Dr. Diana Bianchi — Caring for Two: The Mom-Baby Unit

>> Diego (narration): Mother’s Day is just around the corner. It’s time to show moms some appreciation for everything they do and have done. From diaper changes, carpools, and pep talks, to snapping embarrassing family photos, imparting life lessons, and wiping teary snot from your face with the skirt of her dress when you broke down crying in the car on the first day of 5^th grade. Ok, that last one might have just been me…but still. Moms are the unsung she-roes of our lives. Especially if you consider the 9 to 10 months they carried us in the womb. Pregnancy is by no means necessary for motherhood, but it is necessary for life. And it’s no picnic.

While a pregnant person is single-handedly creating a brand-new heart, a fresh pair of lungs and the rest of the organs they gift us before we take our first breaths, they can experience complications like anemia, hypertension, UTIs, diabetes, not to mention the unrelenting exhaustion—heck I’m tired from just listing them.

Maintaining maternal health during pregnancy can be challenging, but it’s integral for the mommy-baby unit. “Healthy pregnancies, healthy children, healthy and optimal lives,” as goes the vision statement of the National Institute of Child Health and Human Development, or NICHD. And no one understands that better than its director, Dr. Diana Bianchi.

Dr. Bianchi has dedicated her career to caring for the health of the mother alongside the health of the baby. She is a physician-scientist and widely recognized for her contributions to the development of noninvasive prenatal testing that is now used to screen for Down syndrome in a growing fetus. As a senior investigator at the National Human Genome Research Institute, she continues to advance DNA screening technology to detect other genetic anomalies and develop therapies for treatment prenatally. At the same time, she is leading NICHD on their mission to enhance lives in all stages of human development.

I got to chat with Dr. Bianchi all the hats she wears and how her work is connecting reproductive health with pediatrics and rehabilitation medicine.

>> Diego (interview): I understand you love art, particularly the work of Johannes Vermeer, who is probably most recognized for his painting of A Girl with a Pearl Earring. And it’s interesting, I guess I’ve always thought this, but there's such a strong parallel between art and science in that they both tap into like this power of observation—being curious enough about the world to look deeper…

>> Dr. Bianchi: Yeah, I agree. I'm glad that you said that there's this connection between art and science. There's a lot of attention paid to the fact that a lot of scientists and doctors are musicians, but I think less attention is paid to art. You know, sort of my fantasy retirement career is to become a museum docent and to teach the power of observation, as you said. T here's so much that you can learn. And getting back to Vermeer, I'm one of these people who are called Vermeer completists. There are a number of people who make it their life's goal to be able to see all of the Vermeer paintings, of which there are probably around 35, in person. And a number of them I've seen on several occasions, even in different locations, because they travel.

>> Diego (interview): Well having seen so many, which would you say is your favorite work of his?

>> Dr. Bianchi: So, my favorite artwork is the Lady Holding the Balance. She's in the National Gallery in Washington, DC. You could look at the painting in so many ways, particularly with a contemporary view; How are you going to balance your work and your family life? She's weighing pearls or gold, I forget, but she's contemplating the scales, and she's clearly pregnant. So, I'd like to think that she's thinking about what lies ahead in her future and how she's going to balance everything. So, I make it a point, each time I see a Vermeer painting, I want to notice something new that I haven't seen before.

>> Diego (interview): Yeah. What was your last observation when you saw the painting of the girl with the scales?

>> Dr. Bianchi: There's an orange stripe on her skirt that you don't so much notice it in person, but I did buy a poster from the exhibit, and then I had it laminated, and it is hanging in my condo. So, I get to look at it a lot. And it's that orange stripe that jumps out at me and reminds me of the linea nigra, that’s the Latin term for a brown stripe that can be out of woman's abdomen when she's pregnant. So that was one of the things I was looking at most recently.

