The Connection Between Rare Disease Research and Treatments for Common Diseases - Dr. Jules Berman, Pathologist and Author

Michael Carrese: Hi everybody, I'm Michael Carrese. Regular listeners to Raise the Line have heard many times that research into rare diseases should matter to everybody because it's led to treatments for much more common conditions that have improved and saved millions of lives, and statins is usually our prime example of that. Well, today we're going to get into much more detail on this point with someone who literally wrote the book on the subject: Dr. Jules Berman. His 2014 book published by Elsevier, Rare Diseases and Orphan Drugs, Keys to Understanding and Treating the Common Diseases, shows that much of what we now know about common diseases has been achieved by studying rare diseases, and therefore, accelerating progress in the field of rare diseases will lead to yet more advances affecting common conditions. 

By way of background, Dr. Berman served for many years as the chief of Anatomic Pathology at

the Veterans Administration Medical Center in Baltimore, Maryland. He later transferred to the U.S. National Cancer Institute as program director for Pathology Informatics in the Cancer Diagnosis program. He is a past president of the Association for Pathology Informatics, has authored more than 100 science articles and written twenty books of medical interest.  Currently, he's a full-time freelance author. Thank you so much for being with us today. 

Dr. Jules Berman: I'm very pleased to be here, Michael. 

Michael Carrese: So, we always start with learning more about our guests and what first got them interested in medicine, and in your case, anatomic pathology and cytopathology. So how did you end up on that path? 

Dr. Jules Berman: I was always interested in pathology. I went into medical school specifically to become a pathologist later on. Pathology is a lot of fun. You get to solve problems. It's like being a detective every day and I got into pathology during the golden age, when anatomic pathologists could do everything. You could do brain biopsies one minute and then go on and look at hematology slides, dermatology slides, and do autopsies and have his finger in every pie. It was a lot of fun. 

Michael Carrese: And at what point did that scope get constricted and why? 

Dr. Jules Berman: Well, it's turning out, and it's reasonably so, that patients do better when their pathologists specialize in a certain area so that they really know exactly how to handle the kinds of specific specimens that come in. So, if you were having a brain biopsy done you might prefer to have it done by a neuropathologist rather than a general pathologist, and things have gotten specialized that way. I sort of saw that coming and my interests veered off to computers and informatics and using large databases. So, I sort of went off and did that for the remainder of my career in the government. 

Michael Carrese: How did you first get interested in the area of rare diseases to the point where you ended up writing this book that I mentioned?

Dr. Jules Berman: Well, rare diseases basically are the home turf of pathologists. Pathologists are always trying to collect the rare diseases, and that's where they get their expertise. So, it came naturally to a pathologist to want to study rare diseases. But I always felt as though rare diseases were the key to understanding the common diseases, because the rare diseases were like, in my way of thinking, the purest form of disease and they would develop phenotypes -- that is, clinical expressions -- which tended to obscure their origin because there are only a certain number of ways that the human body can manifest the disease. It was obvious to me that many common diseases actually were hiding rare diseases and I wanted to understand the mechanisms of pathogenesis, where you could start off with something rare and go through a number of cellular processes that would lead to a very common phenotype. Just the idea of pathogenesis kept coming up again and again. 

You know, it's something that every med student is taught in their sophomore year, pathogenesis of disease, which is diseases developed through a sequence of events over time. They're not just a thing that happens. The rare diseases have a pathogenesis which begins differently from that of common diseases, but which converges very often to the same phenotype as common diseases. When you understand the steps that occur over time, leading to that converged phenotype, you can often come up with ways of treating or preventing the common diseases and coming up with treatments that are effective against both rare diseases and common diseases, and that was my keen interest.  

Michael Carrese: Give us an example of that. What's a condition that comes to mind that would illustrate that?  

