cc  >> Good evening.  Welcome to Wednesday Nite  at the Lab.  I'm Paul Brandel.  Tonight we are very pleased to  have Arthur Polans  present us information regarding  the role of the UW Eye Research  Institute and help us to keep  an "Eye on Cancer."  So Arthur Polans, welcome.  [APPLAUSE]  >> Well, we'll still see if  you're applauding at the end  of the presentation.  But thank you for the  opportunity to come and speak  you with this evening.  And mine is going to be a tale  in two parts.  The first more substantial  segment of my presentation is  going to be about the research  activities in my lab, and then  the second shorter segment will  be about the role of institutes  and centers and specifically  the Eye Research Institute in  fostering collaborations on  campus which are so very  important to scientific  productivity and the enhancement  of scholarly activities on our  campus.  So to begin with, I'm interested  in the use of nontoxic  natural products as possible  chemotherapeutic agents.  And when you hear the term  natural products, it may conjure  up images of new-age healers,  gems and incantations, but  they're actually the mainstream  of medicine. 

 The treatments of most human  diseases are with the use of  natural products and that's not  simply a historical consequence.  Even in this era of  combinatorial chemistry,  over 70% of the new drugs  entering the market each year  for the treatment of cancer,  the treatment of infectious  diseases, they are natural  products or based on the  structure of those products.  So to begin with, let's show you  a couple of examples.  So Vincristine and Taxol.  Vincristine comes from the  Madagascar periwinkle,  and Taxol from the bark  of the pacific yew tree.  And there are other examples of  chemotherapeutics.  A popular one these days is  Doxorubicin and that comes from  a strain of streptomyces.  So these are plant products and  products from microbes that are  used to treat cancer.  The problem with these types of  chemotherapeutics is that they  don't differentiate well between  cancer cells and normal cells.  So they're toxic. 

 And they have all of those nasty  side effects that you're  probably familiar with when you  think about chemotherapy.  And so that's led us and a lot  of other people to look for  nontoxic natural products that  could be used to treat cancer.  So some of the ones you may have  heard about in the popular press  and EGCG that comes from green  tea or curcumin from turmeric.  And this list is actually very  long.  It would go through the basement  of this building.  But probably the compound that  we know the most about is called  Resveratrol and it will be the  focus of my presentation  tonight.  It's a very simple structure.  Just two rings and three  hydroxyl groups.  Those OH groups.  And it's what's called a  phytoelexin. 

 It's made by plants as part of  their protective mechanisms  against infection.  And you find Resveratrol in  grapes, berries, peanuts, the  roots of some kinds of plants,  but frankly nobody was  particularly interested in this  compound until the early 1990s  with the advent of the so-called  French paradox.  And what this referred to is the  finding that the French, who  have diets high in saturated  fats, nonetheless have a lower  incidence of certain  cardiovascular complications,  and that was thought to be due  to their higher consumption of  wine, especially red wine, which  contains, as a component,  Resveratrol.  Then in the late 1990s, there  was a very important paper  published in science by --,  and colleagues, in which they  demonstrated that Resveratrol  could also, in animal models,  prevent the development of  certain types of cancer, and  importantly, those levels of  Resveratrol that could prevent  those cancer models were  nontoxic.  And so that's led to a lot of  interest in Resveratrol as can  be seen over the last few years  in the increase of number of  publications.  And this is now being studied by  the nutritionists and  epidemiologists at one end of  the spectrum, by the chemists at  the other end, by people who are  interested in heart disease,  people who are interested in  cancer and, as I'll tell you  towards the end of my  presentation, people who are  interested in age related  diseases like diabetes.  So what I'm going to do in this  first segment of my talk is tell  you a bit about the mechanisms  of Resveratrol action.  That is the so-called in vitro  studies that we can do in  petri dishes and in test tubes  to figure out how this drug  kills cancer cells.  In the next part, I'll talk  about pre-clinical studies.  These are the studies that we do  in animals where we've generated  cancer and then treat them. 

