Date: November 3, 1998
Interstitial Cystitis Network - Chat Log (© 1998,
Featuring: Dr. Ada Elgavish, IC researcher
University of Alabama, Birmingham
Topic: Epithelial Wall Transitions in IC: A new diagnostic test proposal.

Review Slide Presentation

Special gratitude to Julie Halbur for coordinating this exceptional presentation.

<icnmgrjill> Greetings everyone and welcome to the ICN Chat for November 3, 1998. We are pleased to have a special guest tonight, Dr. Ada Elgavish. I am now switching the room over to moderation which means that, until her presentation is done, only she and I will be talking in the room. You can, however, whisper to each other. If you have questions which you would like Dr. Elgavish to answer, please whisper them to Julie or myself and we'll put you in the queue.

<icnmgrjill> I'd like to remind you all of our disclaimer... that active and informed ic patients understand implicitly that no patient, or website or presentation on a web site should be considered medical advice in all cases, we strongly encourage you to discuss your medical care and treatments with a trusted medical care provider.

<icnmgrjill> Before we begin tonights presentation, we do have a few ICN announcements

#1. You'll find that we've updated several more sections of the icn patient handbook including a new section on elimination diets, written by bev laumann

#2.. check back tonight or tomorrow for the latest "Fresh Tastes" monthly column which is a wonderful essay on irritable bowel disorders and diet.

#3.. In addition to our great speaker tonight, we're pleased to announce the appearance of Dr. Theoharis Theoharides on November 17, who will be talking about mast cells and ic, and Phillip Hanno, MD who, I hope, will talk more about nerve stimulation procedures. Dr. Hanno just wrote that front page story on the Urology Times comparing the direct sacral nerve stimulation with the new SANS nerve stimulator! More on that later.

#4.. The urology times has given us permission to reprint many of their articles which will begin to appear on the web site shortly. As always, please check our front page, for new features. Also our what's new page is a good place to check at least once a week

#5.. lastly.. the new icn book club is now up and running with new books on ic and related topics that you can order, at a discount, through

<icnmgrjill> For tonight's presentation... Dr. Elgavish has prepared a slide show, which you can view during the presentation or afterwards. To view the slide show, you'll have to open a second web browser and visit then... you can just switch back and forth between the two browsers to follow the presentation and the slide show...

<icnmgrjill> I am so pleased to introduce to you Dr. Ada Elgavish, one of our countries leading IC researchers. Dr. Elgavish is currently an Associate Professor of comparative medicine at the University of Alabama, Birmingham. Dr. Elgavish has been the recipient of several ic research grants from the nih, the STTR program and the ICA. Her work focuses on transitions of the epithelial cells in the bladder or IC patients and she has developed and patented a new diagnostic test for IC. Dr. Elgavish, Welcome to the ICN.

<DrAdaElgavish> Thank you very much, Jill...

<icnmgrjill> Tell us how you first got interested in ic?

<DrAdaElgavish> I became interested in IC by chance. However, the more I heard about it, the more it became a challenge.

I believe in going straight to the point. Therefore, the best way to follow the story of our efforts, will be to have a look at the slides, when you have a chance. In the slides, I am first explaining briefly the structure and function of the normal bladder epithelium, that layer of cells that lines our bladder. Then I present our ideas about the possible succession of events that may lead to IC. Finally, I describe the diagnostic test we have developed based on studies we have carried out in our laboratory. As you can see, this is basic research. Please, feel free to ask any questions that come to your mind.

<icnmgrjill> Question #1.. One of the things that we've all tried to understand about IC is what is happening directly at the bladder membrane. We all clearly understand that the normal protective layer of the bladder membrane...has somehow become damaged or is missing. In your studies, you've focused on the top three layers of the bladder epithelium, right??

<DrAdaElgavish> Actually, not quite. The normal bladder epithelium is composed of three different types of cells, just as you said. However, our studies have focused on the very bottom layer the one that is the farthest from the urine. You may ask why?

<icnmgrjill> why? ::grins:::

<DrAdaElgavish> Because this is where stem cells are located. What are stem cells? Nobody knows exactly. There are no markers that are specific to stem cells. However, there is no way to explain normal "turnover" in the bladder epithelium or wound healing in the bladder epithelium without postulating that stem cells exist. Scientists believe that these are few cells in the basal layer of the urothelium. Most of them are quiescent, that is they just "sit there." However, when a normal superficial cell dies or when the terminally differentiated, superficial cells are injured. For example during repeated infections, stem cells are triggered to proliferate, to replenish the cells that were destroyed during injury.

In studies we have carried out and published, we have tried to demonstrate that this actually happens. We worked with NORMAL human epithelial cells. We "injured" these cells, in cell culture, by exposing them to cell wall components of bacteria. We found that this triggered their proliferation. Here came our first puzzle. Everybody knows that there is no abnormal growth in IC.

