Mink, Ivory, & a Disease Discovered Backwards

In the second part of this programme: the story that scientists from the USA’s National Institutes of Health have discovered a new disease. It’s a rare autoimmune condition, where your own immune system gets too aggressive and starts attacking parts of your body, often to devastating effect. It’s called VEXAS, and the story of its discovery is pretty surprising. Phil Sansom heard from the NIH’s Dan Kastner...

Dan - VEXAS is a fascinating disorder that was recently discovered by a brilliant physician scientist fellow working in my research laboratory, David Beck. And just as an overview, VEXAS is a disorder that we see in middle-aged to elderly men, only men, at least so far, that is characterised by a number of interesting clinical features - recurrent unexplained fevers, pustular lesions of the skin, inflammation of the cartilage in their ears or in their nose, or sometimes in the trachea. And if it's in the trachea, the trachea could actually collapse and lead to the person's smothering, so that's a terrible thing that can happen. Inflammation of the blood vessels. Sometimes an inflammation in the lungs that can lead to a severe respiratory problem. It is a disorder that unfortunately, patients who have it oftentimes are treated with many different anti-inflammatory medications without a beneficial effect. And most of the patients that we see with this disease actually are on high doses of steroids. And even then, oftentimes, they can be quite ill. So this is a very serious disease and a disease where, at least amongst the series of 25 patients that we first characterised, 40% of those men have succumbed to their illness.

Phil - There’s a lot of overlap, with these symptoms, between VEXAS and other inflammatory conditions; after all, inflammation is a huge part of the body’s immune defenses. But you can’t treat these properly if you don’t know the cause. Investigators like Dan are often trying to find genetic mutations that cause specific syndromes, or that are part of a complex web of causes… and with many patients they hit a brick wall. The NIH had thousands of such undiagnosed people. Enter researcher David Beck.

Dan - The way in which the good Dr Beck discovered Vexas is really extraordinary. We had a clinic of patients who have undiagnosed inflammatory diseases. And so David asked the question, how can we find other genes that might be causative in the patients for whom we don't have an explanation? And the usual way that one would do it would be to group together subsets of patients, according to their clinical manifestations, you might take a group of patients that have a certain kind of arthritis and group them together. And then for each group, you would try looking at their genome to find something in common that could explain their illness. Instead of taking that approach he said, well, you know, we've done that before, and we've already sort of exhausted that approach. I'm going to turn the paradigm on its head. I'm going to do things backwards. I'm going to start with a list of genes, see whether or not I can find a common thread that could tie together some subset of patients amongst our undiagnosed patients. And after applying this approach, there were three middle aged men who actually had a misspelling in a particular gene called UBA1, and they all have the misspelling at the same place.

Phil - All three men seemed to be heterozygous for this mutation - they had one normal copy of UBA1, and one messed-up copy.

Dan - The thing that was curious about all this, these were three middle aged men, and they had mutations in a gene that's encoded on the X chromosome. And it looked like they had two different copies of this gene, one normal copy, and one that was the mutant copy. Now, if you have been paying attention to me you know that there's something wrong with this story because of course, men only have, usually, one X chromosome. What's going on here? How can that be?

Phil - According to Dan there are three possible explanations. Firstly, the machine made three identical mistakes. Unlikely, but possible. Secondly, that the three patients were males with two X chromosomes - again possible. But the unusual insight here was realising that there’s a third option. Maybe this mutation in UBA1 didn’t appear in these men at conception, or even early during development. Maybe it’s what called a somatic mutation, a mutation that happened in these men’s adult bodies. Specifically, in their blood.

Dan - These are mutations that arise just in a particular subset of white blood cells, which of course are the cells that are responsible for inflammation. Rather than just thinking it was a mistake, instead David said, maybe what's going on is that this actually is a somatic mutation where a subset of the cells in the blood have the mutation and a subset of the cells don't have the mutation. And that would give you the same kind of a picture where it looks like one normal copy and one mutant copy of the gene.

Phil - Some of this type of white blood cell had the normal UBA1. And some of them had the mutation. The gene sequencing shows you both versions, and so you assume, all of the cells have them both. Except in this case, the researchers guessed that wasn’t true - and turned out to be right.

Phil - They’re really on the hunt now. Where have these mutated cells come from? Well, white blood cells like these are born out of precursor cells. And when Dan went after the precursor cells, the story took another twist.

Dan - It is fact stranger than fiction. We went to the haematopathologist. We were looking at the precursor cells in these patients' bone marrow. And Dr Calvo, the haematopathologist told us, well, you know, there are these funny looking bubble-like structures in the precursor cells in the bone marrow, they're called vacuoles. And all three of these men have these vacuoles. And she was saying, well, you know, I've seen this somewhere before. A few days later, we came back to the haematopathology lab and Dr Calvo was there waiting for us. And very ceremoniously she presented to us two reports. And she said, here Dan, these are reports of your patients from eight years ago, who had these vacuoles. You guys should go back and check this gene and see if those patients have mutations in this gene too. So we did. And sure enough, she was right. These patients from eight years ago had the same mutation. As we started to expand the spectrum, it turns out that in fact, we could find 25 patients.

Phil - They now have 50 patients and counting with VEXAS, which I can now confidently explain, stands for the five key characteristics of the condition. V for vacuoles; E for E1-ligase, which is related to the gene UBA1; X for X-linked, the gene being on the X chromosome; A for autoinflammatory; and S for somatic, because it’s a somatic mutation. I know, I know - let’s just stick with VEXAS, why don’t we.

Phil - The story of VEXAS holds an important lesson for the investigators looking for rare diseases. Sometimes - not always - it helps to start the hunt in the genes.

Dan - This approach is sometimes called the genotype first approach, and this is really the first vindication of this approach in inflammatory diseases. Now, the other big take home message from this is that in fact, these mutations are mutations that are only seen in a subset of white blood cells and where we infer that these mutations probably arose later on in life. And this sort of expands the concept, if you will, of somatic mutation - of mutation that arises in cells in the body. We have known for a long time that somatic mutations can give rise to cancer. But what this new disease Vexas is teaching us is that somatic mutations can sometimes give rise to adult onset inflammatory disease. So that's really an important take home message and leads us to believe that probably there are other adult onset inflammatory diseases out there that maybe, could be, discovered by this genotype first approach. And then the third take home message is the devilishly clever insight that in fact, when one sees two versions of a gene on the X chromosome in a male, it may be mosaicism rather than a sequencing error. And this is going to revolutionise the way that we look at genes that are encoded on the X chromosome in terms of their mutational profile.

Phil - Which is all very well for the future of research, but a nothing conclusion if I’m one of those living with VEXAS. I might have inflamed blood vessels, lungs, cartilage, throat… can Dan help me out?

Dan - Is there anything that we can do for our patients now that we know what's going on? It just so happens that actually one of the patients eventually underwent a bone marrow transplant and the bone marrow transplant has been very effective in controlling his clinical picture. And so this suggests to us that perhaps bone marrow transplantation, at least under some circumstances, may be helpful.