 Thank you for that kind introduction, and greetings to several of you in the audience whom I know in the practicing community here of ophthalmology in Washington. It's actually a very vigorous and vital dynamic practice of eye and vision care. I'd like to spend a few moments this morning talking about orthomic genetics and actually what is now happening in the application of that to care. Let's see if this works. There it goes. Some presentation objectives. I will briefly review some of the history of where genetics has come from historically. And you will by the end of this be seeing a number of ophthalmic photos of various eye diseases, the phenotypes, and then to consider where ophthalmology is going to be incorporating gene discovery in therapeutics. Eye disease in a big hospital like this at Suburban may not seem to have center stage, but in fact, the eye disorders collectively rank in the top 10 of the maladies that affect us as humans according to WHO just a few years ago. Obviously we see eyes all the time. I'm looking at a lot of eyes looking at me. And you see yourself in the mirror in the morning. And when you're looking at the eye, you're looking at the external anterior segment, the eyelids, pupils, sclera, iris, but hidden at the back inside are some vital elements of vision. The neural retinal tissue, the red lining here at the back. Red because of the molecule that is light sensitive, rhodopsin. At the center of the action, the macula, and you're looking at the slide with your macula, it's the fine focus center of vision. There are several major diseases here. We see three of the four major diseases of the eye cataract. A lot of cataracts surgeries are going to be done in the Bethesda and Washington community today. And glaucoma. Glaucoma straddles the front of the eye, where pressure can build up because of an outflow, obstruction of fluid, and that pressure for reasons that are rather indecipherable still at the moment ultimately affects the optic nerve which contains the axons of the 100 million rod and cone photoreceptors in the retina. And then macular degeneration, which is the scourge of vision. What is not shown here is diabetic retinopathy, the effect of diabetes on the major blood vessels that line the back of the eye. But that's the way we look at the eye when I was a resident 30 some years ago. Now we look at the eye as tissues and cells. All of these cells, the light sensitive rod and cone photoreceptors, the rods containing that radopsin that imparts the reddish color to the retina. And the cones which come in three flavors, red, green, and blue, and give us the full spectrum, chromatic spectrum of vision that we all enjoy. Now medicine is moving to cells. These cells have obviously been there a long time in the textbooks, but now we're actually dealing with these on a rather medically personal level. And I'm going to tell you some stories about rod and cone photoreceptors. But back on the thread of genetics in general in eye disease, here are six photographs. These are the kinds of patients who will be seen in the Washington community today. Individuals with cataract. This is a particular special cataract. You can see these white puntate dots, the cerulean cataract. This young child with the one eye is looking right straight at you, but with the other eye is rather askew, strabismus, muscle surgery. Pediatric ophthalmology. The front here, the iris looks good until you can see that it's not attached at the base. There's a dehissence, an iris coloboma, a developmental issue. And at the bottom, three views of the back of the eye. Age-related macular degeneration, a sheet of blood on the back of the eye. Through which vision is going to be distorted and when this blood consolidates and tears up the neural retinal tissue, obviously the vision is going to be the impaired significantly or glaucoma. The enlarged yellowish center missing the axons because of elevated pressure in the eye. And macular degeneration of the Stargardt flavor. Dr. Stargardt, German, two centuries ago. An overt genetic problem of vision. But in fact, all of these have a genetic issue going on. So the public health impact of all of this vision impairment is considerable. Tens of millions of our fellow citizens suffer visual impairment due to diseases that have either a direct genetic basis or result in part from genetic risk. And as we have birthdays every year, the incidence of age-related eye diseases is increasing at an obviously large cost to us as individuals and to society. So while eye care is well advanced, in fact we need to have more effective therapies. Let me just tell you how I'm going to be using words today. Genes, genetics, genomics, and medicine. They flow together. Genes, the biologic code. Genetics, the play out of those genes, let's say in families. Inheritance in families and ultimately affecting society. Genomics, how the gene product, the product that the gene