Gene transfer may confer lifelong sterility in one shot (but it can’t be done with a cookie)
PORTLAND, Oregon––Could mice produce a miracle drug capable of preventing cat reproduction?
If mice could do it unassisted, through normal evolution, you can bet your catnip they would have, long since.
But mice assisted by a battalion of top-drawer genetic scientists are a whole different matter––and that has the Alliance for Contraception in Cats & Dogs, the Maddie’s Fund Shelter Medicine Program, and the Michelson Found Animals Foundation, which has put up most of the research funding so far, very excited about the prospect of spending multi-millions to help the mice and genetic scientists perfect their potential animal contraceptive product.
Cat studies are just the beginning
Cats are not the only target of the new animal contraceptive method, just the first.
The same concept can, at least in theory, be applied to contracepting dogs––or problematic rhesus macaques in the streets of Asia, feral pigs across the U.S., or wild horses, and eventually could become accepted as a human birth control method.
Neither are mice necessary to the production of the potential animal contraceptive product. Mice happened to be involved in the early research simply because mice are the most abundant animals in laboratories, most accessible to scientific research.
Understanding the science behind the potential animal contraceptive breakthrough requires understanding what something called “Mullerian inhibiting substance” is and does.
Scientific literature will not help most readers.
The generally accepted scientific definition, published in a 1993 Endocrine Reviews paper entitled “Mullerian inhibiting substance: a gonadal hormone with multiple functions,” by M.M, Lee and P.K. Donahoe, is that “Mullerian inhibiting substance is the gonadal hormone that causes regression of the Mullerian ducts, the anlagen of the female internal reproductive structures, during male embryogenesis.”
In translation, “Mullerian inhibiting substance” is the chemical, a type of gonadal hormone, that differentiates males from females early in pregnancy.
If a female animal happens to produce that gonadal hormone other than in early pregnancy, the “Mullerian inhibiting substance” may tell her reproductive tract that she is really a male.
Her reproductive tract may then stop producing the ovarian follicles that she needs to become pregnant––apparently with no other known effects on body, mind, or spirit.
Cookies can’t fool Mother Nature
But nature has ensured that producing “Mullerian inhibiting substance” does not happen by accident, and is difficult to induce.
Further, production of “Mullerian inhibiting substance” must be sustained for the contraceptive effect to continue.
“Mullerian inhibiting substance” could not be induced and sustained, for example, just by eating one magical, mystical “spay/neuter cookie,” such as 600 Million Stray Dogs Need You founder Alex Pacheco has raised funds in the name of inventing since 2011.
Even eating a “spay/neuter cookie” a day could not achieve the necessary alteration of basic body chemistry, since nature has designed the digestive process as an almost impermeable barrier to lastingly altering an animal’s biochemistry by eating something.
If eating something is likely to alter the animal’s biochemistry, the animal usually either regurgitates it, or becomes very ill, and/or dies.
What is necessary to produce “Mullerian inhibiting substance” as a birth control device is to somehow trick the animal’s own body into manufacturing it.
Small army of scientists––& big money
While Pacheco has never produced any evidence of actually working anywhere with bona fide scientists, the April 2021 presentation to the Alliance for Contraception in Cats & Dogs virtual conference generating the current excitement was delivered by David Pepin, Ph.D., of Pediatric Surgical Research Laboratories at Massachusetts General Hospital.
Thirteen other Pediatric Surgical Research Laboratories scientists were credited. Among the nine credited funders of the research, besides the Michelson Found Animals Foundation, were the Department of Defense and the Gates Foundation.
The Cincinnati Zoo has also been involved.
With that sort of intellectual and monetary capital involved, results are to be expected.
Gene Transfer ain’t a band leader
The Alliance for Contraception in Cats & Dogs in a “May 2021 update” announced that “Sponsored research of a single-dose sterilant for female cats has just completed a second-year breeding study, and results are extremely promising!
“We believe,” the Alliance for Contraception in Cats & Dogs said, “that this progress could represent the onset of lifetime sterility in these cats while also preventing estrus and related behaviors.”
“This research involves gene transfer,” the Alliance for Contraception in Cats & Dogs explained.
Specifically, the Alliance for Contraception in Cats & Dogs continued, “In human gene transfer, genetic material is introduced into the human body to cure a disease. The introduced gene (DNA) may produce a required protein that is in low levels or entirely absent in the affected individual. Alternatively, the introduced gene may regulate the expression of other genes,” meaning what the genes do, “either increasing or decreasing their expression to produce its effect.
Tried in humans
“In most cases,” the Alliance for Contraception in Cats & Dogs said, “this treatment is used in people who are born with genetic defects that result in a ‘missing’ protein, which can be restored by delivering the gene that codes for that protein, in essence, reversing the genetic defect.
