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#204 - 🔬 At The Bench - Understanding Neonatal Brain Injury with Dr. Donna Ferriero





Hello Friends 👋

In this episode of “At the Bench” in the Incubator podcast family, Dr. Donna Ferrero discusses her work on therapeutic hypothermia and neonatal brain injuries. She explains the development and implementation of therapeutic hypothermia as a treatment for brain injuries in newborns. Dr. Ferrero also explores the signaling pathways and early markers that can help identify patients who will respond well to hypothermia. She discusses the use of erythropoietin (EPO) and the results of the HEAL trial. Additionally, Dr. Ferrero highlights the importance of genetic variants and sex-specific differences in understanding and treating brain injuries. She also emphasizes the need for a multi-omics approach to better comprehend the complexity of brain injuries and develop personalized interventions. We also delve into the future of care for hypoxia ischemia and the importance of collaboration and career development for physician scientists. The value of collaboration with international researchers and the benefits of visiting other institutions and labs are highlighted. Tips for effective collaboration and overcoming challenges in career development are provided, along with insights into the role of leadership in advancing the field.

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Short Bio: Donna Ferriero, MD MS is a Distinguished Professor of Neurology and Pediatrics at UCSF. She is also a member of the Biomedical Sciences Graduate Program and the Weill Institute for Neurosciences. Dr. Ferriero is Director of the Neonatal Brain Disorder Laboratories and co-director of the Newborn Brain Research Institute at UCSF.  Her laboratory has been critical in defining the relationship of selectively vulnerable populations of neural cells during maturation-dependent injury. She received the UCSF Chancellor’s Award for the Advancement of Women and the Maureen Andrew Mentor Award from the Society for Pediatric Research. She is Past-President of the Child Neurology Society and the American Pediatric Society. She is the recipient of the 2000 Sydney Carter Award for excellence and leadership in Child Neurology, and was elected to the National Academy of Medicine in 2005. She received the Royer Award for Excellence in Academic Neurology in 2007 and the Willis Lecture for outstanding contributions to stroke research in 2010. She was elected to the Association of American Physicians in 2011 and to the American Academy of Arts and Sciences in 2013.


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Some featured manuscripts highlighting work by Dr. Ferriero: 

Wu YW, Comstock BA, Gonzalez FF, Mayock DE, Goodman AM, Maitre NL, Chang T, Van Meurs KP, Lampland AL, Bendel-Stenzel E, Mathur AM, Wu TW, Riley D, Mietzsch U, Chalak L, Flibotte J, Weitkamp JH, Ahmad KA, Yanowitz TD, Baserga M, Poindexter BB, Rogers EE, Lowe JR, Kuban KCK, O'Shea TM, Wisnowski JL, McKinstry RC, Bluml S, Bonifacio S, Benninger KL, Rao R, Smyser CD, Sokol GM, Merhar S, Schreiber MD, Glass HC, Heagerty PJ, Juul SE; HEAL Consortium. Trial of Erythropoietin for Hypoxic-Ischemic Encephalopathy in Newborns. N Engl J Med. 2022 Jul 14;387(2):148-159. doi: 10.1056/NEJMoa2119660. PMID: 35830641; PMCID: PMC10542745.

 

Ferriero DM, Fullerton HJ, Bernard TJ, Billinghurst L, Daniels SR, DeBaun MR, deVeber G, Ichord RN, Jordan LC, Massicotte P, Meldau J, Roach ES, Smith ER; American Heart Association Stroke Council and Council on Cardiovascular and Stroke Nursing. Management of Stroke in Neonates and Children: A Scientific Statement From the American Heart Association/American Stroke Association. Stroke. 2019 Mar;50(3):e51-e96. doi: 10.1161/STR.0000000000000183. PMID: 30686119.

 

Novak I, Morgan C, Adde L, Blackman J, Boyd RN, Brunstrom-Hernandez J, Cioni G, Damiano D, Darrah J, Eliasson AC, de Vries LS, Einspieler C, Fahey M, Fehlings D, Ferriero DM, Fetters L, Fiori S, Forssberg H, Gordon AM, Greaves S, Guzzetta A, Hadders-Algra M, Harbourne R, Kakooza-Mwesige A, Karlsson P, Krumlinde-Sundholm L, Latal B, Loughran-Fowlds A, Maitre N, McIntyre S, Noritz G, Pennington L, Romeo DM, Shepherd R, Spittle AJ, Thornton M, Valentine J, Walker K, White R, Badawi N. Early, Accurate Diagnosis and Early Intervention in Cerebral Palsy: Advances in Diagnosis and Treatment. JAMA Pediatr. 2017 Sep 1;171(9):897-907. doi: 10.1001/jamapediatrics.2017.1689.

 

Semple BD, Blomgren K, Gimlin K, Ferriero DM, Noble-Haeusslein LJ. Brain development in rodents and humans: Identifying benchmarks of maturation and vulnerability to injury across species. Prog Neurobiol. 2013 Jul-Aug;106-107:1-16. doi: 10.1016/j.pneurobio.2013.04.001. Epub 2013 Apr 11. PMID: 23583307; PMCID: PMC3737272.