makes. Affect cells and ultimately what the mechanisms of cell processes are and how that plays out in disease and medicine, the treatment of disease. That's what we and you will be doing here today at Suburban. And what we have seen is that we started with genes and we're now squarely in the camp of medicine. But let's roll the clock back two and a half millennia. Hippocrates, blue eyes are inherited. That's an interesting idea. Or speaking in Greek, so I'm translating. Squinty-eyed children have squinty-eyed parents. When a nearsighted person squints through narrowed eyelids, you perceive a little bit better. And if you look at the kids who are nearsighted, you will find that quite frequently the parents were nearsighted. Or Aristotle, 50 years later, further described myopia. And he recognized that blindness can be transmitted between parent and child. And that was an idea picked up later on by Plotarchus. Speaking of the biblical Isaac and Jacob, both of whom had older age vision loss. And he had the concept of hereditary old age blindness. It was that macular degeneration. Now speeding up the clock and going back to 1770, Lorton Dalton recognized that color deficiency runs in families. And it is us poor, feeble men who suffer it as opposed to women. That's because the color genes are on the X chromosome and men have only one. Whereas women have two X chromosomes. And when the men have the color deficiency on one, there's nothing to mask it. Whereas the women have a second copy that usually has a normal color gene on it. And then a century later, Horner recognized that quite frequently men who were colorblind had uncles, mothers, brothers who were colorblind, speaking of X chromosome inheritance. And then going a century further, just a few decades ago, Jeremy Nathan's cloned one of the genes that imparts light sensitivity and ultimately color vision, not with Riddopsin but with the coloropsin genes, Riddopsin and the coloropsins. So if we look at that year 1983, when Riddopsin was cloned, there were very few genes that were captured. But across the three decades span, the vision community has been extraordinarily vigorous in identifying genes related to eye disease. And now there are some 600 genes that are known, 200 that affect the retina, nearly 200, 150, 200 that are affecting the lens and the cornea at the front of the eye. The eye turns out to be, unfortunately, very rich in monogenic traits in which a single gene causes a vision problem. In fact, still about 20% of the identified human disease genes involve the eye and vision. So when we have all of these hundreds and hundreds of genes, what difference does it make? Well, we, we, Medicine, Science, Vision, Research, we are now imparting on the new frontier of addressing these problems at the gene level. In a moment I'll tell you about RP65, a molecule that causes LCA, Labor Congenital Amorosis. But let me defer that for a moment. In this case, however, that there is a defective gene, actually both copies, both alleles of the gene are defective. And by providing an external normal copy, one can restore the cellular function that depends on RP65. Or in the case of parent to child direct transmission, a dominant transmission, one may, in fact in animals you can, but in humans may be able to suppress that one copy that's defective and allow the second normal copy to function throughout life and retain vision. So you'd have to suppress the mutant gene or repair it or just go around the whole system, don't worry about the gene, but deliver some other product that is therapeutic. Let me turn back to this RP65 for a moment. The story starts in 1869 when Dr. Theodore Labor saw several children who were blind, they were born blind, severe vision loss, they had bobbing eyes, nystagmus movements, a sign of congenital severely impaired vision. And a century later when the electroretinogram was invented or identified, used that the responses were found to be non detectable. The electroretinogram is similar to the electrocardiogram, but in this case it's for the retina, the neural tissue in the eye. And that tissue was not functioning. These are pictures that I was taught when I was a resident 30 years ago. So you look into the eye and sometimes you see nearly nothing, but the child's not seeing. Other times you look in and you see darker spots of injury pigment from injury to cells in the eye or you see a disillusion, a breaking up of the neural retinal tissue. So this is LCA, labor congenital amaurosis, Dr. Theodore Labor's congenital blindness, LCA. This is LCA, as I was taught it in the premolecular era. This is now LCA, 19 genes and counting. These genes are functioning at the level of the rod and the cone photoreceptors and the supporting tissue called the retinal pigment epithelium. And these 19 genes in fact are playing right here and the one that I'm going to focus on, RP65, is involved in the vitamin A cycle. Eat your carrots, grandma