Six Questions with Immunologist Josh Milner, MD
How did you get your start in rare diseases?
I knew early on that I wanted to be a doctor, and to focus on a narrow slice of medicine and study something rare. I got my start at the National Institutes of Health when I was in high school, and was placed in an immunology lab with people who study rare diseases all day, every day. During the first week it just seemed to me that immunology is the most fundamental science, and that has stuck. One of the things I'm quite interested in is a rare cause for a common disease, and that's really driven my approach to patient care. My process is to go step by step with someone who has a pretty common presentation, but that looks just different enough that you want to determine if there is a way to find an underlying genetic cause.
Is it possible for a single genetic mutation to lead to more than one condition?
Frequently in immunology, the same mutation causes completely different manifestations of disease. Even within a family carrying the same mutation, one person might have severe atopic dermatitis while another has an autoimmune disease and a third has a predilection to infection. It's sometimes hard to sort out the cause because the sibling with autoimmune disease might not get put together with the sibling who gets infections, and they might even see different doctors, since immune conditions cover a huge number of different specialties. Another issue is that you can have one type of disease associated with a genetic mutation that shuts off its function, and another type of disease due to a mutation somewhere else on the same gene that turns it on. Broadly, mutations that shut immune-related genes off make people more susceptible to infections while mutations that turn genes on make them more likely to have inflammatory disease and autoimmunity. So this complicates things, but also creates more opportunities to figure out what is going on in a patient.
How does a common symptom such as atopic dermatitis, or eczema, relate to rare disease genetics.
Depending on the population, you can see atopic dermatitis in one in ten to one in five babies and children. And it can become very severe and highly disruptive—severe atopic dermatitis has a similar impact on quality of life as type one diabetes. We study a number of immune disorders that present with typical atopic dermatitis, but may be accompanied by other more peculiar or rare symptoms. Some however, present only with atopic dermatitis, and an emerging and really interesting line of investigation is beginning to show that rare mutations could make up a meaningful proportion of the common cases of atopic dermatitis. And if someone told me that there is, say, a one in 10 chance of knowing the genetic reason for my child’s condition, I would want to get that test every time. Recent work has shown that this concept bears out in many different immunologic conditions. Ten or 15 years ago no one was thinking about autoimmune and allergic problems this way. That's really changed.
You've done some really inspiring work attaching treatments to some of the genetic variants you’ve studied. Can you share some of those experiences?
Certain mutations in a particular genetic pathway or circuit can rev it up too much, and we may have an inhibitor that could prevent that pathway from being turned up as much as it is. We've worked on a number of disorders that affect how a signal travels from the outside of a cell to the nucleus, where it turns on a program that starts making proteins—including those that create inappropriate inflammation. By identifying these specific diagnoses, we are able to give patients FDA-approved inhibitors that cut the circuit just enough so that the excess activity is controlled, and the end result is rather incredible. There are some people who have multiple inflammatory problems, autoimmune problems, swollen lymph nodes, and if they get the right diagnosis they can be treated. But perhaps even more excitingly, we've now seen a few cases where a patient was diagnosed with, for example, type one diabetes and they happen to get a genetic diagnosis while their pancreas still has some functioning. If they are put on an inhibitor of this pathway they no longer need insulin. These cases are only rare now because patients aren’t commonly tested for a genetic cause, and because the timing doesn't work just right. So it’s still an open question if the first symptom of a rare disease is a common symptom, like those of type one diabetes, if the condition could end up being something that's treatable.
If you are a pediatrician, or feel that you or your child may have a genetic disease, who should you go to?
Over the last number of years, certain conditions that would only have been in the purview of medical genetics have creeped into the practices of others who specialize in a particular genetic disease. These might be specific types of allergists or immunologists, for example. Patients need to see specialists who pay close attention to their particular set of symptoms, and often that is someone who treats that particular organ system and who has a foot in genetics and genetic research, or it could be a geneticist who works with an immunologist who can ask the broad questions and is most able to use all the tools to find a gene.
What does this all mean for patients and families affected by these conditions?
My heart goes out to families who are affected by these conditions. We want to do everything we possibly can to help shorten your diagnostic odysseys, to partner with you as physicians, and to bring find new avenues to help. When someone comes to me with an unknown immunologic problem, I feel their burden, and want to get to the bottom of it. I get extremely frustrated when an answer doesn't come from step one, step two, or step three, of looking into the genetics. And so I'm driven to fight for the resources to solve that problem. It may not always be in my capabilities, and I have to be honest about that, but my goodness, I can't overstate the degree to which that's also something which is on us, not just patients and families.
