Introduction

Dr. Glenn Olah:

Good afternoon. My name is Dr. Glenn Olah and I’m the president of Winn Feline Foundation, so thank you for being here. Before we get started with our speakers, I was going to talk briefly about Winn. I’m probably speaking to the choir a bit about Winn but, first of all, the title of this Symposium is “Cat Tales of Genetics and Behavior,” 38th annual Winn Feline Foundation Symposium, so we’ve been doing it for a while.

So, Winn. Our mission as a nonprofit, we were established in 1968, so we’re coming up on our 50th anniversary in a couple of years, so that’s pretty exciting. We support studies to improve cat health, and we also have a mission that involves education, and people always forget that component of it. We have two missions; to fund research in feline health, as well as to promote education in feline medicine and health. Anyway, we definitely are probably the leader in feline medicine regarding funding research projects and I’d say, in the last 5-8 years, we’ve started collaborating with a lot of other organizations that are like-minded to Winn; organizations like AAFP, American Association of Feline Practitioners, and AVMF and so on. There are a few others. So, the amazing thing to me is the far-reaching impact that Winn has had in feline medicine, and how often I find out that people aren’t aware of this. I mean, these are big things. If you look at something basic, like blood groups, that was determined by Winn funded research. The discovery, in the 1980s, of feline immunodeficiency virus, FIV. One of the big ones is to find out the inadequacies of the feline diets back in the 80s, to find out that they didn’t have enough taurine in their diets, that was a Winn-funded project from Dr. Pion. Measuring blood pressures, you know, it’s about 30% of cats with chronic kidney disease have hypertension, so all those old cats, we should be measuring those blood pressures. Screening tests; the retroviral tests for FeLV, FIV. Showing that early alteration is safe and feasible; let’s say whether it’s the age of the cat, two months old, or let’s say under two pounds, a cat that is actually safe with the right anesthetic protocols, we are able to spay and neuter these cats safely. Diabetes – that’s a big one – diabetes mellitus. The way to really look at diabetes, you don’t think about it this way. Cats are like people – they’re type 2 diabetics, but they become insulin-dependent, because it’s a little bit more advanced by the time the client needs to bring their cats to the veterinarian. The way I would look at it is, the diet, the weight loss, is your primary therapy. The insulin is a secondary therapy so, eventually, you hope to get them off insulin, and then you have a high-protein diet that can keep the diabetes, hopefully, in remission. We funded those studies in the early 2000s. Dr. Reinero at the University of Missouri is looking at asthma and various treatments for asthma, including stem-cell research, which I think is fascinating stuff, so tomorrow morning I’m going to be talking, just briefly, to the Association, and I will mention some of the stem-cell research that we’re funding, in particular regarding stomatitis. I don’t know if you’ve all seen stomatitis, those painful, painful mouths in cats that are really sad because it can be so painful that it can even lead to the point where you decide that euthanasia is humane. Polycystic kidney disease, I think that’s Dr. Lyons. One of the big things that she’s done is identify the gene that is associated with that particular condition, hypertrophic cardiomyopathy in Maine Coon cats. FIP diagnostics. I’ll talk briefly about that as well tomorrow to the Association. A lot of advances have been happening regarding FIP, I’d say in the last, believe it or not, 3-5 years’ timeframe, and we used to say, wow, what about things 10 years ago, there was a big lull, but the reason that things are sort of accelerating, at least partly, is there are two big things that came on the scene in the last 10 years, and that’s SARS and MERS. Those are coronaviruses in humans, and people freaked out about that, and now they’re looking at coronavirus in cats, and all of a sudden, things are really going forward. Just making a plug for Winn, I’m proud to be a part of Winn. There’s a booklet that’s on all the tables. Please take those. There is a lot of information in there. There are goodies. You can learn more things about Winn. I think Vicki, our executive director, is sitting right over here. I think she said she’d put a KitKat in there? [Laughs]

The format of this Symposium is that there are two speakers. I’ll introduce Dr. Lyons in just a second but, in the center of the table, there is a pad and some pens. Write your questions down there and then, at the end of both talks, we’ll have a question and answer period. I think this is more important for any of the veterinarians out there, for the RACE qualification, if you could fill out the evaluation form, that would be very much appreciated, and then, outside this room, one of our board members, Susan Gingrich, she has made these little magnets you can put on your car to promote Winn, and I think she’s selling them for around $10, and that money would go to research funding for Winn, so if you’re interested in them it would be nice if you would check them out, if you didn’t when you walked through the door.

It is my pleasure now to introduce our first speaker, Dr. Leslie Lyons. Let me say a few words about you. Dr. Leslie Lyons is an associate professor at the University of Missouri School of Veterinary Medicine and Surgery. She is originally from Pennsylvania and received her graduate degree from the University of Pittsburgh Graduate School of Public Health, Department of Human Genetics. Both her master’s and doctorate degrees are in human genetics, specializing in both laboratory and data analysis of human disease gene mapping. In the 1990s, while a post-doctorate at the National Cancer Institute, NCI Laboratory Genomic Division, she helped organize the Feline Genome Project. Dr. Lyons developed a feline genetic mapping pedigree using natural mating and assisted reproductive techniques between domestic and Asian leopard cats. She was promoted to a research fellow at the NCI and expanded her interests by initiating population genetics into these gene mapping projects for the domestic cat. After NCI, she joined University of California at Davis and recently moved to the University of Missouri. Dr. Lyons’ laboratory, The Lyons Den’s, major focus is the genetics of the domestic cat, including genetic diseases, inherited diseases, and population diversity. Dr. Lyons’ research laboratory has had success with identifying the genes causing Persian cat polycystic kidney disease, as I’ve already mentioned, Burmese hypokalemia, the Burmese craniofacial defect, several coat traits in the cat, and mutations causing cat blood group B. Each of these mutations can now be used as a genetic test in cats. The Lyons laboratory has been used to confirm the cloned domestic cat and African Wild cat and also the first green fluorescent protein cat. Studies have included the analysis of original cat breeds and the sites of cat domestication, which resulted in a documentary in National Geographic.

Precision medicine is an emerging approach for disease treatment and prevention that takes into account individual variability in genes, environment, and lifestyle. President Obama announced the Precision Medicine Initiative the State of the Union address in 2015. Most medical treatments have been designed for the average patient. Precision medicine gives clinicians tools to better understand the complex mechanism underlying the patient’s health, disease, or condition, and to better predict which treatments will be most effective. Today, Dr. Lyons will discuss the role of precision medicine in the future of feline medicine.

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Beginning of Dr. Leslie Lyons Audio

Dr. Leslie Lyons:

Welcome to Las Vegas! Viva Las Vegas. Anybody seen an Elvis yet or anything like that? The guy in the taxi asked me where I was getting married. I said “Well, I’m not opposed to that, but I don’t think it’s going to be this trip.” I am most pleased to be back here for the Winn Feline Symposium. I’ve done this once before, and now it’s 38 years or so. I actually did some of my homework and counted up how long I’ve been involved with Winn, and so our first grant, when I was at the National Cancer Institute, was I think ’94 or ’96 or so, and so I’m going to walk you through some of that history of us working with Winn Feline Foundation. I have to say that Winn has always been at my side, sponsoring many of our different projects, so we obtained funding from all kinds of different sources; National Geographic, we’re working a lot with pet food companies, Zoetis has made some donations to Winn, and they have made donations to us as well. We also have a give-direct site for our 99 Lives Project, right at University of Missouri, trying to do like a GoFundMe type thing. So, there are lots of ways to support cat research, and the most direct ways are absolutely through the Winn Feline Foundation, so please, continue to support us and help us do good work.

Of course, I study inbred cats. It took me a while to figure out, why are people sending me cats with bread on their heads? Until I realized it was “in-bread” cats. I was just asked when I’m going to retire, and I’m like, “I’m 53, dude. I’m doing alright!” However, I think we will be moving to looking at more things in just random-bred cats as well in the near future, so I’ll end the presentation with some things about that. As mentioned, precision medicine. This is the new buzzword. Every few years, in genetics, there is a new buzzword. It’s nothing different, if you hear the words One Health, that’s all the same as precision medicine. It’s the same as comparative genetics. I started out as comparative geneticist, doing things in a cat that you would normally do in a human, or a mouse, or something like that, but now, everybody has to always come up with a new word. Basically, it does mean we now have the capability, instead of just doing population-based medicine – here, let’s just give everybody warfarin to help reduce blood clots - now we’re finding out that some people don’t respond very well to warfarin, and so now we’re starting to understand why some of our experiments don’t work, or why treatments don’t work, and it’s because of our genetics, and so Obama launched an official initiative. Primarily, we hear about precision medicine when it comes to cancers, because we do know that cancers are really fine-tuned to the type of cancer you have, what kind of receptors are on that cancer, and then, once the cancer maybe escapes remission and comes back, we now actually genome-sequence that tumor to see how the genetics have changed of that tumor, and now what is the new next chemotherapy that we should give to try to battle that cancer, but it can be done with all aspects of our health, and my job is to make precision medicine work for cats.

I thought I would give you some examples, and here’s myself. Has anyone ever heard of 23andMe or you’ve seen Ancestry.com? Well, I did it, and I did it long enough ago that I still get the answers to my health stuff now that they’ve put a little kibosh on that; the FDA went after them and stuff, and I would tease my mom, too, my brother and I would tease my mom and say, “We’re not really your kids,” so she did it as well and, unfortunately, I am the product of my mother, but I am 25% Italian. My mother is half Italian, so I am 25% Italian, so that did work out, and the rest of me is from the UK, basically, so all my father’s side and my mom’s father was Welsh, so that did actually work out. You can also look at this and see how much Neanderthal you are as well. So I’m 2.8%, which is about the average for everybody else, you know, but why you do things like this, it’s not important that I read these diseases to you, but if you’re of Catholic descent, or of any other large ethnic group, strongly, there are certain diseases that are more common in your population, so one of those is Mediterranean fever. When there are four yellow stars, that means it’s a mutation, you know, it’s on or off. It’s a simple genetic trait. They have very high confidence with it, and look at this, I’m very clean, man! I don’t have, really, any genetic traits I need to worry about, so that means I’ve got to start taking better care of myself. I’m ruining myself from the nurture side. I’m getting fat, drinking too much Coke and, where I have good genetics, I should be appreciating that. Beta thalassemia is something that is very common in Italian populations. I don’t have that. Hemochromatosis is also common in Italians and, actually, my mom is a carrier for that. We had no idea, and then, once we did that, we found that she’s a carrier. This one is alpha anti-trypsin deficiency. My dad died of COPD, but at the age of 84, and he smoked Lucky Strikes all his life, so I know, okay, at least I don’t have the gene that gives you risk factors for having COPD, so hopefully I’ll just stay away from cigarettes as much as I can. The more important thing is we’re getting around to looking at a lot of drug sensitivities, and this is where the precision medicine comes in, that if you go in and you’re epileptic, and you need to be given a treatment, they will now genetically test you to see whether that treatment is going to work on you in the first place, instead of trying it for a couple of weeks and figuring out, hey, that didn’t work. One of them that I noticed here, why I first did this, is that I alcohol-flush. When I drink alcohol, I flush. Well, that’s common in Asians, because they don’t have the right alcohol dehydrogenase. I was like, “Okay, is there an Asian in my background somewhere that I don’t know about?” That’s where we got to agitating my mom and stuff. In the end, I don’t have that mutation. What I have is I do not metabolize sulfa very well, so I found this out also, I take a sulfa antibiotic, I get a rash. So what else has sulfa? Sulfites. Alcohol. So wines that have sulfites in them, you’ll see that I’ll immediately flush because I can’t metabolize that sulfa very well. This is where we want to head, and this is where medicine is heading all the time, whether you do it one by one, testing these genetic traits, or whether you send in your blood sample and you do a whole genome sequence, and so that’s where we are now. You do a whole genome sequence, and you find out every variant in your body and stuff, and so you come up with risk factors. One genetic test that we worry about in cats is the hypertrophic cardiomyopathy. That is a risk factor. We’re going to find that most of our genetic traits are actually risk factors. We’ve been knocking off the easy ones to date, the simple on-off traits, but we’re going to find there are more and more, and now I bet you’ve been hearing about genetic mutations conferring risks to FIP, and so it’s time to try to take a look at those in a population-wide study and see if they actually are working or not, and what those risks actually incur, and so we can see that I have a slightly higher risk for venous thrombosis, but I actually don’t need a lot of warfarin to get rid of that, so that’s good.

So, what about cats? The thing you have to remember, comparative medicine, comparative anatomy, comparative genetics, cats and humans all have about the same amount of DNA - 2.80 gigabases. These are the cat chromosomes. They actually look fairly similar to human chromosomes. Dogs look a lot different. We have 18 what we call autosomes, and the XY pair. This is two X’s down here, so this is a female. This is called a karyotype, and all the genes, and we now know there are about 20,000 to 21,000 genes in the mammalian genome. Cats and humans share, basically, all those genes. Where they’ll vary is some immune function genes, olfactory genes. Cats might have an expanded olfactory repertoire compared to humans, but we all have the same genes. The key we are now finding is actually the regulation, and this is actually making things hard, because the things that regulate genes are not in the coding part of the genome, not in the exons of each gene that make the protein. They’re upstream, and they tell the protein turn on, turn off. Turn on at this time, turn off at this time, and that’s really what is making us different, but those mutations are harder to find.

