Inteview with Dr. Joel Taurog

Kathy:
When you say conventional model what exactly do you mean?

Joel Taurog:
It is a model of predictably induced arthritis… a model where you give rats a certain concoction of things and they get arthritis, which seemed like it might be a model for reactive arthritis, another B27 associated disorder. Meanwhile, as I mentioned, the technology to make transgenic animals was developed in the early eighties. Bob Hammer trained in in Ralph Brinster’s lab at University of Penn, where transgenic methodology was developed. Really, the seminal work that made transgenic animals a reality was due to a collaboration between Ralph Brinster and Richard Palmiter, who was at that time at the University of Washington (I think he still is). So, Bob came from that lab. He and I both happened to come to UT Southwestern in 1986. In 1983, Mr. Harold Simmons, a very wealthy Dallas businessman, gave a large endowment to the rheumatology division here at UT Southwestern. Mr. Simmons himself was suffering from ankylosing spondylitis, so he, I guess, had some interest in having somebody here working on that condition.There wasn’t anybody here at the time with a particular research interest in AS, and so they recruited me--- I was at the University of Minnesota at the time. When I came here we had just cloned the B27 gene and the making of a transgenic model seemed like a reasonable thing to do. I knew that many groups would be making transgenic mice, but I also knew from a lot of other work that rats are more susceptible to arthritis than micein regard to most of the conventional arthritis models.

Kathy:
And that’s because of the makeup of the animals themselves right?

Joel Taurog:
For whatever reason. We still don’t know why.

Kathy:
OK OK

Joel Taurog:
The idea to actually try to do this in rats, that is, to make an HLA-B27 transgenic rat, emerged from a conversation I had with Peter Lipsky, who was the chief of the rheumatic diseases division here when I came in 1986. Nobody had made a transgenic rat before. However, Bob Hammer, during his fellowship in the Brinster lab, had been involved intransgenesis in some other species---sheep, pigs and goats, I believe.. He had a paper from about 1985 where reported making transgenic animals in these other species. So, with Peter Lipsky’s encouragement, I approached Bob with the idea of making a B27 transgenic rat. Bob had just been recruited by the Howard Hughes Medical Institute laboratories here at UT Southwestern. For him it was a challenge to develop the technology in rats, and for me it was an opportunity to have a unique model to study the role of B27 in disease.

Eventually, Bob was successful in developing transgenic methodology in rats, and we observed that rats transgenic for HLA-B27 developed spontaneous colitis and arthritis, plus a few other manifestations. In some ways these rats actually turned out to be a better model for inflammatory bowel disease than arthritis. They get arthritis, too, and we’ve observed some spondylitis in them, but at somewhat disappointingly infrequent rat that has made it hard to study. However, I should say parenthetically thatvery recently we have the model in a way that looks like it will be the useful model of spondylitis than what we originally set out to develop. The spontaneous disease that we observed in the B27 transgenic rats certainly supported the notion that B27 in itself is important in theses diseases, and that finding had a significant impact on the field.

The original description of the rats was published in 1990. Bob Hammer and I continued to collaborate on it for some years after that, I am continuing to work on it. Meanwhile, Bob Hammer has been involved in many other things, particularly in studies involving gene deletion in mice. Beginning about 1990, the method of gene deletion, or gene “knockout,” in mice has had an enormous impact in the last 15 years. Bob collaborates with many people in knocking out genes in mice and he’s also made many, many transgenic animals. So, his interest in this particular project was more on the technical side and mine was more on the functional sideOne of the other authors on the original paper, Jim Richardson, is a pathologist who is still here at UT Southwestern and who is still very helpful in interpreting histologic specimens from our studies in the B27 rats. . The other two authors on the original paper were technicians, one in my lab and one in Bob’s lab, who both left the institution quite some time ago.So that’s the background of our work..

Kathy:
Can you describe how these rats have the DNA microinjected? And then, is that an original?

Joel Taurog:
The technique is to take young female animals and give them hormones that cause them to release a lot of eggs—more than they would normally.