was right, if you don't eat enough carrots you're going to have vision problems because you need vitamin A. And in fact there are enzymes specifically at the back of the eye that process dietary vitamin A and make it available in the proper molecular configuration to function for vision. So let's return to RP65, the molecule, and go about a decade and a half ago, Mike Redmond working just across the street in the laboratory in the National Eye Institute was looking at the genes that are abundant or actually the proteins that are abundant in the retinal pigment epithelium RPE and there was one with a molecular weight of 65 so it gets the name RP65 protein. He cloned the gene for it and everybody admired his technical prowess. He's got a new gene. What does it do? Nobody knew. Five years later Mike knocked out the gene in a mouse and the mouse was blind. So we know that RP65 is critical for vision, rather crude way of finding out but very effective. At the same time in Australia humans were found by a geneticist, humans were found to have mutations in the RP65 gene and they were blind. In fact they had LCA, labor congenital blinds. And then the story moved to Sweden where a dog was found, the Swedish Breard dog was found to have mutations in this gene. And then the story speeded up quite a bit. Here is one of the dogs, a Swedish Breard dog. Actually that's not I'm told a Swedish Breard dog but the gene was put into the dog so that this dog did crossbred etc. But this dog was blind from RP65. And then within a matter of 1998 to 2001 just in the space of a couple of years gene therapy was done to put the normal RP65 gene into this dog and a couple of weeks later you could play frisbee with you. Obviously great story to take down to Congress. Everyone loves dogs, everyone loves genetic stories so he is our best ambassador for vision. Literally Senator Harkin has met him etc. Well looking at the electro retinogram function complex slide but not that difficult. Panel one, two, and three. Middle panel, flat responses, this panel, big waveforms in a normal, in a normal compared to this dog before treatment, no action. This is very dim light and very bright light. A flash of light startles the neurons and gives it these waveforms. And you like big and you don't like flat and the dog is flat. But when you put the gene in, RP65 gene, look what comes back. That's why the dog can play frisbee with you. In fact the dog tells you it's got vision and the electrical function says it has vision. Well from 2001 it was just a major step but only a few years before gene therapy was done for kids who had LCA from RP65. And that was recognized by Science Magazine a year later in 2009 as a seminal event in science and medicine. It was only the runner up. I don't remember what the winner was but I think it should have been the winner. Here is Al McGuire, one of the authors on the first report of treating these kids with blindness. And he is treating a young man injecting the gene into the eye. Let's just look at what that really means to treat an eye genetically. What he is doing here in cartoon is to take a very narrow needle, fine needle and put it through the eye wall underneath the retina. Inject some fluid that contains the vector. Make a little bubble or here another illustration of bubble. Here are the rod and cone photoreceptors. Here is the retinal pigment epithelium where the gene resides. So he puts the fluid next to those RPE cells, provides the gene ultimately and this child is now playing baseball. Well this is, that was RP65, one example of gene therapy for vision. And there are many others. Stargardt macular degeneration I mentioned that showed you a slide right at the outset. Dr. Stargardt, we know the gene it's ABCA4 and there is a company Oxford Biomedical which is quite vigorous in working in gene therapy. In this case they are using lentivirus because this gene our ABCA4 is a monster. It's huge. It has nearly 60, 60 exons. It's a big, big gene. It doesn't fit in most delivery vectors. So you turn to something that can carry a big cargo, the lentivirus. And they have a trial going on. Starrgen just started recently. Here's another one, Usher syndrome. Children born deaf and rapidly going blind such that by age 20 they really have negligible residual vision. Also a big gene. And they have a trial going on for Usher syndrome. Or, and these are direct, these are direct gene therapy, these two, these two trials. Or somewhat indirectly using the same delivery, the lentivirus, but delivering therapeutic vectors, therapeutic molecules, endostatin and angiostatin, delivering the gene that makes the protein and the protein rescues the function of macular degeneration diabetic retinopathy causing new blood vessels, neo vascularization of the retinone. And in aggregate the vision community is quite vigorous in working in the area of gene therapy. Labor congenital amaurosis, RP-65, start of the ball