A Pediatric Medical Geneticist Shares His Specialty

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SS 215: A Pediatric Medical Geneticist Shares His Specialty

Session 215

This MD/Ph.D. is a Geneticist for kids in an academic setting. Today, we have Dr. Ralph Dubardenis, a Pediatric Genetics Specialist. Ralph is an MD/Ph.D. at UT Southwestern and the chief in the Division of Pediatric Genetics and Metabolism.

To learn more about this specialty, visit the American College of Medical Genetics and Genomics. For more podcast resources to help you with your medical school journey and beyond, check out Meded Media.

Listen to this podcast episode with the player above, or keep reading for the highlights and takeaway points.

[01:13] Interest in Pediatrics and Medical Genetics

Ralph has got a view of internal medicine and pediatrics before going to the laboratory. He decided to do pediatrics right away because he found the diseases to be more interesting based on what he saw during his rotations. And he likes working with kids.

He decided to work on genetics in his Ph.D., not realizing that medical genetics is actually a subspecialty.

When he finished the Ph.D., having spent several years thinking about how a particular type of mutation causes a specific type of phenotype, Ralph did an elective in pediatric genetics and fell in love with it. It was one of his first rotations after coming back out of the laboratory.

Ralph was actually trying to decide between pediatrics and medical genetics and ophthalmology. He liked the latter, but in some ways, they’re opposites of each other. Because Ophthalmology is so highly specialized in one incredibly interesting part of the body, but just one. On the contrary, medical genetics is a very broad specialty.

'Medical genetics is probably the most broad medical specialty of all of them because you work on diseases that can manifest across the lifespan.'Click To Tweet

[03:37] Advances in Research

One of the things that drew Ralph to the field is how rapidly the diagnostic technologies have evolved.

He recalls doing an elective rotation in 1998. At that time, there were only a handful of genes that you could sequence one at a time. In 2000, when he started doing his training, there were different types of FISH (fluorescence in situ hybridization) studies.

They look at parts of the chromosomes that you couldn’t really look at using a standard karyotype. Then over the ensuing 10 or 15 years, it became possible to literally sequence every protein-coding gene in the genome in one fell swoop, called the Whole Exome Sequencing. This has been effectively the standard of care for patients with complex phenotypes. 

And so, from being able to sequence a handful of genes one at a time, to 20,000 all at once is incredibly compelling. Ralph says that if you’re the type of person who really wants to connect a molecular mechanism to a very specific disease phenotype, it’s incredibly exciting.

[05:49] Traits That Lead to Someone Being a Good Medical Geneticist

Ralph stresses the importance of having that love of pathophysiology across multiple organ systems.

Secondly, you have to be a little bit of a detective and be attuned to subtle clues. Because sometimes, the physical manifestations are the symptoms. Things that come out on the physical exam or the history can be quite subtle and nonspecific.

And so, you have to be really good at pattern recognition where you’re taking all those different clues and being able to observe a pattern that arises out of all of them.

You also have to be good at explaining complex concepts simply to people and breaking them down to them so they would understand it.

Finally, you have to have an appreciation for the family. Because to them, the patient is the family, not just the individual patient.

[08:15] The Biggest Myths or Misconceptions About Medical Genetics

One myth, Ralph says, is that they can explain everything. The idea is that if you can sequence a lot of genes, you should be able to find any genetic problem. However, the reality is that many of the pathogenic variants or disease-causing mutations can’t be uncovered by an exome sequence.

That being said, Ralph thinks that many clinicians have this attitude wherein they have a good handle of the disease process. And since they don’t understand this disease and they don’t understand genetics very well, therefore, there must be a genetic condition to this disease. But sometimes, this is not the case.

'There's a misperception that if you diagnose a genetic disease, there must not be a treatment for it.' Click To Tweet

There’s also a misperception that if you diagnose genetic disease, then there must not be a treatment for it. With very rare exceptions, at least in 2021, we can’t correct the gene. But there are many Mendelian diseases where there’s an excellent, if not totally definitive therapy. And that list is going to grow exponentially as more molecular therapies, nucleic acid therapies, gene therapies, etc. become FDA-approved.