Kathy:
Sort of like a super-ovulation process…

Joel Taurog:
Yes. And then you put them together with a fertile male, and then check them the next day to see if they’ve mated, and if so, then you kill them and take the fertilized eggs and put them under the microscope. There is a technique with a very fine pipette to inject a small amount of the cloned DNA into the fertilized egg. You can tell it is a fertilized egg because it has two nuclei—one from the sperm and one from the egg. So, it does not matter which nucleus one you inject. I think in practice the sperm nucleus is a little bigger. But, you inject one of the two nuclei (pronuclei) and then you implant the microinjected eggs into another female, a so-called pseudopregnant female that was been bred with a vasectomized male. Since she is bred, she is hormonally receptive to the implantation of the eggs. And so you transfer some number of eggs into each pseudopregnant female---maybe fifteen to twenty -- and then wait for preganancies and pups. When pups are born you have to test them to see if they have integrated the gene into their DNA. Then you have to see if they will transmit it to their offspring. Once you have animals that have integrated the gene and they express the gene, that is, they make the gene product (the protein), and they transmit the gene to their offspring, and they are able to breed, and the offspring are able to breed, then you have a line.

Kathy:
So, in other words, the retired breeders that I am dealing with are part of a much longer line.

Joel Taurog:
A lot of the lines were made originally in 1989 and 1990, and several more were added over the next 5 or 6 years. In fact, we are just now working with another line that was made ten or twelve years ago that we just kept maintaining but had never done anything with—we just kept breeding them.

Kathy:
Is there any point at which it becomes tainted or impure or something shifts?

Joel Taurog:
It is theoretically possible that the genetic locus is unstable, but we don’t have any evidence for that in our lines, and the phenotype seems to be stable…I would guess it depends on which genes you are dealing with.

Kathy:
These genes are stable over time.

Joel Taurog:
Yes. We’ve probable made fifty, sixty, seventy generations or more since then.

Kathy:
Well, rats don’t live that long so it is quite a bit I would imagine. And do you find that this, being your particular interest, the B27 rats have helped other areas like you mentioned inflammatory bowel disease or other kind of autoimmune diseases?

Joel Taurog:
They have been used for drug testing by several different pharmaceutical companies. In the few years after we described the rats, a number of different lines of knock-out mice turned out also to get inflammatory bowel disease, and many investigators have preferred to use these mice rather than our rats. Immunologists tend to prefer mice, since there are many more reagents available for mice than for rats, and there is much more that is known about the mouse immunologically. So, for example the IL-10 knock-out mouse has a phenotype very similar to the B27 transgenic rats in terms of the inflammatory bowel disease. So there’s probably been more interest in that over the years in these mice than in the B27 rats.

Kathy:
And when was that developed?

Joel Taurog:
The IL-10 knockout was developed sometime in the early nineties. There are probably half a dozen or more knockout mouse lines that also get a similar kind of inflammatory bowel disease. The B27 rats are the only one of these models that also get arthritis. Another area of impact that the B27 rat model has had has been in link between gut disease and arthritis. This is observed clinical – patients with B27-related disease often have gut disease, and patients with inflammatory bowel disease often have arthritis or spondylitis. The observation in rats helped reinforced this association.

Kathy:
Are there links between any of the diseases like Sarcoidosis or anything?

Joel Taurog:
No. Sarcoidosis seems to be something completely different. It is true that sarcoidosis and Crohn’s disease (one of the inflammatory bowel disorders) are both T-cell mediated. Maybe they are related in some way, but I’m not aware that they overlap and they seem to be different diseases.

Kathy:
You mean than arthritis and IBD.

Joel Taurog:
Yes.

Kathy:
The rats, I notice, are slightly smaller than other lab rats that I’ve seen. I just wondered if this transgenic addition has anything to do with their size?

Joel Taurog:
Well, they get sick and don’t grow normally. Also, maybe you looked at the ones that have been commercially available, which are the Fischer 344 strain. This strain is relatively small strain. I don’t know if you have had non-transgenic littermates next to them but Fisher rats tend to be a bit small, compared with other inbred lines. Also, if they get sick they lose weight and tend to waste, in fact, when they get really sick. So, that may be what you are looking at.

Kathy:
Even when they weren’t sick they seemed smaller.

Joel Taurog:
They may be a little bit. We actually stopped working with the Fischer line some years ago. We only work with the Lewis line. The Lewis line has a higher prevalence of arthritis and for whatever reason most of the lines we made were Lewis and the ones that weren’t, we backcrossed to Lewis.

Kathy:
I wonder what you think in terms of working with these animals? Do you work with them in the labs at this point yourself?

Joel Taurog:
Other people in my lab do much more than I do. Are you asking, what is my emotional attachment to them or reaction to them?

Kathy:
How would you describe them overall in terms of their usefulness?

