Jeffrey Whitsett, MD - phaware® interview 561

Cracking the Code: How Genetics Is Rewriting Neonatal Medicine

Dr. Jeffrey Whitsett reflects on five decades in neonatal care, tracing the evolution from limited support for preemies to today’s cutting-edge genetic discoveries. Discover how rare gene mutations like TBX4 are reshaping our understanding of lung development and why collaboration with families is key to the next era of life-saving treatments.

I’m Jeffrey Whitsett. I’m a neonatologist at Children’s Hospital Medical Center. I am the Director of the Perinatal Institute. I’ve been there 50 years, taking care of newborns since I walked into a neonatal intensive care unit, even before there were neonatal intensive care units. We take care of about 28,000 babies every year. So, I’ve had an incredible opportunity to see over the years the change in care that’s resulted in the survival of infants, in our understanding of how the lung works, how the pulmonary vasculature works, what leads to pulmonary hypertension, and have treated hundreds and hundreds of babies, and also have been able to follow the course in our whole region of the babies who need critical care for their pulmonary disorders.
 
I started neonatology with Virginia Apgar in Columbia University, walked into the unit first in 1969. We were unable to support babies on ventilators if they had hypoxemia. All we were able to do was give them oxygen. We would struggle to feed them and to keep them from getting infections. Our losses were, in today’s view, extraordinary. It was the application, the understanding of how the lung worked, physiology and nutrition, and care of infants’ skin and temperature control that allowed us to support premature babies through a very, very difficult time.
 
As we got better and better at that, we were able to support babies who had malformations, and stabilize them enough to do surgery, and recognized that many of the babies who had struggled for oxygenation didn’t have respiratory distress syndrome, but had abnormalities in their pulmonary vascular system that led to hypoxemia. No matter what we did, no matter how much oxygen, or learned how to ventilate them, we couldn’t support them to get enough oxygen into the rest of their body.
 
Then, in the last 20 or 30 years, there’s been a revolution in understanding how the pulmonary vasculature works. We’ve developed medications that allow us to treat babies who have pulmonary hypertension. These have developed rapidly with nitric oxide, with various vasodilators that didn’t exist when I started neonatology. They were discovered and used in adults, and then applied in children. It’s allowed us to stabilize, and treat, and bring home babies who otherwise would fail the neonatal transition.
 
Fine-tuning of nursing, of intensive care of machinery, learning the physiology, learning the pharmacology, and learning how the lung develops all together have been able to support babies that now go home that that didn’t survive in the past. 
 
It is so rewarding to see children go home, to see families restored, to have their hopes fulfilled. The most amazing thing is how resilient babies are. If one takes care of all the details around that bedside, these babies go home and they live 70 or 80 years. Babies that I could never take care of 30 or 40 years ago are now going home and living full lives.
 
We still have mysteries. We have genetic disorders and things we just don’t understand. Idiopathic we call it. Understanding the genes, and processes, and environmental factors that lead to respiratory failure and pulmonary hypertension are really, as we understand each of the problems, giving us opportunities to solve them. We have a long way to go, and the application of science to the children is really going to inform how the lung works throughout our life. What we learn in the lessons we learned from neonatal, formation of the lung and perinatal adaptation to air breathing, is informing how the lung repairs after COVID, or influenza, or pneumonia. Learning across the life span will allow us to treat better and take care of our patients better across their life span.
 
I work really closely with TBX4Life. It’s only been active for about maybe three years, from a family, Anton Morkin, who has a child with pulmonary hypertension. He has grabbed us with his vigor, and enthusiasm, and ardor. Together, we have almost 60 people who meet regularly; scientists, clinicians, to solve the problems of TBX4 and other genetic disorders that lead to pulmonary hypertension.
 
We’re realizing that many of the children who really can’t be ushered through that critical window after birth actually have mutations in genes that we use to understand how the whole lung forms and how it works. We’re understanding how genes work to make cells function in the right way. We know those pathways, and those lead to drugs and to new therapies that will allow us to correct some of these abnormalities.
 
It’s this marriage of genetics, cell biology, and clinical medicine, that partnership that is really fueling advances that we could never have anticipated. The technology we use in the last 10 years I couldn’t have dreamed about when I started my career. So, I have great hope that using this understanding and the technology, and depending on working with families and working with their children, informs us of the physiology and the medical issues that they face, and allows us then to apply their experiences to the challenges we have to help them get new drugs or new therapies that will get them through.
 
So, working with patients and families. We need samples. We need biomarkers. We need their histories. We need to know what happens. Do they get worse when they get an infection? Are some medications able to help? Which ones work? Which ones don’t? So, we need careful clinical cohorts with data throughout their lives to understand where there are opportunities for therapy and optimizing their outcomes.
 
I think as an attending physician, you’re leading a whole team, which includes the family around the bedside. My job is to know all the people on that team, their skills, their understanding, and to make sure we’re all communicating, that everyone’s paying attention to every detail around that bedside, to make sure that we have every opportunity to have that child go home to their family.
 
It’s absolutely clear that families love their children the moment before they’re born, well before they’re born. We bond with that family. Yet at the same time, one has to be clear in thinking and mechanically accurate in everything we do around that bedside. But at the same time, understanding the emotions and the feelings that are going around the bedside, to make sure that everyone’s supported. Because if you don’t support everyone, the baby won’t be supported and he won’t go home. It’s emotional. But when you’re doing it, you’re as clear as a bell. So, you can only be emotional after you go home.
 
I trained in New York with a great old Irish nurse, who said, “Doctor, don’t touch the baby. He’ll be fine in the morning.” So, you learn to trust everybody on your team, and gently listen to them, and have them correct you. At the same time, if you’re not understanding what’s in front of you, like, “Go to bed, Dr. Whitsett. Things will be better if you just don’t touch the baby.”
 
The goals are really to understand the whole lifespan of TBX4, or FOXF1, or BPD, or idiopathic pulmonary hypertension, what happens in the life course, and the relationships between pulmonary formation and all the cells that have to be in the right place and at the right time are orchestrated by a symphony of chemicals really, compounds, proteins that make sure every cell is in the right number, in the right place, and doing its right thing. Detailed molecular studies, and genetic studies, cellular studies of how those cells interact give us targets for pharmaceutical development. 
 
If I have a pulmonary artery that’s too clenched, and not letting blood flow through, and I understand what normally happens to which cells [that are] sending them messages to open it up, and have good blood flow and grow right… If I understand those, someday we can put them back in. We can put the gene back in. We can put the protein back in. Even cellular-based therapies.
 
These are very early days, but we have technology that we couldn’t have dreamed about. So, we need to harness that technology in a focused way to make sure that we can recapitulate the normal process of development, to help children who have challenges in that pathway make it through the difficult times in life and get them to have a full life.
 
Most of the babies we talked about at this meeting would not have survived in my intensive care unit, in spite of everything we could do, meticulous care, would not have survived. As I was walking out, I was talking to the young folks that were showing how monitoring heart output and pulmonary vascular remodeling are occurring right in the clinic, and saying, “None of the babies you’ve sent home I could send home when I was training 50 years ago, or teaching 30 years ago.”
 
There’s been a revolution in care because we know those details now and we can help transition kids through. Now, it’s our need to understand the kids we can’t get through, and learn from them. We will get better and we’ll get them through someday. That’s the hope. That’s why we do research.
 
I’m Jeffrey Whitsett, a neonatologist in Cincinnati, Ohio, and I’m aware that my patients are rare.

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