With cats, we could do a 23andMe. In cats, actually, I want to call it 19andMew, which fits well now that I’ve moved to Missouri, which is MU, right, so it all perfectly fits! Most of your coat color genes are actually found. Orange is known, but they’re still doing some work to prove it. Tipped is being worked on, and we’re always still trying to work on silver. Many of your prototypes are known. A couple of other ones are still being worked on by Dr. Gandolfi. She loves the fur type stuff. Several genes are known for structural types. We now have evidence that the Japanese Bobtail has a different mutation than the Manx, but there is something else out there, too, because the American Bobtail and the Toy Bob do not have tails that are caused by the Manx or the Japanese Bobtail mutation, so there’s yet another mutation out there that is causing their tails to be short. In breeds, we know there are about 13 genes with about 15 different mutations that cause diseases that breeders should be monitoring, but there are lots of other diseases that we find in domestic shorthairs as well, and so those mutations are known also.

How have we been finding these genes? When we first started working with the Winn Feline Foundation, we would pick a gene and hope we were right, and that’s called the candidate gene approach, and so we try to look at information from other species, and they give us a clue as to what the possible gene could be for our disease or trait, so that means always, always, whatever I do depends highly on the skill of a veterinarian, so if the veterinarian isn’t doing a good job telling me what the pathology is of a disease, then I’m just lost in the dark, so the better diagnosis I can get, the better I can hone in on this candidate gene approach, so that’s why I’ve loved working at a vet school. It keeps me tuned in with the veterinarians that are learning and creating the new knowledge and also gives us lots of good ties with colleagues around the world to be able to do our studies.

What things have already worked by just a candidate gene approach? Well, the early ones, back in the day, when Henry Baker found the ones for the Korat, the GM1 and GM2. That’s because we knew gangliosidosis in humans. Here we’ve got the exact same presentation in a cat, let’s sequence that gene in the cat, and lo and behold, that’s where the mutations were. Back in the 90s, when the first mutations were being found in cats, that’s what was being done. Gangliosidosis 1 and 2, the mucopolysaccharidosis that University of Pennsylvania works on, porphyrias. This is how we found blood type, and then many of your coat color genes, because all those coat color genes are first found in mice, and then we say “agouti! Let’s go look at the agouti mouse!” and, sure enough, that’s where we find the mutations. It doesn’t work all the time, so notice I don’t have dilution up here. That’s because there are about eight different ways you can make a dilute mouse, and they look the same. They’re blue, they’re grey. You had to actually work through it to figure out which one to look at first and, in the end, it’s melanophilin but, sometimes they work out, and sometimes they don’t. Many of our diseases, one of our most recent ones we found is myotonia congenita, which actually was found in Burmese cats, now that I think about it, out of Canada, and it’s also found, have you heard about fainting goats? That’s what myotonia congenita is. The cats don’t really faint. The goats actually don’t faint, they get stiff, they can’t get their muscles to relax, and so when they get frightened, their muscles contract, they can’t relax, and they kind of fall over. So, just to show you, here is the blood type, so now, actually, we know B blood type, and we know the AB for Ragdolls only, so there’s probably going to be more than one way you can make an AB cat, but it’s very rare. Anyhow, Ragdolls seem to have one of the higher frequencies of it, but that paper just got published by Dr. Gandolfi. It was easy, it was an enzyme in the pathway to put these sugars on the end of your red cells, and so when the Italian student came, and she wanted to work on dog stuff, and I said “Yeah, but you’ve got to work on cat stuff,” she just read the literature and said, “That’s obviously this gene!” and I said “Go for it,” and within eight months, from showing up at the door to the end, we had the blood type mutation. Sometimes it works easy that way.

Other types of studies, we’ve had to do family-based studies. Remember back in the day, I was asking for parents and grandparents, and give me 5 mL of blood from everybody, and we had to keep building up the pedigrees and make them very extended, that was called linkage analysis, a family-based linkage analysis, and it often took a lot of time, because we had to collect all those individuals and stuff, and we had to have hundreds of genetic markers. We didn’t even have genetic markers when I wrote the first grant for the Winn Feline Foundation so, in the meantime, we had to develop those genetic markers, and you really need to know the mode of inheritance as well, and so now you’ll see that we’re starting to be able to get a little washy on our mode of inheritance and still be successful with some of our studies. One of the big ones that worked this way was for polycystic kidney disease at Davis. We had a couple of clinics where we scanned 200 cats at a time and built up the pedigrees, had a pedigree with 100 individuals in it, and we genetically typed the markers, and we can see that one marker is always segregating with the disease, and why did we do it that way? Because there were four different genes known in humans to cause polycystic kidney disease. Why didn’t we just do the candidate gene approach and go after PKD1? Back at that time, we didn’t have a lot of sequence, so it was hard to analyze the sequence in another species, and PKD1 is a really big gene. Actually, all four of these are very big genes, so we could’ve been spending a lot of time just spinning our wheels and, of course, you have to try to do the best approach that you can, or at least the most scientifically sound approach. In the end, we found linkage to PKD1, we sequenced that gene, and we found the mutation for polycystic kidney disease. Other studies that have worked using a family-based approach was both the Abyssinian studies for their inherited blindness, spinal muscular atrophy, that’s in the Maine Coons, and even some of the coat colors were done by linkage studies, but now we’re in the day of case-control studies, and that’s what we’re always talking about now, buccal swabs. There’s enough DNA to do a case-control study, so we’re very happy about that, so just the amount of DNA you can get from a buccal swab. So, if anything, you should always be doing buccal swabs on your cat. Do a buccal swab, put it in a paper envelope, put it in a drawer somewhere. Make sure you mark it very well, which cat that was. When that cat later dies of heart disease, you already have DNA sample on that cat. Every kitten you produce, you should be banking, because, maybe the cat doesn’t get sick; I need a control. So if you have a case, you need a control. A control of an affected individual is their normal sibling, or their normal parent - that’s the perfect control for a case-control study. We don’t need extended pedigrees. We can do things with a lot smaller individuals but, to make up for having less individuals, you have to have more markers. Well, we do have thousands of genetic markers now and, actually, the mode of inheritance you can be a little less sure about that, because you can analyze the data, whether it’s inherited as recessive or dominant or incomplete dominant, so you can play around with the analyses a little bit and get around knowing the mode of the inheritance.

With the case-control studies, prior to being able to do case-control studies, we did all this population study work. You have heard me talk about the breeds, and how genetically distinct they are. Actually, we do know there’s about 8-10 different, what I would call racial populations of cats from around the world. Europe is one of them. Europe is now actually split into the Nordic region and the Iberian Peninsula; cats from Spain and Portugal. Their feral cats now are different from the cats running around the rest of Europe are different a little bit different from the cats of the Nordic region. The cats of the Mediterranean are a little bit different, but the biggest difference is East, Western European versus Southeast Asia. That’s a big, big genetic difference between those cats. We’ve been able to use this, and so when we made our DNA chip, we used these individuals, so these colors mean different groupings of cats. We used this information to help make a very robust DNA chip by picking cats from these different regions. We want good genetic diversity on our DNA chips. We want it to work in all breeds, so these population studies helped us to work on our health studies as well. We’ve gone up to maybe about 30 breeds now, and we didn’t do all breeds, because we knew a lot of breeds would be similar, because they’re just derivatives of one another, and one example is, genetically, one of the first things, when I got involved in the cat fancy was, I got called up to the office in New Jersey, and I was asked, “Is a Persian and an exotic a different breed?” and my answer was, “Whatever you choose it to be is what you choose it to be.” But, genetically, no. Genetically, when there’s only one gene difference; long hair versus short hair, or just a couple of genes’ difference, that is not enough genetic difference for me to detect in any way, so I want to know that, because I want to know, can I use the exotics as controls in my studies of Persians, and the answer is yes. You, whatever you want to do is whatever you want to do, but we are finding that British shorthairs have a lot of Persian in them now as well so, really, I couldn’t tell you the difference between an exotic and a British shorthair, because they’re both short-haired. I can tell the difference between a Persian and an exotic - one ought to have long hair and one shouldn’t – what you do with a long-haired exotic, I don’t know about that. Then Scottish folds have a lot of Persian in them as well, but most of the other breeds, see their different colors, sometimes it doesn’t show up so well, but we know that Burmese, we know that Australian Mist uses Burmese. Havanas are basically just a solid chocolate Siamese, and we know we can pick up the Aussie cat in the Abyssinians, so we know it works quite well on Korats and Birmans are actually quite close to one another, one being long-haired and pointed and one not, but they’re both Southeast Asian cats. We did prove that many cats come from where they say they came from, so the Southeast Asian cats are most closely related to populations of Southeast Asia, such as Korea and Vietnam, and so all the Southeast Asian cats do group down there. This bobtail -see there’s no number on there? That means there’s not a lot of support for the way we drew this evolutionary tree. The Bobtail tends to move around. We now know the mutation. We know it’s the same as the Karelian Bobtails, so we know the bobtail mutation came from the Far East, but it must have some type of a lot of influence from the West, because we can’t place it strongly as a Far Eastern cat, and Menotti-Raymond’s study said basically the same thing, and Abyssinians, they’re kind of in the middle somewhere, so I’m not quite sure where to place an Abyssinian. They’re not Western European, they’re not Southeast Asian, so they’re kind of somewhere in the middle; India, somewhere around there. Most of our breeds, though, do come from Western Europe. The Turkish van, Turkish Angora, Egyptian Mau do tend to cluster with Mediterranean cats as well. Egyptian Maus are not from Egypt but maybe more new ones will be but, historically, they’re actually not from Egypt, so I’m sure people are trying to get them out of Egypt.

This led us to this study, where we said the darker bar is observed heterozygosity, and notice, if we had feral cats on here, it would just be this and higher for feral cats, so I just cut it off to the breeds, and so we can see the breeds that are getting lower, so one of the lowest is the Singapura, and then Burmese is right there with you, and Sokoke, but that really hasn’t established well as a breed. That’s not good, having low heterozygosity. The lighter bar is an inbreeding coefficient, and so you don’t want that high. You want that to be low. If you have low heterozygosity and high inbreeding coefficient, that’s not so good for you. We want to try to push those types of breeds to be thinking about outcrossing programs, and I certainly hope the CFA will help facilitate that and everybody works together to develop rules and regulations that allow that to happen, but this is where we did a study on Korats. It can be done. Korats have pretty good diversity, very low inbreeding, and it’s why? Because they’ve managed their disease genetically. Remember they had the first ones known – gangliosidosis. They have pointed cats they don’t want. They have cats of the wrong color they don’t want, but they’ve always brought in imports, and they’ve always shared their cats around the world. They’re a very low-number breed. Fifty, maybe, per year, and they still have very good genetic diversity, so you can manage your cats properly if you just all work together and do it, and so it might need some outcrossing programs and stuff, but recently the Abyssinians came up, and I didn’t actually realize, just because where they were, yeah, their inbreeding is a little high, and their diversity is a little bit low as well, so now speaking with the Abyssinian breeders about their health program as well.

This is a DNA chip. It’s just about the size of a microscope slide. It’s a little piece of metal, and on there, they imprint 63,000 different little pieces of DNA that are the DNA markers that you are trying to test, and so one chip will have 12 different regions on it, so you can test 12 cats at a time, so now my life is always thinking about 12 cats at a time. I always have to have 12 cats because I can’t re-use this chip, I have to do 12 cats. That’s the instrument. The instrument is no bigger than this table or so. So, now we do our case-control studies on these DNA chips, and the data you get back looks like this. This is what we call a Manhattan plot, because it’s supposed to look like skyscrapers, and what you want is the peak of Dubai. You want to a Dubai tower in your data, and so this was actually the first study we did, it was hypokalemia from the UK in Australian Burmese, and we did very few cats, 35 cases and 25 controls. We tested how low could we go, and we found that we could get as low as using 12 cats, and we would have got a significant…, so you have to test for significance here. This is certainly significant. Every one of these dots is a different DNA marker, and these are all the markers on chromosome 1. Chromosome 2, 3, 4, 5, and so you can see here, boom, that’s where we look, so now you go and look, and now you go back to the candidate gene approach. You know where it lives on the chromosome and where it is, what genes are in that region that affect potassium metabolism. Well, actually, there was one for hyperkalemia in humans called WNK4 so it affected metabolism of potassium but made it go too high, so it’s actually a good gene for analyzing for blood pressure and, sure enough, that’s where we found the mutation. Now, we can do things much quicker, much cheaper. One chip, this analysis, costs about $124 per cat. That doesn’t count the part where you’re actually having to analyze the data and then go look at a gene and the personnel cost, but you can get somewhere pretty quickly in a few thousand dollars now, if you have the cats, if you have the DNA samples, if you have the buccal swabs. Just buccal swab everything!