We explained our results, by postulating that the progeny of the injury-triggered proliferating cells may be maturing at a pace faster than normal. Subsequent studies we carried out supported this possibility.

So, in conclusion, our studies suggested that if the superficial layer of the bladder is injured for whatever reason and the basal layer becomes exposed to the injury, this may trigger rapid proliferation of stem cells and rapid differentiation of the progeny. Under normal conditions, this is great, because this is what allows the bladder to recover. However, we postulated, IF these processes occur time and again, they may result in an increase in the proportion of actively proliferating stem cells.

Based on this, we measured proliferation in cultures isolated from patients with IC and cultures isolated from patients with other urological diseases and, as we expected, the proportion of actively proliferating cells was higher. This has been the basis of the diagnostic test we are developing for IC.

<icnmgrjill> So... the new test that you've developed and patented.. essentially measures the number of stem cells in the biopsy of an IC patient... and then compares it with a control. What you've found is that IC patients consistently have a greater number of these proliferating cells...

Interesting. So.. what's the downside of having a greater number of proliferating cells?? Logically, it would seem that this would be great because this is the repair method for the epithelium. But, in icers, that repair just isn't happening.. Any idea why???

<DrAdaElgavish> As you were asking the question I was thinking what would be the best example to give for this. It is great to have a fast car because the faster it is, the faster you will get to where you want to go. This not always true. Not if the car drives too fast. To go back to our cells, it seems to me that the disease is caused by processes that are activated as part of normal healing. It just does not work at the correct "speed"

<icnmgrjill> Fascinating, here's another question then. Basically, your of the belief that it is through repeated injury or trauma that this develops. Any ideas on what could be the source of the injury. There are alot of people who think that infection is the cause of IC. What's your take on that??

<DrAdaElgavish> You are absolutely right. However, there is a small problem there. There are no bacteria in the urine of patients with IC. This is what has been causing an ongoing controversy among researchers. I agonized over this as well and this is what I came up with. What if the disease is triggered early on in life. What if recurrent injury, for example by exposure to infectious agents, causes injury to the superficial layer and exposes stem cells to bacteria and their products. What if this causes changes in stem cells that are somehow "remembered" by this type of cells with high proliferative ability.

Therefore, I have proposed that even if bacteria ARE NOT present in the bladder when a patient is finally seen by an expert urologist. This does not exclude the possibility that the disease was caused by bacterial injury years before.

<icnmgrjill> Thats a very helpful explanation and theory, Dr. Elgavish. The antibiotic/bacterial debate rages through all sectors of the ic population, between researchers, physicians and patients. Are they any other causes of damage that you think could provoke stem cell activity???

<DrAdaElgavish> First of all, let me respond to the question about antibiotics First, let me remind everybody that I AM NOT a medical doctor. Therefore, you folks should not decide anything about treatments without talking to an expert urologist. However, IF my "theory" is correct, antibiotics may not help, since bacteria may not be in the bladder any longer. Of course, there can be other sources of injury. For example, I know of at least one researcher who is trying to isolate a possible injury agent from the urine of patients with IC

<icnmgrjill> Let's take some questions from the floor. Charlie.. wants to know if there is some work being down to slow down the proliferation of the stem cells?? or to get it back to a normal level??

<DrAdaElgavish> Good idea! However, you have to remember that I have just published these findings. When new ideas are presented, it takes a long time until they are accepted by the establishment.

<icnmgrjill> Question #2 is from Alexa in Vancouver. She wants to know if you have found any factors which would contribute to IC being an autoimmune disorder??

<DrAdaElgavish> I have not worked on this topic. All I can say is that I have repeated a study carried out by another researcher in which we immunized mice with bladder homogenates and observed chronic inflammation in the bladder. However, to the best of my knowledge, nobody is working on this idea right now.

<icnmgrjill> Question #3 is from Terri. She was wondering if there was any effect on the bladder wall of repeated exposure to sterile urine.

<DrAdaElgavish> I have not carried out that type of study, BUT we have carried out some studies in mice in which mice were anesthetized and then catheterized. Through the catheter we could instill in the bladder a solution containing a cell wall component of the bacterium Enterococcus faecalis. This was repeated once a week for four weeks. Before the first instillation and before each of the following ones. We placed the mice in a "metabolic cage" that is a cage, under which we had placed filter paper. We counted the number of urine spots (frequency). We found that the frequency of urination increased in a dose-dependent manner with recurrent instillations.

<icnmgrjill>'s fair to say that you're not testing for an infection as much as you are testing to see if a component of bacteria can increase the frequency and inflammation???