 

Gluckman PD, Wyatt JS, Azzopardi D, Ballard R, Edwards AD, Ferriero DM, Polin RA, Robertson CM, Thoresen M, Whitelaw A, Gunn AJ. Selective head cooling with mild systemic hypothermia after neonatal encephalopathy: multicentre randomised trial. Lancet. 2005 Feb 19-25;365(9460):663-70. doi: 10.1016/S0140-6736(05)17946-X. PMID: 15721471.

 

Ferriero DM. Neonatal brain injury. N Engl J Med. 2004 Nov 4;351(19):1985-95. doi: 10.1056/NEJMra041996. PMID: 15525724.


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The transcript of today's episode can be found below 👇


Welcome back. This is the At the Bench podcast of The Incubator, where we are incubating discoveries. I'm David McCully. I'm a neonatologist at the University of California in San Diego in Rady Children's Hospital. Today I'm excited to continue with our show where we are trying to highlight people who are doing cutting edge physician scientist work related to neonatal health.

 

I'll be co-hosting today's program with Dr. Betsy Crouch.

 

Betsy Crouch (00:52.138)

Yes, thank you, David. Yes, I'm thrilled to be here today. I'm Betsy Crouch. I'm one of the hosts for this At the Bench podcast and the Incubator podcast network. I'm also a physician scientist and a neonatologist; my lab studies vascular stem cells in the developing brain and spinal cord. I'm thrilled today to introduce our guest, Dr. Donna Ferriero, who is a distinguished professor of pediatrics and neurology at UCSF. Dr. Ferriero is the director of the Neonatal Brain Disorders Laboratories, and she's the former co-director of the Newborn Brain Research Institute at UCSF. Her laboratory has been critical in defining the relationship of selectively vulnerable populations of neural cells during maturation-dependent injury. For her incredible achievements, she received the UCSF Chancellor's Award for the Advancement of Women and the Maureen Andrew Mentor Award from the Society for Pediatric Research. She's the past president of the Child Neurology Society and the American Pediatric Society. She is also the recipient of the 2000 Sydney Carter Award for Excellence in Leadership in Child Neurology, and she was elected to the National Academy of Medicine in 2005. She received the Royal Award for Excellence in Academic Neurology in 2007, the Willis Lecture for Outstanding Contributions to Stroke Research in 2010, and she was elected to the Association of American Physicians in 2011 and to the American Academy of Arts and Sciences in 2013. Now on a personal note, as a physician who works in the NICU with Dr. Ferriero, she couples all of these accolades with kindness and humor. I've been mentored by Donna since-I was trying to figure it out exactly, but about 2014, so about 10 years. And every time I run into her, I almost feel badly, but there's some situation where I need to ask her advice. Clinical, research, career direction, grants management, even recently, I needed her help to be admitted to a highly relevant and selective conference. Her advice is welcoming, but also direct and always efficient. To say she is a role model for many of us physician scientists at UCSF is to call Taylor Swift a singer.

 

Donna Ferriero (03:16.501)

Thank you.

 

Betsy Crouch (03:16.606)

It's a dramatic understatement, but sometimes we don't have words to convey the respect, admiration, and gratitude for a mentor. And so I get to say these things to you now.

So thank you for joining us. We're excited to talk to you. And we've previewed our discussion a little bit. Let’s just jump right into it. Dr. Ferriero, you are such a leader in the field of therapeutic hypothermia and neonatal brain injuries. I spent the morning reading through some of your publications, going back 20 years and reliving.

 

David (03:27.143)

Nice.

 

Betsy Crouch (03:53.438)

What must have been such an exciting time as that was coming online? But I'd love to hear from your perspective, how you thought about therapeutic hypothermia initially when the animal studies were performed and then going into the clinical trials around 2000, 2004.

 

Donna Ferriero (04:13.413)

Okay, well, Betsy, thank you for that very kind introduction. I think that's the only time I'll ever be mentioned with Taylor Swift.

 

David (04:24.196)

Hahaha.

 

Betsy Crouch (04:24.909)

I enjoyed that piece as well.

 

Donna Ferriero (04:29.309)

So let's get to therapeutic hypothermia. All the credit goes to Alistair Gunn and his mother who developed the sheep studies that really outlined, determined everything about it, the physiological variables, the temperature, when to do it, how long to do it, et cetera. And from those beautiful studies came two major clinical trials, the TOBY trial, which was total body hypothermia, and the COOLCAP trial, which was just using the head cooling method, which we picked up at UCSF. It was a great opportunity to, that was really my first foray into

really detailed neonatal research. I had done a little dipping in clinical research, looking at outcomes in cocaine exposed babies, but really this was a big study, big challenge. And from that came at least five RCTs that all determined that there was a decreased risk of neurodevelopmental death and disability favoring hypothermia. Then it became standard of care. We instituted UCSF in 2006, along with our new program in brain-focused care, which we call the NICN, Neurologic Intensive Care Nursery, David Rowich and I got that, kicked that off and it became the first in the world. And now there are many throughout the world. I'm so happy to say it's, I think that's probably the greatest thing David and I accomplished together, getting nurses, neonatologists, neurologists focused on the brain and not just the heart and the lungs and the kidneys.

