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News - Research
Jacob Sheep and Tay-Sachs
What Are jacob sheep?
 Jacob Sheep are a very ancient breed that probably originated in Syria some 3000 years ago. Pictorial evidence traces the breed's movement through North Africa, Sicily, Spain, and on to England. Jacob sheep were imported into the U.S. for game parks and zoos around the turn of the century. Additional imports from Britain in the 1950s and 60s enhanced the genetic pool, at the time the breed was dwindling. Active preservation efforts saved what was left of the breed and established a healthy genetic pool which assures the breed's survival.
 The Jacob is a small to medium size breed. Adult ewes range from 80 to 140 pounds, while rams will occasionally obtain weights approaching 200 pounds. Coloring is basically white with black or lilac spots randomly distributed on the body. At least 15% of each color must be present. The fleeces from Jacobs are a delight for hand-spinners and for the connoisseur of natural color. Due to the spotting of these animals, the wool can be spun into a complete spectrum from white through gray/lilac to black. This general information about Jacob sheep was provided by the Jacob Sheep Breeders Association.
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The Odd Connection Between Sheep and Tay-Sachs Disease
by Hanna Bandes Geshelin
What’s the relationship between a Catholic couple with a small Texas acreage, strange spotted sheep named after a biblical story, the administrative assistant of the Rabbinic Association of Greater Dallas (RAGD), and a bunch of east-coast scientists–and why should you care? We are all bound up together in the effort to find a treatment and cure for Tay-Sachs.
A week after I began working as administrative assistant of RAGD, I got a strange message about sheep, a farmer outside of Dallas, and Tay-Sachs disease. The Jewish Federation couldn’t help this man, the operator said; perhaps the Rabbinic Association could? The Rabbinic Association could do nothing. But as an Orthodox Jew I’m familiar with the story of Jacob and the spotted sheep, as a hand spinner I am interested in sheep and wool, and when I was young I had friends who lost three children to Tay-Sachs. Did I say I’m also a writer? I decided to investigate.
I called the farmer, Fred Horak, whose St. Jude’s Farm is named after the patron saint of lost causes. The Horaks raise Jacob Sheep, a nearly extinct breed of unique spotted sheep. He told me that the sheep might hold the treatment and cure to Tay-Sachs disease, but $3000 was needed to transport the sheep to researchers in Massachusetts. As I verified his story, I learned the
following:
Ten years ago a couple of the Horaks’ lambs began to totter and lose their mobility. Then the lambs died. When their veterinarian was mystified, the Horaks, who wanted to get rid of the carriers of this disease, brought the problem to vets at the veterinary medicine school at Texas A & M University (TAMU). Instead of helping the Horaks identify carriers, a researcher
convinced them to breed for this strange disease so that TAMU researchers would have more animals to study.
They began breeding the sheep that they thought might be carriers, as well as raising healthy sheep. Soon the Horaks had about 60 sheep, of which one-third were in the disease-carrying pool. Although the Horaks continued to maintain the carrier sheep at considerable expense, researchers at TAMU seemed to forget about the sheep. Years went by without anyone from TAMU contacting the Horaks. Finally the Horaks decided to butcher some of these sheep; they couldn’t afford to keep them forever.
Then, late last winter Dr. Brian Porter of TAMU called the Horaks saying that TAMU researchers had identified the problem. In June 2008 he went out to the farm, drew blood from all the sheep, and sent it to researchers in New York City who were interested in the problem. Soon the researchers sent back the results: there were eight carriers- six ewes and two rams. The problem was Tay-Sachs disease.
Tay-Sachs has been identified in other animals, most curiously in penguins and flamingos in a few American zoos. But these animals’ genetic make-up is only remotely related to that of humans. These unusual sheep are very similar to humans in the way that matters most for unraveling the mystery of Tay-Sachs disease.
Researchers in the Tay-Sachs Gene Therapy Consortium have put together a plan to use the sheep to find a treatment and cure for the disease. When the Horaks contacted me a few months ago, their problem was money to transport the sheep from Texas to New England, where the research will be carried out. By now the transport fees are covered. However, this initiative, which holds out an excellent chance of finding a treatment and cure for this 100% fatal disease, needs to raise considerably more money. Doctors estimate that between the cost of raising the sheep, maintaining the sheep, and the research itself, they will need $500,000-$1 million. The researchers have already found cures for similar lysosomal storage diseases. They are confident that these sheep hold the key to a cure for Tay-Sachs.
The research plan has come just in time. Some of the ewes are old and have never been bred. Whether they will be able to breed is questionable. One of the rams has never successfully impregnated a ewe. The gene pool is shrinking. This year could be the last year to begin breeding the trait successfully.