 And finally I'll tell you about  what we're up to right now and  what I think are the important  questions to address in the near  future.  Before I start that, we've done  all of these studies in  different kinds of models of  cancer.  The top two: uveal melanoma,  that's a melanoma of cancer that  develops in the eye.  It's the primary malignancy that  originates in the eye.  Cutaneous melanoma, of course,  the skin cancer that you're  aware of.  Those are two adult like  cancers.  Retinal blastoma is one of the  main ocular tumors, eye tumors  of children.  Neuroblastoma is a major cancer  in children that arises in the  sympathetic nervous system.  And then finally for certain  genetic reasons we've also  studied breast cancer.  So all of the experiments that  I'm going to show you have been  done in all of these models of  cancer, and I'm not going to be  focusing on which type of cancer  and which result because they're  all pretty much interchangeable. 

 So to begin with in terms of the  mechanisms of drug action, and  I'll try not to belabor this too  much.  What you're looking at are the  number of viable cells,  over time, as a function  of drug treatment.  And what you can see is if you  take these four different human  cancer cell lines and you grow  them in a petri dish, as shown  by the black bars, those cells  will continue to grow, they'll  clump on one another and they'll  show many of the hallmarks you'd  expect of cancer cells.  But if you treat them with  Resveratrol, you inhibit that  growth.  We and others have shown that  that inhibition is due to both  what we call an anti-prolific--  as well as pro-apoptotic.  And what do those terms mean?  Anti-proliferation means that  the bug stops the cell from  dividing.  And pro-apoptotic, apoptosis is  a form of cell death.  It's a programmed cell death.  Each cell in your body contains  a suicide program.  And if activated, those cells  will die. 

 That's called apoptosis.  So we and others demonstrated  that Resveratrol in this kind of  inhibition of cell growth  compared to untreated is a  result of both antiproliferative  and proapoptotic effects.  As you'll see when we get to our  animal models, we're not  interested in the  antiproliferative effects.  We really want to kill tumor  cells.  So what I'm going to talk about  in terms of these mechanisms is  this suicide program, this  apoptosis.  So how can you demonstrate that  cancer cells are killed by  Resveratrol?  The easiest way is to allow them  to grow in a petri dish until  they're near confluent and then  add the Resveratrol, and what  you see over the next few days  is that the number of cells  disappear until all the cells  in culture are dead.  So Resveratrol can kill these  cells, and if you look at them  with an electron microscope,  what you see is damage to the  cell after you treat with  Resveratrol, and one of the  early events that you see is  damage to what are called the  mitochondria which are the  energy producing organelles in  the cell.  And that's depicted in this next  cartoon.  So here we have a picture of a  cell with a nucleus.  The endoplasmic reticulum, which  is involved in protein synthesis  and storing calcium. 

 And here you have the  mitochondria that produce the  energy of the cell, and they  maintain an electro-chemical  gradient.  So they're like a little  battery.  They have a charge associated  with them.  And in the presence of that  charge, they can retain calcium  and they can retain these very  small proteins called  cytochrome C and SMAC/Diablo.  In apoptosis, you can actually  cause that membrane potential to  change.  So you depolarize your little  battery and when that happens,  these mitochondria no longer  store calcium, they release it  to the cytoplasm of the cell  where it can be toxic and you  also release these small  proteins and they form what's  called an apoptosome.  Leading to the activation of a  caspase-9 which in turn  activates caspase-3.  That is the major executioner  enzyme in this suicide program.  And by activating it, you have  all these downstream steps that  eventually lead to all the  morphological changes in the  cell and eventually the collapse  of the cell.  So we wanted to know if  Resveratrol could activate that  pathway. 

 And I'll go through this pretty  quickly.  This is an experiment where we  load cancer cells with a  fluorescent dye that is an  indicator of the mitochondria  membrane potential.  And what this graph shows is  that when you add Resveratrol,  you depolarize the mitochondria.  So the first step of that  apoptotic pathway gets activated  by Resveratrol.  In this experiment using what we  call western analysis, each one  of those black lines is an  indicator of how much that  protein is present in the cell  cytoplasm, and you can see that  after you add Resveratrol,  compared to controls, you find  more of this protein in the  cytoplasm.  The depolarization of the  mitochondria occurs very  rapidly, as fast as we can make  the measurements.  In seconds to minutes.  The release of the small  proteins from the mitochondria  takes minutes to hours.  And then finally we can see that  hours later both caspase-9 and  caspase-3 are activated by this  drug Resveratrol.  So the apoptotic process is  actually much more complicated  than what I've shown you. 