But I've been looking for evidence of medical concerns in the subjects who were painted. So, a colleague from the Netherlands and I, are making a list of all the paintings, and we've been cataloguing all the medical findings that we've observed. Nobody has really put those together in one study. There have been individual articles looking at various scientific aspects of Vermeer paintings, but no one has really catalogued them. A few years ago, there were, I think, 10 Vermeer paintings at a special exhibit at the National Gallery, and there was a painting of a woman at, sort of a harpsichord or some kind of keyed instrument, and seeing it in person, it looked to me like she had scoliosis. I mean, her spine was not straight. So, I added her to the list, as well. You mentioned The Girl with the Pearl Earring. If you look closely at that painting, she has no eyebrows or eyelashes. And it's not that he forgot to paint them. He's got them on his other paintings.

>> Diego (interview): Yeah, it's intentional.

>> Dr. Bianchi: Yeah, we hypothesized that she had alopecia, which is a loss of hair.

>> Diego (interview): And the scarf, right? That kind of like ties into that.

>> Dr. Bianchi: Yeah, she's got the turban covering her head. And there's no obvious hair there.

>> Diego (interview): That's interesting. I think read that you used to do a similar kind of thing when you were young. Was it that you would look at people on the bus who seemed to have medical concerns and wonder what caused them and what could be done about them?

>> Dr. Bianchi: I think that was one of my early foundational experiences, taking public transportation to my school. It really gave me a chance to observe the other people on the bus. And so, it's not a stretch to see that I landed in medical genetics, where you're looking at things that other doctors don't notice. Like the finger creases or, you know, little tags on the ears, or small details that your average primary care physician doesn't really notice or doesn't' really think is significant.

>> Diego (interview): Right, well, this inclination to notice the little things eventually led you to U Penn for undergrad, and then Stanford for medical school where you worked with the Herzenbergs, who had previously developed FACS technology—and not fax as in scanning and sending documents over phone lines, but F-A-C-S, as in the acronym for fluorescence-activated cell sorter—which allows researchers like you to count and sort different types of cells from blood samples. So, you use this technology to detect how cells from a growing fetus kind of slip into a mother's bloodstream, is that right?

>> Dr. Bianchi: Yeah, we were most interested in nucleated red blood cells, because they were more likely to be from the fetus and the mother. Early in pregnancy, the blood is not being made by the bone marrow. It's being made by the fetal liver, and the cells themselves are less mature. So, we were looking at the passage of these cells from the baby's circulation into the mother's circulation through the placenta.

>> Diego (interview): And the idea was to kind of differentiate them, to test for genetic disorders in the fetus?

>> Dr. Bianchi: Yes. So, the original idea was to be able to physically isolate those cells and then do genetic testing on them. For those people who are listening, it's a great story of resilience and learning from so-called failure, although I don't believe that anything is a failure. So my mentor, Leonard Herzenberg, who's now deceased, and his wife, Lee Herzenberg, had a child named Michael, who had Down's syndrome. He was born in 1960. There was no prenatal testing for Down's syndrome at the time. When Len developed the fluorescence-activated cell sorter, and I came from Penn where I actually had already had five years of experience in cytogenetics, and I knew how to perform a karyotype.

>> Diego (interview): A karyotype is…? just to clarify for anyone who might not know.

>> Dr. Bianchi: Yeah, so, a karyotype, it's kind of old school now, but it's a way of getting a white blood cell to divide and you pop open the nucleus, and out come the 46 human chromosomes, if the person has the normal number of chromosomes. In Down's syndrome, there's an extra chromosome, 21. So, their vision, was to use the florescence-activated cell sorter to isolate fetal cells, and then, do genetic testing and determine if there were three copies of chromosome 21. So, to be able to do a noninvasive way of screening for Down's syndrome. There were other tests that were available at the time, and they were primarily biochemical or protein markers, but they had a very low positive predictive value. The positive predictive value tells you what's the chance that the baby really does have a condition if you have a positive test? And the standard of care, it’s still the standard of care, has a positive critical value of only 5%. That meant that a lot of women got false-positive tests and then went onto have diagnostic tests, like amniocentesis, which involves putting a needle either into the uterus or biopsying some of the placenta from the cervix, when they really didn't need it. Those are diagnostic tests. They're highly accurate, but they do carry a risk of miscarriage. So, they're not offered to every pregnant woman. So that’s diagnosis. Then there’s screening. Screening takes an entire population is looking for factors that indicate a higher risk for a condition. So, if you screened everybody, then you might be able to detect the women who had a higher risk of Down's syndrome. So, we started with looking at intact cells. Ultimately, that really didn't work well enough for prime time or clinical translation. It really took a few more years for DNA sequencing technology to become affordable and rapidly producing results. Because, originally, it took days, weeks, months to get a DNA sequence.

