2023 Innovation Issue: From humans to cows

Dr. Jim Donahue did not initially intend to create a device that could change the way cows are reproduced on the farm. In a career dedicated to working with people, livestock was a new endeavor.

However, through success and failure, the Indianapolis-based fertility doctor is on track to make a big difference in agriculture.

Since 1997, Donahue, 63, has operated Family Beginnings, where he has helped thousands of human families grow. Now—along with a team of embryologists, engineers, veterinarians and students—he is using biomedical technology to advance assisted reproduction in cattle as CEO of ReproHealth Technologies Inc.

“Some might think, ‘Why are you doing this? Why is the fertility doctor doing the cow stuff?’” Donahue said. “It certainly is the most exciting thing I’ve gotten the opportunity to do in my life, because I’m getting to do something totally new that combines literally everything that I’ve done. All of my training in embryology, everything, sort of comes together to do this, and you don’t get that option very often.”

ReproHealth’s origins began six years ago in a human procedure.

In 2017, Donahue was part of a team that performed Indiana’s first intravaginal embryo culture with an FDA-approved device that allowed embryos to grow in a device inside the patient rather than in an incubator in a lab.

Some women have medical conditions that make it difficult for their fertilized egg to progress through the earliest stages of development, before it settles into the uterus lining. Donahue’s procedure allows doctors to fertilize eggs in vitro but still use the mother’s natural body temperatures to incubate an embryo until it is ready to be inserted into the uterus to continue growing.

Donahue’s first patient to use his device gave birth to twins—a success—but Donahue thought he could create an even better device. That led to the establishment of ReproHealth Technologies, which he registered with the state the following year.

Soon, however, Donahue realized another opportunity for such a procedure: cattle reproduction. He said in vitro fertilization in cows is generally inefficient, as only 25% of the eggs collected become an embryo.

“We asked, ‘Why is it inefficient?’ It’s inefficient because the embryos don’t grow well in incubators,” Donahue said. “When you think about an incubator, it’s a big, metal box. It’s at a set temperature.

“[In] a normal embryo developing inside a person and inside a cow, the temperature changes throughout the day, and so that technical issue is getting settled by this device, because it’s literally inside the cow’s vagina at her temperature, so that was solving the problem.”

Farmers and scientists have been using some form of assisted reproduction in cattle for nearly a century, starting with artificial insemination, to improve genetic selection in herds. ReproHealth’s technique can accelerate that process, said Dr. Dave Dixon, who works as a large-animal veterinarian and a veterinary reproduction specialist and is a co-founder of ReproHealth.

“This way, [farmers] can take the very, very top cows in the herd, and that one cow can have multiple calves a year by basically using surrogate mothers,” Dixon said. “Cows that maybe are not as good genetically but are good mothers can raise those other calves.”

Creating the device

Donahue had a hypothesis about how his technology for humans could transfer to bovines, but he needed a device to test it.

To design such a device, he enlisted Michael Whitt, an assistant biomedical engineering professor at California Polytechnic State University north of Los Angeles.

Whitt, who received his bachelor’s in chemical engineering from Purdue University, is a holder of five medical-device patents, including one for a device that aids in early detection of cardiovascular disease.

“I’m a medical-device design guy, and so, literally, I know nothing about cows,” Whitt said. “I’m in vascular mechanics. That’s where my area of research is, so fertility is not something I studied. But I can design a medical device.

“I think Jim is learning the side of the cows, too. I mean, he’s never worked with cows, either. So, we’re learning it, and in some ways, we kind of stumbled into that side of it.”

Through trial and error, Donahue and Whitt, with help from Whitt’s Cal Poly students, developed the device they’ve tentatively called Generova. It is 2 inches long with two caps that seal a plastic vial with wells where embryos can grow once the device is placed inside a cow.

The inventers received provisional patents—a first step in the process of protecting an idea—for the device in 2019 and 2020, and they are awaiting nonprovisional patents in the U.S., Brazil and the European Union, which are some of the world’s major cattle-producing regions.

Creating the device, Donahue said, was about “finding the right people.”

“It’s all a team effort,” he said. “Everybody has different skills. Like any startup, one person can’t do it all.”

A 3D-printed device is currently being used for testing. Donahue is working with medical-device manufacturer Thunderbird Molding Elkhart to mass produce it once ReproHealth is finished tweaking it.

The partners tested a variety of holding designs for the device to keep it from falling out of the cow. Some designs worked; others didn’t. “The failure is OK, and we do just get back on the horse, so to speak,” Donahue said.

Donahue and his colleagues experience “frustration all the time,” he added, but they ask themselves why the design failed, then move toward the solution.