 But what this data demonstrates  is the fundamental steps in  apoptosis are activated by the  addition of this nontoxic  compound, Resveratrol,  resulting in tumor cell death.  I also told what you that the  mitochondria retain calcium.  But if you add Resveratrol,  calcium gets released.  So what you're looking at in the  top part of this image, and I  wish I had a pointer, those dots  are cells, and we're looking at  them with a microscope while  they're alive and while we add  Resveratrol, and the brighter  they get and the redder they get  indicates that the cells are  filling with calcium.  And that gets plotted down here.  So when we add Resveratrol, we  get a rise in calcium, the cell  attempts to readjust its normal  levels of calcium, but in the  presence of Resveratrol there's  a second rise and that lasts for  as long as we can make these  measurements.  So there's a change in calcium  as a result of adding  Resveratrol.  And the consequence of that when  you have these elevated levels  of calcium is you activate other  enzymes in the cell.  In this case, a family of  enzymes called calpains and this  is a simple fluorescent assay  that shows in the presence of  Resveratrol, you get more  calpain activated and you can  block it with specific  inhibitors.  When these proteins, these  enzymes get activated, they  start to chew up the cell. 

 So again by this western  blotting, you chew up different  classes of proteins.  And the top, in this lane you  can see a protein called phodrin  that gets degraded.  This is a major cytoskeletal  protein.  And more importantly,  Resveratrol causes the  activation of calpains,  this PMCA-1, which is a calcium  pump that sits on the surface  of the cell.  So normally when calcium rises  in the cell and starts to look  toxic, it gets pumped out.  But what happens in this case is  that the Resveratrol causes the  very pumps themselves to be  chewed up so the cell continues  to fill with calcium.  So this is just a little  animated picture that when we  add Resveratrol we get a release  of calcium actually first from  the endoplasmic reticulum.  Some of that calcium will end up  in the mitochondria and then  they'll get released, activating  calpain which will then cause  the cleavage of these pumps.  You'll have elevated levels of  calcium in the cell and other  parts of the cell will get  chewed up and the cancer cell  dies.  So if we look at these  mechanistic steps just to  summarize them. 

 We know that Resveratrol  following this greenish line can  depolarize the mitochondria  leading to the activation of  caspase-3.  We know it can cause a release  of calcium to activate calpain  and also to activate this  process all leading to cancer  cell death.  The reason that this is  important is that in some types  of cancer, so for example, in a  number of kinds of breast  cancer, there are mutations that  inactivate that pathway.  So if you make a drug to treat  breast cancer dependent on this  pathway, it won't work.  But Resveratrol because it  activates this, the calpains and  have calcium toxicity it will  still be effective against the  breast cancer cell lines.  So it's this multifaceted aspect  of Resveratrol that makes it a  very potent chemotherapeutic  agent.  I could talk for hours about  these mechanisms.  It's the kind of thing that I  like, but frankly nobody on the  planet is going to be interested  unless this drug does something  important for cancer treatment.  And that I'm going to  demonstrate by showing you some  results from our animal studies.  So we do these studies in mice  primarily. 

 We use transgenic mice.  They're genetically engineered  so they make a tumor and we can  treat it.  We also use what are called  syngeneic mouse models, where we  take mouse cancer lines and  stick them in mice and treat  them.  But often what we do are called  zymograph models where we take  human cancer cell lines, put  them in a special mouse where  they with grow and then we treat  them with Resveratrol.  And in these first experiments  what we do is we take these  cancer cells and we put them  under the skin where they can  grow and then we feed the animal  Resveratrol by sticking a tube  down its mouth so we know  precisely how much drug we're  delivering, and then we measure  the effect of Resveratrol  on tumor growth every day,  for about a five week period.  And so here are two cell lines  that are human cell lines that  actually come from an ocular  melanoma and what you can see is  that compared to these untreated  animals, when you treat with  Resveratrol you get about a 50%  inhibition of tumor growth.  So that's impressive and that's  good.  Neuroblastoma, childhood cancer  we get about a 70% or 80%  inhibition of tumor growth in  these animals and again in  breast cancer lines and  in skin melanoma lines.  So in everything we've looked at  we see an inhibition of tumor  growth by Resveratrol.  It's nontoxic when we feed these  animals Resveratrol. 