 

So, but the question remained, what therapeutic hypothermia was really doing? And that's where I headed back to the lab to try to figure out what were the signaling pathways that might be important in determining how the brain responds. So I've focused on HIF, hypoxia-inducible factor, which is a wonderful transcriptional factor that is responsible for preconditioning protection in animal models. And also in perinatal stroke and neonatal hypoxia, ischemia, improved outcomes. And also I was interested in trying to figure out if there were other early markers aside from MRI that could point to who might need additional therapy because I figured eventually we're gonna come up with adjuvant therapy to hypothermia. I call it “cocktails and ice.” So we, about eight to 10 years ago, we applied for an R35, successfully obtained that nice a year grant to look at, use hyperpolarized MR spectroscopy.

 

Betsy Crouch (07:58.689)

I love that.

 

David (07:59.699)

Mm-hmm.

 

Donna Ferriero (08:17.277)

to measure the conversion of pyruvate to lactate and to see if we could identify through that conversion and through the use of MRI and behavioral studies, who responds to hypothermia. And we're still...

 

struggling to get that paper out because people don't understand the methodology and we're not doing a good job of making it clear but we will get that published. But we do have signals that occur early that tell us who will be a good responder versus a bad responder which then allows you to move to the next step and decide what to give to that poor responder. We thought EPO, we spent a lot of time studying EPO in the lab, in the rat stroke model, in the mouse, with hypothermia, without hypothermia. Unfortunately, even though EPO increased neurogenesis and oligogenesis, it did not prove to be efficacious in human clinical trial. That's Yvonne Wu's outstanding work, the HEAL trial.

 

Could we stay there for a minute and talk a little? I was curious, you know, your reflections on the HEAL trial.

 

Donna Ferriero (09:43.673)

Yeah, yeah, I have very strong feelings, actually. I think, and Yvonne knows, so it won't be a surprise. I give her all the credit in the world for executing the most beautifully conducted study, probably the best ever in neonatal population.

 

Betsy Crouch (09:48.131)

Oh, please, please share.

 

Donna Ferriero (10:07.945)

But my feeling has always been that EPO is a repair hormone, not a compound that is best used early, like against oxidative stress or early cell death or inflammation. So I think you negate the effects of hypothermia if you give EPO. They kind of cancel each other out if you give it too early.

 

Betsy Crouch (10:26.582)

Hmm.

 

Donna Ferriero (10:37.145)

So I have always felt, and Fernando Gonzalez and I have done studies in animals where we've waited a week and given the EPO and shown protection at that stage with increased neurogenesis and oligodendrogenesis... Yeah, so I think if the HEAL trial, which we'll never be able to recreate, had started giving EPO late...

 

Betsy Crouch (10:54.242)

That's fascinating. Yeah.

 

Donna Ferriero (11:05.841)

we might have seen benefit.

 

Betsy Crouch (11:08.982)

Yeah, I've had good discussions with Dr. Fernando Gonzalez, our new division chief at UCSF, I think, as of next month, but also a neonatal physician scientist who will definitely come on the at-the-bench segment in the future for his work as, let's say, growing up scientifically under your mentorship and then really flourishing in the world of neonatal stroke research. But he was also a co-investigator for that trial. And something that he said,

 

Donna Ferriero (11:13.777)

Yes.

 

Betsy Crouch (11:40.55)

which I've really thought a lot about since that point as well, is that giving EPO in the context of that acute injury, he said, however you looked at that data, the babies who got EPO did worse. And so there was definitely something, in fact, not even protective about EPO, but detrimental about giving it.

 

Donna Ferriero (11:56.329)

Yeah.

 

Betsy Crouch (12:05.126)

And as you know, as a person who's also interested in the intersections of neurogenesis and angiogenesis, it's very inspirational for me that we need to know the molecular mechanism and we need to know how these different cells are talking to one another and the time course. And as you alluded to, we need biomarkers, right? To be able to say like, this is the pathogenesis of this interaction at this time point, and that's when it needs to be intervened on.

 

Donna Ferriero (12:33.147)

Mm-hmm.

 

David (12:34.16)

And also to help distinguish the patients, I think that's one of the things you're alluding to is, which are the patients that are going to be responders versus non-responders? Is there a molecular signature that helps to identify them fairly early on where they may be the best candidates for another mechanism of treatment? I think that point was also really important that you were making.

 

Donna Ferriero (12:57.425)

Mm-hmm. Yeah, and I think we're almost there. We do have tools like a planal proton spectroscopy, where we can measure thalamic lactate, for example, which is a great biomarker for outcome. So we could look at that and say, oh, OK, this is correlating very nicely with good outcome. Let's let this patient do well with hypothermia and let's focus future efforts on the ones who don’t respond to current therapy.

 

Betsy Crouch (13:32.622)

So your vision would be something like, or this would be one scenario, is that we would do the therapeutic hypothermia as we're currently doing. And then at the five-ish day MRI, obtain an MRI with, you know, obtain scans with these kind of more precise metabolic and anatomic measurements, and then be able from there to risk stratify into, for example, who should get EPO.