We also did the Cornish Rex, and so gene on chromosome 1, and this was interesting, because this was only 11 cases. Remember, all Cornish Rex are fixed. Who is my control? I’ve got cases, they’re all fixed for being curly cats. There are no straight-hair Cornish Rexes. That’s where we used our population data, and we found the next closest breed, and one of the next closest breeds, actually, was Peterbald, and so we can genetically look to see who the next closest breed is. We used those as the cases and controls, and we found the mutation in this gene that actually causes humans to have no hair and to have poor dentition as well, so it’s an epidermal dysplasia gene in humans. We all have the same genes, just what that gene does in each individual is a little bit different. We’re still going after many of the rexoid breeds, and Dr. Gandolfi is knocking these off one by one. Our most recent one is, I’ll show you in a minute, the Lykoi cat. What has been effective by doing these case-control studies? Already we’ve found hypokalemia, several of the mutations for hypo- or atrichia. Hypotrichia is the Cornish Rex, you don’t have all your hair, but you have most of your hair, so it’s low hair. The Birman gloves we found this way, and also the Burmese craniofacial defect. The Burmese craniofacial defect was a long, long-standing project. That’s one of the first grants I wrote. The first grant I wrote for Winn Feline Foundation was called “Craniofacial Defect and Looking at the Genetic Diversity of Havana Browns,” and both these projects have stuck with me my whole life, and so it started with Havana Browns, and now I’m trying to find cats in the Ukraine, and cats out of Russia to compare to, and I had one of the Ukraine breeders write to me, and I said, “Can you help me get cats out of Russia?” and she goes, “You know, we’re not too keen on the Russians right now,” and I said, “Yeah, I know, but I thought maybe you just might have a friend over there that, you know, wasn’t involved in all this.” We’re trying to get cat samples out of places, and now that we see more cat breeds coming out of Eastern Europe and out of Russia, we’re starting to see new colors, new health defects, all kinds of new, crazy things, so am I going to retire? Well, no, if there are more cats coming out of Russia, there might be more things to work on, but always, I need the base population information.

Just to remind you, the craniofacial defect, this was the beginning of it all. We didn’t have genetic markers, so first we had to develop genetic markers, we had to build up these large pedigrees, and there are a lot of people that really stuck with us. Joanne Arnett and Karen Thomas continue to always help us with this project, and other people came and went, so we appreciate it. The traditional breeders were needed as much as the contemporary breeders, but it does cause an autosomal craniofacial defect that causes this duplication of the upper maxillary, but when you have one copy of this, you have the pretty little face that you want, and that becomes a problem. This is not new to animals, so in horses there’s something called HYPP, which is a hyperkalemia periodic paralysis. That’s in quarter horses, and the thing is, when you have one copy of it, you have big strong muscles, you’re a good quarter horse. When you have two copies of it, then you tie up when you’re a horse. So, selection of a heterozygote is nothing new. We know it happens and, in this case, it happens in the Burmese cats.

Sometimes, these case-control studies fail, and that is because we might not have DNA variants in the right place across all the chromosomes in the right area that we need to look or, sometimes, your mutation is so old, there’s no what we call linkage dysequilibrium around it, so it’s a very old genetic mutation. When we tried to do the Japanese Bobtail mutation, we could not find it by doing this case-control study so, in the end, now what the heck do you do? We’ve thrown all the tools we have at it. Well, there’s still whole genome sequencing. Just so you know, Japanese Bobtail, they have these little hemivertebrae at every little kink of the tail, and so they can have all kinds of tails, either as a heterozygote or a homozygote. Cat breeders have certainly selected for the nice little bobtail that they want, but here was a cool secret that we found out, one that we radiographed the whole cat, because we just were looking at the whole cat, and the radiologist said, “Hey, wait a minute!” and we’re missing one of either a thoracic or, sometimes, a cervical vertebra in these cats. So, Japanese Bobtail cats have, generally, one less thoracic vertebrae and so, sometimes, the ribs get a little confused to where to go but, in the end, it still looks like a normal, long cat. You wouldn’t know that it’s missing one of its vertebrae, but that becomes a very important gene for being involved with the development of your whole mammalian body plan. Who would know that? So, in the end, nothing occurs with these Japanese Bobtails, but it becomes a very important mutation for biology in general.

If you can’t do something by case-control study, what are we left with? Well, let’s just sequence the whole darn cat and see what we can find in that, and so we launched something called the 99 Lives Cat Genome Sequencing Project. Well, it started out as 9 Lives – and that’s what Winn Feline Foundation funded – but then we thought, well, you know, that 9 is not going to be enough, so we wanted to get up to be 100, and everybody has a 100 genome project, and I was like, “We’ve got to make it sexier-sounding, so let’s make it the 99 Lives Project” and, sure enough, everybody decided to play together, so all these different investigators from different universities have sequenced their cats the exact same way. It’s a public database. It will all get put into the public NCI. Healthy cats are just as important as unhealthy cats, so if you just want your cat sequenced, then we’ll put it in there. I think we’re doing an Aussie cat with Roger Brown, and I don’t think there’s anything wrong with his cat whatsoever. That’s good - we need healthy variants in there to say, “These are not the DNA variants you should be looking for, because these are the healthy ones, this is in a healthy cat. Go look somewhere else for the variant you want,” and I’ll show you some success in some wild cats that we have done as well.

You don’t need to worry about this, but this is how we’re doing it. This is where, when I say I want back-up blood samples, so to whole genome sequence something, you need about 3 to 5 mL of blood to do that, so buccal swabs, we’re not so keen on that. It can be done, but we would much rather not do that. We’ve made these DNA libraries and, actually, our lab doesn’t do it, we contract with Washington University or the DNA Missouri Genomics Core. We use the same technology. The cats might not be at the forefront of genetics overall, but we get to sit back and watch everybody else make mistakes, and so I sit there, and I watch them make their mistakes, and I say, “Okay, we’re not going to do it that way.” The key was to get everybody to use the same technology, because then you’re comparing apples to apples all the time. We have a company that does the analyses for us and, as I said, NCBI is the government place where you have to put all your short reads, all your DNA sequence into, so it’s all going to any other researcher who can use this data as well.

So far, we have already analyzed 83 cats, and 74 were domestic. At the end, I’ll tell you about the wrap-up with precision medicine again. Fourteen different institutions and some zoos are participating. We found inherited blindness in a black-footed cat and, also, of all things, Pallas cats have PKD. Why is that funny? Because people thought Pallas cats were the progenitors for Persian cats for a while. Well, no, they’re not, but lo and behold, they have PKD too. That’s just kind of weird.

Right now, we’re doing an analysis, or we’re getting ready to this summer, where we have Birmans that are coming in from Sweden with restrictive cardiomyopathy. Dr. Dodman is going to tell you about his Tufts cats. Cornell has put about 10 cats into this project. Michigan, with Simon Petersen-Jones, he’s looking at another blindness. Some people are just putting in other cats. We’re doing another Burmese with feline orofacial pain. We’re doing a Toyger. Nothing’s wrong with the Toyger. Nothing’s wrong with the Aussie cat. We’re looking for Siberians with hypertrophic cardiomyopathy, and Nosferatu, which I just love that name, is a Sphynx. Nosferatu. That cat, I think, has HCM as well. Black-footed cats have amyloidosis. Lions have a type of vitamin A deficiency. If they don't have vitamin A as they’re growing as young cubs, their skull doesn't grow properly, which then presses on their spinal cord, and they’re done for, you have to put them down and stuff, and so a lot of big cats are getting in on the project, too.

What has been successful so far? We have found Persian retinal degeneration. We have found a retinal degeneration in Bengal cats, as well. The Scottish Fold mutation is now published and, unfortunately for Scottish Folds, we have been able to show that you can have one copy of the mutation and, I'm sorry, you still have osteoarthritis. Before now readmitting to that, while genetically, now I can absolutely prove it. Now it would be nice, what's the next step just with white deafness. The next step would be, let’s take all the cats that we know have the mutation and cats that have mild and severe osteoarthritis, and let’s see if we can find, there are probably modifiers that cause it. Same with polycystic kidney disease. Most cats live to 14 and don't die of renal failure from PKD, but there were a lot of cats that died at two or three years of age and had severe PKD. There are modifiers to these genes, just like any cat with a melanophilin dilute mutation looks grey, but we know Russian Blues, British Shorthairs, Korat, Chartreuse, they don't look the same blue. Those are all genetic modifiers that tweak everything in our body, and then also, spasticity was recently discovered and, also, a group in France have confirmed that.

So, with retinal degeneration, there are now four retinal degenerations known in cats, two in Abyssinians, one in Persians, and one in Bengal cats. They all present the same way; different timeframes, though. If you do an eye exam where you dilate the cat’s eyes, you will see that you can't see the blood vessels in the back of the eye. They’re there, there's just not a lot of blood flow, so you just can't see them so well and so, over time, what's happening is these are the photoreceptors, and we can see that they’re degenerating over time. This happens to be the Bengal cats, so by 62 weeks, actually, there's just no photoreceptors there. Now, cats trick you. They think they're sighted even though they’re blind, right? So, if they have one or two photoreceptors still there, somehow, they can still see. Best way to check it out is with a laser pointer. Don’t try to put something in front of their eyes. They can sense and feel all that movement, but a laser pointer will very much help. Are there probably cats that have two copies of these recessive mutations and can still see and are older? Probably are, because our body is very redundant. Other genes take control and help fix things in our body - that's why we survive, but that ought to be the rare cases. Does that mean you should breed that cat? No, because the next mix of that mutation in another genetic background, that cat might have very severe retinal degeneration as well, and you can do this with electroretinograms as well, so very early, as five, seven, nine weeks with a Bengal cat, we could see that the biggest peak is the earliest time, but we could see it dropping off - by even three months of age, we knew these cats were going to go blind, but they acted perfectly sighted up through a year, and one of the cats that Barbara Gandolfi adopted, it was chasing a laser pointer for two years and then, suddenly, it was all gone.

With our 99 Lives project, first we did 9 Lives and we sequenced three trios of cats, because we had no other cats in the database. We’re just starting from scratch, so we thought we’d be clever. We sequenced a sire that was blind, an offspring that was sighted, and a mother that was sighted, but she carries the Bengal PRA, so she's a carrier of the Bengal PRA. Notice they have bobtails and curled ears, white body and, our favorite color, silver, right? So, we thought, wow! We can get bang for our buck for this one group of cats. That's what you can do with cats – you can't get people to do that. I’m not sure why, but you know.

To show you the process we go through, so this is for the blindness. There are millions of DNA variants that you're going to find; 16/16 million that we found in these three cats. How are we going to find the one we want? Well, you use the segregation of the disease with you. You know that the male has to be homozygote, because he's recessive, and the other two cats have to be carriers, so you plug that into the computer, and you say, “Kick out all the variants that don't fit that type of mode of inheritance, and then, also, give me the ones that affect the protein in the most dramatic way,” and sure enough, and then also, we did a case-control study with those cats, too, so we knew where to look. We knew what chromosomes, so we could throw out all those other DNA variants and, in the end, we had one that's called a stop-gain. That means the protein has been altered and actually shuts off, and we looked at that one, and that was the right one in AIP 01 that caused Persians to be blind. If that would have been wrong, you could see we still had a few to work through, but the problem is there are lots of modifier genes down here. These are mutations. These are the mutations that are going to regulate diseases so, fortunately, we had one that was on-off, just affects the coding part of the gene, where we’re going to start finding ones that are harder, and we're going to have to sift through these other mutations. How do we get this number lower? Having more cats in the 99 Lives dataset, so if we have more normal cats. My plea to you guys is, let’s get every breed represented in the 99 Lives data. National Geographic gave me the money to put every one of the racial populations in, so we have every one of the racial populations represented. Let's get every breed. Every breed, it costs $3,000. Come on, you guys are good fundraisers. Get those raffle tickets out there and make some bake sales, and it can be any cat you want! A healthy cat is just as good as an unhealthy one. Of course, we want to look at health, too, so to try to get bang for your buck, maybe find a cat that has more than one goofy thing going on, but that's where we want to try to head. The better this database, the faster we can weed things down like this.

We did find this mutation as well, and this was actually one of the first ones that I worked on when I was at the NCI as well, so this cat is sitting this way because it has generalized muscle weakness. This is one of the presentations of spasticity, so it's in Sphynx and Devon Rex cats. Back in the day at the NCI, boy, I did free blood testing for a whole bunch of Devon Rex cats but, in the end, we didn't get very many cats that were affected. Well, what’s kind of happening is, people that are coming new into the cat fancy, and particularly in Europe and Eastern Europe, they’re not as good at checking out pedigrees as you all are, and so recently, this has been gone for a decade or more from the United States. Well, this has cropped up new in Europe, and so the cat that we sequenced was born just two years ago with spasticity, and it came out of Italy, and so we needed a fresh blood sample for sequencing, and we sequenced this cat, and sure enough, found the mutation. This is a DNA sequence, and we found the mutation that causes this trait for the cats. It causes what we call a splicing error. Exons want to splice together. There are introns in between them, and we don't really know much about what the introns do, but they’re probably part of regulation, so it messes up the splicing, and so the gene gets all gets messed up. Where your nerves are, what it basically does, you need acetylcholinesterase inside your nerves, for the transmission of the signal. COLQ is the gene that we found the mutation is in, and that holds the acetylcholinesterase into the membrane junction for the nerves, and so with this kind of dangling around and not being held well into the nerve membrane, then that's why the cats get spasticity.

One of our newest things – have you seen the werewolf cats? I have to admit they're rather cute, or I don't know, it depends, is the Sphynx cute? I don’t know. It’s all what you love as a parent, and the thing is these are cropping up in different places, so that, as a geneticist, there’s no way these are cropping up in different places being the same gene. We have been able to do a case-control study, and we have found the gene for this, but we have found there are at least two different mutations, so the cats found in Virginia have a different mutation in the same gene than the cats found in Tennessee, and then there are cats found other places too, and so we're still looking around for some of their mutations but, in the end, they basically don't have an undercoat and so, actually, we did a resident project, and so they have the top coat of hair. They also have this roaning, where one hair is black and one hair is white. The cat’s black hairs can come in different colors, but they always have white hairs too, so that, in other species that's called roaning. They have this roaning type thing, and then, see how dense your hair is supposed to be? They don't have all the undercoat of hair. This is where cats have their top coat, but not the undercoat, where Cornish Rex, or the other way around, completely different genes, and that's how they present, so we know two mutations in the Lykoi cats now as well. So again, we did this – now, this had to start with a pedigree, because it’s brand new, but what you do for case control, you pick the most unrelated cats of the pedigree and do a case-control study for them, and so we were able to find this mutation.

