Peter K. Gregersen, MD
The ROSE Study: Improving clinical care by finding the cause
Patient Awareness Day
The Lifecycle of Endometriosis: From Diagnosis to Coping with Disease
Sunday April 17, 2016
Lenox Hill Hospital, Einhorn Auditorium
I am a rheumatologist by clinical training and I knew virtually nothing about endometriosis until three years ago when Tamer Seckin came to my lab and said, “You should be interested in this”. We spent a couple of hours together.
I went to Columbia Med School, pretty good med school, and I learned virtually nothing about this disease, of course it was a while ago. But I just started thinking about it and I had been working on the genetics of autoimmune disorders for the last three decades and we have discovered a lot of genes and we are now figuring out how they work. One of the things that was intriguing to me about this was not only was the problem completely understudied, but there is clearly a huge genetic component. And that has yielded insights in disease into mechanisms for autoimmune diseases and there is no reason why it should not happen for endometriosis.
I am talking here, representing our group, which is Margaret DeFranco who is in the audience, and we have a new person starting with us, Mushmoom Khan. We now have a full-time MD-PhD student working on this problem, and of course Tamer Seckin has been critical in facilitating all of this.
Endometriosis, like all the diseases that we are interested in that are complicated, cardiovascular disease, autoimmune disease and cancer, it is genetically complex. Right now we know there are about ten genetic loci involved in endometriosis and that is based on studies of 10,000 people. I can tell you we have defined 100 genes that are involved in rheumatory arthritis, we had to study 70,000 people and each time we learned more new things. Some of those genes are rare but very, very informative about what is going on with the disease. There is a poster child of rare genetic variance leading to therapies and that is a gene called PCSK9 that is associated with low cholesterol. There are now three drugs that just came out in late 2015 to treat cholesterol based on that observation ten years ago. And that gene variant only occurs in a few percent of Hispanic populations. If you can find the gene and you can figure out the mechanism it can lead directly to diagnostics and drugs.
There is a lot more to do with just general mapping but there is huge opportunity to look at large families with endometriosis. Very little has been done. This has got to come from you, the community to identify yourselves as being members of these large families because those large families are going to have a whole myriad of genetic reasons why it is running in the family. It is not going to be just one gene that explains that. And your family could have the variant that really explains mechanism. It is very important to do that.
The other thing we need to do is we need to identify measurable things, biologic things that go with the disease. It was mentioned here several times there are no blood tests, there are no diagnostics. You have to do a laparoscopy to find the disease, otherwise you cannot diagnose it.
This whole problem of the genetic complexity of diseases and their heterogeneity is the central problem for all of biomedical research. We need to bring endometriosis into that mix. We think about the factors with genotype, genetic variance and environment and there is an element of chance with all of this. We can talk about all of those things impact on complex genetic traits, complex human traits; physical appearance, your IQ, your personality, we know these things are really, really strongly heritable. But in the case of IQ people have studied 30,000 people with different IQs – no genes have arisen – that is because there are probably thousands of genes and each one has very little effect. These are very complex problems but the example of our immune disease shows that you can actually find genes if you get large enough populations and you think creatively about what you are finding.
The way that we now think about mapping for disease is not to map on the whole disease, which is really complicated, even with Noemie’s help we may not be able to get subsets that we can map on. We need to find simple, measurable traits that actually are involved in causing the disease, and once you have that relationship you can actually figure out mechanism. And mechanism leads you to diagnostics and therapy.
When I first heard about endometriosis and this retrograde menstruation idea I said “well there must be something about the cells that are in the endometrium that are different and how are we going to look at those?” Well, there is a woman named Linda Giudice who was mentioned here who is a fantastic researcher at UCSF who has examined the endometrial lining of the uterus and shown a lot of genetic variation. But you cannot go around biopsying the uterus of thousands of people. What we are doing is collecting menstrual effluent. And we are doing that because that is the likely source of cells that are initiating these lesions. As far as I know there is no one else in the United States doing this. There are people in the Middle East actually that are doing this and finding differences. What we want to do is find those differences, relate them to genetic factors and relate them to the presence of disease.
We do that by collecting menstrual effluent in a Diva Cup, which perhaps you know of, this allows collection in large populations, we can get these samples overnight they are stable with overnight shipping. We have spent the last two years characterizing the cellular diversity of these samples and one of the things that we found, just in the last month or two, is that the stem cells that Tamer mentioned that were discussed, there actually seemed to be two types of cells that have stem-like properties and they look very different under the microscope. If you take any menstrual effluent and put it in culture you will get cells that look like those on the left. But it is clear that some people have cells that look like those on the left and some that look like those on the right; they sort of look like stromal mesenchymal cells and epithelial cells. There are publications in mouse showing that if you take cell lines of these two types and put them into the peritoneum of immune-deficient mice you will get endometriosis. We actually think that somehow the genetics is regulating the quality of these cells, what they do, what is the relationship? Do they turn into each other? Do people with endometriosis have different amounts of these different cell types? Do they behave differently with people with different genetic risk factors even though they do not have endometriosis? Do they talk to each other? Do they turn into each other? And are they present, the analogues of these cells, in lesions? We are about to start with Tamer to look at these lesions, at surgery, and from people who have given us menstrual effluent beforehand and try to relate those two phenotypes to each other.
But the beauty of this is it is a really rich source of material that you can collect in populations, not just in 20 or 30 people with disease. This is the kind of thing we have been doing in autoimmunity for a while. Really the most important ingredient for this is collaboration. This cannot be done by me sitting in my lab. It cannot be done by Tamer doing his fantastic surgery, it needs patients, clinicians, research nurses, data scientists like Noemie, clinical scientists and basic scientists to all come together and collect the data that we need and study, in this case, menstrual effluent. We will start looking at blood but that is likely to be less informative I think than looking at the cells that are actually, probably initiating these lesions. We started the ROSE study, the Research Outsmarts Endometriosis, Margaret DeFranco is in the audience. Call this number (516-562-ENDO ) and tell us your story and give us some menstrual effluent.
Thank you very much.