rolling. Here's Usher syndrome and Starrgarts, soluble flit. Many of these currently are being done in outside the U.S. But we expect that they will be moving here into the states soon. What else do you do with genes? You've got genes. What do you do with them? Well, how about using them for medicine to inform people of their fate? Here is an interesting story that I would commend to you, New York Times, July 9, last summer. And this is for ocular melanoma. You can read it online. Cassandra Catten, age 18, noticed a vision problem, went to her ophthalmologist who said, Cassandra, you've got a problem. You've got a tumor. You've got a cancer in your eye. It's growing. It's broken up the retinone. We're going to have to do something. In this case, the doing something literally is to remove the eye and nucleate the eye. Because you can't contain this cancer. You take it out at the source, take the eye out, put in a prosthetic shell so that cosmetically you and I wouldn't notice. But obviously you're losing an eye, Cassandra. Well, ocular melanoma, melanoma, skin melanoma, it's a pigment cell condition. So it is the pigmented uveal tissues of the eye. Here at the front of the eye, the iris has a pigmented tissue. And you can see the iris melanoma kind of fluffy, elevated. It's a growth on the iris. Bad, bad, bad sign. That eye is in serious jeopardy. Or looking at the back of the eye here is a tumor, a melanoma, a ball of melanoma growing underneath the retinone. About 2000 Americans will be newly diagnosed this year. And half of them are going to die from metastases. But the story becomes extremely interesting for these patients. But also for all of cancer, by the work of an ophthalmologist, Bill Harbour, working at Washington University St. Louis, who collected these cases and began to do proteomics on them. And sorted out the cases as people who didn't die and people who did die and compared those, and came up with a critical difference. People who died, he found had mutations, an alteration of the BAP1 gene in 84% of those metastatic tumors. BAP1, breast cancer, BRCA1, associated protein 1. And his findings suggested that BAP1 suppresses metastases. And so if you, it's a negative, double negative statement. If you make mutations in this, you cause metastases. So if we, and this paper published in 2010 was rapidly turned into a medical diagnostics test by Castle of Biosciences in 2011. And you can order it here in suburban. Turning back to Cassandra, the question now is which class is she? Class 1, over the span of five and six years, they don't die. And this is a composite of several hundred cases of oculomelanoma. Or is she in Class 2 with a median survival of just over four years? It turns out, read it online, she has Class 1, she's all set. But the second part of that same story is another individual who falls in this class. That is medicine, folks. You can't always fix things, as all of us know. But you have to work with patients and give them information that they can act on. And I think this is first class medicine. Well, what about this rumor that people don't want to know what they've got? Let's stick our heads in the sand. Don't think so. People want to know about the genetics in their family. These, I make a joke, are two of my favorite magazines. And in one year, 2007, science has human genetic variation, breakthrough of the year. And Wired Magazine says your life decoded. People are very interested in their genetic status. So how does ophthalmology deal with this? We've got 600 genes to deal with. And we're just scratching the surface. How do we deliver on the promise of diagnostics and genetics for people at a time when opportunities are expanding? How do we handle a large variety of these infrequent monogenic diseases in which one gene is converted into a disease? Several years ago, the I Institute initiated a project called I-Gene. Because several years ago, there were boutique laboratories, research laboratories that were doing genetics for one or two genes. If you are interested, just go back to your computer and Google I-Gene. And this will come up so you can get the information yourself and participate if you wish. It's a national network of these boutique laboratories that in aggregate are testing 35 genes, excuse me, about 100 genes for 35 diseases. And the scheme here, this is under the National I Institute. So our scheme is, yes, it's important to provide diagnostics to people and genetic information, but it's also critical for research to know the medical characteristics of those people. This slide breaks out into three parts. The patient and the physician, part one, sends a sample to coordinating center in Kerry. I see you sitting there. Kerry, raise your hand. Kerry is running that right across the street. And the center sends it, distributes a sample to one of many laboratories that are boutique research laboratories at the moment. They've got special