Next one is interesting. We found this by sequencing as well. It’s called an auto lymphoproliferative syndrome. It’s in British Shorthair cats. Every one of their lymph nodes just blows up and becomes gigantic, and the cats are just months old when this happens and, of course, the cat has to be put down; there's really no good treatment for this but, in a recessive condition that we had some ideas of what it would be in humans, and what we did is, we didn’t have a lot of cats - British Shorthairs in Australia - this was in Australia and New Zealand. We took two affected sibs, sequenced those, and then we said, okay. In our data analysis, these two sibs are affected. They must share the same recessive trait. No one else, in our other 84 cats, no one else can even have that mutation, because it's rare, and by doing that we can track down, very quickly, and then you go back to the candidate gene approach, because you're not going to only find one gene. Then we went back and said, “Well, how does this present in humans?” There were a couple of different genes to look at and, sure enough, one of them was what we wanted it to be. This has been submitted for publication as well. Now we found this one so, again, this is frameshift, where it knocks the frame of the reading frame of the sequence out of place but now, look, this says 33,000 down here. Now, because our database is getting bigger and bigger, this modifier pile is getting smaller and smaller, so if I had to still look at 3,000 mutations, I'm not going to do it, but we’re getting smaller and smaller, so that's good.

To show you some successes in some other cat populations, the fishing cat is here. We’ll be looking at amyloidosis. This is a cousin of the Asian Leopard cat. We’ve also looked at the black-footed cat, and then the Pallas’ cat is right here, is another, kind of in the same grouping as Asian Leopard cats, so we're trying to get every one of the felids also into the 99 Lives project, because zoo populations are just like a breed. They’re a closed population, you can’t keep bringing cats in from the wild and, sure enough, they get inherited diseases as well.

There is a little black-footed cat. Cute, isn't he? Yeah, he'll rip you a new one! We wanted to test all the cats. There’s only maybe 50 cats in the United States, so we wanted to test all the cats to make sure who's clear and who isn't, because now we have to use genetics to manage this population, and I was like, “Can you buccal swab one of these?” and they just laughed, and I said, “Okay, pluck some hair,” and sure enough, we can do a DNA test, once we know the mutation, we can use plucked hair, not shed hair, but we can use plucked hair, so they just plucked some of the hair out of the cat, and we were able to test it. It's a small African wildcat. Smallest little guy. Very endangered. Very aggressive little monster.

Then we have the Pallas’ cat and, historically, people thought, oh, this is the Persian! Well, we proved that not to be true, but these cats ended up, and we did the same thing, who wants to sequence PKD1 in a Pallas’ cat. Like I said, PKD1 is a big gene, so it's actually cheaper and faster for me to spend $3,000, sequence the whole darn cat, and then we can do other things with that sequence as well, and look in the PKD1 gene and, sure enough, we found a unique, dominant mutation in the Pallas cats and, unfortunately, we’re finding that, probably, the progenitor cats from Russia have this mutation and stuff, so this is going to have to be managed in Pallas cat population as well.

For whole genome sequencing, we've found Japanese Bobtail, the British Shorthair disease, black-footed cat, Pallas’ cats, and then Niemann-Pick type C. This is a type of lysosomal storage disease. It causes a neurological problem, and this is exactly what precision medicine is about. We had a cat come to our hospital on referral. It had a neurological disease that they couldn't figure out. First they thought it was a shunt. No, it wasn't that, and the cat just wasn't getting well, wasn't getting well with any treatments, so it came to us for referral and had Neurology take a look at the cat, and so the final decision was it probably has some type of lysosomal storage disease. We need a liver biopsy to know which one. The owner no longer wanted to do anything more with this cat, so that's it, we can't do anything more with this cat to finish the diagnosis. I was like, “Okay, here we go, let's see how strong our 99 Lives dataset is.” We sequence the cat. We know which genes are top lysosomal storage disease genes and, sure enough, a recessive homozygote mutation in this cat that we have not been able to find in hundreds of other cats. That's one of the things we do to test, it’s is it in any other cat? So, we found through what's the precision medicine approach; you use your whole genome sequence to help do your diagnosis. Now, in humans, they can do this in about 26 hours, because they have all the databases all set up to do all the analyses and stuff. We can do the sequencing and all that in that amount of time. We have a good database. We just don't have the computing power to do it that quickly, so it took us several weeks to do this, because we had to wait in line, but it does work, but still, it’s not going to work all the time, but I was very pleased with this, and this is submitted to the Journal of Veterinary Internal Medicine.

A project we’re working on that we haven't been able to solve: Oriental Shorthairs that came from Italy with these cute little cobby ears. In the end, they also have this kind of domed head. They have this severe hydrocephalus, so their brain is very compromised. This is one of my favorite stories though, because the females that have hydrocephalus don't seem to be able to get pregnant. Carriers can. But the males with hydrocephalus, they can breed left and right! It just tells you, you don't need a brain [laughter]- but women do, apparently! Not all of them are this severe and, in fact, these cats are as cute as can be. A teeny bit clumsy; other than that, you don't know that there's anything wrong with these cats, actually, and look how compromised their brain is, actually. So we know where this gene lives. We’ve done a case-control study. We know exactly where it is. It's not a coding mutation, so that means I'm looking at modifiers all over the place. So, guess what, that guy got moved down a notch as far as priority.

We are looking at, in Australian and UK Burmese, there’s Ehlers-Danlos syndrome. This is also called cutaneous asthenia and other things as well, where they have really stretchy skin, and so now we're going to collaborate with people to look at this as well. We’ve sequenced a couple of these cats, but we have no case-control study to tell us where to look, so we're hoping, with the next analysis with more cats, we might weed it down a little bit more. We’re looking for dwarfism in the cats. We know where this gene is but, again, it’s not a coding gene, so it's a regulatory gene, and the thing is, this is going to be a novel cause for dwarfism. This is not near any known human gene for dwarfism, and there are still lots of undiagnosed blind people. There's lots of still undiagnosed dwarf people so, if we find this and have the gene, we can say, “Hey, go look in your dwarf people and see if that explains it.”

Bengal PRA is a novel blindness gene, so we're working with human physicians to test their undiagnosed patients for mutations in the same gene. We still hope to look for progression of PKD. We haven't really moved forward on that so much.

Let's wrap this up. I think we're close to wrapping this up. So, in the end, these are the variants of the cat. Just a bit of a summary. I think, maybe, you might have more details in your handouts there of what some of them are - I tried to update them before I came here - but I want you to realize that our laboratory has found 36 mutations in 25 genes. That’s been my 20 years of work, so 32 publications, and three different investigators, Rob Grahn, Barbara Gandolfi, and myself.

Newest things have been in the myotonia congenita. This is out for publication in British shorthair. Finding spasticity was really cool. Bengal PRA is not submitted yet, because we have to prove, functionally, that's the right gene. Lots of different color mutations. As I mentioned, the blood types. Hopefully, blood type is up there somewhere. Recently, also, we worked to figure out that Asian leopard cats, because Bengal people have selected for some of the colorations of Asian leopard cats, sometimes, when you have an Asian leopard cat, allele, its variants mixed in with domestics, you get a completely different presentation, so that's charcoal, is when you have an Asian Leopard cat variant at agouti with the melanistic mutation, the recessive mutation in domestic cats, so that combination will give you charcoal cats as well.

I just want to say, we have received, over 20 years, $300,000 or so from the Winn Feline Foundation, which is about $15,000 a year, but we have 32 publications out of that, and Winn Feline Foundation has helped to find 36 different mutations in the domestic cat.

Things that we continue to work on are, Dr. Gandolfi loves the hair types. We just sequenced a wire-haired cat as well. We’re still looking at dwarfism. We know where American Curl is, hydrocephalus. Still always looking at silver but just, honestly, the problem is it's a modifier, it's one of those regulatory mutations, and so that just doesn't jump at the highest part of my list, when I have diseases to work on, but other things, we’d like to look at stones in the mouth. One thing that I haven't solved, or two things, really, are silver, and the lymphosarcoma in the Oriental Shorthairs. So we're still trying to solve those things. We have a new project on amyloidosis. We have kind of a resurgence of this, where we have genome sequence two amyloidosis cats for Abyssinian and two for Siamese. We know to analyze them separately. We’ll also analyze them together, and then we also have black-footed cats with amyloidosis as well, so we’re trying to do this by a sequencing approach but, always, if we can get more samples of amyloidosis, that would be very helpful, and then also trying to look at Ragdolls, where they have only one uterine horn and one kidney; not really sure what to call that disease, and a few other diseases are moving along as well, and we’ll probably look at those mutations for FIP to see whether they are showing any true risk for FIP or not, as well.

Just to wrap up with project cost, whole genome sequencing a cat now costs about $3,000; $2,000 for the sequencing, making the library, shipping samples, and $1,000 for the analysis or so. Humans are trying to get to the $1,000 genome project, so we're getting close, so as human prices come down, our prices will too. No, this doesn't include personal cost, when we start looking for genes and stuff as well. Still, the DNA array projects are very useful as well, and so it's about $124 per one cat on an array, and if we, say we're working with Burmese, we can probably get away with 15 cases, 15 controls. Now, note all the cats we've already done, we can use those as controls, so sometimes we don't need the control samples and stuff. So, this localizes the mutation, but it doesn't tell us what it is. The genome sequencing will find the mutation, but now you’ve got to figure out which one of those 16 million are the right one. So, you’ve found the mutation, you’ve just got to figure out if it's the right one. So, again, lymphosarcoma we’d like to look at. We haven't quite given up on silver. I know it's there and stuff, it's just hard to move it up on the priority list. We've looked at a couple of genes, we thought we had it, and we were wrong so, in the end, regulation is key. It's going to become harder to find some of these mutations, but we have a lot of great tools in our ability, such as, for example, orange. We know where orange is, but proving that orange is orange is still hard, but that mutation ought to be coming out soon. As mentioned, humans do this in about 26 hours, where critical cases, kids that you must solve the problem right away, come into the Critical Care Unit, they genome sequence them, and they can get a therapy back to these kids. It doesn't happen all the time. We’re finding about 60% of the important mutations are actually in the regulatory region, so I, fortunately, I've been working on easy ones for some reason and been finding them in the coding parts of genes. Now it becomes a little bit harder. So, humans have the same problem, is that most of 40% of the time, they can find their mutation right off the bat. The other 60% of the time, they have to work pretty hard to find it. So, we look for the variation of PKD. The idea is to start looking at more complex things, like obesity and asthma and infectious disease and, just like the same thing in humans, but, in the end, how about behavior? I think it would be great to hear about behavior, because everybody wants to look at domestication. While wild cats are on the fractious end, our friendly breeds are on the nice and feral cats are someplace in between, but they kind of overlap. Can we find the mutations that make a wildcat fractious and make a domestic cat friendly as well, and so behavior studies are certainly at the high end of the spectrum for complex diseases, and where we would like to go. So, with that, that's the end, and I’m happy to any questions. [laughter]

Dr. Glenn Olah:

I’d like to introduce the Winn board members in the audience. Just to introduce the board members, there are actually 11 board members. I think we should have nine of them here today. Over here we have Dr. Brian Holub, Janet, our new board member here, Dean, Vickie Fisher in the back, Drew in the very back, waving. Oh no, that's Lorraine, I’m sorry. I don’t have my glasses on! And Susan is somewhere I think. I already got Drew in the very back, Vicki our executive director over here as well, next to her husband, Bob. If I forgot anybody, my apologies. Alright.

I'd like to introduce our next speaker, Dr. Dodman. Dr. Nicholas H. Dodman is one of the world’s most noted and celebrated veterinary behaviorists. He grew up in England and trained to be a vet in Scotland and, at the age of 26, became the youngest veterinary faculty member in Britain. Dr. Dodman immigrated to the United States in 1981 and became a faculty member at Tufts University School of Medicine. At Tufts, he became interested in behavioral pharmacology and the field of animal behavior and, eventually, founded the Animal Behavior Clinic - one of the first of its kind – at Tufts in 1986. He's a diplomat in veterinary anesthesia from the Royal College of Veterinary Surgeons, board certified by the American College of Veterinary Anesthesiologists and the American College of Veterinary Behaviorists. He devotes his time to his specialty practice of animal behavior. He has also written various bestseller books regarding animal behaviors as well as two textbooks and more than 100 articles and contributions to scientific books and journals.

Today Dr. Dodman will provide information on the common presentations of three compulsive behaviors in cats: Wool sucking, psychogenic alopecia, and feline hyperesthesia syndrome. Regarding a phenotypic study of wool sucking funded by Winn, he will list potential causes and preventive measures that can be taken to reduce the occurrence of this troubling and occasionally lethal condition. Also, he will discuss findings of a Winn-funded study to locate atypical genomic regions in the Birman cats affected with this condition.

