by Stav Brown, BS1
1 Sackler School of Medicine at Tel Aviv University, Tel Aviv, Israel
Through interviews with leaders in the field, we present here the second piece in the series “Plastic Surgery Perspectives” dedicated to providing residents and medical students a perspective on future career options and possible fellowships within the field.
This piece includes contributions from Dr. Eric C. Liao.
Why did you choose this specific field of research?
I wanted to choose a research area that aligns with my clinical interests. Clinically I am focused on the repair of congenital cleft and craniofacial anomalies, and I serve as the director of the cleft and craniofacial center at Mass General and Shriners Boston. Since the mid-2000s, the way we identified patients with clefts is commonly from the prenatal ultrasound study. I do all the prenatal consults myself. Not only I do the repairs when these children are born, I wanted to take a step forward to figure out why these malformations happen, since through this understanding you can immediately make an impact both in diagnosis and treatment. Today we can identify congenital anomalies from a blood test, carry out gene sequencing and we can get a genetic understanding of what genetic alterations cause craniofacial anomalies. But often times even if we can find the gene and the mutation we don’t know what these genes do. So today we have personalized medicine and only roughly 10% of the genes in the human genome actually have some functional understanding. So we have a long way to go, to figure eout the function of the 90% of genes in the genome. Further, when we do know the function of genes, we still need to be able to discern when genetic variations in those genes affect protein function in a way to disrupt craniofacial development. To do these studies, we employ human stem cell, mouse or zebrafish models, to find out what those genes do. This is the work our lab is focused on.This is also where we as surgeons have an advantage since we actually have our hands on the patient. I am able to draw the blood, use the specimen and take those cells and make them into stem cells. Those stem cells can grow a whole new person or a whole new animal. This technology is called induced pluripotent stem cells (iPS) and by doing that, we can recreate the human condition, for example a craniofacial anomaly, in a dish and study how these cells behave when we manipulate these genes. This way we can figure out what these genes do. In the future, we will be able to figure out if the baby carries these genes and mutations from a simple blood test.
So how does that render treatment?
Well, we are not quite there yet. However, we can correct these mutations before the embryo is formed or develop screening tests in a dish to prevent the craniofacial anomaly. This sounds like a crazy thing to do but it’s not actually. The most common example is neural tube defects or spina-bifida. Say 20-30 years ago, pediatric surgeons used to fix babies who are born with neural tube defects every week. These procedures are rarely done these days because of prenatal folic acid supplementation that decreases the occurrence of spina bifida. A neural tube defect is an embryonic defect where you have multiple layers of the embryo not formed. Unfortunately, folic acid doesn’t help clefts and people have looked at that. So all the cell and animal models that we are now generating to study gene function, embryos with key mutations and genes that affect clefts or stem cells from humans that have key mutations in genes that control how the middle face is formed, all those assays we can use to screen for drugs to fix the way they behave. And the compounds we screen come from drug libraries that consist of FDA approved drugs. We screen for molecules that can mitigate these craniofacial anomalies in the cell or animal models. The example of a prenatal drug being given to the mother to prevent a severe congenital problem was just recently published two years ago in the New England Journal. We just need to find it for clefts. So that is the pipeline.As a surgeon-scientist, it’s really exciting because not only do you meet the families, take care of the patients but you also fix their problem and along the way you learn a lot of genetics, you learn biology, you learn to train the next generation: students, post-docs, residents to also do that type of work. Sometimes when people think that research is very separate from patient care, especially basic research. I would disagree. I would argue that research is actually the most patient focused in the sense that it enables you to impact patients that you never get to meet, whether it’s clinical research, translational research or fundamental research.
How has this field changed since you started?
One of the big changes that have occurred in technology is gene editing. Knowing the genetic sequences is one thing but being able to change it in a precise way is another. Now we can do it much quicker and in a much more specific way. We need to have models to test the function of genes since we can do the sequencing and we find differences between people, but whether or not this variance is actually significant is a whole different story. For example, we have known about BRCA since the late 1990s. In my adult practice I take care of patients with breast cancer, often I meet patients that had a genetic testing with BRCA, but most often the gene variant is “of unknown significance”. It is of unknown significance because genetically, to tell whether a gene variant is significant for disease, most times it is a statistical argument. Have we looked at this gene variant in a population? The error rate can be high, as high as 50%, like the flip of a coin, basically useless. The best way to do it is to develop an assay, a cell based or animal-based assay to test that functioning gene. However, most gene variants aren’t tested to that rigor.
What are your main interests in your field?