“Currently there are hundreds of human gene transfer clinical trials underway for a wide variety of conditions, including cancer, HIV, heart disease, and muscular dystrophy. The effects of gene transfer in animal models and human clinical trials have been observed for at least eight years,” the Alliance for Contraception in Cats & Dogs said, “and suggest that some of these alterations may be permanent.”
New genes are usually introduced to humans, the Alliance for Contraception in Cats & Dogs explained further, “using a virus that has been engineered for that purpose. These viral vectors deliver the gene but do not replicate, reducing the possibility of safety issues.”
Tried in animals, too
The same approach can be used to transfer new genes into animals. In fact, this has already been done thousands of times, as part of the animal testing required before any new drug or therapeutic treatment can be legally used in humans.
“In the case of animal contraception,” the Alliance for Contraception in Cats & Dogs said, “gene transfer could be used to introduce genes into the animal, which could suppress reproduction in a variety of ways, depending on the gene used. The advantage of this method is that the transfer could produce long-term term or even permanent effects eliminating the need for re-treatment.”
The Alliance for Contraception in Cats & Dogs summarized “the results of two gene transfer studies to produce contraception in female cats, both using “adeno-associated virus to deliver relevant genes.”
More about “Mullerian inhibiting substance”
One of the two recent studies focused on the use of Mullerian inhibiting substance.
Summarized the The Alliance for Contraception in Cats & Dogs, “In female mice, a single treatment “resulted in contraception during the 24 weeks of the study.
“The Mullerian inhibiting substance gene was [then] introduced into the thigh muscle of three female cats. No adverse effects were observed at the site of the injection and blood chemistry parameters remained normal for all cats, indicating the treatment was safe. The treatment suppressed estrus cycles in the females, but after a few months cats returned to normal, likely because the Mullerian inhibiting substance gene used was not the feline gene, and cats may have mounted an immune response to it, making it ineffective. A follow up study is planned using the feline Mullerian inhibiting substance gene.”
Improved anti-GnRH delivery (FedEx & UPS don’t work)
The Alliance for Contraception in Cats & Dogs also described gene transfer research targeting “Gonadotropin-releasing hormone (GnRH), which controls fertility in both males and females.”
The anti-GnRH approach to birth control, both in animals and in humans, has been researched for more than 40 years. Anti-GnRH pharmaceutical products already in use as animal contraceptives include Deslorelin, Suprelorin, Gonazon, and GonaCon.
What is new is scientific investigation of a way “to deliver a gene that codes for a monoclonal antibody against GnRH,” instead of a vaccine, which would bypass the need for booster injections to maintain suppressed reproduction.
Cats disconnect the mouse gene
After a mouse study induced infertility for a year, the Alliance for Contraception in Cats & Dogs said, “To test this approach in cats, three female cats were given an intramuscular injection of adeno-associated virus containing the gene encoding this antibody. No injection site reactions or adverse effects were observed in the cats,” but the injection did not achieve long-term contraception.
“Again, it is likely that the monoclonal antibody was seen as foreign by the cats, and inactivated due to the cats mounting an immune response,” the Alliance for Contraception in Cats & Dogs theorized.
But “feline specific” genes might work
The bottom line, for the Alliance for Contraception in Cats & Dogs, is that “Although neither cat study achieved long-term contraception, both demonstrated that gene transfer could be used to express proteins regulating animal reproduction.
“Studies are progressing that use genes that are more feline specific, with the goal of extending the duration of effect in cats, and in the future, dogs. The potential for this method to deliver a ‘single shot’ lifetime suppression of fertility is there.
“Evaluating whether a gene transfer treatment results in permanent sterility requires patience and a multi-year breeding trial,” the Alliance for Contraception in Cats & Dogs cautioned.
“Even so, due to the success thus far, Michelson Found Animals is shifting from a grant-based research project to a drug development phase,” the Alliance for Contraception in Cats & Dogs announced.
“Something promising on the horizon”
“Most approaches need to be ‘boostered’ in some way,” Alliance for Contraception in Cats & Dogs executive director Joyce Briggs told the Maddie’s Fund online periodical Shelter Medicine, whereas “The gene transfer method is essentially self-boosting.”
Continued Shelter Medicine, “To dispel any apocalyptic speculation: The transferred gene is not integrated into the cell’s DNA. It sits inside the targeted cells – in this case, feline reproductive organ cells – producing a protein continuously throughout that cell’s life. This,” in theory, “results in lifetime sterility.
The Michelson Found Animal Foundation, Briggs said, has “pledged to take the technology through the regulatory approval process. That will involve studying the safety of the procedure over the years that are required by the Food & Drug Administration for a claim of permanent sterility. It will also let us study whether it will suppress the hormones that can cause health problems in intact female dogs and cats.”