<DrAdaElgavish> Absolutely correct! It is not necessary to assume that the entire bacterium should be there. A component of the cell wall, as we have tested, or a chemical produced by the bacterium and secreted may have a similar effect.

<icnmgrjill> Question #4 is fron Ken and Joy. They were wondering if you worked directly with IC biopsies?? and if you've spent much time reviewing the results of cystos on IC..(hydrodistentions)

<DrAdaElgavish> Yes, I do work directly with bladder biopsies. The miracle of having a good collaborator at work! We receive a telephone call from the OR.

A minute later, a research assistant is dispatched to the OR to pick up the sample. In short, the biopsy is processed for cell culture within 1-2 hours after it is removed from the patient. This has been the secret of our success in isolating cell cultures from patients with IC. As you will see in the slides less than 1 mm bladder biopsies are cut by us into minuscule pieces and are placed in a dish. They are "babied" for about 7 days, being "fed" special

medium every other day. Under these conditions, only uroepithelial cells survive. These cells are then transfered to small wells on a microscope slide, 4 wells on each slide. We call these secondary cultures. These cultures, isolated from patients with IC or patients with other urological diseases have served for our studies and the diagnostic test.

<icnmgrjill> Question #5 is from me. You are the current recipient of two IC grants currently in progress, both, for your diagnostic test. Can you tell us what you think of the future of the IC research community? As a researcher, do you have the resources that you need to do the job well??

<DrAdaElgavish> That is better. Actually, I have right now only one grant, from the NIH. This is a Phase I STTR grant to Diacell, Inc, a company I have established to develop the diagnostic test. As to the rest of the question

<icnmgrjill> (small business technology transfer grant.. If I remember those initials correctly)

<DrAdaElgavish> We live in constant anxiety that funds for our research will be discontinued. One reason is the simple fact that monies are limited and there are a lot of good researchers. Secondly, as in any competitive field, there are dogmas and it is very difficult to receive funding for new ideas.

<icnmgrjill> Is there anything that we, the IC patient, can do to help you (and other researchers) do your IC work??

<DrAdaElgavish> There may be. First, you have to be informed....And this you are certainly doing. If an idea seems to be useful, you may lobby for funds to further develop that idea. As far as I know, this is what started the interest in IC in the first place, enthusiastic effort of a few patients.

<icnmgrjill> One question is anonymous. An ICer wants to know if there is any way to donate a biopsy sample to your research??

<DrAdaElgavish> I work with the Director of the Division of Urology at the University of Alabama at Birmingham. In order to be included in the study, you would have to be first evaluated by an expert urologist. As I explained before, tissue biopsies have to be processed within 1-2 hrs. Therefore, I am now trying to get several Centers interested in the diagnostic test so I can invite researchers to Alabama teach them the technique. This would enable other centers to carry out the diagnostic test.

<icnmgrjill> Ahh... we have one last question! Ken and joy want to know if there is any possible that yeast toxins could cause epithelial damage?? There has been much debate about IC'er's potentially having excessive yeast. Any comments??

<DrAdaElgavish> I cannot comment, only because I have not done any studies with yeast toxins per se. However, sure, it is possible.

<icnmgrjill> Thank you so much.. Dr. Elgavish.. for donating your time this evening! Your presentation was fascinating, enlightening and we truly wish you the best in your research studies in the years to come. We, the ic patient, honor all IC researchers this year and we especially honor you for sharing your thoughts with us tonight!

<icnmgrjill> ::::as she stands and applauds::::
<DrAdaElgavish> It was a pleasure...
<icnmgrjill> Folks.. let's show Dr. E our appreciation!
<ICN_KEN> Than you DR
<Carol_L> Thank you for your time and presentation, Dr. Elgavish
<icSueC> THANK YOU !!!!!!!!!
<Darla> Thank you very much DR. Elgavish.
<hb1> THANKYOU!!!!!!1
<ICNJulie> thank you Dr. Elgavish for speaking to us tonight and for researching IC.
<alex> thank you dr.
<Terri> clap, clap, clap.....Thank You!!!!!
<kim> We really appreciate your efforts!
<vamprilla> Thanks doc for your time and info
<Charlie> thank You Dr.
<Carol_L> Thank you for caring enough for ICers to do research on IC
<DrAdaElgavish> I am asked whether mechanical
<DrAdaElgavish> injury may cause IC
<kim> We appreciate your efforts and time! Thank-you
&alt;DrAdaElgavish> We should test that...
<EMT-1> thanks doc for your help and efforts
<icnmgrjill> Thank you so much...

© 1998, The IC Network, All rights reserved. This transcript may be reproduced for personal use only. If you do so reproduce, we ask only that you give credit to the source, the IC Network, and speakers, Dr. Ada Elgavish & Jill Osborne. For additional use, please contact the ICN at (707)538-9442.