To me, everything about this story has been amazing. If you believe in coincidence, that things happen randomly and occasionally fortuitously, then this saga shows an amazing series of coincidences. If you don’t believe in coincidence, then the whole ten-year saga of the Jacob Sheep shows evidence of divine providence.
Now it is our turn to play a role, and in spite of difficult financial times we need to open our wallets and support this effort. There is no time to lose.
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Adopt A Sheep Project
by Justin Ungerleider
I have undertaken to raise money to support Tay-Sachs Research, in memory of my brother, Evan Lee Ungerleider and all those who have lost their battle with Tay-Sachs disease. Please help to make a difference in the quest to find a treatment and cure for Tay-Sachs, so that future children and families are not left to suffer.
It has recently been discovered that Tay-Sachs Disease is present in the population of a rare breed of sheep called Jacob Sheep. Amazingly these animals’ genetic make-up is very similar to humans in the way that matters most for solving the mystery of Tay-Sachs Disease. We have to raise funds to help care for the Jacob Sheep who will be the subject of the research to find a treatment and cure for Tay-Sachs. The cost of caring for one sheep is $125 per year. You can help to feed a sheep for a whole year or part of it. The sheep will soon be transported from Texas to New England where the research will be carried out. If you decide to support this project you will receive a certificate with the name of your sheep and its picture. Your support will help to maintain those sheep in the flock that will become part of the research project being developed by the Tay-Sachs Gene Therapy (TSGT) Consortium.
I can be reached at ungy09@yahoo.com for more information.
To “Adopt-a-Sheep” donate online at http://ntsad-ny.org/donations.html or return the form below.
Click here for a printable version.
________________________________________________________________________
____Yes, I would like to Adopt-a-Sheep. Enclosed is my donation of
____$125 to feed one sheep for a year
____$62.50 to feed one sheep for 6 months
____$31.25 to feed one sheep for 3 months
____I do not want to Adopt-a-Sheep, but please accept my donation of $_________.
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All donations are tax deductible to the full extent of the law. A copy of the latest annual report may be obtained, upon request, from our organization, or the Office of the Attorney General, Charities Bureau, 120 Broadway, New York, NY 10271.
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Jacob Sheep Shed Light on Tay Sachs Disease
By Fred Horak
via ALBC January/February 2009 Newsletter
 The American Livestock Breeds Con servancy has long been committed to conserving genetic resources and diversity in livestock and poultry so that a genetic warehouse will be available for the future of agriculture. Conservation of our genetic resources rests on individual commitment, and successful stewardship of our agricul tural inheritance rests on people working together. We usually think of genetic con servation as saving the "good genes." This is a unique situation involving the conser vation of "bad genes" in a rare breed with a story that may not have an ending for several years. The story includes a wide cast of characters: Jacob sheep, shepherds, doctors, scientists, and moms and dads and their afflicted children. The story needs more characters: Jacob sheep breeders and some special Jacobs.
Unconfirmed suspicions: In 1999, Fred and Joan Horak of St. Jude's Farm in Lucas, Texas, took two lambs to Texas A&M University suspecting an acute case of a skeletal congenital defect known as occipital condylar dysplasia. Researchers at the University of Missouri had described this congenital defect several years earlier as a genetic problem in Jacob sheep, but the source of sheep used in the study were not disclosed. Because congenital de fects in any breed should be identified and monitored for the health of the breed, Fred and Joan planned to disclose the suspected skeletal problem they encountered and the familial source so other Jacob breeders could avoid similar problems.
 An unusual suspect: The pathology department at Texas A&M called with two messages about the Horaks' lambs: first, the defect was not occipital condylar dysplasia but a lysosomal storage disease; second, would they be willing to have a team from Texas A&M visit to draw blood from their other sheep, collect tissue samples, and review their pedigree records to identify the source of the disease? The Horaks agreed. While Fred went with Drs. Katherine Bretzlaff and Barbara Lewis to draw blood and collect tissue, Joan met with Dr. James Womack to review the pedigree records of their flock. At the end of the day a prime suspect source was identified as the sheep Turner 183K. How ever, more breeding and DNA tests had to be done to prove the source, and the nature of the lysosomal disease had to be identi fied and proven.
There are various types of lysosomal disease, a congenital disease that, in sim ple terms, can be characterized as the ab sence of an enzyme that breaks down the waste product from the spinal cord-brain connections. The buildup of waste affects the brain and leads to loss of coordina tion, appetite, and sight; recumbency; and, eventually, death. The confirmation of the disease was good news and bad news: the sheeps' pedigrees ran back to foundation Jacobs, but the foundation stock carried a defective gene. A congenital defect in a foundation ram, in a bottleneck breed rep resenting a gene puddle rather than a gene pool, was a concern.