 

Donna Ferriero (14:01.473)

Exactly. Or other drugs. There are a whole host of drugs like melatonin, for example, which is safe and can be given to kids. And other drugs that may be down the pipeline. We haven't mentioned stem cells yet, but that's potential. We know we've done studies since where we can give the stem cells in the nose. The stem cells don't engraft, but they're just these little factories that provide necessary products that aid repair. And in all of those studies, we gave them late.

 

David (14:50.992)

Yeah, that's really interesting. I think especially just thinking about the timing, as you're really alluding to here, is really important. I think one of the things that's just really inspiring about your work in general is how you've gone so many times between a clinical scenario, studying it in a research environment, and then coming back to the clinical scenario and applying it.

 

One of the things that we've emphasized in our early interviews is just how the diseases that we tend to study are really heterogeneous and how in order to do a clinical study, it's important to have a large number of patients. But the challenge is that the patients develop their clinical scenario through so many wide range of potential mechanisms.

 

And so therefore, it's sometimes very difficult to figure out which are the patients that are benefiting from this therapy and which are the ones where there's maybe increased risk or no benefit and how better to treat them. One of the things I was noticing in some of your recent work is the idea of modulating the immune system, that there's a important interaction between the immune system and the developing blood vessels in the brain and things like that. And I wondered if again there you're thinking of how to subcategorize the patients or is that a way of dividing them or a way of potentially identifying a new approach to treat them?

 

Donna Ferriero (16:29.557)

See again, I think it's timing. Timing is critical because Xena Vexler has beautifully shown that if you eliminate microglia early, you'll make the stroke worse. So you have to try to figure out who's playing and when they're up at bat because you just can't do this blanket shotgun approach.

 

Donna Ferriero (16:58.825)

For example, suppressing inflammation because we know that some inflammation's good. It's getting rid of cargo and cells that are detrimental to the brain.

 

David (17:18.911)

That's great. One thing I was just wondering, as you were talking, like the timing of these things is just such a challenge as well. Like it takes, you know, so long to develop an animal model. And now there's so much more emphasis on studying human tissue to be able to understand mechanisms of disease. I was wondering if you could talk just a little bit about how you're thinking about that. I mean...

 

I use animal models and I use genetic models in mice to do my work, but a major criticism is that it takes so long to develop a genetic model in mice of the disease I study. How are you thinking about, as you're trying to identify new ways of intervening in newborns with brain injury, how you are thinking about doing this more and more quickly using more human-oriented studies?

 

Donna Ferriero (18:14.821)

Yeah, I think, so I think about in two ways. First, I think about the clinical side where we can look at the MRI and decide what's happening. Like take, for example, stroke. On day one, you might see a little diffusion change, but that stroke evolves over at least a week. So we need to figure out what's happening over that course of time.

 

The best way we can do that, I think, is to try to get a hold of, I think many people have benefited from Eric Huang's brain bank, neuropathology brain bank, including Betsy, where you can actually study tissue. The problem with that is it's dead tissue, we need to try to figure out how to exploit living. And that's where maybe human organoids might come into play to study how cells interact as they develop. So I think it's very critically important.

 

David (19:28.544)

That's great.

 

Betsy Crouch (19:32.158)

Yeah, I could jump back in here. We've alluded to it a little bit, but I think I wanted to, it's funny, I was rereading the therapeutic hypothermia literature and really fascinated by the kind of the biphasic or like the classic diagram that now everybody shows who talks about therapeutic hypothermia in your 2004 New England Journal about neonatal brain injuries. And I think, you know, working from that framework, I guess one question that is foundational that I'm missing is, why does it work to cool? Who had the idea that for secondary energy failure specifically? You said previously it was Alastair Gunn.

 

Donna Ferriero (20:34.197)

I think they were looking at ways to suppress metabolism. And they looked at the cardiac literature. You know, people have been doing this in humans since the 1920s, 1950s. I don't know when it first started packing babies in ice and doing open heart surgery and realizing that those kids did better. And so the simplistic view in my mind is that everything kind of shuts down. And we know that when you cool a brain, protein synthesis really comes to almost a complete stop except for cold stress proteins. So we're now looking at those cold stress proteins to see if they somehow, their upregulation somehow correlates with spectroscopy with the cold stress with outcome in the animals to see if that might play out beneficially.

 

Betsy Crouch (21:52.498)

Great, okay, so just to be clear, that cold stress protein upregulation would be protective in some way. What do those cold stress proteins do?

 

Donna Ferriero (22:08.118)

Yeah, it's unclear exactly, but it has, they have multiple effects. They affect inflammation. They work through ERK. They basically provide energy where energy is lacking. So they have a number of functions and there are a couple of important ones like RBM and MP that are probably key modulators.

 

Betsy Crouch (22:43.794)

Yeah, thank you. I'm just putting this together, but it's like all the folks who are now studying hibernation and these different states. What is the process that fish, the African killifish, goes through? Anne Brunet's lab studies this at Stanford. But there's this process where there's this species of African killifish that can, as it's going through development, just pause.

 

Donna Ferriero (22:49.452)

Mm-hmm.

