Michelson Grants Research Findings To Date: A Look Back on Seven Years of Grant Funding

It’s hard to believe that the time has passed so quickly, but this October marked the 7th anniversary of the Michelson Prize & Grants program! As we celebrate this milestone, we’d like to share with our readers the important progress that has been made since then in the field of nonsurgical sterilization. Through the tireless efforts of our grantees and their research teams, the dedication of our diverse and talented Scientific Advisory Board, and the generosity of our funder, Dr. Gary Michelson, we have made significant steps toward the development of a noninvasive spay/neuter method for companion animals and we hope that you will share our enthusiasm after reading this update.

A major goal of the Found Animals Foundation is to develop a single-dose, permanent (10-20 year), nonsurgical sterilant that renders male and female dogs and cats infertile. Our desired product must induce sterility as well as suppress reproductive hormones and behavior (such as estrus, matings) in treated animals. If made available to the ~3500 shelters in the U.S.A., such a sterilant could guarantee that every animal adopted would be incapable of reproducing, thereby eliminating the birth of unwanted litters that ultimately end up back in the shelter system. Nationally and internationally, such a product could also be administered by paraprofessionals to feral and free-roaming dog and cat colonies. We envision that this nonsurgical sterilant will be a total game-changer for the care and management of shelter, feral, and free-roaming dogs and cats all over the world and could eventually eliminate the euthanasia of shelter animals altogether.

Thirty-five Michelson Grants in Reproductive Biology, totaling about $15 million in committed research funds, have been awarded to scientists around the world since 2009 to perform research leading to the development of this sterilant. Grants have been awarded to scientists in the U.S.A., Canada, Argentina, Australia, the Netherlands, New Zealand, and Scotland.

To date, scientists performing this research have targeted one of three sites in the body that are essential for reproduction. These are:

  • the hypothalamus, the part of the brain that contains cells which initiate reproduction by secreting the hormones kisspeptin and gonadotropin releasing hormone (GnRH);
  • the pituitary gland, a pea-sized organ at the base of the brain that responds to secretion of GnRH by secreting luteinizing hormone (LH) and follicle stimulating hormone (FSH); and
  • the reproductive organs in the abdomen (ovaries) or scrotum (testes) that respond to LH and FSH by producing eggs, sperm, and hormones such as estrogen and testosterone that cause reproductive behaviors.

Scientists have endeavored to block normal reproductive function at these sites using one or more of the approaches described below. Some of their findings are bulleted under each approach.

Gene Silencing

Genes in all body cells encode for, or express, proteins/peptides that are active building blocks or enzymes. In the gene silencing approach, scientists inject an inactive virus (either a lentivirus or adeno-associated virus) intravenously that has a nucleic acid fragment inserted that is an exact mirror image of the gene that they want to silence. The mirror image (interference RNA) attaches to this gene and prevents its ability to express its protein. One of the first Michelson Grants awarded was to silence genes in cells of the hypothalamus that express kisspeptin and neurokinin B (NKB). These proteins/peptides normally induce GnRH secretion.

  • A gene silencing construct to silence kisspeptin and NKB genes in the hypothalamus disrupted female rat estrous cycles but did not completely ablate fertility; studies are now underway to enhance specific delivery of this construct to the hypothalamus in high concentrations.
  • Genes that express dog and cat kisspeptin and NKB in the hypothalamus were cloned and respective genomic structures were determined. It was discovered that the dog kiss1 gene is the most divergent of all mammalian species known.
  • Genes expressing kisspeptin and the kisspeptin receptor in the hypothalamus were cloned in the dog. Investigators demonstrated that estrous cycle stage influences kisspeptin signaling in dogs.
  • Silencing of the genes that express androgen receptor proteins in the testes induced long-term spermatogenic arrest and sterility in male mice.
  • Dog testes (seminiferous tubules) were shown to express functional piRNA binding proteins called “PIWI proteins” that are essential to spermatogenesis; in normal reproduction, these are critical mediators of egg and sperm maturation. They could be a good target to silence in efforts to induce sterility.

Gene Therapy

Gene therapy also uses a lentivirus or adeno-associated virus, but the nucleic acid fragment inserted is a functional gene that expresses a protein. This approach is used to treat a variety of human diseases and has been able to express a blood clotting factor for more than 10 years in dogs with hemophilia. The Foundation has approved studies to use gene therapy to express antibodies to GnRH, to express gonadotropin inhibiting hormone (GnIH), and to express Mullerian Inhibiting Substance (MIS).