The long engagement: Between 2000 and 2004, Fred and Joan continued to breed suspect carriers and non-carriers so Texas A&M could verify their findings and identify the type of disease. They hoped Texas A&M would be able to identify the specific type of lysosomal problem and de velop a "test" to identify carriers and make it available to concerned Jacob breeders so the congenital defect could be eradicated with minimal loss of genetic diversity. Over the years, Fred and Joan kept and bred carriers, and brought affected sheep to Texas A&M for testing, but finding the lysosomal type and the specific enzyme seemed elusive. What was known and confirmed was that the defect was a simple recessive gene and the source was Turner 183K; possible additional carriers arose but were unconfirmed.
In December 2002, Fred sent an article to the Jacob Sheep Conservancy, Jacob Sheep Breeders Association and ALBC de scribing the lysosomal disease, symptoms, and source and asked for Jacob breeders to report any suspect cases. There were some reports of "sickly" lambs that died or were butchered, but breeders did not deem these remarkable and cause of disease or death was not confirmed, and animals dying from congenital problems are often buried in unmarked graves. As the years passed, Fred and Joan kept a remnant of the car rier group and hoped for a breakthrough in identifying specific lysosomal type and that a test for carriers might be found. Since the Jacob breed is not commercially significant, hope for breakthrough research had low priority.
The human element: When Dr. Porter of Texas A&M called Fred in the summer of 2008, Fred expected it to be another "nothing new, no time or money for research on a disease in Jacobs" type call. The news was stunning: according to Dr. Porter, the lysosomal disease in the Horaks' Jacob sheep was exactly the same form as a lysosomal disease fatal to children: Tay-Sachs disease. Further, Texas A&M had developed a test for poten tial carriers. Dr. Porter then asked if the Horaks still had potential carriers in their flock. Hearing a "yes", Dr. Porter said he would visit them in a couple of weeks to draw blood to be sent to Dr. Edwin Kolod ny, Chair of the Neurology Department at New York University Medical Center, for DNA and enzyme tests. The carriers were identified and confirmed.
Dr. Kolodny is a member of the Tay-Sachs Gene Therapy Consortium founded in 2007 (www.tsgtconsortium.com), a group of research scientists in the U.S. and U.K. with the goal of initiating a state-of-the-art gene therapy clinical trial for Tay-Sachs disease in the next four years. Tay-Sachs disease has various forms: infantile (fatal at age 5), juvenile (fatal at 15) and late-onset (about age 30 but debilitating rather than fatal). In addition, there are about 40 Tay-Sachs-type related human diseases including epilepsy, muscu lar sclerosis, muscular dystrophy and even Parkinson's disease. Currently, Tay-Sachs and many of these related diseases are incurable, and some are fatal. The genetic similarities between sheep and man and Tay-Sachs and other neurological diseases are as close a match as we may ever get.
Another member of the Consortium, Dr. Miguel Sena-Esteves of the Massachu setts General Hospital and Harvard Medi cal School remarked: "The goal of identi fying and eliminating Tay-Sachs in Jacob sheep in order to conserve the breed is a noble goal. But we who are working on a human gene therapy cure are very happy that you did not succeed and kept the car riers for the last decade. These sheep are genetically significant."
The arrangement for your involvement: Additional Tay-Sachs carrier sheep need to be identified so a sufficient number of af fected sheep can be placed in gene therapy trials. The Horaks have given their carrier flock of eight Jacobs to the Consortium and Dr. Kolodny has offered the lysosomal carrier test at no cost to all Jacob sheep breeders. Why test? For the sake of finding a cure for human disease and conserving the breed. Who should consider testing for the defect? Jacob breeders who have sheep descended from Turner 183K; Jacob breeders who have had lambs dying be tween the ages of six and nine months that show signs of loss of coordination, ataxia, loss of appetite, blindness, or recum bency; Jacob breeders who want to know that a sheep is not a carrier of this lethal defect and be able to pass that assurance on to other breeders. To become involved, contact Dr. Edwin Kolodny by email at Edwin.Kolodny@nyumc.org.
Breed conservation does represent a genetic warehouse from which we may need to draw in the future. Part of the task is to identify how each of us can add to the content of the warehouse.