expertise in your gene, if that's what you need. The information comes back, goes back to the patient. That's medical care. At the same time, the individual signs a consent right up front that says, anonymize my information, keep it safe, but use it. Use it for research so that we can understand what these diseases are and how to proceed. So we've got a unified medical care research venture going. We've got, has a registry, consent, contact information, the phenotypes, meaning the medical characteristics, the genotypes, the gene level, and a repository of samples. It has been well received across the country. All but five states have participating sites. I keep telling Kerry to take a site visit to Vermont to encourage them. She wants to go to Hawaii and Alaska instead. And we're enrolling about a thousand patients a year. I think, Kerry, that's your saturation point. A lot of hands-on work, but the importance is to couple what happens in this hospital, the medical venture of patient and physician, medicine, to get that information put together with the genotypes so that we can move on with understanding the interplay between phenotypes and genotypes. Diagnostics is moving on, as we all know. Now we're at the level of sequencing the entire human genome for individual patients, and particularly with suburban couple to Johns Hopkins. This is state-of-the-art medical care. It's tricky because the information is so vast, 20,000 genes you're looking at or something. The information is so vast that it becomes an analytics problem and not a cost of sequencing problem. The cost has dropped over the past six, seven years from a million dollars for your genome to a thousand dollars for your genome. That's not the cost. The cost is the analytics and the medical information to extract from that. Ophthalmology has been front and center in this. This is a page 2010 science magazine, affordable exomes fill gap in rare diseases. Yes, a lot of our diseases are rare diseases, whether they're cardiology diseases or ocular diseases. In this case, what was featured was the Litsky family, Betty and Carlos, four wonderful kids born with vision, no problem. Unfortunately, three of them are now blind. And despite all of these boutique laboratories in vision looking for this gene in the Litsky family living in Miami, it was elusive until a group just shotgun the human genome in this family and came up with a new gene, DHDDS. It turns out to be an enzyme that put sugar groups on the rhodopsin molecule and the rhodopsin molecule I mentioned was cloned by German Athens in 1983. And without those sugar groups, the rhodopsin molecule, the light sensitive molecule of the eye doesn't function and so the kids lose their vision. And now therapy ideas are moving forward in animals for DHDDS. So far, I have spoken only of these single gene causes you the problem diseases, single gene diseases, monogenic diseases, Mendelian, Gregor Mendel diseases. But there's a whole world of patients seen in this building who have what are called complex genetic diseases. In general, these are the most common that affect us. And they are due to risk factors that ultimately impair together collectively impair cell function and cause disease to happen. Most common of those blinding conditions for ophthalmology is age related macular degeneration AMD. And at the bottom, what was unfolding was a panoply of pictures and normal fundus, the optic nerve, the blood vessels, the macula, the reddish retinal tissue. And with aging, a number of individuals develop these spots, their lipid accumulations, their debris accumulations, they're called drusen. And those drusen predispose, heavily predispose to one of two things, either atrophy, death of tissue or hemorrhage. And for either of those, when you have this in the center of your vision, you can't see through it. You are blind, legally blind at least 2200 from loss of central vision. You've got your peripheral vision, you can get around. But you can't drive, you can't play cards, you can't watch TV, you can't read. Two million Americans are already legally blind from AMD. Many more are at risk, and we're all getting older. So let's get on with the show and do something about it. But this is a complex disease. There's no single gene to be looking for. You've got to look for the risk conveyed by a gene. And in fact, well, here's just an illustration of cartoon form of havoc this causes with vision. And then a seminal event happened just a few years ago, 2005, when five groups simultaneously identified the CFH gene, complement factor H gene. Just parenthetically, I love being part of the vision community. We don't do it one time, we do it five times. You worried about, is this report true or not? Well, this article of this issue of science has three independent groups publishing the same gene, identifying the same gene for AMD. And I would congratulate Emily Chu sitting here, who with Rick Ferris and John