  • Gene therapy delivering antibodies to GnRH causes sterility in rodents by blocking hypothalamic GnRH.
  • Human GnIH inhibits secretion of reproductive steroid hormones in cat ovarian tissue.

Immunocontraception

Immunocontraception describes induction of antibodies to essential reproductive hormones so that the antibodies bind to and block these essential reproductive elements. The mechanism is similar to that of inducing antibodies by injecting inactivated bacteria or viruses that cause disease, except that immunocontraception relies on creating antibodies to “self” antigens. Dogs and cats have been immunized against GnRH for decades and shown to be infertile for 1 to 3 years after a single administration. Work funded by our program is in progress to provide slow or repeated release of vaccines against GnRH in the hypothalamus, the GnRH receptor in the pituitary, or other reproductive proteins.

  • Administration of a GnRH vaccine on a subcutaneous three-dimensional adjuvant matrix that mimics the body’s response to infection resulted in recruitment and activation of (antigen presenting) dendritic cells and long-term persistence of antibodies to GnRH secreted by the hypothalamus.
  • A study is in progress in mice to release GnRH vaccine from a slow-release subcutaneous implant “smart” device that releases the antigen when circulating antibodies to GnRH fall.

Targeted Delivery of Cytotoxins

Some scientists are trying to destroy cells in one of the three sites that are essential to reproduction by delivering toxins exclusively to the target cell, and not to other body tissues. This methodology also is used to destroy cancer cells in patients receiving chemotherapy.

  • Investigators discovered that the gene sequence expressing the kisspeptin receptor protein (reported in public databases) in rat hypothalamic cells was incorrect and nonfunctional. The correct sequence was determined and confirmed, and the National Center for Biotechnology Information corrected the database based on that funded research.
  • In a study of attempted toxin ablation of pituitary cells secreting LH and FSH, our investigators have found that gonadotropes are resistant to toxin ablation. Others have demonstrated that toxin degradation within structures called “endosomes” may be limiting efficacy. In fact, it has been estimated that only about 1 in 10,000 internalized toxin (ribosome inactivating proteins) escape endosomal destruction. A research team of Michelson Grant awardees is now adding “endosome escape” substances to the toxin ablation constructs to enhance efficacy.
  • Administration of a GnRH agonist implant (deslorelin) to kittens within 24 hours of birth blocked receptors on pituitary cells from access to native GnRH. This resulted in delayed onset of puberty, to 42-91 weeks of age, compared to normal onset of puberty at 15.5 +/- 1.7 weeks in control kittens. Investigators hypothesize that neonatal use of a higher dose of deslorelin might prevent puberty altogether. A similar study in dogs is ongoing.
  • Scientists discovered that Sertoli cells in the testes require a different mechanism of inducing cell death than do the primordial germ cells that produce sperm because of different phagocytic/endocytic functions.
  • Administration of (toxic) reactive oxygen species linked to FSH that target the ovaries and testes caused germ cell death in mice.

Our grantees’ work is frequently published in peer-reviewed journals and presented at international conferences. If you would like to learn more about any of our funded projects, be sure to check out the full Michelson Grants Research Findings listing on our website!

Three New Members Join the MPG Scientific Advisory Board

The Scientific Advisory Board of the Michelson Prize & Grants in Reproductive Biology has gained three new members: Drs. Thomas Conlon, Kevin Morris, and Marcel Van Duin.

Thomas Conlon, PhD, is an Assistant Professor in Pediatrics and the Director of the Powell Gene Therapy Center Toxicology Core at the University of Florida. As the Director of the Toxicology Core, Dr. Conlon facilitates efficient, cost-effective, and rigorous preclinical testing of gene therapy vectors, with a special emphasis on recombinant adeno-associated virus (rAAV) vectors. Dr. Conlon has also collaborated with the University of Florida College of Veterinary Medicine to identify and treat two types of cardiac problems experienced in dogs.

Kevin Morris, PhD, has been actively involved in cancer research in both academic and biotechnology environments for over 20 years. He has served as the Principal Investigator on a wide range of studies in animal sheltering, pet overpopulation, and the field of human-animal interaction. Dr. Morris is currently serving as the Co-Principal Investigator on the American Humane Association’s Canines and Childhood Cancer Study and is also a member of the Board of Directors of the Alliance for Contraception in Cats and Dogs (ACC&D).