Joel Taurog:
Well, I think they have been very usefulover the years. I have probably also been a little disappointed,but I am also very hopeful. First of all we still really don’t understand what is going on, what the role of B27 is. That was the original goal and it has remained so for fifteen years and we still don’t have the answer. Also, my original intention was to look at arthritis and spondylitis, not inflammatory bowel disease, and we have ended up studying IBD at least as much as arthritis. On the other hand, as I said earlier, we have recently made a modification so that we now have a combination that seems to get arthritis and spondylitis with high prevalence, but and doesn’t develop IBD. So, I’m more excited about it than I was originally, although we haven’t published these new findings and it is still a little premature. We want to make sure that the result repeats in subsequent generations. If it turns out to be reproducible, then we will have a very useful model for identifying the role of B27 in AS. Meanwhile, there are other investigators who have been using these to look at inflammatory bowel disease, particularly Dr. Balfour Sartor at the University of North Carolina and his colleagues and some of his former fellows. They have probably done much more with this in terms of gut disease than we have. So that is nice.

Kathy:
Dr. Sartor and who else did you mention?

Joel Taurog:
Well, he has some former associates. I think one of them is in Germany--Dr. Rath and one of them is in Canada--,Dr. Dieleman. They have published several papers and are continuing to work on IBD in these animals.

Kathy:
So they work with B-27s too.

Joel Taurog:
Yes, they are working with these rats. A little bit is in collaboration with me but most of them are just doing it on their own. One of my former fellows in France, Maxim Breban, has done some other work with the rats. There are a few other academic investigators working with them and some pharmaceutical companies have used them. For example, Genetic Systems, a company in Massachuestts, studied IL-11 as a drug in the rats and have shown that it is effective both in IBD and in arthritis. Anyway, over the years there have been a series of papers by us and by others, and the rats have been my main professional occupation.

Kathy:
Maybe this is a naïve question, but is there a royalty that you get off the rats?

Joel Taurog:
Well, a little bit. The one Fischer line is licensed to a commercial breeder, Taconic Farms. It was originally licensed to a a little company in the San Francisco Bay Area called GenPharm Later, Taconic bought them out. Taconic is more of a conventional animal breeder in upstate New York. So, Taconic has been the one marketing the rats. I have not made very much from this licensure, probably not even enough to pay my parking at the University or my phone bill, but it has been something. Also, initially, the B27 rat story was quite novel. In the early and mid-1990’s I got invited to a lot of places and met a lot of people and got a certain amount of visibility. I was invited to Switzerland, Mexico, England, France, Germany, Italy, Australia and several places around the U.S., and I have a certain reputation in the field, so it was a sort of career boost in a way. In retrospect, it it would have been better if we had just worked on the rats for another few years before getting all of the publicity.

Kathy:
At the time when this first occurred, and you started making these rats, was there any kind of other public reaction to the fact that they were transgenic?

Joel Taurog:
Well there were plenty of other transgenic animals; they certainly weren’t the first transgenic animals. Really, the only trouble I’ve really ever had in terms of what you might call animal rights activism is just with the veterinarians here at UT Southwestern and with the committee that oversees and approves animal projects. Over the years they have tended to get stricter and stricter and come up with more restrictive and sillier rules. Originally, I think they were appalled to see these animals with diarrhea and arthritis. We actually had a meeting with the entire animal resource center personnel, and I showed them pictures of people with inflammatory bowel disease and its complications and patients with bad arthritis. I explained to them that this is what we working to try to prevent. Better in rats than in people.

Kathy:
Did it make an effect?

Joel Taurog:
Yes, I think it did. They backed off and they said, well now we know what to expect with these animals. Generally it has not really been a problem. You know, I say, well look, throughout all of human history rats and mice have been nothing but pests and a nemesis, spreading countless amounts of disease and spoiling countless amount of food. Rodents havecaused misery and suffering to humans since time immemorial. So, finally, in the last hundred years now they are doing something for us instead of the other way around. I certainly don’t condone causing any more suffering in animals than necessary, but I certainly don’t have any sympathy for the view that there is no difference between species and that we have no right to use animals for experiments and that sort of thing. I have never actually met anyone who says, sincerely “I don’t believe in animal experimentation or inflicting any suffering on animals, and therefore I do not want to benefit from anything that was ever developed using animal experimentation, and I don’t want my children to benefit.” To take that position would mean never taking any medicines, undergoing any surgery, etc..

Kathy:
Yes, I agree it is really complicated.

Joel Taurog:
I don’t think it is complicated at all. I think it is pretty straightforward. There seem to be people who think they can design the world better than the Creator. This is what we were given… we were given a lot of disease and we were also given animals to use under certain conditions to help us understand and treat, or even better, to treat disease.

Kathy:
Do you know of anybody who is doing any kind of alternative research with these particular rats or any other transgenic rats?