 There's no change in behavior.  There's no anemia.  There's no weight loss.  There's no damage to major  organs; the kinds of things that  happen when you treat with toxic  therapeutics.  This is an example of a  transgenic mouse that makes a  retinal blastoma, that eye tumor  that grows in children.  And you can see where the arrows  are marking large tumor masses  in an untreated eye.  And here you have one in a  treated eye.  So about a 70% or 80% of  inhibition of that tumor growth.  Even in these animals that are  genetically engineered to make  the tumors.  Yes?  >> Do you know why that targets  just the cancer cell and not  normal cells?  >> I'm going to get to that. 

 That's a great question.  If I could answer that question,  actually, that's sort of the  million dollar question, the  brass ring to all of this.  And I'm going to talk about that  in just a moment.  So whether the tumors grow under  the skin or in the eye or other  places we plant these tumor  cells, the Resveratrol can  inhibit tumor growth.  But if you look at the kinetics  for this tumor growth it tells  you something really important.  So what we're looking at are the  size of the tumors over time,  and in the untreated animals  they continue to grow, grow and  grow.  And if you feed them  Resveratrol, they're inhibited.  And that's what I've told you.  And, in fact, these tables are  taken from this end data.  But what's different from this  from what I've showed you in the  in vitro experiments is that  we're never able to kill all of  the tumor cells. 

 We inhibit growth but we never  cause tumor regression back down  the baseline like we do in petri  dishes.  And that's very important.  You want to eradicate the tumor  not simply inhibit it.  So why in the world aren't we  seeing complete tumor regression  rather than just inhibition?  The clue is that we take  sections from tumors of  untreated animals and those that  have been fed Resveratrol, and  this is called tunnel staining  and what it does is those dark  cells are tumor cells in a very  large field that are dying.  And in untreated tumor there are  very few dead or dying tumor  cells, that's to be expected.  But what really surprised us is  that there aren't dead or dying  cells in the treated specimens  either.  So that was a little confusing.  We showed you all of those  in vitro results where we were  killing tumor cells through  apoptosis.  Now we feed these animals  Resveratrol and the tumor cells  aren't dying.  We're just getting inhibition of  tumor growth. 

 Why is that the case?  And the answer has to do with  the amount of drug.  So when we feed an animal  Resveratrol or if I feed you  Resveratrol, there's very  limited uptake in the gut, in  the stomach and in the  intestines, and if you look in  the blood of a mouse that's been  fed a very large amount of  Resveratrol, there's less than  one micromolar of Resveratrol in  the serum.  Very low levels.  And in fact, they're also very  short lived.  It only lasts about five  minutes.  So when you feed large amounts  of Resveratrol, you get a little  blip in the blood that can then  cause tumor inhibition.  The reason there is so little,  as shown on the second line, is  because it gets rapidly  metabolized in the liver.  Those hydroxyl groups that I  showed you on Resveratrol get  modified.  They have sugar-like groups that  get stuck on.  They have sulfation that takes  place. 

 And that makes the product more  soluble and the animal excretes  the Resveratrol.  So you put a lot in but you only  get a small amount for a very  short period of time and that  results in inhibition of tumor  growth.  What we've shown most recently  is that these modified forms are  actually inactive so it doesn't  just make them more soluble, it  blocks their cancer effect.  So this is another in vitro  assay where you can see  untreated cells growing.  These are the ones that are  treated with Resveratrol where  you see the inhibition like I  showed you before and then we  chemically synthesized all of  those metabolites.  And none of them are effective  against these tumor cells.  So when you eat Resveratrol, you  metabolize it very rapidly  leaving you with very small  levels for a very short period  of time that's inefficient to  cause tumor cell death and,  therefore, you don't get tumor  regression.  So if that's true, can we raise  the levels of Resveratrol in  order to kill tumor cells?  The answer is yes.  So I know that this is a rather  disgusting image but what you're  looking at are mice now where  we've allowed a tumor to grow to  a very large size, and instead  of feeding these animals  Resveratrol, we take a syringe  and we inject is right next to  the tumor a so-called  peri-tumor injection.  When you inject with vehicle  alone there's no affect on the  tumor. 