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Beginning of Dr. Nicholas Dodman Audio

Dr. Nicholas Dodman:

First of all, let me say it's a very special day today. You have me on, probably, one of the most unusual days of my entire life. This is, actually, I've retired! Half a hour ago so this is me kicking my feet up, hanging out. Unlike Dr. Lyons, who is just a young whippersnapper in her 50’s, I happen to have already crossed the 70 threshold, and I'm pushing 71 in a little while, so it's been a wild ride. Forty-six years in veterinary medicine, thirty-five years at Tufts, but it ain't over yet, because Dr. Lyons and I are continuing to do the study that Winn has helped us with on the genetics of the cat, and we’ve got a number of other genetic projects and other projects and things I'm interested in. We’re going to talk about Sonic Hedgehog and the dwarf syndrome. Unlike Leslie, who is a geneticist par excellence, my knowledge of genetics is kind of ropey, because when I went to veterinary school, they didn't really know, I mean, it was shortly after Watson and Crick, I think. I mean, it was just a few years ago when I thought a genome was a small person who worked in the French underground, but then I remembered that was a metronome. I thought a triple repeat was something that happened after eight gherkins. I thought a Manhattan plot was some evil scheme hatched up by terrorists in midtown New York. I thought multidimensional scaling was coming at mountains from different sides with crampons on, but I've learned differently, but still, my knowledge is a little bit creaky, but my geneticist friends keep me straight. The fact is that, if you’re going to do these studies, which I’m going to get to eventually, you need two parts, as Leslie alluded to, and that’s why she likes to work at the veterinary school, where people could do the phenotyping, which is the actual look of the behavior, and how it actually presents. It isn’t accurate. The genetics isn’t worth a hoot. Then, at the other end, you’ve got the geneticists. So people like Leslie and myself, other colleagues, Dr. Gins myself, Dr. Ostrand and myself, work together like dumbbells, except we are smart. Two ends of the same block, and the phenotype has to be good on the genotype; the genotype has to be good with the statistics, and so on. So, that's my admission.

It’s also a tricky time. Everything's happening at once in my life, because as I'm retiring into something else, I’m morphing for about fourth different time. All the other stuff, like jumbling and I just had to let it go. I want to work more independently, on my own clock, doing my own things, and maybe have a little bit more free time but, because of the retirement, I'm also selling my house, buying a house, had my 27th wedding anniversary a few days ago, daughter just graduated from UPenn Medical School. It is just all happening. I haven’t been as busy in – and here we are.

This is an unashamed advert for my next book. My first book was 1997, was The Cat Who Cried For Help, and that got me onto Good Morning America and a few big TV shows. This is one that comes out next month, but you’ll see, what it actually is is, Dr. Lyons pretty much went over through the beginning to the end, from the soup to the nuts the things that she's found or discovered, all the wonderful things, the genes and the publications over the many years. Over my years as a behaviorist, which is really, the first part was anesthesiology, but around 1990 I switched into full-time behavior and, since then, we’ve found all kinds of interesting things, and it's in dogs and cats and horses and parrots and all creatures, great and small, so I’m just going to say it's more eclectic. Leslie is much more focused on cats, and I’m sort of all over the place – I’m a jack of all trades and master of some. So, the top title, which you can't read, says Neurotic Dogs, Compulsive Kittens, Anxious Birds: The New Science Of Animal Psychiatry. That was an early rendition of a mocked-up cover. They said, “It cannot be the new science of psychology,” you know, Pavlov would roll over in his grave! Actually, it’s really more like psychiatry, and there are the labrador and the parrot and, actually, the cat is represented by the tail underneath the couch.

One of my interests over the years has been, really, psychiatric conditions that manifest in animals. They’re human psychiatric conditions and, as Leslie said about the genome, we're actually all on this planet, we’re all mammals together, and we have a lot of DNA, just different switching and so, to me, it is not a human world surrounded, like the sun, surrounded by myriads of little tiny stars and planets; we’re actually all in this together, and I don't find it surprising at all that animals have thoughts and emotions that are very similar to ours, that sometimes they can be disturbed, sometimes because of bad experiences, sometimes because of genetics that incline them to tricky behaviors, so OCD became a focus, because that's how I first got into behavior, with an epic experiments in horses where, as an anesthesiologist, I was looking at the effect of morphine in horses, and we discovered that we actually created a compulsive disorder in the horse by giving, just temporary, while the morphine lasted. I’m doing my research on morphine because I wanted to kill the pain after surgery, but horses are unusual, they get excited. We were studying why they got excited, and there we go and create these so called stall vices, like cribbing and weaving and digging and circling. How could we do that without medicine, when horses in the field and in the stable, they do it anyway? What if, was the thought, that nature’s own morphine-like substances, the endorphins, were somehow involved. In that case, if you take a drug like Narcan, which they use to reverse opioid addiction in addicts that are in overdose, we could give it to a horse, it will stop. What a great idea! And we did, and they did stop, in their tracks. It was such an amazing moment, one of those moments you hope for all your life, and I was working with a Professor Shuster, who was the medical school pharmacologist, that he changed his whole career, from being studying drugs of addiction, to studying behaviors of addiction. The lady who owned the horse, she changed from being a highly-paid executive at a company in Boston, went back to university, did a PhD in biochemistry, and I changed from being an anesthesiologist to being a behaviorist. So, having studied horses, which I’ve done over and over again, and come up with lots of new treatments for OCD, some of which has translated into the human realm, too; we have papers and patents out on that. We also then studied dogs with acral lick, and then I thought, what would cats have that would count as a feline compulsive disorder? A couple of things sprung to mind: The wool-sucking pica, which I’ll talk about first; psychogenic alopecia, which is a dead ringer for human trichotillomania, which is compulsive hair pulling. You know, I’m so freaked out I’m pulling my hair out, that some people do it all the time; and feline hyperesthesia, you’ll see maybe is or maybe isn’t a compulsive disorder, and I’m intending to think that it isn’t.

This is the cycle of OCD. This is the OCD help page on your web for humans, so this is the so-called cycle. So, you can break into the cycle any way you want to, but let’s say we’ve come in with anxiety. If you are an animal, whether it’s a person or a cat or a dog or a parrot or some other species, if you’re genetically programmed, if you have the genetic inclination – not everyone does - your anxiety can lead you into a bizarre, repetitive disorder, which results in a manifestation of some natural behavior that’s just expressed over and over again. Really, the mechanism has kind of gone awry; you cannot turn it off. The anxiety caused you to do this thing repetitively. In humans it would be, say, hand washing because you’re concerned about germs is a classical one, and after you’ve washed your hands, it brings about relief, but after relief, you start to think about it again, you know, “but what if I didn’t get completely clean?” so you then start to become anxious, and so then you get into the compulsion again, and that’s the cycle, it goes around and around. The same thing with animals. The purists would say you can’t say that an animal has obsessive compulsive disorder, because you can’t prove they obsess, and no, you can’t. We can’t access animals’ thoughts, yet. I mean, the stuff going on with imaging studies, where you can sort of almost see them thinking - you train them to lie still in an MRI unit – but, really, you don’t know, but I can tell you, from an interpretive side, which real scientists don’t do, but I do, they look for all the world like they’re obsessing. They look like that thought is constantly recurring. Can animals have thoughts? Of course they can. When they were first noticed, these repetitive disorders, it was in all creatures, great and small. An elephant, on the left, in a zoo, in a situation of confinement, suitably genetically primed, expresses that by engaging in a normal behavior of walking but, when you can’t go anywhere, because you’re chained, you walk in place, which is called weaving, and you weave your head from side to side, and your trunk goes to the left and to the right, and all the animals, none of the ones in the wild do that; it just doesn’t happen in the wild, it’s only in captivity, only in zoos, and even in the San Diego Wildlife Park, where they’re free to walk, they obviously were confined before, because they’ll do it in the middle of a field, so it gets ingrained, and the big cats here will walk in circles. Any old big cat will circle, because in nature, they would normally walk miles and miles and miles in search of prey and have a big home range territory, and round they go, around in circles, wearing a groove on the way to.

I’ve treated, indirectly, polar bears. One in the Saskatchewan Zoo that was walking compulsively, and we treated it with Prozac. I figured the dose out for them. It was published. Shut it down, just completely got the dose right, it stopped pacing. It has always been an interest of mine, is why they do it, how they do it, what’s the genetic priming, what are the anxious circumstances, what is the mechanism and what’s the treatment? What are the genetics, because the genetics underneath will tell you, not just the gene, the gene tells you maybe the protein the gene is making, but that leads to a pathway, that protein works it this way, then links with this, which links with this, it goes to that, and you can see this whole pathway, which you can then intervene, treatment-wise, to fix. These are the human OCDs. These were originally called stereotypies. They didn’t become compulsive disorders until a famous publication by the head of Child Psychiatry at NIMH, National Institute of Mental Health, Dr. Judith Rapoport, who wrote a book called “The Boy Who Couldn’t Stop Washing” and, when she got back to her office after a national book tour, New York Times bestseller, she got all these messages on her machine, saying “My dog does that.” Being a smart woman, instead of just going, “That’s crazy,” which some people still do - “Animals, you can’t learn anything from animal” - she said yeah, let’s try out the human anti-obsessional drugs, like Prozac and Paxil and Zoloft, let’s try it out in these dogs. They respond exactly the same way, over exactly the same course of time, and so she wrote a paper in the Archives of General Psychiatry in 1992, which explains that this is a wonderful model study of OCD. Her angle as a human and MD, was we could study the condition in people by looking into what these dogs are doing in many ways, especially genetically, that’s an easier model to study.

There I’m just recapping, the compulsive disorders’ natural behaviors form excessively. There’s nothing abnormal about them. If you take a spectrum of OCD, whether it’s pyromania, that you run around setting fires, and you keep thinking about lighting things on fire, which you might only do once every month or two, but it’s a problem if you keep setting buildings on fire! It might be trichotillomania, where you’re pulling your hair out, but a little bit of grooming is not unusual, and with the cats with the psychogenic alopecia it’s the same deal. Genetic and environmental factors come together, so this makes it very difficult to study because, if you have the genetic makeup, but you’re not put in the pressure cooker of life, you don’t have the anxious circumstances, you may never express it, even though you are genetically prone to it. On the other hand, if you have a genetic inclination and you have the right circumstances, then it will express. If you take pigs, another species, if you put them in the pressure cooker, which is in these horrible stands they are in, with iron bars down either side, they’ve got nothing to do, about 20% or 30% will chew chains and bite bars. They don’t all do it. They don’t all have the susceptibility to it. In humans, it’s about 2% to 3% of the global population that’s affected with obsessive compulsive disorder. It’s a major condition, and it’s very debilitating, and you typically don’t die of it. It’s really lifestyle-altering. It affects you, it affects your family. Especially hoarding, which is one of them, and there was a woman killed by her collectibles when they collapsed on her. So, this is probably not an OCD. Glass of water please, I’m not going to drink it, I’ll just knock it over on purpose. [laughter] My cat does that. I should point out that, although I have an interest in OCD across the species, the fact is I’m also a cat person. I was raised with cats, I had cats when I was a kid, I had cats when I was teenager. When I was in university for five years, I didn’t have the facilities to have a cat. I was never there, and a little tiny room. I had one towards the end of that, but then after that, I have always had cats, usually in a pair. Right now, I have one. His name is Griswold, and he’s stone deaf, which I’m afraid my little son discovered. He’s like “Griswold, Griswold!” He said, “Mom, Dad!” We’re both vets, mom and dad, so he said, “I think he’s deaf!” Sure enough, he’s as deaf as a post, and he has neurological things going on, too. He goes on the counter and bounces his nose off and starts jumping fits around the counter, and he jumps onto the counter, he jumps, and then falls all the way back, and so it’s sad to watch, but he’s happy.

Here we go. Wool sucking and pica which, in my view, Leslie was saying how, genetically, some things kind of ride together and, even though pica, which is literally the indiscriminate eating of inedible objects, looks a lot different from nursing on some woolen substrate, but not really, because they overlap, because some cats that nurse on the woolen substrates will also ingest the substrate, so I think it’s not really pica, actually, because it’s really a texture-specific eating disorder, so they don’t eat everything, they just eat some things, things that feel good. It has something to do with taste or touch that they really enjoy. Wool sucking, just generally, sucking or chewing on woolen, cotton, and synthetic substrates. Wool is the favorite. They’re not shy; however, some won’t go for acrylic -not snobs – and other synthetic substrates may progress to pica. Cloth, hair, plastic, shoelaces, electric cords, paper or wood. Plastic is a big one. For some reason, running gear too. If you have silky running shorts, the cat will take the lid off the laundry basket and go in there and pull them out and they come out, and it looks like you’re living with a nine-pound moth. Could it be a kind of nursing behavior? Could it be something to do, like children who are weaned too early I believe, may, like veal calves will nurse on something, like in humans would be thumb sucking. In veal calves it could be an umbilical hernia or, on the calf next door. Could it be something to do with early weaning? Something like a facsimile of thumb sucking? It begins, sometimes, this suckling behavior, directed at the fur of fetal sibs, and it can generalize to a variety of substrates once the cat is separated from the group. All these were sort of theories, which I think you’re going to see that the Winn funding has helped us to establish.

This is a little video of a wool-sucking cat that belonged to a photographer at the veterinary school. He allowed us to photograph his cat and, if you just looked at this, you saw about three seconds of it, you think it’s not that bad, really. It’s interested in something inside that woolly blanket, but it sort of goes on and on, so on its own, like hand washing in a person, not too abnormal, but when it doesn’t stop, and you’ve got the kneading, and you’ve got salivation, and they chew with their premolar teeth on the side, not so much the incisors, there’s a pretty classical pattern of what they do and, like I mentioned, some of them will actually ingest these things they chew. They bite things off.