“I wish I could say it was, it was a much, much shorter timeline to introduction,” Briggs concluded, “but the good thing is we have something so promising on the horizon.”
$25 million reward still dangling
The gene transfer experiments appear to indicate the closest approach yet to anyone actually claiming the $25 million Michelson Prize in Reproductive Biology, offered since October 2008 for the development of a single-dose nonsurgical sterilant, preferably to be administered by injection, that will be effective and safe in both male and female dogs and cats for 10 to 20 years.
The award-winning product, the Michelson Found Animals Foundation announced when the prize was posted, must “ablate presence or action of sex steroids”; be easily made at a reasonable cost, defined as $5.00 to $30.00 per animal treated; be “suitable for administration in a field setting”; and have a “reasonable pathway to regulatory approval.”
$50 million in grants support search
Progress toward developing such a product is supported by the $50 million Michelson Grants in Reproductive Biology. This program provides funding of up to $250,000 per year for up to three years to researchers who have already presented “proof of concept studies in vitro, in rodent models, in target species (dogs and cats), in one gender or one species.”
The Michelson program requires that “Research animals must be placed in adoptive homes if terminal studies are not essential.”
Five years later, Michelson Prize & Grants in Reproductive Biology director of scientific research Shirley D. Johnston said in 2013, the trustees had committed $11.3 million in grants to 23 research groups, after reviewing 83 research proposals and receiving 234 letters of intent to apply for funding. About $38.7 million remained uncommitted.
Reduced reliance on rodent studies
Among the funded approaches, 13 were investigating “targeted delivery of cytotoxins,” the method including chemosterilants; seven were investigating immunocontraception, which seeks to use the animals’ immune systems to prevent conception; and five were investigating genetic methods, including gene silencing and gene therapy.
The Michelson Prize and grants had been publicized to more than 10,000 neuroscientists, oncologists, pharmaceutical chemists, immunologists, virologists, molecular biologists, and reproductive physiologists, Johnson said, via booths at 43 scientific conferences and ads in 78 professional publications.
In August 2016 the Michelson Found Animals Foundation tightened the funding guidelines for grant applications to eliminate approaches which had already proved to be unviable and/or relied on rodent studies instead of focusing on results in dogs and cats.
We is smarter than @#$%
Suggested ANIMALS 24-7 editor Merritt Clifton on November 5, 2008, “One idea, still completely untested,” as of then, “would be to use gene therapy to modify the fecundity of animals. The idea would be to introduce altered genes into the animals, which would take over control of their reproductive systems. Similar techniques are now experimentally used in fighting many severe human illnesses with a genetic component.”
This now appears to be the direction in which the most promising research is leading.
IMHO if we can apply the sterility thing to humans, we’ll have it just right.
Jamaka Petzak says
Agreeing with @joel posting before me, and praying with all my being that there can be a successful, non-harmful, lifetime sterilant for cats (and other species, but first, cats). Sharing to socials with gratitude and hope.
Susan C. McDonough says
“Her reproductive tract may then stop producing the ovarian follicles that she needs to become pregnant––apparently with no other known effects on body, mind, or spirit.”… We should be doing this to people.
Also, I think the AVMA will fight this because it will eliminate the need for spay/neuter, which brings them a lot of money.
Doing it to people? If they ask for it, do you mean?
Joyce Briggs says
Thank you, Merritt and Beth, for covering the exciting progress toward an injectable sterilant for female cats and, hopefully, for dogs. To clarify, the presentation by Dr. Pepin you reference was in mid-2018 at ACC&D’s
International Symposium. That presentation does share the foundational work for this approach and news. However, it is the subsequent work that has generated the two years of breeding trials, whose success to date in female cats we announced earlier this year and that we think heralds a permanent loss of fertility. Once the most recent studies are published, more details will be able to be shared.
Your article mentions an early academic study by P.K. Donahoe about MIS. Dr. Donahoe has used MIS as a way to protect fertility for women receiving chemotherapy on cancer treatment, as well as for a novel treatment for cancers of the female reproductive tract. MIS acts by arresting the growth of and protecting the limited supply of primordial follicles during treatment, preserving them for later. MIS’s impact on reproduction made Dr. Patricia Donahoe consider it might serve as a cat sterilant.
Dr. Donahoe was the first female surgical resident in Boston and the first female professor of surgery at Harvard University. She is currently the Director of Pediatric Surgical Research Laboratories and Chief Emerita of Pediatric Surgical Services at Massachusetts General Hospital. Dr. Donahoe is as celebrated a researcher as she is a surgeon, with massive contributions and with over 230 peer-reviewed publications, many of them related to MIS. She brought in Dr. Pepin as a collaborator and he is making his own deep mark on creation of tools for our field. We are thrilled about the contributions of both these important researchers to this work.