>> Diego (interview): Right, is that now kind of like standard practice to use non-invasive prenatal testing for all pregnancies?

>> Dr. Bianchi: It is evolving to standard of care. It's one of several options that are offered to pregnant women if your high risk, meaning if you're over age 35 at the time you deliver, or your fetus has a structural problem on an ultrasound, like a heart defect or a stomach or intestinal defect. Then you could be offered this as a screen, or if you have a family history of having a previous child or a relative with Down's syndrome, for example. And so, you'd be high risk, and insurance and state Medicaid, many state Medicaid programs, will pay for it. The big question is when will it become the first tier, where every woman can have it as the first test? And it's moving there. I think the cost has to come down a little bit, but well over 10 million tests have been provided globally. So, it's gone from original studies that were funded by NIH back in the 90s to now, really, transforming care globally.

>> Diego (interview): Got you.

>> Dr. Bianchi: But it's also led to a secondary set of issues, and that's the fact that the mother's DNA is also sequenced. And so, we're finding out things about the mother's health that we didn't expect.

>> Diego (interview): Interesting. Like what?

>> Dr. Bianchi: Well, one of the things that we realized over the last six years or so is that unusual results from the genomic sequencing might be a sign that the pregnant woman has cancer, even though she's completely asymptomatic.

>> Diego (interview): Whoa.

>> Dr. Bianchi: So, we are running a study called the Identify Study, in partnership with the National Cancer Institute. So, it's NHGRI and NCI, in which, we are asking pregnant women to be referred to us who have these very unusual results.

>> Diego (interview): So, when you say, "unusual result," what does that look like?

>> Dr. Bianchi: The unusual results tend to be multiple aneuploids. So, you get a result back that says monosomy X. So, one copy of the X chromosome. Trisomy 21, trisomy 18, trisomy 13.

>> Diego (interview): So, all these things kind of compounded.

>> Dr. Bianchi: All these things at once, and you wouldn't see that in all living fetus. If that really happened, that fetus would've been miscarried a long time ago. There's something unusual going on that is triggering that result. So, the recommendation would be to confirm it with a diagnostic test, and to qualify for our study, then the woman would have to have a normal set of fetal chromosomes with the diagnostic test. So, now you have this unusual result and an apparently normal fetus. What's going on? What's happening is a solid tumor is shedding fragments of DNA into the pregnant woman's circulation. So, now you have the pregnant woman's DNA, you have the placental DNA representing the fetus, and you have the tumor DNA. It’s all getting sequenced and getting mapped to the human genome, and the algorithm, or sort of the computer package that tries to analyze these data, can't figure it out. Because this is not compatible with human life. So, you get a non-reportable result. That’s kind of the lay interpretation of it.

>> Diego (interview): Yeah, yeah, yeah.

>> Dr. Bianchi: The funny thing about these tests is that they were not designed to detect cancer, but they do. And I did kind of a much smaller proof of principle study of this when I was still at Tufts, and one of the participants had anal cancer and she had bleeding from her rectum during pregnancy, but every doctor told her it was just hemorrhoids, which are very normal for pregnant women. If she hadn’t had the test, she would not have known, so she felt very strongly that her baby had saved her life.

>> Diego (interview): Wow.

>> Dr. Bianchi: So, I think at first people were questioning whether this study was worth doing. But we all feel pretty good that we hopefully have saved some lives, as a result of the study.

>> Diego (interview): Yeah, for sure. Well, that's kind of been a concerted effort on your part, to study the health of the mother alongside the health of the baby throughout your career, not just taking like the OB-GYN or pediatrics route. Again, this kind of harkens back to this idea of making observations: you saw the need to kind of study them in tandem, which then led you to create the Mother-Infant Research Institute during your time at Tufts. So, why do you think there is this kind of gap in research, and why do you think it's so important to study and treat the mother of the health and the baby at the same time?