This is a chapter in The Cat Who Cried For Help. It was a cat called Lucky, the wool-sucking cat. That was Lucky’s real name, and that was a sweater hanging upside down on the line that the owner said “I give up. I’m going to leave this sweater on the ground, because otherwise he’s going to find all the other stuff, might as well have all the damage here.” It’s like dedicating one chair to a furniture-scratching cat, and that was what happened. It looks like someone has been at it with a scattergun. So, it’s a nuisance, really. I know a woman who had her wonderful woman skirts, and the cat would actually break in like a thief into this cupboard, eat the woolen skirts and pants and whatever, and then she’d have to take them to have them expensively repaired. She would put them in there, and he’d break in a second time. It’s just like they’re a terminator; they can’t be stopped. So, it becomes an expense. It was for her, but also some of the cats who ingest things actually do get intestinal obstructions, which can, if not treated early, usually surgery, it can be fatal.

Risk factors are being an Oriental breed, so looking at it from Leslie’s talk, it’s the cats on the right-hand side, the Asiatic genetic makeup type cats. Oriental breeds. Siamese, 50% of all the ones that are affected, so the Siamese seem to be king pins in this, but then there’s the interaction of, perhaps, some other genes. Maybe being more anxious and having an overdose of these genes. It could be more than one gene. It could be some of these switches that turn things on and off, also, that Leslie was talking about. We would look at it, because it’s just one of the many OCDs that I’ve thought about, and we did publish a paper, so it’s a publication, and we have another one or two to follow, published in the Journal of Veterinary Behavior, and Clinical Applications of Research a little while ago, December 2015.

I want to point out the first author there, Dr. Borns-Weil was my resident in Behavior, and she pulled together all the data. She came along after we had started the study, where we had all this raw data, we had all these files, we had all these Excel sheets, we had the statisticians lined up, and I said to her “I’d like you to see this project to conclusion,” and she did, and she worked on it, and she thought about it, and she did tremendous work, so I hope you will her name in connection with Winn Feline Foundation going forward in the future. She is a very good person. She pulled it all together for us. I ended up the senior author, last. We looked at 204 Siamese and Burmese cats. It was meant to be 100 of each, but we overlapped a little bit, so we went to the 100 Birman, 100 Siamese. Half of each group was affected and half was a control, for comparison, and this was the behavioral side, so we took the behavior of all the cats, and we analyzed it, which we had done before, with the bull terriers with the tail-chasing and found amazing things. It turns out they had autism, which we also did with the Dobermans and found out that, actually, the Dobermans also have a form of pica very similar to the Siamese cats and, actually, when we MRI’d their brains they have brain structure that is exactly similar to people who have autism, almost precise, down to a small area of the brain, like there was some problem in the right anterior insula in the cerebral cortex. Same in the dogs, same in the humans, a problem in the corpus callosum, which connects the two sides of the brain. Same in the dogs. Same in the humans. Everything was cookie cutter. In the dogs, we found markers for autism and everything. Everything is falling into place. So, we wanted to see, how do these cats match up? Is it something that travels with it? Is there another condition that’s riding on with it? Is there some environmental thing that’s triggering it? I guess this was the design. We wanted to look at all these factors. We wanted to see if there were differences, and we looked at things like – signalment means age, breed, sex, neuter status, and so on – we looked at physical characteristics, even apple-headed versus non-apple-headed, which it turns out wasn’t significant. We looked at medical conditions that may or may not travel with it, appetite, environment, environmental experiences, weaning age, number of litters, source. There wasn’t much we didn’t look at. The survey was pretty wide. So, the results, I’ll do it in more detailed form, but in this sort of general way, was early life experiences, such as premature weaning, litter size of less than three, and rehoming earlier in life, were linked to an increased risk of wool sucking in Birman cats. Later life experiences, such as lifestyle, number of cats in the home, resulted in an increased risk of wool sucking in Siamese and Birman. We had a little bit of a confusion here though, because it turns out that, genetically, we look at things on the surface, and they seem to be what they are, but when you look at them genetically, they might be completely different, or things you think are different are actually the same. So, when we came to look at the Siamese cats, and this was Leslie’s work, using this climbing mountains from different directions, with the multidirectional scaling, it turns out that the Siamese weren’t all pure Siamese. So, anybody who had a cat that had color points thought their cat was Siamese, and so that actually put a lot of cats in there that weren’t pure enough for our analysis to work well, but the Birmans, the other one group we looked at, how could you miss a cat that’s got white feet? So, they were clumped very closely together on a plot, and so for genetics, it was much better. So, I think, even in the behavioral study, the findings across the board were what they were, and I’ll show them in the next slide, but while some of the things applied to Birman and not so much to Siamese, I think it’s because the Siamese weren’t so genetically homogeneous.

That’s just the summary of the details. Birmans versus control Siamese versus controls. In red, these are identical, right? More affected cats were kept as pets. Now, what that means is they come out of the breeders, and they are rehomed into some other home. More of the controls are used for breeding. That means they’re kept more with the breeders, and they might be with a bunch of other cats. Fewer than three housemates, which is more likely to happen when you’re rehomed with an owner than if your cat is in a cattery with other cats, and it’s exactly the same in Birman and Siamese cats. The differences, which I say might be artifactual, but the Birmans for sure, and this is the pure group, more likely to be have weaned at less than seven weeks which is, with those Birmans, and probably cats in general, clearly wrong, and having fewer than three sibs, so if you’re early weaned, and you have a small litter, you’ve got a bigger chance of having this problem. If you’re acquired at a younger age, .28 versus .57 years, you’re more likely to get it, but when you looked at the Siamese, one thing that came out, even though they were a motley crew, the greater percentage of the cats engaged in this behavior. So, yeah, it was more common in them, and they had longer bouts, and much more severe behavior, so the Siamese were the most severely affected, and my understanding is, and I’m not as good on my history of cats as Leslie is, but my understanding is that the Birman breed was pretty much almost wiped out in the Second World War for some reason, and it was reconstructed, bringing a lot of Siamese in, and maybe that’s why the Siamese is this sort of motherlode of genetic glitch, and the Birmans kind of inherited a fair amount of that.

I studied more on hypotheses that environmental stressors, such as early weaning, may be associated with increased risk of wool sucking, and they have found the development of wool sucking is differentially affecting Siamese and Birman by early environment. I think I would almost interpret that as, if you’re weaned too early, you have very little company, you have too few litter mates, you’re in a house with very few cats, if you’re with an owner who doesn’t really know really much how to interact with a cat, how to enrich the environment, and you have the genetic glitch, then you’re going to show it. So, genetically, we knew. This happens to be Burmese, a pica family. It’s a very small family, but we knew this is one of these genealogies that, if you have an affected one, and you see at the top, this male/female pairing with a blue and a yellow dot, is affected, and you can see the yellow dots travelling around. Well, eventually at the end, you’ve got a pretty complete picture, so that’s just some of the earlier work, before we got into these more serious genetics, I think Dr. Moon created that plot just from family tree stuff. I think, truthfully, like in people, it’s all in the genetics. In people, they can’t find the gene, and the reason is because people are outbred. The population in general, there are a few clusters that aren’t, and these are the ones that the geneticists want to look at, like my friend, Dr. Gins looks at the Amish, who are very inbred, and they have certain conditions, apparently. One of them is a bizarre form of dwarfism, where actually, not like achondroplasia, not like the dachshund or the munchkin cat, though that’s different, I guess, but they’re just very small, but everything is in total proportions, but they’re very small. When they have that problem, they don’t have schizophrenia, which is another problem in that community, so the dwarfism thing protects against schizophrenia, so sometimes you could look at the behavior, and you could make some deductions. That actually led Dr. Gins to come up with a theory. He thinks he’s discovered the secret of bipolar, and he thinks he knows the gene, and he thinks you can turn it on and you can turn it off, so it’s all in the genetics. We know that, and we thought we’d try and find out what was going on.

There’s the cat chromosomes it’s a terrible picture, I got it off the internet. Leslie’s is much nicer. There they are, and there is, I don’t have to explain it, the Manhattan plot, that Leslie made for us. This is the second part of the study, so we did the phenotype looking at the behavior, and then we sent samples to Leslie and Barbara Gandolfi, and they produced this Manhattan plot from that output from the genetic machines, and there were a couple of interesting points there. You can see this big blue one. This is obviously something pretty strong. Leslie explained it, so I’ll just say this particular high-rise building here on chromosome 18, although you like to call it by a different nomenclature, right? F2? F2. That’s very promising, and there’s another peak down here that’s on chromosome 2, what I call chromosome 2, is interesting. So, that’s kind of where we’re at right now, and it turns out these two peaks riding inside the area they were identified, were several interesting genes, but the most interesting ones were something called NCALD which is something to do with calcium physiology, calcium flux and function inside of the brain, and the other one was also a sort of CNS gene, where ataxia, depression, migraine, learning difficulties and so on, so they are the two interesting ones. We wanted to look at it further, so the study is not over, this is not the be-all and end-all, these aren’t necessarily the genes even so we’ve self-funded to try and look further into it, so another $3000 a pop for looking at the whole sequencing, which is now in Leslie’s lab and Barbara’s. They are working together. I think the results are out, but the analysis is going to take longer. We’ll know if these are involved and I sort of really hope that the NCALD comes off, because we’ve been working separately now with my old friend, Dr. Schuster, the pharmacologist. He is always thinking, at the age of 86 now, and he’s only just retired, he puts me to shame, but he said, “You know, I think calcium has something to do with OCD,” and I said, “That would be great, because we just found this NCALD gene, and apparently, what it is, is he looked at two versions of the same drug. There’s a drug called acamprosate, which is used, particularly in Europe, to treat recovering alcoholics and, in a way, you could think of alcoholism as being a compulsive disorder, because the addiction to say nicotine or ethanol, it’s pretty easy to taper somebody off, but what happens is it’s never over, and it’s never over, which one day at a time, one more drink and you’re back on the wagon, it’s never over, and that, I think, is an OCD, so I think that’s the obsessive compulsive components of cigarette smoking and, even after you’ve not had a cigarette for 10 years and you walk into a particular environment, you have to resist the urge all over again. The nicotine addiction, you can wean a lab animal off of nicotine in about a week, so why is this going on for 10 years? The fact is, with the alcohol thing, with acamprosate, it’s known to treat the recovering alcoholic to help them on their way, and most people use calcium acamprosate. It turns out the sodium acamprosate doesn’t work, so the literature is like 900 pages long about acamprosate and treating this condition, and people are on either sides of the fence, but one thing’s for sure; when you use the sodium salt, it doesn’t work; use the calcium salt, it does work. So Schuster said, “I’m going to try calcium alone in mice.” So, we have a model of compulsive disordered mice with a repetitive disorder, and we gave them the calcium, it stopped. So, we’re now doing it in horses, and we’re finding out that horses with a horse compulsion, they’re stopping, so we’re sure there are publications out from years ago where people have suggested treating OCD with calcium; it’s gone, it’s swept by the wayside. We’ve found them in retrospect, but they’re out there, and there’s another crazy idea he had, with the risk of boring you, is he learned, because there’s a component of goat’s milk called caprylic acid, and you take this salt of that sodium octanoate because it’s the same thing as sodium caprylate. You take this goat’s milk thing and, it’s used to treat some kind of tremor in people, and Schuster has essential tremor. It’s not Parkinson’s, but when he’s thinking very hard, his head goes to the side like this. It gets him into trouble at the lecture. Someone’s lecturing to him and he’s going like [---], so I see this guy in the front row looking at me like I’m insane. He is always in the literature about repetitive movement, so it turns out that this goat’s milk is a treatment. Nobody knows how it works. He decided to try it in his OCD mice. It worked, and actually, then he found if you give the calcium followed by the acamprosate, you have like a 2+2 is 5 treatment, so we’re giving the horses calcium followed by caprylic acid. The first horse we did was raised on goat’s milk, because its mother was used for milk for thoroughbreds, so they took the baby away real early, of course. Wouldn’t you know, the horse cribs or bites on the edge of his stall, of course.

So, enough of those genes. We are sequencing three severely affected Birmans. We’re particularly interested in the NCALD gene, and it’s one of the papers is calcium, Obsessive Compulsive Disorders: Cerebral Calcium Deficiencies of Possible Etiologic Pathogenic Factor in OCD. So, we’re getting in the calcium horse, so I was delighted to find an NCALD.

Alright, enough of that. I would have liked to have looked at the genetics at the behavior of psychogenic alopecia also, but the trouble with psychogenic alopecia is that it’s so easily confusable with a medical condition. The wool sucking isn’t. A wool sucker is a wool sucker. A tail chaser is a tail chaser, but I’ve had cats come into the clinic, and there’s this cat, the pattern is classical: inside, down the abdomen, inside the back legs, and I said I think it has it, but let’s just call in Dr. Stewart, the dermatologist, for a final say. So she comes in, puts on a x 10 loop, looks down and says, “I don’t think it is, Nick.” I’m like, “Why not?” and she says, “Look at this. Put the magnifier on.” Little red dots. That doesn’t happen in an OCD. You don’t get lesions. They just chew the hair off, so you have broken hair shafts; they’re like tearing the hair out, there’s nothing wrong with the skin. So, she goes, “I think it’s an allergy.” I said, “What are you going to do?” She said, “I’m going to use long-acting injection of triamcinolone acetate,” which is her favorite steroid. She injects it. Three weeks later, the cat’s not licking anymore. If it responds to corticosteroids, it is not an OCD. There are other things, too, that can cause hair to fall out, so it’s was a bit confusing, so we wanted to stay away from it, but I’d really like to look at it. If I did all the rule-out tests, I’d really like to look at this one next.