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Jacob Sheep Breeders Find More Tay-Sachs Carriers
By Dr. Edwin Kolodny and Fred and Joan Horak
via ALBC January/February 2011Newsletter
The American Livestock Breeds Conservancy and Jacob conservators have played a significant role in identifying the source and limiting the spread of a lethal mutation in Jacob sheep (ALBC NEWS,Vol.26, Issue 1; Vol.27, Issue 2). The mutation, now known as the G444R mutation in the hexa gene, was first suspected in 1999 in two affected sheep which were presented to Texas A&M's veterinary clinic. The initial diagnosis, reported to Jacob breeders in 2002, was gangliosidosis - defective lysosomes not processing and expelling nerve cell lipid and fat waste residue. New York University Medical Center's Department of Neurology (NYU) got involved with the project and did extensive DNA testing on Jacob blood and tissue. They compared the Jacob sheep DNA to sheep, cattle, and human DNA and found a specific genetic mutation that caused the skipping of a critical part of a gene that produces Hex A, the enzyme that processes a vital lipid in nerve cells. The initial gangliosidosis diagnosis was now specifically identified as the G444R mutation that causes a form of Tay-Sachs disease (TSD) in Jacob sheep.
NYU also discovered that the DNA sequence of nucleotides and amino acids in the Jacob is 86% and 89% similar, respectively, to human DNA. This discovery presented a unique opportunity not only to eradicate a fatal, autosomal recessive mutant gene in a rare breed but also provided a large animal model to address the fatal human disease, Tay-Sachs. Affected Jacob sheep die at about eight months; affected children die at about five years.
Either Jacob parent can carry the mutant autosomal recessive gene. Carriers appear normal and live a normal life. But breeding a mutation-carrying Jacob to a normal Jacob results in a 50/50 chance of producing another carrier lamb. A carrier Jacob bred to a carrier Jacob results in 25% chance of an affected lamb, a 25% chance of a normal lamb, and a 50% chance for additional carriers. Identification of carriers helps avoid the loss of foundation bloodline Jacob genetics. To identify carriers, the Neurogenetics lab at NYU offered free DNA testing for the mutant gene for any Jacob sheep breeders who wished to identify carriers in their flock, reduce the number of carriers in the Jacob population, and prevent the production of affected sheep (ALBC NEWS, JSBA Newsletter, 6/10). The NYU lab sent test supplies, instructions, and did the testing at no cost to the Jacob breeders.
Dr. Bai Zeng and Paola Torres processed 443 DNA samples from 10 participating shepherds located across the U.S. They identified 51 mutation carriers, a carrier incidence of 11%; 17 different flock names appeared in the names of carriers, and 90% of the shepherds' flocks had one or more mutation carriers. NYU spent about $45,000 on testing supplies, mailings, and DNA testing. Participants received a report of mutant gene/normal gene for each Jacob tested. In many cases, breeders with identified carriers also received corrected and extended pedigrees based on complete Jacob ancestry records, including the AMBC (now ALBC) records held by the USDA Library in Beltsville, MD. These bloodline ancestry records helped point to the source and spread of the mutation. Turner 183K, a bloodline foundation ram and the apparent source of the mutation in North America, was born of imported Jacobs and the primary suspect is Turner's Supermom. Over the past two months, the lab has received few new requests and some breeders who requested and received testing materials have not submitted DNA specimens to the NYU lab. Since most concerned Jacob breeders have responded and the Jacob Sheep Breeders Association judged the mutation as "by no means a common problem" and "very unlikely that any breeder will ever see a problem," the two-year period for free testing will be curtailed.
The G444R mutation in Jacobs has not been eradicated but over 40 carriers have been identified by DNA testing and the source and spread of the problem has been documented. The knowledge gained by testing and identifying carriers will benefit the breed in general and, moreover, is critical knowledge for conserving the original bloodline. Knowing which Jacobs are carriers opens two courses of action: avoid selecting carriers for the Jacob gene 'puddle' or, breed a known carrier to retain the foundation bloodline genetics and test the offspring of carrier matings until a clear, better replacement is produced. This conserves the genetics and diversity of the breed. In fact, several sites that collected Jacob semen and embryos for cryo-preservation were notified of the mutation so they can take appropriate action in the future. Conversely, mutant gene semen and embryos are being cryo-preserved so the mutation will be available in the future.
The G444R mutation in the Jacob has taken several steps forward as a large animal model of the human form of TSD. Four TSD-affected Jacob sheep were placed in a clinical program similar to the program used for TSD cats, the small animal model. Two treated Jacobs have passed a longevity milestone but the final results and significance of this first clinical program for Jacobs will not be known for months. These tests will then have to be repeated and results confirmed, a process that will consume the next few years.
In concluding this final article on a congenital mutation in Jacob sheep, the authors wish to acknowledge and thank the Jacob shepherds who collaborated on this project and whose contribution toward identifying carriers and the source will help conserve foundation Jacob genetics. The consortium of scientists and doctors extend their gratitude to the Jacob breeders who have offered to donate carriers to this research project, and the New York University School of Medicine, the National Tay-Sachs and Allied Diseases Association, Cure Tay-Sachs Foundation and the Tay-Sachs family foundations that supported the testing and research.
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