[10:31] Crafting His Day in Patient Care and Research

Ralph says that people tell you that when you go through physician-scientist training, there’s this triple threat. You’re going to see patients, teach, and do research. It did for him and he’s grateful for that. But that’s not the case for everybody.

Ralph did a five-year training program. It was a combined program between pediatrics and medical genetics at the Children’s Hospital of Philade

Then he did a year of Pediatrics internship. And then for the next several years, he went back and forth between pediatrics rotations and medical genetics rotations. Then for the last year and a half, he went back into the lab and essentially started an intense, basic science postdoc.

He also served as an attending for a couple of years after finishing his training while still functioning as a postdoctoral research fellow. In 2008, he got his first faculty position at UT Southwestern, where he has been ever since. That’s how he set things up for himself.

For most physician-scientists who want to have a wet lab, doing research, it’s going to end up being an 80/20, split, give or take, – 80% in the lab and 20%, doing clinical care. 

Having been on the faculty for 14 years now, Ralph’s setup has changed. He still has a large, very active research lab. But he has also taken on more administrative, and at times, a little more clinical responsibilities. He built up a significant component of research in his lab around inborn errors of metabolism. These are Mendelian conditions that are caused by mutations in metabolic enzymes.

[13:11] Integrating Clinic and Research

When he became the division chief in 2014, they decided to integrate the clinical activities of the division with the research environment. 

So if any patient that presented to the clinic to be worked up for a Mendelian condition of any kind, including inborn errors of metabolism, could be recruited into a research study. This would allow them to do next-generation sequencing and next-generation metabolic profiling in the patient. They have informatics tools that allow them to integrate the data to really pinpoint where the defect is.

'We've been able to understand a number of Mendelian diseases on a deeper mechanistic level and we've also discovered new diseases.'Click To Tweet

The way things work for Ralph now is that 75% of his time is in the research laboratory, and the other 25% is split between direct clinical care and administrative work. He makes sure that the clinical division is operating efficiently and that the individual doctors in the group are advancing on their own career paths.

[14:44] What Happens When You Lack the Ph.D. and You’re “Just an MD”

Ralph mentions that he had two really important scientific mentors. His Ph.D. advisor is a geneticist who’s one of the most prominent medical geneticists in the country – and he was “just an MD.” He went through medical school, and then he got some research training and became an incredible experimental scientist.

During his postdoc, the mentor he had is now the president and CEO at Memorial Sloan Kettering. He’s one of the most prominent scientists in the country. And again, he was MD trained, not formally Ph.D. trained.

All that being said, Ralph clarifies that what you get out of doing a Ph.D. is formalized training in the experimental method and techniques. But what you don’t get out of doing an MD/Ph.D. is a guaranteed faculty position or a research project necessarily, that is going to be the one that will launch your research career.

While there is value in doing a Ph.D., Ralph knows plenty of people who haven’t done it that way.

'It's a myth to think that you can't go on and become a really top-tier scientist without a Ph.D.'Click To Tweet

The other thing that people sometimes miss, is that if you’re an MD, and you are not primarily a researcher, you can still be engaged in research projects in ways that are very useful and rewarding.

[17:55] Collaboration with MDs

In their study on Mendelian diseases, they have recruited over 1,000 subjects over the years, and he has recruited no more than 10% of them.

The other 90% have been recruited by astute clinicians who are not primarily researchers but have chosen to participate in this project. They’re great at identifying patients that have something that they think they’re not going to be able to figure out with conventional diagnostics.

The other half of his laboratory studies metabolism and tumors. Their clinical collaborators are surgeons and medical oncologists, not primarily researchers. They allow Ralph to go into the operating room and study the metabolism and tumors of these patients directly, which would not have been possible for them to do without these generous clinical colleagues who collaborate.

[19:04] Taking Calls

Ralph says they don’t take in-house calls overnights. In his division, they typically take the service for a week and do consult for that week. They’re usually working with medical genetics residents on the team.

The call will come in, either from one of the inpatient services who have a question about a possible metabolic or genetic condition. Those calls are coming sometimes from outside providers who have a question about one of their outpatients.