Paul Sanjuvani at the I Institute were front and center in the Klein article of CFH gene. So what does this tell us? It's only a gene. Well, this tells us a lot. This is the complement cascade system, the immune system of the body. And within a year, two more complement components, factor B and complement component C2 came on the scene, more risk factors for AMD. This says that AMD is a cousin of other chronic diseases that have a play with the immune system, Alzheimer's, Parkinson's, cardiovascular disease. These are cousin diseases in invoking the surveillance mechanisms of the body. And quite remarkably, if you add up these three genes, 74% of the risk of developing AMD is accounted for. These are heavy big players. Here is a schematic, simplified schematic of the complement cascade system. CFH sitting in the middle plays in all three pathways. Here is C2, here is C7, here is factor B. So AMD is somehow invoking activity of the immune system. And obviously, that last slide gives us some therapeutic targets to consider. Well, I'd like to roll the clock back to 2005 for just a minute. Here are the Mendelian single gene monogenic traits. In 2005, there were 1700, and at that point, vision ophthalmology had identified about 450 genes that caused vision problems. In other words, the vision community owned, very strong word, don't mean to imply anything, but contributed a quarter of the cloned disease genes. Whereas the complex traits were poking along here a different scale at fewer than 10. And then AMD came on the scene. It was number eight or nine in diseases for which risk genes had been identified, rather seminal accomplishment 2005. Here it is. This was the only gene identified, only disease gene identified in 2005 for common complex disease. By a year later, 12 months later, here's a second macular degeneration gene. And here we have a cardiovascular problem, prolonged QT interval or inflammatory bowel disease, rare company 2006. 2007, medicine catches up. 2011, oh my goodness, here's the state of medicine. This is now, what, a year and a half ago? 249, 250 medical traits, common complex diseases, 1600 genetic studies. The entire genome is populated with knowledge about the diseases you and I see today at suburban and at NIH. But I don't want to imply, as some people think I do, I don't want to apply that life is merely genetic. It's bad enough to have the complement factor H gene, because that increases your risk of developing AMD fourfold over not having it, or sixfold for another AMD locus. But if you smoke, watch out. That fourfold goes to ninefold, and this sixfold goes to 22. So life is complicated, but a lot of what we deal with is genetic. So how do we find these genes? The first three kind of dropped in our lap. Total surprise to me, Emily, thank you for pursuing this. But how do we find the rest of the genes? The I Institute a few years ago under Haman Chen organized a group, a research group, 24 different research groups, and they pooled their cases, several thousand disease cases, and I didn't schedule it this way, but there was news yesterday that this group, their paper has just been accepted in Nature Genetics to be coming out soon, which will report a total of 17 loci, 17 genes conveying risk for AMD. That takes concerted action. And it's bad enough to remember all those gene names, but the important thing is, those genes begin to cluster. We talked about the cluster in the complement immune system, cascade. Some of the genes cluster in lipoprotein pathways, others in matrix pathways, others in angiogenesis signaling pathways. So now we're getting a flavor of the complexity of AMD. And the I Institute is doing the same thing for glaucoma. Glaucoma has been recalcitrant. No real genes. Yes, there are tigromyacillin gene late night, when was it? 20-some years ago. But other than that, genes have not been found. But getting together a group under auspices of the National I Institute, they just last fall published a whole genome scan, and there were two loci that popped up. So we hope that genes will be found. But actually the lesson on this is kind of curious. This group met three weeks ago, and what they concluded is their clinical input is off base. The genetics is fine, but it's not coming up with things because the clinicians are saying they really don't understand the concept of glaucoma. That's an admission for our clinician, right? But it's an important part of how this field moves forward, to take genetic information or the lack thereof and have it feedback into medicine. So how many genes do we need? Is 17 enough? There's a lot of information that just flashed up here, but let me run this real quickly. If we take those three genes that accounted for about 74% of the risk, the first three major genes, it turns out that we classify 74% of the true cases, but we would miss on 31% of the controls. Not bad. Two to one. The problem is, many, many more people are