Joel Taurog:
Well, I don’t know what alternative means. Medicine and science are experimental; and biology is an experimental science. So, if you want to know if something is an effective treatment for a particular condition, then you test it. There are well worked out, well understood procedures for demonstrating that interventions of any sort, whatever they may be, whether they are drugs, or they are devices or surgical procedures or incantations. Whatever it is that you want to do to try to affect the course of a disease, there are well worked out ways of trying to obtain valid information as to whether those things are effective or not. So, as far as I can tell, there is really no such thing as alternative medicine. The term seems to be used to refer to interventions that have not been subjected to those procedures. That somebody, for whatever reason – ignorance, greed, laziness, etc. -- just wants to have some effect without going through the trouble of testing it and demonstrating it. So, whatever it is you want to learn about, whether it is some herb or drug or standing on your head in a field and meditating, whatever it is, you can test it and find out whether it has an effect or not. So, as far as I am concerned, to say that something is alternative just means, that for whatever reason, you don’t believe that it needs testing or verification. You want to believe that it has some effect without subjecting it to testing, either because you want to sell it or because you want to just indulge in wishful thinking. To answer your question, I don’t know what people are doing with the rats. I know that there was one, I wouldn’t call it alternative, but it might be considered that by some. I actually think it is very creative. There is a strain of bacteria, a Lactobacillus, which is a normal gut flora but is resistant to stomach acid. You can swallow it and it will survive it the stomach and get down into the intestine and it willcolonize the intestine. I think it was originally developed to treat Clostridium difficile. Sometimes when people get prolonged courses of antibiotics, the antibiotics can have the unfortunate side effect that they will kill off a lot of the normal bacterial flora in the gut. Clostridium difficile will then overgrow and produce a toxin, which can cause a very serious and sometimes fatal colitis. There are antibiotics than can suppress the C. difficile, but it tends to recur when these are stopped. Anyway, this Lactobacillus species can be used to colonize the gut of someone infected with C. difficile. It will overgrow and crowd out the C. difficile and the person will eventually be cured. , I believe there is at least one publication describing how this Lactobacillus was given to the B27 rats and it had a positive effect on the inflammatory bowel disease. Again, whatever intervention you want to do, you can test.

Kathy:
Absolutely. I think we are talking semantics. I think that if we are talking about a controlled diet and looking at that diet very closely as it is still biochemical. I understand that. But, I just meant that exactly that type of example that you gave is great because that is the kind of information that I am looking for.

Joel Taurog:
Again, I think it is the same kind of mentality, that somehow drug companies whose work is scrutinized very carefully by the FDA and by various other regulatory agencies and are accountable to all kinds of people for what they develop, they somehow are evil and greedy. But, some character who just concocts who-knows-what and calls it a supplement or an additive or alternative medicine, and is under no supervision or regulation of any sort by anybody.

Kathy:
Well. Not necessarily.

Joel Taurog:
…And has done no work to document that what he is selling is afficacious. Somehow, he is not greedy and he is not evil. That mentality doesn’t make much sense to me...

Kathy:
Well, no. I mean, there are plenty of treatments that I’m talking about that have been tested, for example, acupuncture. There are regulations for acupuncturists and for them going through certain…

Joel Taurog:
There was a very recent acupuncture study applied to osteoarthritis in the Annals of Internal Medicine and, although there was some tiny little effect, it was so minimal that for practical purposes you would say it was ineffective. In fact, in a couple of groups, the sham acupuncture was more effective. At least for that type of arthritis, it is clearly not an effective treatment. It is widely used and may be relatively harmless, but anyway that’s a different issue…I never tried acupuncture on the rats. I don’t know how you would do that.

Kathy:
Yeah, I haven’t gotten that far yet either, but it would be interesting to try it. What do you think about rats’ having consciousness?

Joel Taurog:
I guess it depends on what you mean by consciousness. They obviously have some kind of consciousness, since they have awareness, and they react to things. Basically people and animals are fundamentally different. Animals may have consciousness, but they don’t have the free choice that people have. That’s what makes people, people. People have moral choice. They have free choice. Animals, as far as I know, don’t. I don’t think you would ever find an animal who was a born again member of some religious group. For whatever reason, we live in a culture where the distinction between people and animals is blurred.… It starts out with children, very young children who watch cartoons where animals act like people, and they are read books in which animals substitute for people. In some ways, like Aesop’s fables, this is nothing new. I think it becomes more real when you grow up with television cartoons and you think that animals can talk.

Kathy:
Do you work with the rats themselves in the labs as I asked you and do you ever have particular favorites or kind of anecdotes that you can talk about doing certain things?