 But when you inject Resveratrol,  that whole tumor mass  disappears.  It leaves these scabs which is a  result of the solvent and we've  changed solvents now.  So we've rectified that problem.  When you inject Resveratrol  next to the tumor like this,  you increase the amount  available to the tumor by about  a thousand-fold compared to when  you feed an animal Resveratrol.  So by this method, by direct  injection near the cancer, we're  able to cause tumor cell death  and tumor regression and that's  shown in these kinds of stained  slides.  In A, panel A up there, that's a  tumor from an untreated animal  and it has a lot of dividing  cells.  But if you look at one that's  been injected with Resveratrol,  there are fewer cells,  and you'll have to trust me  that when you look at this  as a pathologist, there are  profiles characteristic  of apoptotic, dying cells.  And if I had shown you a tunnel  stain it would be all dark.  So by increasing the amount of  Resveratrol, we can cause tumor  cell death and the tumors start  to disappear.  Everything that I've shown you  up to now is in regards to  primary cancers. 

 Whether they start in the eye or  under the skin.  But very few primary cancers are  of concern.  It's the fact that they  metastasize.  They send cells off to other  parts of the body, especially to  major organs, where they grow,  compromise those organs and  that's what causes the  individual to die.  So does Resveratrol affect  metastasis?  And the answer is yes.  In the experiment what we did is  we implanted human tumor cells  into the liver, a site for  metastasis, and then we either  left them untreated, and what  you're seeing are these large  white masses are the tumor  growing even on the surface of  the tumor; and then over here  smaller masses in those animals  which have been treated with  Resveratrol.  And you can section your way  through these tumors, excuse me,  through these livers.  And what you see outlined is the  tumor mass in an untreated  animal compared to a treated  one.  And there's about an 80%  inhibition of tumor growth in  the case of a metastasis.  So the Resveratrol is effective  at inhibiting tumors whether or  not they're primary tumors in  the different parts of the body  or whether they're metastasis. 

 These are all affects of  Resveratrol directly on cancer  cells.  Now for tumors to grow  they need blood supply.  To grow beyond about a cubic  millimeter, they need new blood  vessels to feed them with oxygen  and nutrients.  And that process is called  angiogenesis.  And so what we and others have  shown is that Resveratrol not  only affects cancer cells but it  affects these new blood vessels.  So this is just an example of a  glioma, a kind of cancer, and  when you treat with Resveratrol,  you eliminate about 50% of those  new blood vessels.  So Resveratrol again is  multifaceted, affecting  different apoptotic pathways so  kill tumor cells and also affect  the development of these new  blood vessels so that you  restrict the size of the tumor  and decrease the metastatic  opportunities.  We've gone on to study these  in vitro.  So you can take the endothelial  cells that make up these new  blood vessels and you can put  them in petri dishes and they  will divide and they will  migrate and they'll form tubes  shown in panel A.  This is an in vitro correlate of  these new blood vessel  formations and then if you add  increasing amounts of  Resveratrol you actually  decrease the number of these  blood vessels. 

 And we've gone on to study the  chemistry, and there'll be a  quiz on this afterwards.  I'm not going to go through  this.  I'll just say that just like we  looked at how Resveratrol  affects cancer cells, we've also  looked at the biochemical  pathways in endothelial cells  to see how they affect these  blood vessels from forming.  So what are we doing right now?  Well, in terms of clinical  interest, Resveratrol is of  interest to people in cancer, in  heart disease and,  as I mentioned earlier, in  age related diseases and it  likely will be the case that the  National Institute on Aging at  the NIH is going to run tests  with Resveratrol seeing if it  can prevent or retard  development of age related  diseases like Alzheimer's and  Type 2 diabetes.  These's also a great deal of  interest in pharmaceutical  companies in terms of  Resveratrol's role in treating  Type 2 diabetes.  There's been a lot of popular  press that Resveratrol is the  fountain of youth, that it may  be like a low restricted caloric  diet and enhance aging.  And also, as I've told you,  there's interest in use of  Resveratrol as antiangiogenic  drug, not only in cancer but in  a lot of other diseases  including problems in  ophthalmology where folks like  Jim Allen in the front row have  spent a lot of time trying to  treat people who have leaky  blood vessels in their eyes,  for example in some forms  of age-related macular  degeneration.  So Resveratrol has caught the  interest of a lot of very  different kinds of scientists.  So as I showed you the main  problem is that the only way you  can get Resveratrol today is to  eat it.  And when you do, you're not  going to reach therapeutic  levels of the drug. 