in this normal group who will not get AMD. So when you do the multiplication and misclassify a huge population, misclassify it one-third of the time, it turns out that in seven of eight people you say are at high risk, you're wrong. That's not a very good test to use. So in fact, you do need a lot of genes and this is going to be a very complicated process in complex diseases. Maybe that's why they're called complex diseases. I'd like to just wrap this up in a few minutes. What's next? Here are some seminal events in medicine. Polio vaccine. Many in the room are old enough to remember the excitement that this generated. And then a decade and a half ago, cloning a mammal. Oh my goodness, the world was going to fall apart. This was seminal. And a decade ago, the Human Genome Project, Francis and Craig Ventner. Seminal events. I'd like to, and they all made well in time and time, but here's a seminal event for ophthalmology. Published Nature a year and a half ago. This, folks, is a mouse eyeball grown in culture from single mouse embryonic stem cells. This is a seminal event. Yoshiki Sasai did this work. We had him speaking across the street last year. He started with mouse embryonic stem cells and they grew into not a monolayer of cells, but in fact, organized a whole organ. The eye. All that's missing is the lens and this thing could see. The eye could see, but how do you connect it to the brain? Well, we've got to figure that out. And when that's figured out, we will be able to grow new eyeballs for people. That's a bold idea. A year ago, I took that idea to the National Advisor Eye Council, the oversight body for the NEI, and said, let's consider being bold. Let's consider being audacious. The Eye Council took that up and they came up with the term audacious goals challenge. This was an aspirational slide a year ago, but it's now reality because two weeks from now, a week from Sunday, two weeks from Sunday at the Bolger Center in Potomac, we will have 200 people comprising all of these disciplines together to think about how to stimulate innovative, visionary thinking to take vision forward. So stay tuned, please, because this will be two weeks from now. Obviously, it takes a little time, but I'm pleased actually that a mere 12 months after proposing the idea, in fact, we're able to act on it with 200 clever thinking innovative scientists getting together to envision the opportunities again. We'd like to be at the edge of current technologies or maybe even beyond where we are. Ten years to make things play out would be our goal, and that's a long time. I don't want to do science fiction, so let's stay in the ballpark, but let's actually think about what we can imagine doing. Can we connect an eyeball grown in a dish into the brain? I have no idea. But if one could, what would be the implications of that kind of thinking? So the Institute will invest a significant part of its resource, our resource, your resource, because it's tax dollars, into thinking the next decade and two decades ahead. Well, that's it. I thank you for your interest, and I think that we are moving ahead, and I think all of medicine is just leaping forward now. This started, one measure is a decade ago, with Francis and others working on that human genome. It has proven to be seminal for medicine, for research, and now for patient care. Thank you. I have a few comments or questions, but obviously, yeah. When you do replacement of genes, is it a one-shot of a therapy, or do you have to have repeated replacements, and is there self-generation, would you give? Well, that's a very interesting question. Could you paraphrase it for us? That's an interesting question. So when you do gene therapy, do you do it one time, or does it take repeated dosing? You can do it one time in most cells, and particularly cells such as a pigment epithelium that don't divide and replicate. The gene goes in, it snuggles next to the chromosome, the genetic elements that are in the cell naturally, and then acts, as though it had been there a long time and it stays there. That is certainly the case so far for the dogs that were treated, our representative to Congress, just died a decade after the therapy and had not lost anything that he had recovered. So it looks like it's a one-shot deal. And actually, buried in that is a seminal problem for the pharmaceutical industry. How do you price it? How do you cure somebody? One shot. How do you price that one shot? Is there a special place that the central nervous system has as a sanctuary away from some of the immune system out in this matter? We think so. The neural tissue, the retina tissue at the back of the eye is relatively protected from immune attack, but it's not actually totally isolated. It is simply, the immune system is slower to act with it. So we're not totally immune, but it does give us a head start. You just snuck that in on me. So do the viruses cause a problem? I thought you were