Marcel Van Duin, PhD, is the Senior Director, Therapeutic Area Head Reproductive Health Research at the Ferring Research Institute in San Diego, CA. Dr. Van Duin has over 25 years’ experience in various leadership positions in the pharmaceutical industry, including as the Head of Pharmacology at Organon Research in Newhouse, Scotland, where he was responsible for all pharmacological research in the areas of reproductive biology, oncology, immunology, and toxicology, as well as the animal research facilities.

Says Dr. Gary Michelson, the founder of the Found Animals Foundation, “I am delighted to welcome Drs. Conlon, Morris and Van Duin to the Scientific Advisory Board. Their expertise in gene therapy, molecular biology and reproductive biology strengthen our Board.”

These newest members join nineteen other elite experts in the fields of reproductive biology, neuroscience, veterinary medicine, immunology, and toxicology on the Scientific Advisory Board. As a group, they review grant proposals and guide the Michelson Prize & Grants program toward our goal of finding a nonsurgical sterilant for use in male and female cats and dogs.

We are very excited to welcome these new board members to the fold and look forward to the exciting new projects that the Board will be reviewing in 2015!

USC Michelson Center for Convergent Bioscience Breaks Ground

A new era in medical research began in October, as the USC Michelson Center for Convergent Bioscience broke ground on the University Park Campus of the University of Southern California (USC).

The new building, made possible by a $50 million gift from Dr. Gary Michelson, the founder of the Found Animals Foundation, and his wife Alya Michelson, will add 190,000 square feet to the campus and will accommodate about 25 to 30 investigators working in collaborative, shared lab spaces. In addition to the flexible labs, the building will also hold a Center for Electron Microscopy and Analysis, a nanofabrication facility, and a suite of microscopy imaging technology – all to be outfitted with top-of-line tools and equipment. The Center is expected to be completed in 2017.

The creation of the USC Michelson Center marks a new collaboration between the USC Dornsife College of Letters, Arts and Sciences and the USC Viterbi School of Engineering. Says Dr. Michelson, “USC is well-known for producing entrepreneurs in a wide array of disciplines, and the USC Michelson Center will now help leverage the university’s network of scientists and engineers to tackle challenges in health, biomedicine, and many related fields.” Further, Dr. Michelson predicted that the Los Angeles area will soon become an epicenter for biomedical research.

The Michelson Prize & Grants team is especially excited about the USC Michelson Center, as its promise of integrative research coincides with our approaches in reproductive biology, toxicology, immunology, and many other disciplines to find a single-dose, nonsurgical sterilant for cats and dogs. We look forward to hearing more from the Center!

MPG Scientific Advisory Board Visits the Cincinnati Zoo & Botanical Garden

The Scientific Advisory Board of the Michelson Prize & Grants in Reproductive Biology program recently held their final meeting of the year, but this was no typical board meeting – this month the Board found themselves at the Cincinnati Zoo & Botanical Garden spending time with Bactrian camels, a cheetah, and the only Sumatran rhino in captivity in Northern America. They even got up-close and personal with several free-roaming peacocks (who tend to think they run the Zoo)!

This exciting trip was made possible through the generous hospitality of Dr. Bill Swanson, the Director of Animal Research at the Zoo’s Center for Conservation and Research of Endangered Wildlife (CREW), and one of MPG’s Scientific Advisory Board members. Not only did Dr. Swanson volunteer to host the Board meeting, but he also graciously gave the Board a “backstage tour” of the Zoo the following day.

In addition to holding this meeting in a new and exciting venue, the meeting format this time around was also very different for our Board. Rather than evaluate new proposals for funding consideration, the Board took a close look at the 33 projects that it has approved over the past 5 years in order to draw important conclusions about which approaches and targets appear to be the most promising, and to develop clear ideas about where the program should head in the future. While the Board is very excited about all of the Michelson Grant research findings generated since it awarded its first grant in 2009, strategic planning exercises like this will ensure that we are seeking out and funding projects that are most likely to quickly help us reach our goal of developing a nonsurgical sterilant for cats and dogs.