 So we spent some of our time on  formulations.  So, for example, instead of  having solid Resveratrol that  you chew as a tablet, we've made  it soluble so that we can  present it to a patient  intravenously.  That way we can control the  amount of drug and the duration  and, therefore, make it more of  a therapeutic compound.  And we've done that in the top  panel by sticking it in nontoxic  solvents that make it solvent.  We've also made it soluble by  modifying those hydroxyl groups,  so we've made it a prodrug  that's it soluble can be  presented to the animal or the  person and then the body itself  cleaves it back to the normal  parent compound.  We've also studied Resveratrol  with colleagues, our  collaborators, in combination  therapy.  So for example, in immunotherapy  using that with Resveratrol.  The idea being that two drugs  are better than one.  Those are some of the things  that we're doing.  We're also beginning to enter  clinical trials. 

 So with our colleagues  at MD Anderson, we hope in the  new year to begin the first  pediatric cancer trials  using Resveratrol.  Some of our other natural  products are already in clinical  trials at other institutions.  So we're sort of a soup to nuts  laboratory where we do basic  science, preclinical science and  we try to move things into the  clinic to see if we can affect  the disease, we take that  information back to the lab in  order to improve our  formulations and the treatment  to these patients.  And this is what we call  translational research.  What do we think are important  questions?  Nobody actually knows with  certainty what Resveratrol binds  to initially in a cell.  So we are on the hunt for what  is the real binding target for  this protein.  If you know that, you can  understand how the drug works  and you can design a better drug  in order to, for example,  increase the affinity of binding  to its target.  There's controversy about  how and if Resveratrol get taken  up into cells, so we're studying  that and this gets to  the question that I was asked  a few moments ago.  Really the brass ring is why  doesn't Resveratrol kill normal  cells?  Normal cells have calcium,  normal cells have mitochondria,  why does it preferentially  affect cancer cells?  Nobody really knows.  But perhaps cancer cells and  normal cells don't have the same  target. 

 Perhaps they don't have the same  uptake mechanism.  And perhaps they don't have some  of the same biochemistry in the  cell to affect the normal cells  compared to cancer cells.  So ultimately a lot of the basic  biochemistry we're doing is  directed towards answering that  question.  I want to give credit to those  people who actually do the work  in the laboratory and they're a  great group.  But I want to use this slide to  emphasize that virtually nothing  that I do can be done without  collaborators.  Especially Dan Albert who does  all those studies with mice for  us.  And that list is actually much  longer.  This is just some of the UW folk  and we collaborate with people  off campus.  And that's really necessary to  do science.  And this is my segue to the  second part of my presentation  because I've been asked to speak  about the importance of  institutes and centers and about  specifically the UW Eye Research  Institute. 

 If you're very, very lucky, you  may be in a department on this  campus where the person next  door to you is the very person  you'd like to collaborate with.  That almost never happens.  We're a big campus.  The technology and the expertise  is spread out over the whole  campus, and you probably don't  even know the people today who  will be your best collaborators.  That's the situation we live  with.  So you need institutes and  centers to cross all of these  department and school boundaries  in order to find your best  collaborators.  And I'm going to emphasize this  in showing you what should be  familiar, the aerial view of our  campus.  So the lake up top.  The stadium down below.  The west end of campus near  Shorewood. 

 And then the east end all the  way near State Street.  It's almost three miles in  length and in some parts almost  a mile in width.  I don't even know how many  faculty and staff we have,  but it's thousands.  And there's no way  you could know them.  And to illustrate my point, I'm  going to press this button and  you're going to see names pop  on this screen.  These are just some of the  vision scientists on our campus.  And so you find them on the west  end of campus in the Medical  School, in Pharmaceutical  Sciences.  You'll find them in the School  of Veterinary Medicine.  In the School of Education.  You'll find them in the College  of Engineering. 

 You'll find them in CALS,  and you find them throughout  Letters and Sciences.  They're spread out over the  entire 3-mile distance of this  campus.  It's faster on my computer.  [LAUGHTER]  I think we're only  to engineering at this point.  But the UW Eye Research  Institute has members now from  more than six different schools  and colleges on campus, more  than 22 different departments.  It's basically an elaborate  dating service where we bring  people together to see if they  can develop a relationship.  The idea is that we try to  foster collaborations in  research and education.  And we try, very importantly, to  integrate not only what we do in  the sciences but with folks in  humanities, the arts and social  sciences.  And we literally have members  from everybody from  the A in arts to Z in zoology  on this campus.  And the whole idea is to create  a scholarly community where  people can meet one another, to  bring new technologies to bear  on questions and to just  basically get new perspectives. 