 

Betsy Crouch (23:12.406)

Like just absolutely take a break, shut everything down, and then resume without any problems within six to 12 months. And evolutionarily, they think that this came about because in this area of Africa where the fish is from, they can go through severe droughts where the fish needs to sort of like revert back to, you know, a state, like almost like a spore like state that can survive.

 

Betsy Crouch (23:42.958)

I think it's helpful for me when I consider like the different ways that we're seeing these systems play out through evolution and how we can borrow through those different systems.

 

Donna Ferriero (23:53.321)

Exactly.

 

David (23:55.152)

Yeah, that kind of comparative biology is really helpful just in terms of understanding like basic mechanisms of survival, but things that we can, you know, learn from and potentially use as therapeutic intervention.

 

Betsy Crouch (23:58.726)

Mm-hmm.

 

David (24:10.556)

I was wondering, one of the things you mentioned recently or that came up in some of the things that you were writing was just sex-specific differences. And I wondered if cold stress response is different between males and females or if the things you're finding in your molecular studies are obviously different between males and females.

 

Donna Ferriero (24:32.389)

Yeah, that's a great question. I don't know the answer to the cold stress signature, but certainly we know clinically and in our animal models, especially with stroke, boys do worse. So why is that? And there are a number of people looking at different pathways trying to figure that out.

 

Betsy Crouch (24:57.686)

Hot topic. David has some good insights on cumulative, would you say cumulative genetic burden, David, and its effect in males and females?

 

David (25:10.772)

Well, that is, I was starting to get to that idea by asking that question. I've been studying congenital diaphragmatic hernia, Donna, and I'm interested in the role the genetic variants play in disease severity and response to different interventions. So it's just interesting, just the publication of the EPO trial and publication in the CDH world of tracheal occlusion and that in some babies there is a benefit to tracheal occlusion, a high-risk fetal intervention. But we're wondering, I think just like you, how can we fine-tune this type of therapy that has significant risk? And we're wondering, is there an underlying series of genetic diagnoses in patients with CDH that would help to predict whether or not they'd be better or worse responders to that type of intervention?

 

I was wondering, you know, males and females is one thing. Looking for individual molecular signatures that help to identify patients that respond to therapeutic hypothermia is another. But I was wondering, you know, are there other things that you think might be underlying how a baby responds to the injury of hypoxia ischemia and that would help to, you know, better even more finely tune their treatment based on their genetic profile? Should we be doing any kind of genomic diagnosis in babies with hypoxia ischemia or what do you think about that?

 

Donna Ferriero (26:48.925)

Well, I like genomic diagnoses for everything because, you know, for years, we, when kids come out and have motor problems, we say have CP and kick them out the door and so many of those kids now are being diagnosed with genetic underpinnings for the cerebral palsy. So cerebral palsy is not a diagnosis. It's just a description of a motor impairment. So I think genetics are incredibly important.

 

Betsy Crouch (27:00.374)

Hmm.

 

Donna Ferriero (27:18.949)

I think the environment from which the fetus comes is incredibly important. Not just the placenta, but the mother. There have been elegant studies using pomegranate juice in moms to show that the babies whose moms drank pomegranate juice ended up doing better.

 

Dave Holtzman's lab actually a long time ago did those experiments in mice, not just prenatal administration but postnatal administration of pomegranate juice. There's also simple things that we do and don't do that probably contribute to recovery. So, you know, 20 years ago, nobody thought about repair. They always only thought about what was happening immediately in trying to stop that immediate cascade. But now we know that there are a number of things that are protective, like good nutrition, for example, and reduction of painful stimuli, which is a big thing in the nursery and can impact severely on brain development. So those things are all layered on top of the injury that the baby experiences.

 

So I like the idea we're starting to feed our babies during therapeutic hypothermia.

 

Betsy Crouch (28:53.954)

Yeah, that's true. Now we are. David, do you do that at UCSD? Do you do a little bit of trophic feeds?

 

David (29:04.12)

Oh yeah, that just happened recently. Yeah, I think that's interesting for sure.

 

Betsy Crouch (29:10.818)

Sorry, Donna. And pomegranate juice? What's the mechanism? Should I be drinking pomegranate juice to promote regeneration of my middle-aged brain?

 

Donna Ferriero (29:21.046)

Yep. Antioxidant therapy.

 

David (29:25.428)

But I like that idea, you're kind of reposing like a multi-omics approach where like, it's not just the genome, it's not, you know, even the proteome, it's like epigenomics, it's everything kind of combined together. Yeah, that are, you know, having a role in the mechanism of injury and disease severity, and, you know, begin to give you an idea of how you could modify things. But it also demonstrates the complexity.

 

David (29:53.872)

It's one thing where you have a series of experiments where you're trying to control every single variable and you can show that this one intervention changes the outcome. But like in a patient where there are so many variables you don't even know about, let alone are you trying to control, makes it so much more difficult to figure out how to intervene and do it successfully.

 

Donna Ferriero (30:14.761)

Right. I mean, look at kangaroo care, for example. You know, who would have thought that just holding a premature baby close to your body, skin to skin, would improve outcome? That's such a simple thing to do.