'Trying to figure out where among the 20,000 genes that mutation might be, requires a lot of careful literature review.'Click To Tweet

Ralph adds they don’t have any formal inpatient service in genetics. But they take care of a lot of inpatients. 

Kids with inborn errors of metabolism will often show up in the emergency room in a metabolically unbalanced or decompensated state with metabolic acidosis, high ammonia levels, hypoglycemia, etc. And they’ll get admitted into the hospital.

And so, they get admitted into a general Pediatrics service. But then they round on the patient every day, multiple times a day, and make sure that they’re putting them back together metabolically.

[21:12] How Close Are We to Sequencing Everything in Newborn Screening

Ralph wants to clarify that one thing people may not realize about medical genetics is that they are intimately involved with newborn screening, particularly for metabolic diseases.

When the baby is born, a blood test is done usually on day one. The blood test is examined for levels of metabolites that could indicate a treatable inborn error of metabolism.

The goal is to pick these children up before they become symptomatic. They put them into therapy so they don’t get subjected to the severely, metabolically decompensated state that leads to permanent organ damage, particularly, the nervous system.

In terms of how close are we in decoding everything from sequencing, Ralph believes we’re still not that close. 

There’s significance in having genetics together with the metabolic information because it allows for some clarity. As of now, sequencing as a standalone test doesn’t stand up to the metabolic analysis.

'The problem is not detecting sequence differences, the problem is interpreting them.'Click To Tweet

What’s exciting about what’s going to happen in the next 10 years in newborn screening is that the number of diseases on the screen will start to very rapidly increase. There are a lot more diseases that they can test for right now than they can treat in the genetic disease space.

But as more and more molecular therapies come online and get FDA-approved, those diseases now should be added to the newborn screen.

[27:51] The Training Path

'You have to be a researcher, if you want to be a medical geneticist, that's not true. Most of us are straight clinicians.'Click To Tweet

Training in genetics is a residency, not a fellowship. The minimum amount of training is one year in some medical specialty such as internal medicine, pediatrics, or OBGYN.

Then go into a medical genetics residency, which depending on the program, is a minimum of two years and sometimes many programs and another year for a research project.

There are also tailored, combined programs like Ralph did, wherein in a single program, you can become board eligible in both a general specialty – pediatrics and medical genetics, for instance. Those programs weave together training in the two areas.

[30:21] Message to Future Primary Care Physicians

Malformations and multiple different organ systems or developmental defects in multiple different organ systems is something that should trigger the idea of maybe getting a genetics consult.

Ralph feels that taking a really good family history is sometimes a lost art. But in genetics, that is a really important part of the patient encounter.

In the metabolism space, try to recognize signs of an inborn error of metabolism, rather than a metabolic episode that’s more normal. For example, one hypoglycemic episode, as opposed to a metabolic decompensation period would suggest there’s a Mendelian defect.

Lastly, if you have a patient in your practice or in the emergency room, that you think might have an inborn error of metabolism, it could be intimidating to figure out what test to be ordered.

But if every baby that showed up in the emergency room with a hypoglycemic episode got urine ketones, a venous blood gas, and ammonia level, and electrolytes with an anion gap, and blood sugar, you’re going to be more than half the way towards knowing whether the patient has an inborn error.

And if they do, put them in the right category, even before you get into specialized tests. So these are basic things that every medical student, and certainly every pediatrics resident, should know about.

[32:44] The Most and Least Liked Things

Ralph always finds it fascinating that you can have a single change among the billions of base pairs that cause multi-organ system problems. He also loves the fact that if all of the problems in the patient rippled out from this one change in the DNA sequence, it provides insights into the importance of that gene in human physiology.

On the flips side, what he likes the least is the challenge of recruiting patients because there aren’t enough people they can train in the specialty.

[35:10] Final Words of Wisdom

If he had to do it all over again, Ralph would still have chosen the specialty because he loves what he does.

Finally, he wishes to tell students who might be interested in this field to do an elective rotation and you will see interesting cases, even if you ultimately decide that this isn’t something you want to do.


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