 Psychologists have a very  different perspective about how  the retina in the eye works  from somebody who studies  biochemistry and so we bring  those different perspectives  together in order to look at  problems with new eyes.  How do we do that?  Three ways.  First, we support, financially,  faculty who are doing research.  And there will be construction  that will have a new Eye  Research Institute as part of  that so we'll also provide space  for some of these people.  We foster training.  We're responsible for the next  generation of vision scientists,  so we train postdoctoral  fellows, graduate students,  undergraduates, high school  schools.  Also special students, the  medical students, residents and  fellows.  And we create a comprehensive  curriculum on campus in order to  give people a better foundation  in the vision sciences.  And finally, and very  importantly to us, we try to  integrate all of those  activities with the public.  Not simply by doing forums like  this but by working with  organizations that are  interested in vision such as the  Wisconsin Council for the Blind  or Prevent Blindness Wisconsin. 

 We hope in our new space that  there will actually be rooms  available for those public  organizations so we're not just  simply collaborating with  ourselves but we're  collaborating with the public.  This is the organization of our  institute.  We have a director,  Dr. Daniel Albert.  And he's helped by two groups.  An external advisory board made  up by the folks from the public  and a leadership committee  made up of faculty.  And here is our current roster  of advisory board members and  you'll see that they come  not only from Madison but from  Appleton and Eau Claire.  They also come from Milwaukee.  They come from other states.  Indianapolis, Houston.  Because diseases don't care  about geographical boundaries  so why should we. 

 And this is the current  leadership committee.  And I show just to emphasize  that we have folks from Vet Med,  Letters and Science,  Engineering, School of Medicine,  Education, and so on.  Again living up to our goal of  having different folks with  different concepts about vision  brought together to make the  decisions in the institute.  I said that we support research.  I just want to give you one  example.  So we have right now a  competition to stimulate  new types of collaboration.  People who haven't collaborated  before.  Give them a little bit of seed  money in order to bring them  together.  And I'll give you just one  example of that.  Here we have Chris Murphy. 

 He's the one in the white lab  coat.  [LAUGHTER]  Chris is at the School of  Veterinary Medicine, but he's  interested in the cornea,  that clear structure in the  front of your eye.  And he's especially interested  in how wounds heal.  And that requires cells to  divide and to migrate and to  move into a wounded area so that  you can have a functional  cornea.  Then we have somebody in our  institute like Paul Nealy.  Paul's an engineer.  He's interested in  nanotechnology.  So what do Paul and Chris have  in common?  And the answer is that in order  to get cells to migrate properly  it depends on their  microenvironment.  So the environment in which a  cell lives determines which  genes get turned on and off,  whether a cell can divide,  whether it can migrate in order  to be involved in wound healing.  And up until recently  you couldn't create these  microenvironments in the lab  to study them. 

 But now with nanotechnology  you can.  So what you're looking at is a  single corneal cell,  an endothelial cell from Chris'  lab, growing on a surface that  Paul Nealy made which is now  actually smaller than the size  of the single cell.  And they can study the behavior  of this cell, how to get it to  migrate and to orient properly  in order to enhance wound  healing in the cornea.  And that will have implications  for wound healing in other parts  of the body as well.  So our institute brings together  people like this from a School  of Veterinary Medicine and  Engineering using very different  techniques in order to answer  a very common and important  question.  I could go through dozens and  dozens of those vignettes,  but time doesn't permit that.  So if you're interested in  learning more about the  activities of the Eye Research  Institute you can, one,  go to our web site at:  vision.wisc.edu  There we have a list of all the  faculty and their research  programs.  We also have a quarterly  newsletter that describes what's  going on.  You can pick it up  electronically.  Or if you'd like to receive a  hard copy you can email us or  call us and we'd be happy to put  you on a mailing list. 

 And finally, because it really  is a sincere part of our  mission, we invite you to  contact us for lab tours.  If there's a particular area of  vision, whether it's in cancer  which I study or whether  it's in macular degeneration, or  in cornea or glaucoma, whatever.  We're happy to provide lab  tours.  You're a lot more interesting to  talk to than our colleagues so  we really do welcome you to the  laboratory setting.  And I believe somewhere, perhaps  in the back of the room,  side doors, we actually have  cards with this information  that you can take home with you.  So that's the end of my two  parts of my tale and I'm happy  to answer any questions and  thank you for your attention.  (applause)