 

Betsy Crouch (30:32.394)

Oh, I listened to the AAP had this journal club talking about that study, 2021 New England Journal, Kangaroo Care in low and middle income countries. And it was phenomenal. And yeah, I mean, I always want to know exactly what's going on. But just the fact, I mean, I think everybody might have anticipated that it would have improved outcomes. But the reduction in infections, I thought, was,

 

Donna Ferriero (30:59.013)

Yeah. Amazing.

 

Betsy Crouch (31:04.27)

Yeah, yeah, and I'm so curious to know if it's the, is it the microbiome effect and just the decrease in the number of caregivers that you have by doing immediate kangaroo care. Something we'll have to talk about in another episode.

 

Donna Ferriero (31:41.489)

Yeah, I have a grandson who was born at 27 weeks. My daughter-in-law developed HELLP, and the only way to get everybody to survive was to take that little guy out. And they started kangaroo care right away. Fortunately, Terry Ender was his neonatologist down in Irvine.

 

Donna Ferriero (32:04.365)

So he got the best medical care as well as parents who lived in that nursery day and night providing kangaroo care for him.

 

Betsy Crouch (32:15.85)

Yeah, so Dr. Nils Bergman is the, Bergman was the, the neonatologist from Sweden who was on that call, who was just so instructive and yeah, I mean, it was phenomenal what he was talking about how kangaroo care, the babies who did the worst were those who received fewer than 10 hours. 10 hours is a lot. The babies with the best outcomes were the ones who got 20 hours a day of kangaroo care. That is...

 

David (32:45.224)

Remarkable. Yeah.

 

Donna Ferriero (32:45.342)

Yeah.

 

Betsy Crouch (32:45.614)

challenging, I would think. Well, anyway, it just speaks to how you start talking about one topic, and then it can move to another. Do you want to speculate on how kangaroo care is affecting the brain, Donna? No. OK. But I guess I think one of the many things I enjoyed reading was your developmental neuroscience paper from 2022, where you talked about this paradigm of HIE treatment and said treat early and treat again. Is that how you think about the future of care for hypoxia ischemia?

 

Donna Ferriero (33:28.433)

Yeah, I'm thinking of it in terms of multiple, you know, if you go back to that little graph that my daughter drew for that New England Journal article, you think about treating the oxidative stress, excitotoxicity, then treating inflammation in the beginning, middle, and toward the end. And you treat, think about cell death and allowing some to happen and some not to happen.

 

Donna Ferriero (33:56.457)

When to intervene and then you think about repair, which I think is the most important.

 

Betsy Crouch (34:02.346)

Yeah, that's overwhelming and really exciting at the same time.

 

Betsy Crouch (34:15.318)

But how early do you think we should intervene? Do you think in the future we'll have, you know, perinatal or, you know, during the birth process we'll know which babies are in the process of developing HIE?

 

Donna Ferriero (34:35.421)

Yeah, well, I think we've got good data to show that even in utero, we should be thinking about who's at risk and who's showing signs of needing intervention. So just as soon as you recognize that something's going wrong and then tailoring the therapy based on where you are in the developmental cascade.

 

Betsy Crouch (35:01.982)

Yeah, I mean, very good epidemiological work also, you know, looking at babies who are IUGR, babies who have perinatal infection, the controversial role of hypoglycemia. That was Emily Tam under your guidance, right? So, yeah, I think lots of exciting things to come.

 

Donna Ferriero (35:16.881)

Yep.

 

Betsy Crouch (35:26.498)

All right, David, should we go to, I'd love to hear what Donna has to say about kind of physician scientists career development. And I think you had a great question about collaboration specifically.

 

David (35:40.388)

Sure, I can do that. There are so many aspects of your career that are really inspirational, I think, to physician scientists. One of them that we have tried to emphasize here is just the importance of collaboration and career development for physician scientists, but to make our work exciting and highly translational. And I have to say as a trainee and then junior faculty member at UCSF, I was so impressed with the level of collaboration that you were doing, Donna. It really seemed like people were coming from all over the world to be able to work with you. And I didn't know how to begin to think about that, but it just demonstrated to me the importance of collaboration, that people are going to be asking interesting questions in a slightly different way.

 

They're going to be able to answer those questions using different approaches. Can you just talk a little bit about your thinking around collaboration, and how you got started?

 

Donna Ferriero (36:48.373)

Yeah, sure. Well, you know, for me, my career in neonatal brain injuries started out as a collaboration. I was actually in a postdoc studying the development of neurons in the rat retina, you know, miles away from where I ended up and the then chief of neurology at the county, Roger Simon, who was a big stroke person and did a lot of work on looking at an NMDA receptor and excitotoxicity. He said, why don't we do some of this stuff in a baby model?

 

And there started my career in neonatal brain injury. So I owe it to Roger for piquing my interest and it was so much more relevant to where I ended up in terms of neonatal neurology. So it started out as a collaboration.

 

The other thing is people have requested to come work with me from all over. And the benefit of that is you learn from people who have different experiences. Like I've had a number of people, a number of physicians, scientists come from Korea.

 

they do things differently there in terms of care, which makes them think differently experimentally. So Yunsil Chang is an example of that. She's a neonatologist who's done a lot of work with stem cells for lung and brain. And she did our initial work with EPO.