Dr. Jules Berman: Well, of the sort of hidden rare diseases in the common diseases, I mean, it's again, it's what you're always taught in your medical classes to look out for. So, you know, cirrhosis is extremely common in the population, especially the population that have alcohol abuse issues. But even though cirrhosis is common, a certain number of those conditions are going to be caused by hemochromatosis, which is a rare disease. Emphysema is very common, but a certain percentage of those cases are going to be caused by Alpha-1 antitrypsin deficiency.You can mention almost every common disease and you'll find that there's a variant, which is a rare disease. Even hypertension. A certain percentage of people within a general population with hypertension will be people with Little's disease, which is a sort of hypokalemic type of hypertension. Especially in instances where you have an uncommon type of presentation to a common disease, you're almost always going to find a rare disease. 

One study, which I thought was very clever, was that the team had noticed that they had a number of cases of splenic thromboses, and although to have thromboses in the body is very common, to have them in the spleen is not so common. When they looked at those people and screened them for genetic abnormality, they found that the patients that they had with splenic thrombosis had a JAK - Janus kinase gene mutation. They basically had a rare disease, which is responsible for the splenic thrombosis.

There’s a term, phenocopy, which is a disease which has a non-genetic origin for a disease that is well known to have, in most cases, a genetic origin. An example might be pulmonary alveolar proteinosis. That's a disease that has an origin in a genetic defect in the way that surfactant is handled and that alveoli are cleared in infants. But you can see pulmonary alveolar proteinosis in adults as well. It's seen in many different conditions, including conditions where there is dust. Anything that can cause an amount of debris accumulation in alveoli, which the lung just can't handle well, produces a phenotype of pulmonary alveolar proteinosis. Well, when you study the genetic disease, you find that a treatment for that genetic disease is a macrophage colony stimulating factor which helps people who have infants who have pulmonary alveolar proteinosis on a genetic basis but will also help people who have pulmonary alveolar proteinosis developing because they just have too much clogged material in their alveoli because of exposure to dust.

If you have a rare disease and you think about the phenotype that results from the rare disease, you can often find that same phenotype occurring much more commonly in acquired disease, and the treatment for the rare disease can often help people with the acquired disease. We all know the story of statins that were really first developed for people with a rare hypercholesterolemia, but which is now used on...I hardly know anybody my age who isn't

on a statin. 

Michael Carrese: Including me! 

Dr. Jules Berman: Botox was, I think, originally developed for a type of congenital rare 

Torticollis called wryneck. Well, now it's used for a thousand different things where you need to loosen up muscles. It’s just the way it works.  

Michael Carrese: So, how would you characterize the penetration of this awareness in the medical community?  I mean, are you feeling satisfied that people get this, or are you frustrated that more people don't understand this and it's not more widely integrated, let's say, into medical curricula and so forth and so on? 

Dr. Jules Berman: Very ambivalent because on the one hand I think that the awareness of rare diseases has gone up tremendously in the last decade or so. I mean, I think the NIH in particular

is much, much more aware and willing to give funding to rare disease research than it has been in the past, and of course, the Orphan Drug Act of the FDA has made it much more conducive to get pharmaceutical companies interested in treating rare diseases. But they still very often -- especially in the appeals for funding -- miss the point almost entirely. 

Let's say you're doing research in a very rare disease. The typical approach is to say, “I'm doing rare disease research. Rare disease is very important. On aggregate there are many, many people who suffer from a rare disease, maybe dozens of millions of people just in the United States, so we should fund this research that I want to do on this particular rare disease because of that, and these people, even though there are not many of them who have this disease, they're just as deserving of a treatment as anybody else.” That's sort of been the approach.

I’ll tell you, I consider it to be the wrong approach because they're not studying rare diseases at all. They're studying a disease that happens to be rare, and they're asking for money that's targeted to rare disease research. What they should be doing is saying, “Look, this is a

very rare disease and it involves whatever - immune deficiency, DNA repair deficiency or whatever the class of rare disease it's involving -- and when we learn something about this class of disease and we can start to figure out how to treat people with this rare disease, we will also be learning how that process works in a normal condition and in all disease conditions that have a phenotype that involves that process.” That's the argument that they should be making, and they very seldom make that argument in grant applications. 

Michael Carrese: Why is that, do you think? 

Dr. Jules Berman: Because they're concentrating on that disease, which again, it's a very narrow focus. Everybody, especially I think today, when you're studying to be a researcher, you're so focused on what it is you're researching that you often can't see how your research might affect other areas. You're not looking at the other areas, you're looking at what you're studying. People have to get out of that mindset where they're just looking at a disease. There's almost no such thing as research in a disease.