Joel Taurog:
Well, the founder of the line we call 21-4 was the subject of an exciting story. This rat actually founded two lines. . This female was pregnant, and she was looking sicker and sicker and it didn’t look like she was going to make it. It ened up that Bob Hammer did a caesarian-section at 1 AM on the weekend to save that line, and we ended up with two valuable lines out of it. Also, among the offspring, for whatever reason, the one male with the high gene copy number was able to breed, and this turned out to be necessary to preserve this line. Usually these males are sterile because they have an inflammation in the testis and epididymis. So, again, there were several rather improbable events in the establishment of this line.… Also, the whole thing was improbable, just the fact that we got high copy numbers in the genes, because when we tried to do it later, it turned out to be very difficult to recreate. The success of the whole project really resulted from a series of improbable events.

Kathy:
That’s good!

Joel Taurog:
I can’t say I particularly enjoy working with the rats, per se. , However, when something interesting occurs, it’s a nice feeling. I certainly don’t enjoy killing rats. I don’t like it, but you have to do it. One has to be a little bit careful because you can become desensitized…

Kathy:
And what is their typical lifespan?

Joel Taurog:
The ones that get sick… usually, by six or eight months, they are looking pretty bad. We usually don’t even keep them that long. The ones that are healthy can live for a year and a half or two years…. but, we usually don’t keep them that long… but they can.

Kathy:
So, in other words, not all of them get sick and that’s what’s the question.

Joel Taurog:
Well, in the lines that are disease prone-- they all get sick. Lines that aren’t disease prone don’t get sick. The females tend to get worse inflammatory bowel disease (for whatever reason) and the males tend to have more arthritis.

Kathy:
But, the lines are bred to make them sick, I mean, to produce sickness.

Joel Taurog:
Well, we have some lines that are sick and some that aren’t and we need the ones that aren’t as controls. You always have to do controls. Valid science always requires controls. That relates to what I said earlier. The main problem with what are so called “alternative treatments” is that usually there are claims but no controlled studies have been done to substantiate them.

Kathy:
What do you think about me working with these rats? Do you have any opinions about this?

Joel Taurog:
What is it exactly that you have been doing with them?

Kathy:
I have been working with them and doing uncontrolled studies per say and uncontrolled testing with them, I think in terms of what you are saying… I work with them to use different kinds of supplements to their environment, to their diet to encourage increased health. Basically, I’m working with them the same way I work with myself so that I would use certain foods to see if it had any kind of effect to reduce diarrhea, fatigue, etc. – which it did seem to do…

Joel Taurog:
Do you have an animal facility?

Kathy:
No, this is off site. I’ve been doing this off site.

Joel Taurog:
I mean, is there any kind of supervision? I think, again, for something to mean anything you have to have a comparison. If you are going to treat animals with something then you have to treat equivalent animals with something that is a controlSince we licensed the rats to Taconic anybody who wants can buy them and they can do whatever it is they want with them. But, I think for it to mean anything, if it is not just a waste of time and money then you need to do controlled studies. The license that we have stipulates that people aren’t allowed to just take them and breed them. If you do breed them, there is a breeding fee that they charge. There has been any number (I don’t know how many zillions) of diet studies over the years. But, I’m not sure how much has been done with the newer models with inflammatory bowel disease. I always just say if you are going to do it, then you should do it right, which may mean getting some help if you are not a scientist. Otherwise, then, how do you evaluate it? These rats are not so easy to evaluate in terms of disease activity. You can look at their weight; that’s one thing that’s easy. Also, if there is a dramatic change in the stool character, then that’s worth something. But, then, the other things we do require histology or measuring inflammatory markers in the gut itself. It takes some technology to do that. But, you can weigh them; I guess that’s relatively easy.

Kathy:
Well, I’ll be working with some vets too, who will be able to do some of those things too, and we will put some of that stuff intopractice. But, I see what you say about the controls and that’s really great. I understand the point.

Joel Taurog:
I think, Richard Feynman, the Nobel Prize winning physicist, said it probably better than anybody when he said, the purpose of science is to try to insure that you are not fooling yourself… I mean that’s what the scientific method is all about. Because, when it comes to our knowledge about the natural world we don’t have revelation…we have to figure these things out for ourselves. The scientific method is the generally excepted way that we do it. There are other areas of life where that isn’t necessarily the case. But there are also a lot of things that are testable and people might not think of them as science, but you can test them scientifically. If you want to know if prayer or meditation is doing a something in a given situation, there are potential ways to test it if one wanted to pursue that.

Kathy:
Well, that’s really good advice and I will keep it in mind… I’ll put some controls in place. Thank you.