Anyone who keeps up with Rett research knows that the different mouse models of the disease have given us a rich knowledge base. But have you ever stopped to think of how scientists get access to these crucial models? Today we share with you a conversation between Cathleen Lutz of The Jackson Laboratory in Bar Harbor, Maine, and Monica Coenraads, Executive Director of the Rett Syndrome Research Trust. Jackson is the gold standard for the colonization and distribution of mouse models of disease.
MC: Thank you, Dr. Lutz, for spending some time with us. Tell us a bit about the background behind Jackson Laboratories.
CL: Jackson Laboratories was established by Clarence Cooks Little and Roscoe B. Jackson in 1929 as a genetics institute. Financial support came from Detroit industrialists such as Edsel Ford and Roscoe Jackson, president of the Hudson Motorcar Company, with land donated by family friend George B. Dorr. Of course, Bar Harbor has a long history of philanthropic summer residents who supported the Laboratory, for example the Rockefellers had settled on Bar Harbor.
Off the coast of Maine may seem like a strange place to have a genetics facility. The advantage to the location is that at the time there wasn’t any air conditioning, so the ocean breezes really kept the animal facilities cool. In the early years we didn’t have the ability to do genetic engineering, so essentially we relied on spontaneous mutations that resulted in interesting things to study.
MC: I’ve recently learned of veterinary schools setting up facilities to diagnose animals with spontaneous genetic mutations. For example, it’s possible that a dog with a mutation in MECP2 would be taken to vet and a bright geneticist might be able to diagnose the animal. This would allow different species to be studied without having to do all the expensive and time consuming genetic engineering involved with making models.
CL: In fact I just attended a seminar on this. Recently a naturally occurring form of ALS was identified in dogs. What is particularly interesting is that the canine form of ALS progresses slowly, unlike the human ALS where patients usually die within 5 years of diagnosis. The key question is what is genetically protecting these dogs?
MC: The hope is that genetic modifiers are protecting these dogs from their mutations in SOD1, an ALS gene. And if you can identify these modifiers it may open up avenues for intervention. We have the same situation in Rett. Currently RSRT is funding a project in the lab of Monica Justice at Baylor to look for genetic modifiers in the Rett mice models.
How many disease models would you estimate that Jackson has?
CL: We have over 5000 different strains here at the Jackson Laboratory.
MC: How many new strains are imported every year?
CL: We’re importing about 600 new strains every year.
MC: Is Jackson struggling to keep up given such large numbers?
CL: We have over 1300 strains live on the shelf and over the years have worked to meticulously manage the supply and demand of the strains so investigators can get a jump start on their experiments. We also scale up our colony sizes for individual investigators who need a larger supply of animals than we currently may have. For strains that have low demand, those mice are available from our cryopreserved stocks. Cryopreservation involves either freezing embryos or sperm. Dr. Robert Taft at Jackson has been on the cutting edge of that technology and recently published his technique that helps recover sperm much more easily. Animals can then be recovered from cryopreserved stocks as needed.
So instead of having to super ovulate 50 or 60 females, fertilize, and bring embryos to the two cell stage for cryopreservation, all we have to do is take two males and freeze down the sperm and that particular model is completely archived. We cut down on shelf space and cost.
MC: When a laboratory needs a particular strain which is cryopreserved, that means you don’t have a live colony; what do you actually send them?
CL: It depends on where the requesting laboratory is physically located and the level of their expertise. Cryopreservation is still a rather novel technology so some labs are not equipped to handle the technique of thawing sperm and doing in vitro fertilization (IVF). In those cases we can take the sperm, thaw it and do an IVF to donor females and then we’ll send them live mice. Alternatively we can send frozen viable embryos. This works well especially if the lab is an international customer because we have all kinds of handcuffs regarding transportation of live animals and tissues outside the country.
MC: How many scientists do you estimate have purchased from Jackson?
CL: Last year over 19,000 investigators from 50 countries purchased 2.7 million mice.
MC: That is unbelievable! How is Jackson funded?
CL: We are a not for profit organization with three prongs. We are a research organization; a resource organization, that’s the mouse distribution portion of our institution; and we run courses and conferences where we teach people the latest technologies.