 

Betsy Crouch (38:13.463)

Mm-hmm.

 

Donna Ferriero (38:35.774)

And, you know, I went to visit their nursery way back when and they were taking care of 22 weekers. Or I should say they weren't taking care of 22 weakers. They just stuck them in an incubator and left them alone, which is what we seem to be doing these days in the Grove where we're not handling these babies so much and they have improved outcomes.

 

David (38:50.109)

Exactly.

 

Donna Ferriero (38:58.085)

So I've learned from my different and my trainees. Oh my gosh, you know, I had the joy of having Stephen Miller come do a fellowship with me. And he really opened my eyes to all the imaging data and wealth of information that we had here.

 

And then we've had that Canadian pipeline through the years with Stephen Miller and Hannah Glass and Emily Tam and Dawn Gano and on and on. It's just been fabulous to have all of them. And then close collaboration with people like Linda DeVries and Utrecht, who's a

clinician but really knows how to think scientifically about the problems that we're facing. I’ve enjoyed talking with Doug Gould about Col4A mutations.

 

David (40:29.812)

Can I follow up on that just for a second? I think one of the things you emphasized there was the importance of going to different places and seeing how different people think about different issues. It's one thing to read another group's papers that they publish, and you get an idea about what they're thinking about. But it's also really helpful to go and see what goes on in their NICU, what goes on in the environment that they're working in, or what the lab environment is like to have a really strong collaboration just because there's all these subtle things that go on in each different place that are really important and help to frame your thinking, I think, a little bit more clearly. That's difficult to convey in what you write or even what you might talk about on a show like this. I mean, we get to interview people, but I think it's hard to really get a good sense of what you're actually dealing with in a clinical scenario or in your lab without going there. And sometimes, you know, those sometimes are just like a one day kind of situation where someone just drops in and gets to see, you know, how you set up an experiment. But sometimes it's like a week or sometimes it's several weeks or even longer. But those can be just so helpful for helping you establish a really strong collaboration with a collaborator.

 

Donna Ferriero (41:52.113)

Yes, definitely. I remember going to visit Linda DeVries and following her in clinic where she did everything. She was like the occupational therapist, physical therapist, neurologist, a neonatologist. And I just realized how broad her experience is and how much she could learn by following those babies through childhood.

 

Betsy Crouch (42:25.174)

A lot of our listeners, I would say, are probably early career. And a collaboration can certainly be transformative in all the ways that you've described. Sometimes I've experienced this too, where people tell me to be careful in collaborations. And to be totally honest, I've largely ignored that advice. Because I don't want to do my science fearfully. I want to do my science with a spirit of generosity, which it seems like that's what you've embodied as well. Do you have other tips on how to collaborate, how to best collaborate?

 

Donna Ferriero (42:52.383)

Thank you. I think kind of laying out a game plan at the onset, like trying to figure out what are the questions we're gonna ask, who's doing what, how do we get this written down and who does the writing and just kind of being clear upfront about the roles that different people are playing.

 

Betsy Crouch (43:31.906)

That's great advice. Thank you.

 

Betsy Crouch (43:37.45)

Again, you've been so inspirational to me, but I think what's fun is also to live amongst the group of physician scientists you’ve influenced at UCSF and beyond. David, I think, would consider himself as one of them as well.

 

David (44:05.695)

Yes.

 

Betsy Crouch (44:07.658)

Are you optimistic about the future of pediatric physician scientists? What do you think that we should be doing better?

 

Donna Ferriero (44:16.073)

Oh, absolutely optimistic. You know, it just brings me so much joy watching people flourish in programs that really support physician scientists like the PSDP, for example, which has such a great track record for encouraging people and getting them to the next stage. I think one of the hard things is getting from that K to R transition and not giving up while you're trying to make that transition and trying to look for opportunities that make it a little bit easier during that time period. I think it's just a matter of, you know, it's we've all written.

 

Betsy Crouch (45:21.093)

There's a woman who's a scientist at the University of Colorado, Julie Seigenthaler, who's very helpful on Twitter with what she's going through scientifically. And she recently posted that she had a grant that was not discussed. And she said, well, I find myself in good company. And I thought, that's a winner, right? Right.

 

Donna Ferriero (45:38.065)

Yeah, exactly. Yeah, you can't give up. I mean, I've gone from triage to funding. You know, you just kind of have to get it back. Look at the comments, try to figure out what they didn't like and redo it. Just, you know, swallow your pride. Why didn't they understand this?

 

David (46:06.58)

Donna, can you give an example? I think sometimes that is helpful. Can you think of one scenario where you thought you had really worked out a mechanism or something where you thought it was very clear what you were going to do and it just wasn't received well that you then learned from and had success on the next round or just anything specific that comes to mind?

 

Donna Ferriero (46:33.637)

Yeah, I think I'm trying to think which of the many grants. I think I got into HIF a long time before a lot of other people did. So there wasn't really a big base of understanding around HIF signaling. And the problem was really, I didn't make it clear what question I was asking and how I was going to answer it. So, you know, I had to figure out what I was doing wrong to make it right. Giving your grants to other people to read, of course, is critical.