My career grew up through cancer research. I was actually a staff fellow before I was at NCI, before I had become a working pathologist in Baltimore, and if you were to ask somebody what they were studying at NCI, nobody would have given the name of a disease. They would say, “I'm studying the steps in development of cancer. I'm studying how the basic mechanism of carcinogenesis. I'm studying regression and tumors.” They would be studying an aspect of the biology of cancer. Now when you ask somebody what they're doing, they'll give you the name of a disease, and that's if you're lucky.  

I was actually talking to one guy who was a very respectable data scientist and I asked him what he was doing. He said, “Well, I'm studying…” and he gave me an acronym. I wasn't familiar with the acronym. I won't even say what it is. And I said, “Well, what does that stand for?” He said, “I don't know.” I said, “What do you mean you don't know?” He said, “Well, I'm a data scientist. They give me the data to analyze and it really doesn't make that much difference to me what it is that I'm looking at.” I asked, “You can't even say the name of the disease? Do know what organ it's involved in? No, he doesn't know. 

Michael Carrese: Oh my goodness. Yeah. 

Dr. Jules Berman: That’s a real conversation I had. So, I really do think that people have got to open their minds, widen their vision. Things will get better if they do. 

Michael Carrese: Yes, and sort of connect the dots. Well, it's sort of an echo of the specialization we talked about in pathology at the beginning. I mean, things have become hyper specialized in almost every way in medicine, and part of it is probably the need to publish. You have to find something new to write about and all of that. But anyway, that’s very, very interesting. You also talk about how research into rare diseases can inform prevention strategies for more common diseases. Can you explain more about that?  

Dr. Jules Berman: Well, yes, again, it goes back to the idea of pathogenesis being sequence of events that occur over time. When you start figuring out the pathway of pathogenesis -- what events occur at what time -- every single event becomes an opportunity to stop the progress of the disease. When you start thinking about pathogenesis -- and it's easiest to think about pathogenesis starting with a rare disease because very often a rare disease begins with the root genetic cause that starts everything rolling -- you can start to identify points in the process that converge with those of common diseases and if you can interrupt that point, you don't get a disease. You don't get the rare disease, and you don't get the common disease. 

If you want to look at examples, you can think of rare diseases as being sentinels of the many cases of common diseases. One of the outstanding examples is from the 70s or so, was that of a rare cancer -- angiosarcoma of the liver -- occurring in a bunch of people who worked in different geographic locations, but always had the common denominator of exposure to vinyl chloride. So, vinyl chloride was causing a rare disease, which was angiosarcoma of the liver. But because that rare disease was picked up, you could stop people being exposed to vinyl chloride -- and presumably that same carcinogen can cause other more common diseases -- but you picked it up because you noticed the difference in a rare disease. You can see differences in occurrence in rare diseases that you simply can't see in a general population of disease. If you have something that increases the number of lung cancers by thousands, you don't even notice it because there are so many lung cancers. But when they saw basically a cluster of around six angiosarcomas of the liver, they deduced that there was a carcinogen loose in the environment that was causing cancer. 

Another example, I guess, is the pre-cancers. There are many pre-cancers that are considered to be rare, but every pre-cancer is a step on the way to a more common cancer, and if you figure out what's causing a pre-cancer, you're almost always going to find something which is going to cause a more common cancer. So, by identifying an increase in any particular pre-cancer, which I consider most of them to be rare diseases, you can have a great effect at reducing the incidence of much more common cancers. 

Michael Carrese: This is all making a tremendous amount of sense, even for a non-scientific person like myself. I'm also interested in getting your take on what you see happening in rare disease research, particularly because of the advancements in genetics. You know, we've had quite a few guests on that are speaking in very optimistic ways about phase 2 and phase 3 clinical trials using CRISPR and other sorts of things. What's your take on what’s happening?