It is actually a feline version of trichotillomania, like I said. Anxiety leads to the repetitive behavior which is directed at self, and that occurs in people, and it occurs in parrots. Parrots are really interesting, because not every person and not every parrot, but one of the features of certain versions of trichotillomania is that the people, as they are doing it, they kind of go off into a dream, and they look around, they find that eyebrow hair, they find a particular one. They look for it. Usually a new growth, and they pluck it out, and then they look at the shaft, and they may chew on it. It’s called trichophagia. Then they discard it, and then they’re off again. The parrots take their beak, and they look down on their chest, and they look around for a new feather, like a little new growth, and they pluck it out, and they hold it in their little gnarly hand, and they inspect the hair shaft, and then they rip it into bits, it looks like a fan, and then they discard it. So even down to the details of behavior, the parrots look like it, the people have it, the cats have it. It’s an OCD, but we can learn so much, just talking about the biological importance. It’s biology. It’s the biology across the mammalian species. So, we can learn about cats from people, we can learn about people from cats, we can learn about people from dogs, and even parrots.

There are a couple of slides, inside the back legs, maladaptive grooming, out of context, repetitive and intense. Oftentimes, there is a stressor moment, and I don’t think I’ve ever not seen a cat that had a specific stressor moment, and one was a cat I wrote about in that first book again. It belonged to the now deceased Dr. Bob Fleishman a great vet from Northboro, MA, board certified in pathology, but running a general practice, and he had a cat, which was a calico and female which, actually, trichotillomania affects women more than men, and it affects female cats more than male cats. He had this cat, and he adopted another one out of the goodness of his big heart into his house. When the other cat came in, that day, the calico hid, wouldn’t come out, started to strip its hair out. So, the arrival of the new cat was a stressor, and we’ve seen that the stressor incident puts them right into this, and then they never stop. We did try to stop it; we used one of the, in those days, we were big on the Narcan approach. Used something similar to Narcan and had his wife medicate the cat every day, but the trouble with that particular medicine, it’s really, really bitter and, after about a month, she couldn’t catch the cat to give it the medicine, and he said “To hell with it, it’s just going to have to have it the rest of its life.” I said, “You could always give the other cat back,” and he said, “No!” Find it a new home, he wouldn’t, so that’s how it ended up. The treatment was working, too. Actually, I forgot. That is the cat. That is Bob Fleishman’s actual cat, and those arms are actually my wife’s arms from about 28 years ago. It looks anxious, and its face, it’s got a sort of frightened, starey look, and its ears are going back, and it just looks like an anxious cat. Here it is a shot of alopecia. The pattern is like, if you took a cat - I wouldn’t want to do this - by the scruff and by the rump, and you pressed it down onto some ink paper, the stain on the underside of the cat would be exactly where psychogenic alopecia strikes. If someone comes in and says it’s got fur on the outside of his back leg, it’s not it. It’s not a stressful incident, and having an anxious temperament, so I thought, even in the early days, with the horses, when I was sitting out there like a tent on fire, on high counting horses cribbing, I noticed that the ones who did it were much more active, so if there’s six horses in the barn, one had the cribbing that I was studying, five of them would be resting with a rubber lip on their leg, just hanging out, waiting for something to happen, like my dog Jasper, and others, like my dog Rusty, would be like it’s looking at the stalls, and it’s crib, crib, crib, so it seems to be a type A personality; an anxious, nervous, a worrier. My dog, Rusty, does the worrying for Jasper, because Jasper is always asleep. So, genetic predisposition, we’re sure, because of Oriental breeds overrepresented in the Siamese factor I mentioned. Other stressors involved, no spontaneous onset in the Tufts Cummings School of Veterinary Medicine caseload. Arose at any age, but often around puberty or earlier, which is the human situation, too. More common in females, mostly indoor cats. Never seen in a wild cat, which stresses the importance, if you’re going to have cats indoors, of company, environmental enrichment, exercise, games, training. You’ve got to get with the program, and our houses, typically, are not set up for a dog or a cat or much else, apart from us, you know the TV and all the remotes and that kind of stuff is for humans. You have to think like a cat to make an environment fit for a cat, if you’re not going to let it out and letting it out wouldn’t be a very smart thing to do these days.

There’s a little tiny, tiny family tree from Dr. Moon with one affected cat bred twice, leading to litters that had affected ones. She was looking into the family tree aspect along these family studies that Leslie was talking about. It happens in families. So, there’s a typical look of a cat with the condition. That’s atypical. So somebody brought that into me from the vet, and they said, “The vet thinks the cat’s got psychogenic alopecia.” I said no it’s probably got allergies, and it’s ripping itself open.

Here’s a cat. This is called Pia, P-I-A is the cat’s name, and Pia started to pull its hair out when its lady owner, who was a very highly-qualified human surgeon, went to England for a conference that lasted a week, and she decided to stay a few more weeks and just enjoy London, and she left a cat sitter, who came in, did the litter and the food. Then the cat, when she came back, she said, “I thought it snowed.” There was all white fur lying all over the place and, suddenly, she realized it’s her cat’s fur. That was what precipitated it and, incidentally, the other thing it did was bite its nails, because nail-biting is a mini-OCD in people and responds the same way to treatment, and this cat, I think maybe in one of the videos, it’s very poorly lit, but you’ll see it, it does a lot of nail-biting, too, which it didn’t do before. If it was better lighting, if we turned off all the lights and blew it up, you would see plucks, and you see like a little snowflake of white fur comes floating down. Poor old Pia.

Condition number three, because we’re getting short on time. Feline hyperesthesia. Is it a compulsive disorder? Because they do compulsive grooming. They turn around, and they start grooming at their spine, the base of the tail, or the tail, and yes, they do respond, sometimes, to anti-obsessional drugs like Prozac, but a lot of people don’t know that Prozac, in clinical doses, actually has anticonvulsant properties. So, I think, probably, number two, it’s a partial seizure, and it started actually here, this area. It was the California-Nevada-something tristate veterinary meeting, and I had said this is a compulsive disorder, and two sage, older vets, who looked like the two guys in the Muppets show sitting in the balcony, and they say, “I don’t know that is a compulsive disorder, because I’ve seen some cats who were doing it, and then suddenly they spin on the ground, and they go into a full-blown grand mal seizure,” and the other one, “Yeah, I’ve seen the same thing myself. Hmm!” So ever since then I was thinking about seizures, and everything I’ve done has indicated to me that’s the root. I’d really like to spend more time looking at it. It is more common, again, in the Oriental breeds of cats, and it’s very well known in Siamese. I think – yeah, that’s the tail of one of the first cats I ever treated; Jean-Paul the Siamese, whose tail was a rat tail because he ripped it off. What with that we know is, bursts of aggression, so I was called in to see Jean-Paul, because he attacked a student, bit him badly, and he had to go to hospital for IV antibiotics, and I went. They said, “You’ve got to come, you’re the behaviorist.” I was a brand-new behaviorist at the time. I rushed along there, and the cat was nice as can be, with a rat tail. We treated it. That was treated successfully with an anti-obsessional medication, but they respond equally well, and sometimes only to anticonvulsant medication. So, a stressor can be a factor. There are the same breeds again, the ones down at the right side of Leslie’s slide, the ones from the Asia department. Indoor cats only, so this is a stressful situation, and age of onset is atypical for an OCD, because OCDs happen before or during puberty, both in humans and in all the animals we’ve studied. They don’t start at five or four years old, because that’s too late. This starts later in life, and later in life is oftentimes when seizures start, and they do other things. Dilated pupils, their skin ripples, they have this frenetic grooming, and then, sometimes they have tail swooshing, or a fixation looking at that, and then they will run away like crazy, they run and they run looking over their shoulder, like being chased by somebody, and there’s no one there. Sometimes they see things. I had a picture once on a video, and I’ve seen it in my clinic. The cat, you stroke it on the spine – that’s what hyperesthesia does, heightened feeling – stroke it on the spine, and all of a sudden, it looks at the corner of the room and then ducks, and then other side, just like a little spaceship has come in and taken off, like little green men. I’ve seen it twice, as though they see things. An MD in the front row one time, he said, “Have you considered this as a possible model or schizophrenia? Have you tried treating it with neuroleptic drugs, the anti-schizophrenic drugs, the anti-psychotic drugs?” I said, “No, actually, I haven’t.” I almost got it published. I wasn’t sure I wanted my name on this, but there was a person who was a very senior human psychiatrist, Dr. Hollander from Columbia, and he has a journal called CNS Spectrums, and he said, “We haven’t got a model for it, can you publish this?” I said, “I don’t know enough to want to have my name on it at this point.” Sensitive to touch, may appear to hallucinate, mood swings from affectionate to aggressive, aggression may be self-directed, in terms of biting or ripping at their tail, or it could be aimed at people, which is kind of scary. I had a photographer come in to Tufts to take a picture of one and, as he’s filming it, all of a sudden the cat turns on him, and he said, “Eek!” and the cat leapt right at him, and the last thing you see before he dropped the camera is this cat flying into it. Sometimes, like I say, it’s associated with it. The late great Barbara Stein was a veterinarian who saw this as a seizure problem, and she said there are many different varieties of feline hyperesthesia, from the frenetic grooming. She had four different types and ended up with frank seizures. She was on my board.

This is a more typical version of it in a little Siamese. That looks pretty normal, just grooming, but they often do that head shake, and then they go do a stare. Groom, groom, groom. No good reason for grooming that much, that often, and then staring, big pupils, you see. That’s a minor case, really. This is a more major case. It’s a cat called Katie, and you’ll notice that Katie has a short tail, because when Katie’s owner came back one day, she found that she’d pretty much bitten the tip of her tail off, and their whole kitchen was covered in blood. This is not normal. Having a battle with your own tail. Very angry for no reason. The kitchen was covered in blood. It was like a seizure mannequin and she said, “I’ve got to get help,” so she came to see me, and I put Katie on Prozac, 3 mg a day. Absolutely, completely normal. Absolutely, “stone bomb” normal. In the days when I thought it was an OCD, but I say the Prozac has this anti-epileptic property to it, and then they interviewed a vet in California, and they said, “Dr. Dodman says Prozac can be used to treat this condition.” He says, “Well, I wouldn’t use Prozac in an animal, because well, it’s new, it’s trendy, and it’s expensive,” and he was wrong on all three counts. Anyway, you get the picture with Katie.

Another feline OCD, which is Munchkins. I learned this from Dr. Solveig Pflueger who is probably known to some of you, and she was somewhat instrumental, I understand, in developing the Munchkin breed. She said if you have a Munchkin cat, you’d better know where their stash is, because they will steal your jewelry. Any shiny object. They’re kind of magpie cats. If your earrings are missing, if you know where their stash is. They don’t do anything with it, they hoard, so they’re a hoarding cat, and hoarding’s a real big thing in psychiatry. I went down to see the head of clinical studies at the National Health, NINH, Dennis Murphy, who’s now retired. He leaned over the desk, and he says, “You don’t have an animal model of hoarding, by any chance, do you?” because it’s such a serious condition, it’s so hard to study it, and it doesn’t respond like the normal OCDs. “Yeah, a Munchkin.” “I would love to study them from the point of view of ones that hoard and ones that don’t, or some other comparison.” So many things to do and no more time. That’s not really true.

So, treatments. Some people out here might know someone with a cat, or have a cat that has some of these things. Physical strength might be necessary in extreme examples, like the Katie, Delila’s cat. It might be necessary to prevent self-injury while medicines work. It’s really a lot of medicine, but I don’t like to put these Elizabethan collars on cats or dogs or horses. I think physical methods are stopping; they’re kind of primitive. It’s like putting someone in handcuffs because they steal, or chopping off their hand, like they do in some of the Middle Eastern countries. I think you need to address the underlying stressors. I think you need to enrich the environment, get the cat a life. I think you need to consider medication, which would be the SSRIs, which is the Prozac family or, for feline hyperesthesia, the anti-convulsants. There’s another group of drugs. Ones we found out, in animals with OCD, we found out drugs called NMDA blockers, drugs that block glutamate in the central nervous system, which is the primary, the numero uno, excitatory neurotransmitter in the central nervous system. It’s not a small player, it’s a big player. If you block that, you block OCD in mice, you block it in dogs, you block it in horses. We took the idea to Harvard. The professor said, “Okay, I’ll try it in my people, but if you crazy vets are right, I’ll eat my hat!” Well, it was delicious. We took out a patent on it, which went nowhere, but we do have a publication on it in Clinical Psychopharmacology in 2010, and now we hope to have one coming out in the future, because we’re still working, Schuster and I. He’s sitting there, he’s 86 years old, with his bag of apples and peaches, which he always eats for lunch, and I’m sitting there with a clicker counter and score sheet with horses, calcium and the goat stuff. We’re at the next visit, I think on July 17th we’re going to east Long Island to look at another horse.

So yeah, medications, and that’s me, because we’re nearly out of time, but I’d love to hear your questions.

Leslie is going to be here, too. Let’s let the moderator come up. Thank you very much.

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Beginning of Question and Answer Audio

Dr. Glenn Olah:

If you have any questions, can you write them down on the piece of paper? There are some pens and pieces of paper on your table. We’ll have some people walk around and get those questions.

Audience member:

I have a question for Leslie, and I know her a little bit in the fact that she and I have spoken at the same program. I followed with FIP; she talked about genetics. You said you’re 25% Italian. I want to know what percentage Italian the Italian is?