Most of the research and courses are funded mainly through NIH grants. A large portion of our Mouse Repository is also funded through NIH program grants. The rest of the funding required for running the Repository comes from the fees we charge for the mice we distribute. The proceeds go right back into the operation to acquire more mice and outfit new facilities to expand the program. It’s very expensive to distribute mice because we have to maintain high health standards so that any institutions can receive mice knowing that they are free of viruses and pathogens that could contaminate their facility. We also have philanthropic donations.
MC: When I was the Director of Research at the Rett Syndrome Research Foundation we financially supported the importation and colonization of several Rett animal models at Jackson. That was money very well spent as those mice have now been distributed to hundreds of labs and have formed the foundation of much of what we have learned about Rett Syndrome.
You shared that in 2009, 95 different labs ordered Rett mice. The first Rett mouse model made by Adrian Bird was published in 2001, so Jackson had it ready for purchase in 2002. So eight years later almost 100 researchers bought this mouse.
CL: Yes, there is still a lot of demand for that animal, partly because it’s one of the better models of neurological disease. But it’s always going to take more than one model to really dissect what it is that you’re looking for. So if you want to ask specific questions it’s very helpful to be able to utilize more than one type of mouse model. So one model may have a point mutation, another may have a complete exon deleted, yet another may be a conditional mutation so you can just make that mouse gene defective in certain tissues and not others. When you put the collection all together it makes for a really good research resource…your toolbox, so to speak.
MC: I want to acknowledge the scientists who have developed the Rett mouse models: Adrian Bird, Rudolf Jaenisch and Huda Zoghbi. All of them quickly deposited their mice with either Jackson or the Mutant Mouse Regional Resource Center, thereby giving the research community at large access to the mice. This type of sharing does not always happen and I’m so grateful that they set a high standard for our community in terms of accessibility to these models. I hope that it’s a standard that others will follow.
MC: The recent ability to manipulate rat embryonic cells now makes it possible to create rat models of genetic disease. Does Jackson plan to expand into rat models?
CL: We’ve really talked about it a lot as genetic engineering in rats has come a long way in the last few years. One problem is that sperm cryopreservation in rats is still not as efficient as it is in mice. And the housing of rats is so much more expensive because they are so much bigger than mice.
So we have to realize analyze what the advantages of working in rats versus mice are.
MC: Rats are considered smarter than mice.
CL: Yes, they are. They are probably a better model for studying behavior, as well as learning and memory, which will be important in many neurological diseases. But the advantages of studying diabetes in a rat versus mice, for example, is less clear. There is a rat repository in Missouri run by John Critser. I think that Jackson will basically rely on the Missouri repository, working with them when and if needed.. But certainly we’d like to see the cryopreservation and the sperm recovery be just as easy and cost effective and efficient for rats as it is for mice so that we could we could cut the cost and make the process feasible.
MC: I wonder then how many labs would purchase rats. It would be a big learning curve to switch and the costs would be so much higher.
CL: Yes. That’s absolutely true. So there again I think researchers will really need to ask themselves what the advantage to using rats is for their particular research.
MC: Jackson also does its own research and has some high profile scientists on staff.
CL: We have 35 staff scientists on site working right now in a variety of areas. We have cancer biologists, neuroscientists, bioinformaticians. We have investigators who specialize in metabolic diseases like diabetes and obesity. We try to be as diverse as we possibly can in that respect.
MC: And why do you think the scientists would choose to work at Jackson and not at an academic institution?
CL: There are many factors but I think one of the attractions is the availability on site of all of the different mouse models. Also the sheer size of our operation means we can offer economies of scale. The per diem costs of mouse experiments are much lower than they would be at other institutions. That is a very attractive feature for scientists. If researchers need large numbers for their studies then this is the place to do it.
MC: Is there anything you would like to say to families of children with Rett Syndrome?
CL: I’d Iike to let people know that our mission at the Jackson Laboratories is really for the families, for the patients, and for biomedical research. We have, as I described, the repository and the disease model resources. It is quite an undertaking and we really feel that it is within our scientific mission to be collecting these animals and to be making them as readily available to the scientific community as we possibly can. That’s why we’re here and we feel that over the years we’ve really developed the expertise to do that and to manage the sheer numbers of strains that we have live on the shelf.
MC: Jackson truly provides an important resource for the scientific community. Thank you, Dr. Lutz, for sharing some of your knowledge with us today.