One of the biggest pieces of advice I give to trainees is: within your field you want to tackle the biggest problems. I take care of adults and children. For adults I mostly take care of patients with breast cancer, and I have a clinical research program in breast reconstruction. These days, we’re moving away from autologous reconstruction and favor one-stage prepectoral breast implant reconstruction because it is less invasive and observes the central caveat of plastic surgery, applying the reconstructive ladder. In my pediatric practice, I take care of patients born with orofacial clefts, and I have a fundamental research program that focuses on the genetics and development of facial clefts. Not just understanding this genetically and developmentally, but also try to find drugs that will ameliorate it in certain degree.
Tell us about a clinical case/aspect that has shaped the vision of the field for you.
That’s a great question. In Joseph Murray’s book, “A Surgery of the Soul”, he says: “Progress is made in the intersection of disciplines”, “Surgeons are privileged to be observers of biology”. These are the two concepts in my mind when I take care of children. I am taking care of a family with 13 kids, four of which were born with complex fronto-nasal dysplasia, where they had bilateral Tessier 4 clefts and problems with formation of their eyes. One of the kids has colobomas and others have anophthalmia with extremely shallow orbits, one even has absence of eyelids, exposing the empty orbit. Really very sad. When I started my practice 12 years ago took care of the first patient in this pedigree, the gene sequencing technology was slow and expensive, and I was just starting out, I didn’t have a lab yet. But I knew this case highlights a very interesting biology with a genetic basis. Then about 4 years later this family came back with the second child of this family that had this problem. At this point, science progressed, next generation sequencing is faster, cheaper, and now I have a whole lab, funding, collaborators, and most importantly, great students and fellows in the lab., I was able to fix the kid like I did years ago, but now I am also able to collect the blood to do gene sequencing and figure out what is cause. At that time, my lab was using animal models, however, we didn’t have the expertise with human stem cells yet. Then they had another kid, and this time I was ready. I was able to collect blood from both parents and from the other kids I took care of, induced them into human stem cell models, so now we have all the cells growing in the lab and cell-based models of these complex anomalies. Now we have developed a robust pipeline for additional rare congenital craniofacial conditions, so this type of research translation really made me realize our advantage as a surgeon-scientists.
What role does technology play in your field?
CRISPR-CAS9, gene-editing, parallel sequencing, WGS have been the major technological developments in the past decade. For example, most neonatal units around the world diagnose metabolic disorders through a traditional set of tests to figure out what enzyme is missing. However, in some centers we send the samples off for sequencing in addition to the standard battery of tests. Surprisingly, the sequencing results are so fast, and they actually come back before the regular clinical tests. It’s totally changed the way we take care of patients – for personalized medicine, congenital disorders.
What most excites you when you anticipate the future of the field?
The practice of plastic surgery is very dynamic. In fact, it doesn’t matter what you do as a plastic surgeon, it’s important to realize that change is normal and how to adapt to change. What is exciting for me every day is that not only do we have some of the best experts in clinical surgery and clinical medicine that allows us to collaborate and take on really complex clinical problems. The problem is that sometimes clinicians don’t talk to basic researchers and engineers. As a surgeon-scientist, you are the bridge builders and when you can actually walk in both worlds and talk the talk, that is actually the most fun. People might feel or be told that being a plastic surgeon and a scientist is difficult, but I think it’s the most fun because every day I get to do the coolest things; I get to help babies and their families with their problem, my research coordinator brings the cells into my lab and then that day we can make them into stem cells or sequence them and then we have animal models. Every week I go back and forth between the clinic, the operating room and the lab and get to do these amazing things. I always teach my students that at the beginning they are consumers of knowledge, but very quickly, within a few months in the lab, they become generators of knowledge and figure out the exciting science that nobody knows about.
For a resident interested in incorporating basic science into their clinical career, what advice do you have?
I believe that the best time for doing research during residency is actually at the end. It’s because you need to be strategic in what type of research you do and how to get your funding. The work you do in the lab has a very direct impact on you getting that first grant. If you do research in the middle, you’ll be away from science for a number of years when you finish clinical training and that research is not going to directly lead you to that first grant. Getting that first grant helps you getting that second grant, and so on. If I knew someone who wanted to be a surgeon-scientist, I would teach him how to do research before starting residency and mentor them when they’re residents so that they’re able to do research at the end of residency. At MGH, we are trying to identify people who already want to do research for their careers, then short-track them in 4.5 years and when wen they’re fellows, they do a postdoc and we give them junior faculty awards so that they have some funding to be able to compete more successfully for their first faculty grant.