 

David (47:17.904)

I was going to ask that is like, how did you recognize that limitation and then learn from it? Like, did you get input from someone else or?

 

Donna Ferriero (47:25.921)

I've always gotten input from other folks.

 

Betsy Crouch (47:30.966)

How did you establish those relationships to ask other folks to read your grants?

 

Donna Ferriero (47:35.205)

Well, it depends on what the area is, but my former post-doc mentor, Steve Sager, who I think is a brilliant man, can read anything and tell you, you know, what you're not asking correctly. So I would ask him, he wasn't doing anything with hypoxia and ischemia. He was able to answer my question, “Why am I not getting my point across here?”

 

Donna Ferriero (48:12.133)

So finding people who are critical might hurt your feelings a little bit, but you gotta go up against the wall, I think.

 

David (48:23.652)

Yeah, I really agree. This is definitely a thing that is challenging. I mean, we all want to hear that we're doing great, exciting work and that we're, you know, so smart. But really, they push yourself. You have to, you know, find people that are going to be critical and see where the limitations are, where the flaws in your thinking are, what the unanswered interesting questions are. I mean, that's where you're going to, I think, push things forward. It’s great to hear that from you.

 

Something that's also really inspiring about your career is just how this has, I think, enabled you to be a great leader. I'm just wondering, you've had some really important leadership roles at UCSF and nationally, and I wonder, did you seek those out? How do you think about them? I mean, did they enable you to push the field or?

 

What do you think about them? Would you recommend them or what are the limitations?

 

Donna Ferriero (49:31.969)

The limitations are vast. The leadership in societies was just important to me and of course I wanted to be an integral part of pushing the agenda of our scientific societies, both child neurology at UCSF, I was Vice Dean for Academic Affairs. I had been chair of the Committee on Academic Personnel, so I'd spent a lot of time reviewing files. And I loved faculty development, so I thought I would put my name in the hat for Department Chair. And I got the job, but I didn't realize it was not all about faculty development. There was a lot about faculty misconduct and that part I didn't like very much. I threw my name in the hat kind of late. And one day I was in clinic seeing a patient. I got a call from Sam Hawgood and he said, I'd like you to be the chair. And I said, okay.

 

I liked being chair of pediatrics. As a neurologist, I was kind of an outsider because at that time my home was neurology and I've subsequently moved back to neurology. But I felt like I had things to offer. The department at that time had never had a female chief chair and had very few women division chiefs. I found it appalling that pediatrics had so many women and smart women. So it was really, that was a lot of fun. However, I applied for my R35 and the stipulation of that grant is you have to spend 50% time doing research. So I retired from being chair. To go back to the lab.

 

David (52:03.732)

I mean, I think one of the strengths, I think one of the strengths about being a physician scientist is you just have to be a really good critical thinker and also be able to collaborate. And so naturally those things can lead to an outstanding leadership development. And clearly you've demonstrated your ability to do that. And so thankful that you have done all that you've done.

 

Donna Ferriero (52:32.121)

I'm just bossy, you know, I'm just a bossy person. I like telling people what to do. You're welcome.

 

David (52:41.3)

Thank you for doing it.

 

Betsy Crouch (52:45.002)

Well, and I think just to reinforce your comments on elevating the status of women in the department by taking this role that was really important for us in the department to conceptualize women leaders, we need to see women leaders. And I had this really poignant conversation one time with Carla Pugh.

 

Donna Ferriero (53:02.626)

Exactly.

 

Betsy Crouch (53:09.962)

who's a black woman surgeon scientist at Stanford. And she says, you know, to the extent that we women can stay in academia, we can make an impact. When you leave, it's harder to make an impact. And yeah, I've kind of taken that with me too, but you lived it already.

 

Donna Ferriero (53:21.469)

Mm-hmm.

 

Betsy Crouch (53:30.602)

I feel like we just scratched the surface, but we'll have to leave all of that for another time.

 

Donna Ferriero (53:32.165)

Yes, I've talked your ear off.

 

David (53:34.984)

No, not at all.

 

Donna Ferriero (53:46.421)

Great. Well, good luck to all those young people listening in. It's a wonderful journey. Enjoy every moment of it.

 

David (53:59.06)

Thank you so much, Donna. It was really a pleasure to be able to talk to you.

 

Donna Ferriero (54:02.673)

Yes, David, good to see you again.

 

David (54:04.672)

Great to see you and thanks Betsy for hosting this show, this episode. So we're excited to continue with a series of interviews where we're gonna be highlighting neonatal or neonatology physician scientists and really anyone who's doing research related to newborn health. I think our next episode will feature Krithika Lingapan, who's a lung biologist at the Children's Hospital of Philadelphia and has been studying sex-specific differences in babies with bronchopulmonary dysplasia. So again, I think we'll be able to hit on some of the similar themes that we talked about here today with sex-specific differences and just thinking about mechanisms of disease and tailored approaches to treatment. So thank you all for tuning in to this episode of At the Bench and we'll look forward to talking to you again soon.

 

Betsy Crouch (55:04.155)

Thanks, David. Thanks, Donna. See you all next time.

 

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