>> Dr. Bianchi: Well, that's a great question. They're so intimately intertwined, you know, both metaphorically, as well as physically, that you really can't separate them out. In fact, you know, when you think about it, the fetus really doesn't have an advocate. It's unclear whose patient the fetus really is. I mean, been trying to promote the concept of prenatal pediatrics, because there are a lot of things you can do, even when the fetus is in utero, to treat the fetus, but so many of the experiences, the exposures, maternal diet, maternal health, maternal medications, affect the fetus, as well. So, you really do need to consider them as a unit, because what's happening to the mother profoundly affects the health of the baby. So, for example, if the mother has hypertension, those children, 10 years later, have a higher risk of having hypertension. You know, the influences are profound and long lasting.

>> Diego (interview): And it's not just the mother that affects the child, right? The child can have effects on the mother. I think I read that fetal cells continue to circulate in the mother years after she's given birth.

>> Dr. Bianchi: Yes, so they don't so much circulate, but they are finding a happy home in the mother's organs. So, that was one of the surprises of our research was finding out that fetal cells can persist in the mother for decades after delivery. I remember very clearly an ah-ha moment, when one of my postdoctoral fellows in the lab called me into the microscope room and said, "Take a look at this!" And it was a thyroid biopsy from a woman who had had part of her thyroid removed, and this woman's thyroid was part male and part female. It's very clear to identify the male cells, because they have a Y chromosome. So, you can clearly see what's male, what's female, and the only male exposure she had was from her son. She never had a blood transfusion. She was otherwise healthy. So, it was the first time that we saw evidence that fetal cells had gone in and tried to repair a thyroid. So, we think that some of the cells have stem cell capability—some of them must have the capacity to divide and differentiate. And in fact, we showed that in a mouse model. But we also showed that there were certain types of injuries or diseases that seemed to draw in the fetal cells, and particularly with injuries or diseases associated with inflammation, you always found more fetal cells. So, presumably, there were cytokines or something else drawing fetal cells to the damaged organ.

>> Diego (interview): That's crazy.

>> Dr. Bianchi: Yeah, so I mean, especially as we're coming up on Mother's Day, we think a lot about how fetal cells really can contribute to the repair of maternal organs and improve maternal health.

>> Diego (interview): That's so cool. Add that to the list of mom super powers. Well, I do want to pivot back to your main focus of research, which is reproductive genetics, if I’m not mistaken. What can you tell us about, you know, how the field has advanced since maybe even the development of prenatal screening?

>> Dr. Bianchi: So for us, it’s never been just about detecting that there's a condition present. We’re working on developing a prenatal treatment for Down syndrome. We know that the fetal brain in fetuses with Down syndrome is already growing more slowly in the third trimester. What if you could give the mother a medication and encourage neural cells to develop and to migrate in a way that is more typical? And we've recently come up with a proof of principal study that was just published in the American Journal of Human Genetics showing that a natural compound called apigenin, which is found in fruits and vegetables, and thought to be a safe molecule, improved development in a mouse model of Down syndrome.

So, we fed the male and the female mouse in the cage, and at the time they were mated, we mixed apigenin into the chow. So, we treated the mice from the time they were conceived. There was a lot of improvement—it wasn’t perfect, but the benefits clearly outweighed any disadvantages. So, the vision for the future would be you have a pregnant woman. She now knows through testing that her fetus has Down syndrome. She would like to do anything possible for that baby, eventually. So, she comes to us. She would've had an amniocentesis. We would have the cells, the amniocytes, from that fetus. Those are used to make the diagnosis of Down syndrome, but we could also use them to test different compounds that are in our little virtual pharmacy that we know work and we know are safe, and then, we find the best one, based on cells from that fetus. And then, we prescribe the medication for the pregnant woman and hope for improved outcome.

>> Diego (interview): Yeah, that’s great. Well now, I did want to ask about something that is quite literally connected to the mother and the baby. And that’s the placenta. NICHD has invested $91 million dollars into the Human Plancenta project. Can you tell me what you hope to find and how it came to be?