Dr. Leslie Lyons:

The Italian? Barbara is in Italy right now. So, Barbara is 100% Italian. She’s from the University of Milan. So, often I talk about Barbara Gandolfi. She’s my cohort in crime. I call her the Italian, and so she’s in Milan right now, actually, visiting her family for about three, four weeks and stuff and boy, she’s about as Italian as you can get! She has learned to like hockey. She can’t watch football, she can’t watch baseball, but she’s like, “Maybe this hockey thing I can kind of like,” and she loves hot dogs, of all things, hot dogs, and she has discovered food trucks. Now, when I was growing up, you didn’t eat at the food truck. That’s where the truck that came to the miners and stuff like that, so you didn’t eat at the food truck, but now, it’s like fine cuisine, and there’s competitions for food trucks, so she knows the whole food truck schedule in Columbia, Missouri. Barbara’s great. Hopefully going to work hard to keep her at Missouri as much as we can, but we’ve got to work on funding for her as well.

Dr. Glenn Olah:

This question is for Dr. Dodman. “Cats who turn aggressive after requesting stroking, why? Why is it seen more in non-pedigree cats?”

Dr. Nicholas Dodman:

Well, cats, I think the simple answer is overexcitement, so they get very excited, and this is not really a neurological or a psychiatric condition. I mean, my cat, Griswold, when I got him, he was very big on that. So, you’d pet him, he’d get very, very excited, very worked up, and then he’d do some little frenetic grooming, but it wasn’t the feline hyperesthesia. He just would do it like what some people call love bites. They nip, and they nip, and they nip. Well, my wife, the vet, she’s pretty strict. So, she would bop him on the nose with a finger and say “No!” but he couldn’t hear. So, he’s like, “What?” and then she’d walk away. I did the opposite. If he did that to me, I would just walk away, and actually, he almost never does it now. It’s just, they get overexcited, and they’ve got to do something, whether it’s a grooming or a nipping. I just think it’s a cat thing, like knocking stuff off shelves, which he also does. If I leave a pen or our cell phones on the counter, he just does it on purpose.

Dr. Glenn Olah:

Question for Dr. Lyons. “For 99 Lives, for a breed without specific issues, what is the benefit of having one cat of breed sequence? How do we select the cat to represent the breed?”

Dr. Leslie Lyons:

Any healthy cats are important, because, as I’ve showed, there are 16 million variants in any given individual; me, you, or the cat. So, the thing is, a lot of those variants are good ones, or just do nothing, actually, what we call neutral variation, and so having a good, normal cat of a different breed, different breeds have different subsets of genetic variation as well, so having just a normal cat in there will help tell us, don’t look at any of the variants that this cat has, and so it helps weed out all the variants that are good things that are in our body. We need that genetic diversity, that’s the whole important part. So, any normal cat is extremely helpful. It is nice to have healthy cats too, because we want to study health, but I greatly encourage anybody to put in a normal cat.

Dr. Glenn Olah:

Dr. Dodman. “Do you believe hormones contribute to overgrooming?”

Dr. Nicholas Dodman:

Well, I don’t think they contribute much, although I shouldn’t say an absolute, definitive no. It sure is more common in females, but most of the females are already neutered, so it would have to be an effect of priming early on. I guess I’d have to say no, with a reservation, at this point. I mean, in the study that we did, we looked at neutering and un-neutering and sexes. I know it was wool sucking, but nothing came out of that, so I’m thinking psychogenic alopecia, there is this distribution. Who knows. Maybe it’s an early priming. I certainly couldn’t testify to it. One quick tip that I do learn from people in audiences, one time I was talking at a cat talk in Seattle. I was talking on feline hyperesthesia and another person, this time not two old men in the Muppets box, it was a lady vet from the back, and she said, “Feline hyperesthesia. I know it well. Have you ever looked at their cholesterol triglyceride panel?” and I said, “Why, no, I haven’t.” She said, “Well, if you do, you’re going to find out it’s completely off the charts, and sometimes she was implying not... I think triglycerides were sky high and, actually, sky-high triglycerides can cause seizures. I saw that in one dog that was a crazy bull terrier with all kinds of weird, wacky stuff. I said, “I think it’s having a seizure.” Took blood. Triglycerides, instead of being in the low hundreds, were up in the 2000 range. I treated it with the statin Lescol, which is a statin drug, and it got better. It was only a case series of one, but maybe these things have a bearing, too.

Dr. Glenn Olah:

Again, Dr. Dodman. “Have you seen many, or any, examples of obsessive grooming of one cat on another?” The questioner says he knows one that plucks fur from the other cat and won’t stop.

Dr. Nicholas Dodman:

Yeah, we’ve come across that. In humans, it happens, too. Some mothers, they don’t actually have trichotillomania, where they pull their own hair out, they pull the kids’ hair out. So, it’s kind of trichotillomania by proxy and, actually, Dr. Solveig Pflueger told me that the Ojos Azules cat they actually will overgroom and pull out their owner’s hair. If they have long hair, the cat will actually pull your hair out, and so she had long hair. I don’t know if she still has it, I haven’t seen her for years. She had very long hair. She had a Ojos Azules cat, and she had to have it so that it lived, I think it went and spent a lot of time when she was sleeping, and it went in the house next door, because she had to be out of the way of the cat, or she’d start losing her hair. So yeah, that happens, too, and the veal calves, back to them and the stress. They not only suck on themselves if they’re deprived early in life, they’ll groom on the nearest thing, which could be the next cat.

Dr. Glenn Olah:

Question for Dr. Lyons. “Regarding Devon Rex’s hypoallergenic progress? How effective?”

Dr. Leslie Lyons:

Many people have falsely thought that Sphynx and Devon Rex and maybe Cornish Rex are hypoallergenic, and that’s not true. All cats produce an allergen that people are allergic to, just some cats shed more or less, or have more or less long hair, so even a Sphynx is producing allergen. A lot of it is in their salivary glands, but a lot of it also lives in their anal glands, so they pick it up from their anal glands, and then spread it all over their body, isn’t that wonderful? People have also said poodles are hypoallergenic as well. Well, I’m told that poodles, their hair just grows more slowly, so they don’t shed as much. So, it’s not true that Devon Rex or Sphynx or any of these breeds are hypoallergenic. There is probably some truth to the fact that some cats probably produce more or less allergen than other cats, and maybe particularly in the Siberian breed, that there might be a much higher frequency that people have noticed. Other cats we didn’t notice, because people haven’t gone up and sniffed every cat to see if they are allergic to it or not. So, there’s probably some truth to that. I think there are probably cats that produce high and low amounts of allergen, but whether they produce hair or not, it has nothing to do with whether they’re producing allergen or not.

Dr. Nicholas Dodman:

At least cats don’t lick your face like dogs do!

Dr. Glenn Olah:

This is a question for you, Dr. Lyons, again. “Do you only want cats that are pure breeds for a whole genome sequencing, or do you want domestic shorthair cats with health issues?”

Dr. Leslie Lyons:

Anybody can play, so absolutely, the random-bred moggies are just absolutely great cats to have included as well. However, we want to make sure we have good health records on the cats. Unfortunately, the cats that I’ve put in from the different racial populations, we actually don’t have good health records on those cats, so we have to be careful of how we look at our data, but you have a normal house cat, and would like to put in the 99 Lives project, it’s absolutely more than welcome. I’m just thinking about putting my own cat in at some point, but we’ll see, she’s kind of a little pudgy. Big boned, you know. I could look at obesity with her! Yeah, so any cat is quite welcome to be in the 99 Lives project. Everyone is very important.

Dr. Glenn Olah:

Question for Dr. Dodman. “Could inappropriate urinating behavior in cats be considered an OCD behavior or treated with drugs?”

Dr. Nicholas Dodman:

I guess you could think about it that way. I mean, there are some that do seem very obsessive. I mean, it’s a natural, normal behavior, but if you have an anxious cat, who is stressed and does it over and over again and is hard to control, maybe so. I’ve often thought furniture scratching could fall into that category, too. I’ve seen cats that are minor league furniture scratchers, and then another cat moves in, or some stressful situation, they go absolutely nuts, because that’s a marking behavior, too, so if not furniture scratching, and the response to drugs? Sure, I don’t think many people would raise their eyebrows if you said I’m going to treat this major-league furniture scratcher, like my cat, Griswold, which is not being treated, but I probably could treat him with Prozac, and we know with urine marking that Prozac is the most effective treatment. When I first got into this, I was told urine marking cats, by a behaviorist who shall remain nameless, said, “Very often the solution is they have to be put to sleep, because people can’t live in this latrine situation, it’s causing breakups of marriages, selling of houses. You just have to give up.” Now, with Prozac, 100% of cats respond with a 90% to 100% resolution, simply with Prozac. I would say you need a good cleanup, too, with a decent product like Zero Odor. They’ve changed the formulation recently, but that used to be 100% percent fixed. I knew the chemical, and it bound to the sulfur containing minor groups. So yeah, it’s no longer like it was 25 years ago, like, “Oh God, what am I going to do here?” Try amitriptyline, try this, try that. Nowadays, it’s like, “Yes, I can help you,” and with litter box problems, 100% yes, I can help you.

Dr. Glenn Olah:

Another question for Dr. Dodman. Alopecia. The questioner wants to know if you’ve heard of the use of L-tryptophan in milk proteins in a food of Royal Canin called Calm? I think Hill’s also has the c/d, where they add the milk proteins and Zylkene.

Dr. Nicholas Dodman:

I do believe in L-tryptophan. Actually, I’ve done some studies with dogs, for aggression, but the fact is that, in Europe, they very often use either L-tryptophan or the 5-Hydroxytryptophan, which is the next in line, because L-tryptophan goes to 5-hydroxy, which you can buy at CVS, (5HTP on the bottle) which goes to serotonin. It’s just an amino acid. You can add it to the food. You will stoke the fire of serotonin, so you’re increasing the production. The only difference between it and Prozac is Prozac is, if you think about a bathtub, the tryptophan is turning the taps on to fill the bathtub quicker, and Prozac is when you plug in the bath to keep the water in more, and they can actually work together in tandem. Sometimes you go to Prozac, no response. You go with tryptophan, they work. I believe that L-tryptophan is very useful as an anti-depressant, anti-fear, anti-aggression, anti-compulsive, it’s got all these possibilities, but the milk protein I cannot handle that stuff. What I mean is I don’t even believe it works. There are a few companies out there – now people have gone all alternative medicine on us, it’s gone back to the ages before there was a veterinary degree - they’re using all these alternative treatments. I mean, it’s based on the fact that, supposedly, if you drink a glass of warm milk at night, you’re going to feel tired and relaxed. So, Ah! Good idea! We’ll take out the milk protein, and we’ll give it to them and call it a whatever it is, or stick it in some diet. When it goes down to the stomach, it’s going to be broken down. I talked to a behaviorist, Danny Mills, in England, about that, and he said, “The secret to the milk protein is it’s encapsulated, so it's not broken down in the stomach, so when it goes into your intestines it’s broken down.” So, it’s going to be completely dismantled when it gets there, and I just think there are a lot of king’s new clothes stuff around, but when you consider the placebo effect in veterinary medicine rises about 35%. In humans, you can give a human a blank tablet, and say, “This is a placebo,” and a large number of them, particularly with a certain dopamine gene glitch, who will automatically feel better, even though they know it’s placebo. Well, the animals don’t have that insight, but the owner does. So, if a dog is given, a cat is given, a horse is given a placebo, they’re going to think they’re seeing something because they want to. They’re living on blind belief, so if you give the milk protein, you’re going to get lots of vets who say, “I gave it, I’ve had a couple recently, they did that.” It doesn’t matter about one or two, because the owner is going to come back and tell you lies. It happens with everything. You have to have experiments that are designed to eclipse the placebo effect. It’s got to show 70% improvement, not 35%, for it to actually be real.

Audience member:

“I wonder if the milk protein, when it’s broken down, if it has more purines than again dopamine or serotonin more like tryptophan and amino acid sequences?

Dr. Glenn Olah:

This is a question for Dr. Lyons. “Is there a genetic component to FIP? Should siblings of FIP cats not be bred?”

Dr. Leslie Lyons:

I don’t think we just really know the answer to that. Certainly, we have shown that there might be a higher susceptibility in some lines of Birman cats, so we’ve published that with Dr. Petersen, but no, right at this point, I wouldn’t recommend not breeding a sib. I mean, many sibs are on general 50% alike, but that can range from 0% to 100%, so 50% is just an average, so you could have a totally different set of genes in a sibling that, even if you did have a cat that was susceptible to FIP from a genetic point of view, the sibling might not be whatsoever, so I have never been a big proponent of that.

Dr. Glenn Olah:

One more question for Dr. Lyons. This is the last question. “Regarding dilutes’ silver variant, how can the silver variant gene affect dilute gene?” There is an example, I think. The brown tabby female carrying the dilute, the silver male who appears as a blue silver, the male comes from a silver male and a brown patch female carrier dilute.

Dr. Leslie Lyons:

This is a Lorraine Shelton question. Where’s Lorraine? I don’t really know. I mean, to me, you should have like a smoke dilute cat, if it’s a solid cat. If it’s an agouti cat, then the band in between the blue should be white, and so you should still, as far as I know, should just have a normal presentation of silver, but on a blue cat, but Lorraine, where are you? It’s time for you to get into action. She was in the back there somewhere. So, that might be a good question for her. So not quite sure. Pictures always help.

Dr. Glenn Olah:

Thank you. That was the last question.

Dr. Vicki Thayer:

Please take your folders with you. Please come back to New Jersey and myself. We want to have these adopted. She would feel very bad if you didn’t take those home and enjoy what we’ve put in there, and I certainly brought the Kit-Kat bars that came in my suitcase from Oregon and hope that the TSA people didn’t confiscate them. Please enjoy, okay?