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Of dogs and men

Posted September 17, 2011

Lou Gehrig died of amyotrophic lateral sclerosis (ALS, or Lou Gehrig's disease) in 1941. More than 60 years later the disease is diagnosed in about 5600 people each year. Luck has not been a word used much when it comes to ALS. But that may change soon with the help of man's best friend and the scientists who study them.

Researchers from the University of Missouri and the Broad Institute have found that the genetic mutation responsible for degenerative myelopathy (DM) in dogs is the same mutation that causes ALS in humans. DM causes progressive loss of function starting in the rear legs and moving forward, ultimately rendering the dog completely paralyzed to the point of respiratory failure. ALS similarly culminates in complete paralysis and respiratory failure.

Before the dog discovery, rodents with introduced mutant genes causing ALS were the only animal model of ALS. DM dogs are better models because the mutation occurs naturally and produces a spectrum of consequences more like that seen in humans. DM has been known in several breeds of dogs for more than 35 years, but only in 2008 was the responsible gene identified in a collaborative study funded by the AKC Canine Health Foundation (CHF). The SOD1 gene has been found in many breeds, most notably Wire Fox Terriers, Pembroke Welsh Corgis, Boxers, German Shepherd Dogs, Rhodesian Ridgebacks and Chesapeake Bay Retrievers. In dogs, the gene is recessive with variable penetrance. Despite the fact that Fox Terriers have the highest incidence of the SOD1 gene, DM is seldom reported in the breed, leading to questions about the effects of genetic background on SOD1 penetrance---effects that might impact the understanding of ALS.
Almost Human

Anyone who shares their life with a dog knows they seem almost human; researchers are finding that to be even more true than pet owners. The mapping of both the human and canine genome now makes isolating candidate genes for various diseases easier. Matthew Breen, Ph.D., CBiol, FSB and his colleagues at North Carolina State University use comparative cytogenetics to hone in on genetic causes of cancers.

Comparative cytogenetics takes advantage of the fact that humans and dogs have a shared evolutionary genetic background, but that these genes are shuffled and distributed differently among the human's 46 chromosomes and the dog's 78. For example, regions of genes on human chromosome 22 are redistributed among dog chromosomes 10, 26, and 27. Breen's lab uses this redistribution to zero in on genes associated with various cancers, including brain cancer.

For example, humans with a type of brain tumor call meningioma sometimes have a deletion of a large part of human chromosome 22. This region contains about 550 genes, one of which, NF2, is a prime suspect because it resembles many other cancer-associated genes. Millions of dollars have been spent by human cancer researchers looking at NF2.

Dogs also get meningiomas. In dogs, NF2 is found on dog chromosome 26. But in a CHF funded study, Breen and fellow researchers found that dogs with meningiomas don't show deletions in dog chromosome 26 associated with NF2. They do, however, show deletions in chromosome 27. This suggests that researchers looking for genes responsible for human meningioma should redirect their search to a relatively small region of human chromosome 22 that contains the deleted region of dog chromosome 27---reducing the number of suspect genes from about 550 to about eight. But the story doesn't end there, because the most significant chromosomal aberration in dogs with meningioma (found in 70%) is actually in dog chromosome 17 which is found in a small area of human chromosome 1. This area could be prime hunting grounds for other genetic causes of meningioma in humans.

Lymphoma is another area in which dogs and humans share research benefits. Lymphoma is one of the five most common tumors in dogs, accounting for 20 percent of all canine tumors. Untreated, lymphoma progresses to terminal stages in only a few months. Chemotherapy affords remission for some, but not all, dogs, and for highly variable intervals of time. It's difficult to know ahead of time which dogs will respond. Because of the expense (about $3000 to $6000) and unknown outcome of therapy, many owners forego treatment. In fact, of the approximately 300,000 cases of lymphoma diagnosed in dogs each year, only about 9000 are treated. In another CHF-funded study, Breen and his colleagues discovered genetic markers that are highly predictive of whether and how long a dog will respond to single-agent doxorubicin chemotherapy or to (more expensive) multi-agent CHOP chemotherapy. The test is anticipated to be available to veterinarians in 2012. By working with human cohorts the Breen team will now be evaluating the possibility of using the same markers to predict human lymphoma patient response.

Other CHF-funded studies look at novel therapies for diseases, inlcuding lymphoma. Nicola Mason, BVetMed, Ph.D., of the University of Pennsylvania's School of Veterinary Medicine, has shown for the first time that dogs that develop a type of lymphoma known as Activated B-Cell Diffuse Large B-Cell lymphoma in humans share the same aberrant signaling involved in B-cell activation, driving B-cells to be continuously overproduced and to be resistant to cell death. Injecting an experimental peptide into affected dogs' lymph nodes has shown promising results; further testing is underway to see if systemic treatments will work when the dog is injected intravenously before human trials can begin. In another study, Mason is working with targeted antibody therapy that has shown to be successful in humans and working to develop canine-derived antibodies to target hemangiosarcoma, and eventually other tumor types such as osteosarcoma and lymphoma.
Man's Best Friend

Dogs share a long history of scientific service.

* The earliest report of dogs in research was in the early 1600s when William Harvey studied their circulation and performed transfusions. Transfusions are now commonly performed in humans and dogs.
* Perhaps the best known canine research subjects were Pavlov's dogs, which contributed to behavioral conditioning knowledge used in human psychology and canine socialization, training and clinical therapy today.
* A dog named Marjorie was the first animal to survive on insulin after having her pancreas removed; insulin therapy is now a mainstay of human and canine diabetes management.
* More than 50 dogs received heart transplants before the first was attempted in a human. Although heart transplants are still not available for dogs clinically, many cardiac procedures developed in dogs for humans are now used in veterinary medicine.
* Lancelot, a Briard blinded from a hereditary disease also found in humans, made history as the first large animal to have his vision restored with gene therapy. Now children with this same mutation are undergoing the same gene therapy with encouraging results.

The difference in dog research now, however, is that a high percentage of dogs in cutting edge research don't live in research colonies but in family homes. They donate blood or buccal swabs, and may participate in clinical trials.

Dogs and their DNA are contributing to studies of diseases of ophthalmic, cardiac, neural, immune-mediated, orthopedic, behavioral---virtually any disease shared by the two species. Dogs are an ideal species for such studies because they share a large part of their genomes and their lives with us. They live in our homes and experience the same environmental influences. Their size and complexity is more like the human body's compared to most laboratory animals. The diseases they develop are usually spontaneous, like ours. The variety of pure breeds makes isolating genes easier among a uniform genetic background, and the presence of pedigrees makes identifying the heritable nature of disease over generations possible. The less stringent testing regulations makes trial therapies available using dogs years faster than comparable ones with humans.

And dog researchers are doing it cheaper. "For every cent we spend on canine health research we probably save a dollar in human health research," says Breen.

Researchers more than ever are adhering to the concept of One Medicine put forth by the physician Rudolf Virchow (1821-1903), who wrote: "Between animal and man there is no dividing line---nor should there be. The object is different but the experience obtained constitutes the basis of all medicine.

Helping dogs helps people. But dog lovers already know that.

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