first talking about what's used currently, AAV, adeno-associated virus. It seems AAV seems not to cause a problem. Lente is of greater concern. It's part of the HIV-AIDS axis. And so those lentiviruses are engineered quite specially and specifically to remove elements that might cause cellular proliferation, tumor growth, etc. So far, with the lentiviruses that have been put into the human body, they, therapeutically, they are not causing a problem. I'm sure at some point there will be something that happens. But in general, I think it's a safe statement that prudence, medical prudence, research prudence, can't overcome the problem. Turning that around, the origin of diseases? I'm not a virologist. I would look to Bob Nussinblatt sitting back there quietly, who knows a lot more in answer to your question. In this case, the viruses that are being used are the genome of the virus, codes for some very specific elements. And those elements have been taken out, re-engineered and put back together. So these viruses are disabled historically. Do they cause? Well, they can be. There are examples of genes in the wrong place, or genes from one organism, one species, and another species. And it is thought that they were deposited by a naturally occurring viral vector. So in fact, viruses genetically can cause mischief. Yes. Absolutely. That's the point of it. I would encourage you to go to iGene and you can read a little bit about it. But this is a public database, public in the sense that through research permissions, one gains access to it, one gains access to securely coded information. There's no private information, individual information. But one can and research can drill down to that individual level because of the consensus that are in place. So what about commercial gene testing? Specifically, the question is phrased for common complex diseases and for AMD. Again, go to Google, type in AMD gene testing, and I'm sure you'll come up with a bunch of commercial sites. What do you make of it? Talk to Carrie next to you. She'll have the answers. But here's my answer. I showed you the example of the mischief that is caused by imprecise information. The genetic testing that is being done by these services does nothing more than we do. And consequently, they are going to be mislabeling a considerable number of individuals who will not be getting AMD, but think they may because the testing is imprecise. So it's a risky area, difficult area. Could you comment on the process of getting this wonderful science out into the hands of practicing clinicians who are out there slugging it out every day? How is that working? How is it working in the eye world to engage day-to-day practitioners? I am pleased to be an ophthalmologist because I think the ophthalmology community is the best. Oh boy, I shouldn't say that. But it's very good. And ophthalmologists seem to be curious people, people who are curious, and they are incorporating genetic information as rapidly as all of medicine is. Now, one of our strategies with the iGene genetic testing, in fact, was to engage community ophthalmologists. And as that map of the United States all coated green, except for six states, the practice community, in fact, is participating in this. And the American Academy of Ophthalmology meeting every year, like all professional societies, has specific sessions on genetics testing and implications for practice. Do you focus on competencies or basic knowledge or both? It seems to me that quick way to get this engaged, doctors understand how to function with this data rather than knowing which exon. That is a critical, critical issue. And again, I'm going to point to Kerry because she thinks about this, as does her compatriot next door, in how does one use genetic information. So you're a practicing physician. You're seeing a patient with Stargard. What do you do with the information when it comes back? It is going to be necessary for all of medicine to be teaching genetics hard, core genetic knowledge in our medical schools as they are doing. Other comments or questions? Yes. So how do you tailor therapy to the cells and parts of tissues that are in particular need? Well, for the RP-65, the congenital blindness, labor congenital blindness, RP-65LCA disease, that is an enzyme deficiency in the retinal pigment epithelium. So you put the vector right next to the pigment epithelium. You flow the fluid right onto the pigment epithelium in the operating room right here when retinal surgery is done. So you can get the gene in physical proximity to the tissue. Let's say that there's an extraocular muscle problem. It is easy to put a needle to the muscle, deposit some fluid and have it suffuse through the muscle fibers. So in fact, for ophthalmology, for the eye as an organ system, the eye is very amenable to genetic intervention, I would think. Other comments or questions? No, please join me in thanking Dr. Segal for one question.