On the day following our meeting, Dr. Swanson treated the Board to a tour of the Cincinnati Zoo & Botanical Garden, which included stops along the way at CREW’s facilities, the Zoo’s veterinary hospital, and meet-and-greets with Humphrey and Jack (Bactrian camels), Harapan (Sumatran rhino), and Savanna (cheetah), one of the Cat Ambassadors of the Zoo.

What the Board found was that Jack (Humphrey’s son) loved to have his picture taken, Harapan enjoys a good nose rub, and Savanna purrs just like any other house cat (although much louder).

The Board also learned about the crucial conservation work CREW is performing on a daily basis. Through advanced animal research and plant research, CREW is working to secure a positive future for endangered species. CREW’s current Signature Conservation Projects include exceptional plants, rhinos, small cats, and polar bears.

The next MPG Board meeting will take place in February 2015 and, although it won’t include visits with endangered species or exotic animals, it will bring the Board another opportunity to review new and innovative proposals in the search for a single-dose, nonsurgical sterilization method for cats and dogs. The whole Michelson Prize & Grants team looks forward to it!

 

Michelson Prize & Grants Featured on NPR!

The Michelson Prize & Grants in Reproductive Biology was recently featured on 89.3 KPCC-FM, the Southern California National Public Radio affiliate, to discuss the success of the program to date in the search for a single-dose, permanent, nonsurgical sterilization method for cats and dogs.

The story features insight into the Michelson Prize & Grants program from both Aimee Gilbreath, Executive Director of the Found Animals Foundation, as well as Dr. R. Scott Struthers, the President and Chief Scientific Officer of Crinetics Pharmaceuticals and a current Michelson Grantee.

The story comes at an exciting time for the Michelson Prize & Grants program, as two more grants get underway. Cristina Gobello, MV, DVM, Small Animal Specialist, DECAR, a Professor and Investigator at the Laboratory of Reproductive Physiology at the National University of La Plata and the National Research Council of Argentina, recently began her second Michelson Grant-funded project, a four-year grant totaling $132,576 titled, “Prepubetal administration of a long term release GnRH agonist in domestic dogs: A Pilot Study.” Dr. Gobello recently completed another three-year project funded by the Michelson Grants totaling $91,638.

Additionally, Sergio Ojeda, DVM, a Senior Scientist in the Division of Neuroscience at the Oregon National Primate Research Center will begin a two-year grant totaling $471,487 in October for his project, “Engineering viral vectors to target the cat hypothalamus with sterilizing molecules.”

As the sole funders of the Michelson Prize & Grants program, Dr. Gary K. Michelson and Alya Michelson are proud of the continued commitment that researchers such as Drs. Struthers, Gobello, and Ojeda are making towards finding a single-dose, permanent, nonsurgical sterilant for both cats and dogs. Says Dr. Michelson, “I am excited by the progress we’ve made in the nearly six years since we launched this program. We congratulate Drs. Gobello and Ojeda on their newly approved grants and thank Jed Kim and KPCC for their thoughtful coverage.”

For more information about all Michelson grantees, visit our Current Grantee Profiles and Research Findings pages.

New Advisors Appointed to Scientific Board

The Michelson Prize & Grants welcomes two new members to the Scientific Advisory Board: Dr. Margaret Barr and Dr. Amy Ross.

Margaret Barr, DVM, PhD is a Professor of Virology and Immunology at the College of Veterinary Medicine in Western University of Health Sciences. Her research includes investigating the molecular epidemiology of canine parvovirus and rickettsial agents in Southern California. Dr. Barr also serves as project director for the Snow Leopard Functional Genomics Initiative, which studies the immunogenetics of captive and wild snow leopards.

Amy Ross, PhD, is the President of the Board of Governors of the University of Southern California Alumni Association. Her background is in Experimental Pathology, which led to more than 25 years of experience in the bone marrow transplantation and cancer diagnostics field. Dr. Ross’ research focused on the detection of tumor cells in the circulation of breast cancer patients as a means of targeting early relapse.

Dr. Barr and Dr. Ross will join the twenty other world-class advisors on the Board dedicated to guiding the MPG program toward the goal of a single-dose nonsurgical sterilant. To read more about our advisors and their areas of expertise, please visit our Board Bios page.

The Michelson Prize & Grants Goes to Europe!