“You invent as you go along, which is part of the excitement,” he said. “Perseverance is the No. 1 thing. You just keep trying, and if you have something that will solve a problem, it’s probably going to be OK.”

Working with Kate

Once Donahue and Whitt had a device, they needed a cow to test it on.

Ten-year-old Kate, a black angus who lives on Dixon’s farm in Rensselaer, is that cow.

Dixon has performed embryo transfer in cows since 1995. In 2014, he co-founded a livestock veterinary service called StockVets LLC.

“It’s exciting from the aspect that it is a completely new procedure that, if we can get it scaled to the masses, it will radically change IVF as we know it,” Dixon said.

ReproHealth’s fourth co-founder, embryologist Katie Russell, left the company last year.

Donahue and Dixon determined Kate would be the perfect test candidate after they studied an ultrasound of her ovaries and found she had a high antral follicle count—a key measure of fertility.

So it was an exciting moment for the team in November 2022 when Kate produced the first-ever cow embryo cultured in an intravaginal device.

Here’s how it works: A veterinarian first retrieves eggs from Kate. The eggs and sperm are placed together and then into the device. The device is sealed and placed inside the cow, then removed five to seven days later. The embryos then will be collected and either inserted in a recipient cow or frozen. The ability to freeze embryos allows a farmer to match supply and demand.

“To think we grew an embryo in a cow in a device is kind of amazing,” Donahue said.

Kate’s embryo was transferred into another cow, who did not get pregnant. Donahue and Dixon are planning another trial with Kate early next month. If successful, they will transfer her embryo to a recipient cow, who they hope will be pregnant in July.

“It’s being able to do the whole procedure on the farm and allow the cow to be her own incubator,” Dixon said. “They’ve already proven to be a better incubator of their embryos naturally than our box incubators. It not only will give us more success, but it allows them to keep that procedure on the farm, which gives the local farmer and local veterinarian more control.”

Donahue grew up in south Florida and went to medical school at the University of Miami. He never spent time on a farm, but he said farmers and human reproductive endocrinologists speak a similar language.

“We are all biology majors,” he said. “I like to think the farmers know their biology, and we know our biology. We all seem to get together really well.”

ReproHealth’s device can also be used in sheep and goats, but cows are the first priority.

Donahue’s hope is that, in five years, the company’s intravaginal culture approach will become the fourth type of assisted reproduction for cattle, along with artificial insemination, embryo transfer and in vitro fertilization. That would help Donahue work toward his biggest motivation, which is the potential ReproHealth’s device has for alleviating food insecurity.

“There’s people who don’t have enough food, and you see that on the news all the time. And so could we turn this little device into an IVF lab, essentially, to help them make more protein and help those people more immediately?” he said. “That, to me, is probably the most important goal if we can do that.”

Gaining interest

ReproHealth’s efforts have garnered attention over the past two years.

The company has received about $260,000 in investments from the Purdue University Research Foundation, Iowa-based Ag Ventures Alliance, Memphis-based AgLaunch365, and friends and family, along with a grant from the Dairy Farmers of America.

It has also participated in accelerator programs sponsored by the Dairy Farmers of America, Purdue and AgLaunch365.

“The farmers that took us into the [AgLaunch365] program want to use our technology and want to invest, and they’ve made an investment already,” Donahue said. “And it’s kind of nice having actual users that want to invest in the trials.”

Interest from the Kansas City, Kansas-based Dairy Farmers of America provides validation for ReproHealth’s efforts, he said.

Matt Musselman, the organization’s vice president of farm affairs, said he finds it intriguing that Donahue wants to help improve assisted reproduction in cattle.

“I think to me, what is really exciting is to see a medical doctor like Jim who is applying his technical skills and know-how to help solve a problem in agriculture,” Musselman said. “And it’s great to have someone of his caliber that’s focused on helping our dairy farmers be more successful. For me, that’s a pretty neat thing.”

Mitch Frazier, CEO of Indianapolis-based AgriNovis Indiana, said ReproHealth represents an extension of central Indiana’s agbioscience industry, which includes Indianapolis companies Eli Lilly and Co. and Corteva Inc. and Greenfield-based Elanco Animal Health Inc.

“Innovators like Jim hold a special place in that economy, not just today, but as we build the next chapter and the next chapter of the agbioscience economy as it relates to animal health,” Frazier said. “It will be these new innovations that today are an idea that have become an innovation that will soon become a product and could be a category-defining product.”

As ReproHealth works toward finalizing a device design and welcoming a calf, Donahue knows his work is ongoing.

“Over the past two years, we’ve learned that this is where we’re going,” he said. “Would I have known that five years ago? No. I think that it’s very hard to predict the future, but you have to try. I’m a big believer in … you have to try things out. Failure is OK. Not trying something is not OK.”•

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