers, but right now they are screening for known recessive genetic conditions. Many of these conditions are very rare, but the technology is there, so for some couples who really want to avoid having a child with an inherited condition, this is an option for them. But we’re not talking about screening for eye color, hair color or height, things like that, those types of characteristics right now.
Q: What are some of the bigger issues you and your peers are facing in the field of reproductive genetics?
A: I think one of the major issues that we struggle with is that there is an inherent uncertainty with genetic test results. So we can perform a genetic test, and we may identify a chromosome abnormality or a small deletion in a fetus, but we cannot always accurately predict what that means. We will look at other similar cases reported in the literature or databases, but there is often a wide range of clinical features that are associated with that particular finding. Our inability to be able to provide the accurate information is what causes us the most anxiety. On one hand, we want to make the best use of the advances in technology and genetics, but we also need to be responsible about how we utilize genetic testing. We also know that when we test a fetus, it may reveal information about a parent or potential information that could affect their relatives. For example, it’s not unheard of for us to test a fetus, find a deletion, and then find that same deletion in a parent. And should that deletion result in the loss of a gene that could cause cancer or some devastating neurological condition, we’ve now learned more about that family than we ever intended to. So we have to think about the implications of genetic testing beyond just testing the fetus, and we have to realize that there is uncertainty, and that [some parents] may have to make decisions based on limited information. The field continues to evolve and as you study children with these conditions, we will learn as we go, but that’s kind of the down side of genetic screening. We’re not in any way perfect, but we can at least give them some idea of what to expect.
Q: You’re celebrating your 30th year at Penn. What has kept you in your field—and here at the University—for so long?
A: Penn has provided me with extraordinary opportunities during my career, and now is my opportunity to give back. It’s my opportunity to mentor young trainees and young faculty members to help them have successful and productive careers. It’s a chance to build new research and clinical programs to advance women’s health, to think creatively about how we can provide high quality care in the future. It’s an exciting time in health care—it’s a challenging time—but the opportunity to impact the future of care that’s going to improve the health and quality of life for women and their families is what’s important to me.
Q: What are some of the big-ticket items on your own plate right now?
A: One of our biggest initiatives right now is to develop a trans-disciplinary research program on preterm birth. We’re pulling together a team of investigators from across the University—medicine, engineering, microbiology, physiology, nutrition science, genetics, Wharton—to start to think differently about what causes preterm birth. And this could be very exciting for us here at Penn—we’re hoping to become a national center for research on preterm birth. Preterm birth is a major public health problem. One in every eight babies is born prematurely in this country, and here in Philadelphia, it’s even higher. All of our approaches to treat preterm birth have fallen short of what we’d like to achieve. So we need to really understand the mechanisms of preterm birth in order to reduce the preterm birth rates in this country. The rates are starting to decline nationally, but they’re still high. Preterm birth is associated with significant infant morbidity and mortality, and there is a national imperative led by the March of Dimes to reduce the preterm birth rates in this country. If we understand, then hopefully we can design more effective interventions to prevent preterm birth.
Q: Pregnancy is such an intimate life event. Have you ever found yourself becoming attached to your patients, and vice versa?
A: That’s the nice thing about ob/gyn because you will establish a meaningful and often long-lasting relationship with your patients. Sometimes you first meet a patient when they’re a teenager or a college student, and then you have the opportunity to follow them through their reproductive years, deliver their children, and then care for them during their post-reproductive years, so really, a lifetime. It’s not just the woman you care for—but you often get to know their families, and for some of us, if you’re here long enough, you’ll also get to take care of the next generation. It’s not uncommon to be taking care of a mother and her daughter at the same time. It’s really very special. I look back on what we’ve accomplished and I’m very proud of the department. The level of engagement and commitment from a very talented faculty makes my job pleasurable. Together, we are making a difference in women’s health care.
Originally published on January 16, 2014