In February, Michelson Prize & Grants Program Manager Becky Cyr had the incredible opportunity to attend the 11th International Symposium on GnRH in Salzburg, Austria. The three-day program, which attracted 170 participants from 35 different countries, was packed with sessions on the hypothalamic-pituitary-gonadal axis in cancer and reproduction. This was an important meeting for the Michelson Prize & Grants program, because every attendee was studying an aspect of gonadotropin-releasing hormone (GnRH), the master control hormone for reproduction. GnRH has long been a target for a nonsurgical sterilization method in animals, because it is evolutionarily conserved among different species and both males and females. This means that if someone can engineer a vaccine to immunize against GnRH for the lifetime of an animal, or deliver a cytotoxin to target and permanently kill or inhibit GnRH neurons, we could have a contender for the Michelson Prize. About 1/3 of our funded projects involve targeting GnRH neurons.

Because this meeting’s attendee base was such a receptive audience for our goal of developing a permanent, nonsurgical sterilant for companion animals, the Michelson Prize & Grants program organized an evening session on the second day of the conference, during which four Michelson Grantees presented their research approaches. The session began with a brief overview of the MPG program’s background and goals, our international research grants, and prize philanthropy model. Then, Drs. Auke Schaefers-Okkens (Utrecht University), Scott Struthers (Crinetics Pharmaceuticals), Doug Jones (Iowa State University), and Greg Dissen (Oregon Health & Sciences University) presented specific approaches that they are currently using with Michelson Grant funding to immunize against, ablate, or inhibit GnRH neurons. The session was very well attended, and attendees had stimulating questions for our grantees.

The GnRH symposium was a great success, and we are proud to have been a sponsor of such an important meeting. We’re looking forward to a busy conference season this year, with the upcoming Society of Toxicology Annual Meeting & ToxExpo on March 23-27 in Phoenix, AZ, and Experimental Biology on April 26-30 in San Diego, CA. We hope to see you there!

New Michelson Prize & Grants Website Launches on World Spay Day

February might be our favorite month out of the whole year. Not only is it Spay/Neuter Awareness Month, but today – February 25, 2014 – is also the 20th anniversary of World Spay Day.

If you’re reading this blog and you’re already a fan of the Michelson Prize & Grants program, the importance of spay/neuter is certainly not lost on you. Not only does it bring about specific health and behavioral advantages, like eliminating or reducing your pet’s chances of developing certain types of cancer and stopping your pet’s hormonally influenced reproductive behaviors, it also prevents the birth of unwanted litters. With an estimated 6-8 million cats and dogs entering animal shelters in the United States each year, spaying and neutering (also called “sterilizing”) our companion animals continues to be of utmost importance.

To celebrate World Spay Day’s 20th anniversary, we are very excited to announce the official launch of our new Michelson Prize & Grants website. We hope that you’ll take a few minutes of your day to browse through our new Frequently Asked Questions feature to learn more about our program, scroll through our easier to navigate Research Findings to read important conclusions drawn from completed Michelson Grant-funded projects, and review our Michelson Grant Application page for clarified instructions on how to apply for a research grant.

This year also marks the 5th anniversary of the Michelson Prize & Grants program. We continue to seek out new researchers who can join us in our mission to develop a permanent, single-dose, nonsurgical sterilant for male and female cats and dogs, and are very enthusiastic about the 30+ projects we have approved for funding to date through the generous contributions of Dr. Gary K. Michelson and Alya Michelson.

Dr. Gary K. Michelson Donates $50 Million to New USC Bioscience Center

Dr. Gary Michelson, founder of the Michelson Prize & Grants program, has donated $50 million to the University of Southern California for the construction of a new bioscience research building on campus.

The USC Michelson Center for Convergent Bioscience will bring together researchers of multiple fields from within the USC Dornsife College of Letters, Arts and Sciences and the USC Viterbi School of Engineering. USC News stated that the goal of the 190,000-square-foot center is “to turn the biological sciences into a quantitative and predictive science, fast-tracking the detection and cure of diseases.” With building completion expected three years from now, the Michelson Center will soon become a hub of scientific breakthroughs in health and related fields.

Many Michelson Grantees take a similar interdisciplinary approach in their research toward development of a single-dose nonsurgical sterilant for cats and dogs. We hope to one day fund the innovative researchers at the USC Michelson Center for Convergent Bioscience with Michelson Grants.