>> Dr. Bianchi: Yeah, so it was before my time. So, it was really the brainchild of the previous NICHD director, Dr. Alan Guttmacher, who felt that there was a need to be able to study the placenta in real time and noninvasively, because you can see a placenta, you can examine a placenta. They're easily available in the delivery room. But by the time the baby's delivered, it's too late to intervene. So, the idea was if you could study it in real time during pregnancy, you might be able to improve prenatal care.

>> Diego (interview): So, the earlier the intervention, the better.

>> Dr. Bianchi: Absolutely. You know the human placenta is a fascinating organ that replaces the functioning of many other organs during fetal life. You know, your endocrine system, your lungs, your digestive system, etc., and yet, it's tossed out at the time of delivery. But it's also the barrier between the mother and the fetus. So, it has an immune component, as well. And we’ve been very interested in it recently because of COVID. You know, why is it that there doesn't seem to be vertical transmission of the SARS-CoV-2 virus to the fetus in most cases? And it’s probably because the ACE-2 receptor is not expressed in the placenta. But the placenta is also a very vascular organ, and there certainly are ACE2 receptors in the blood vessels. So, we do see evidence of damage in the blood vessels of the placenta, and that may have long-term consequences for the babies whose mothers got COVID during pregnancy.

>> Diego (interview): Yeah, well, now that we're kind of talking about NICHD and the hat that you wear as its director, I know you guys have kind of crafted a new strategic plan in 2020. So, can you tell me what the new goals and objectives and themes are behind it?

>> Dr. Bianchi: Yes, so, you know, a lot of people think that we only fund research on child health because of our name, and in fact, we only fund 18% of research across NIH on child health. Virtually every institute and center has some research on going in child health. So, that's one thing to recognize, and then, we have a very big portfolio in reproductive health, and we also house the National Center for Medical Rehabilitation Research. So, how to bring all of those areas together was a challenge that involved hundreds of people, and it was also our first strategic plan in 20 years. So, during that whole process, we came up with a new mission statement, a new vision statement, and really gave our communities, as well as our internal staff, the opportunity to shape the vision for the future. And fundamentally, it broke down into five themes. We started with 270, but we got it down to five, and they involve human development, basically, reproductive health for both women and men, because we also have a $30 million portfolio in male reproductive health and contraception, which people don’t think about.

And then a whole theme on pregnancy as a marker for lifelong health. So, if you think about it pregnancy is a stress test for a woman. It's also a time when she's interacting a lot with the healthcare profession. So, if you get hypertension during pregnancy, you're much more likely to become hypertensive later on in life. And similarly with type-2 diabetes. So, we call it a stress test, and it's a great opportunity, because women, at the time of pregnancy, are very interested in improving their health. Whether it's maintaining a healthy weight or exercising more, it's just a time where there's a lot of curiosity about one's body and what's happening there, to really change health habits. So, that was the third theme. The fourth theme really encompassed all child health but also emphasized adolescence and the transition to adulthood.

We across NIH there wasn't a lot of emphasis on adolescence, and there's such an important transition going on at that time, and also, for children with chronic diseases. It's a very difficult thing to navigate, to go from your safe space where you have a healthcare team that knows you, that's taking care of you for many, many years, and then move to adult medicine, where nobody knows you. So, there's a lot of research that needs to be there.

And then, the last thing was, how do we develop drugs and devices for specific use in our populations? So, whether it is developing devices that appropriate for children or pregnant women or people with disabilities. Or studying how drugs are metabolized in a pregnant woman is very different from a non-pregnant woman. That was fifth theme. So, it was a huge amount of work. It was an amazing group of people who participated in it, but it really gave us a framework for the future.

>> Diego (interview): Yeah, it seems like such an expansive range of themes, but the fact that you guys have identified them, and are trying to tackle them, it's very admirable.

>> Dr. Bianchi: Well, thank you. I want to give credit to all of the people both, again, from NICHD, from other institutes, and our external consultants, who helped us pull it together.

>> Diego (interview): Great. Well, with that, I want to thank you for your time today.

>> Dr. Bianchi: Excellent. Well thank you for inviting me. It was a great pleasure.