Dr. Jules Berman: What's happening is wonderful. The people who are doing this research and using the new methodologies to make more rapid advances are all heroes in the medical world and should be heroes in the world in general. But - and I always have a “but”-- you have to look at it again when you move back a little bit. It's often quoted that there are 7,000 rare diseases. I’ve got to tell you, that number is ridiculously off. There are many, many, many more than 7,000 rare diseases. In fact, in a sense, we're inventing new rare diseases every day through precision medicine. 

You can think of precision medicine as essentially a machine for making rare diseases because the way it works is that you find a subset of a disease -- and the subset is all characterized by a specific marker, very often a genetic marker -- then they try to find a treatment for that subset of disease so that they could find a new sort of tailored treatment for a subset of disease picked up by precision medicine that will respond to a drug. But what they're really doing is picking out a rare disease from the common disease. It's just that the disease doesn't have a name, it just has a biomarker when precision medicine is working correctly. You can think of it as being a machine for making more rare diseases. 

There are so many rare diseases and very often, the rare infectious diseases are not counted. The rare environmental diseases are not counted. The rare diseases of unknown origin are not counted. If I said that there were 50,000 rare diseases, I don't think anybody could prove that that's an exaggeration. 

So, when you look at all the advances that people are making, they're making them as one-offs. Even though they're heroes and they're doing something great, it's not going to make a dent because there are too many rare diseases. It's not the right approach. The approach that I want, and the one that I wrote extensively about in my book, is to come up with a really good biological classification of diseases that essentially create related classes based on pathogenesis, so that when you have a discovery within a class of diseases, you can apply it to all the other diseases in the class. Then, you can make some really good numeric progress in coming up with treatments for diseases because then you're not just treating a one-off, you're using the one-off to find general rules for treating a class.  

Michael Carrese: As you know, Osmosis is a medical education company and one of the things we like to do is have our guests give us some direction because we like filling knowledge gaps, we like busting myths. Aside from all the other things you've mentioned already, which have been quite illuminating, is there another topic that you wish medical students and providers understood that you don't think they do right now, and you would say, “Osmosis, could you make a video about that, please?” 

Dr. Jules Berman: I guess if I were asking Osmosis to make a video, I would ask for a video on how to write an NIH grant for rare diseases. Maybe another one on instruction on how to apply for orphan drug developmental status from the FDA. Just practical things. I think that people are sort of lost in knowing how to start these projects. You've had a number of people, as I've listened to them, who've come on and told their story of how they've managed to move from nothing to coming up with potential cures for rare disease. But I think you need somebody who knows how these things best work to describe the general method for applying for a successful grant: the key things you want to include in a grant application for rare diseases, who to contact at NIH to get some guidance while you're developing your grant, and for orphan disease development status, who to talk to at the FDA. I think those would be very useful for the kinds of people who watch the Osmosis videos.  

Michael Carrese: That's a terrific idea. This is a reality once you get out in the world. NIH is so important for funding things, so that's a terrific idea. We just have a minute or so left, and we also like to get our guests to provide some advice broadly to the learners and early career professionals in our audience about how to approach their careers. What are some lessons learned in the path that you have taken that you think would be valuable for them?  

Dr. Jules Berman: Well, I'll tell you what is very seldom said, which is very obvious and I wish that more people would say it, and that is that you've got to read books. It's amazing to me. I know in the field of Pathology Informatics, which I spent many years in after I was at NIH, people just don't read books. They go to meetings, and they don't have a really good perspective of a narrative idea of a field or a problem. You get that from reading books, especially books, not to toot my own horn, but single author books where the author has picked up sort of a theme and developed a narrative story for that theme. There's really nothing like it, and the people that I know who read books like that are standout. They're different from people who don't read books. They have a much richer perspective on what they're doing and what's happening in their field. So, I would just say, you know, go out, find some books, read them. 

Michael Carrese: Yeah, and get some help connecting the dots in this incredibly complicated field, right? 

Dr. Jules Berman: Yeah.  

Michael Carrese: Well, that's terrific advice and a good point to end on. I want to thank you so much again, Dr. Berman, for taking the time to be with us today.  

Dr. Jules Berman: It was a great pleasure and thank you very much for having me.

Michael Carrese: I'm Michael Carrese. We want to thank you for checking out today's show and remember to do your part to raise the line and strengthen the healthcare system. We're all in this together.