As a married couple, Drs. Larry Suva and Dana Gaddy share a laid-back, joking rapport that is highlighted by a mutual respect for one another. But when it comes to their joint research efforts, the two are serious about solving the health problems that have hit“closer to the bone.”
Long before Drs. Larry Suva and Dana Gaddy became partners in life, they were collaborators in the field of musculoskeletal research.
They met at a small science conference in New Hampshire in 1997, as Gaddy—an assistant professor at the University of Arkansas for Medical Sciences (UAMS) who had established her career as a “card-carrying reproductive endocrinologist”—began focusing her scholarly attention on menopausal bone loss; Suva, an assistant professor at Harvard University, was already established as the “bone cancer guy,” devoting his career to understanding the skeletal consequences of disease.
“The ‘bone group’ I was in was very dogmatic in their views because they had been ‘bone people’ for a long time and were not necessarily receptive to an interloper coming in with a new perspective, even though that’s what I’d been hired to do,” Gaddy said. “They wanted me to bring in new ideas, but do it their way. Because I came from outside of the field, to me, bone was just another system to learn. I was excited about it.”
Gaddy found that not only was Suva’s group more open to her as a new researcher in the field, but they were also much more fun.
“We thought she was a post-doc and that we should make her feel comfortable because the guy we thought was her boss is a nice guy, but he’s a bit stuffy,” Suva said. “So, a bunch of us tried to rescue this post-doc, who turns out, was a tenure-track faculty member. That created a little bit of interaction, as you might imagine, but that’s what got us, our field, interested in what she had, because she brought a very unique aspect of reproductive endocrinology to the bone community.”
The two departed the conference as newfound collaborators whose work together would extend over the next two decades as they published on a variety of diseases, including breast cancer, Down syndrome, and bone anabolic treatments.
“It really stimulated a whole plethora of research,” Suva said. “Dana was incorporating skeletal ideas into a grant she was writing. I, and our other colleagues in the U.K., started reading the grant, helping to edit it, and she ended up getting funded.”
After traveling to England for a project at Oxford University, Gaddy’s career took off and she settled into her faculty position at UAMS.
“My career wasn’t just launched by our interaction—it was a very fertile environment for me as a new person in the field and there was huge opportunity to make a contribution; (but) it likely would not have been so successful if it hadn’t been for Larry and the folks I met at the Gordon Conference,” she said. “It really helped to have Larry’s expertise in editing, to get the bone language and the salesmanship down; that’s really one of his great strengths, and it continues to be critical to our success.”
In the meantime, in 2000, Suva, who had begun working in the private sector, began looking to return to academia.
“I had a job offer in Pittsburgh, and then this opportunity in orthopedics in Arkansas came up,” Suva said. “Dana was in Arkansas, so I said, ‘Oh, Arkansas? Pittsburgh?’ I chose Arkansas.”
By 2002, Suva was an associate professor in orthopedic surgery and director of the UAMS’s Center for Orthopedic Research. He ran a large lab, which was one of the highest-ranked core research facilities in the state, and enjoyed a continued research collaboration with Gaddy.
In 2002, they were also married.
Taking Research ‘Personally’
More than a decade into their partnership, Suva and Gaddy were at another science meeting, this one in Colorado, when they attended a session on hypophosphatasia, a rare genetic disorder of alkaline phosphatase, an enzyme mutation characterized by the abnormal development of bones and teeth caused by defective mineralization in the body. In humans, it can be quite debilitating.
“A really good friend of ours who works as one of the world’s clinician experts in the disease shows a picture of a tooth from a child with hypophosphatasia; the tooth had come out, roots and all,” Suva said. “A month before, our granddaughter had been at our house eating a grape and her tooth came out in the grape. We both thought, ‘That looks just like Olive’s tooth! Olive has that disease!’”
Their granddaughter hadn’t been formally diagnosed, so the couple called the genetics department at Children’s Hospital in Arkansas and asked a colleague if Olive could be tested.
“We took her in, and there it was—she had hypophosphatasia,” Suva said. “It all happened from science.”
Because hypophosphatasia is extremely rare and the musculoskeletal system was their area of expertise, Suva and Gaddy took matters into their own hands, starting a project that not only would bring them to the Texas A&M College of Veterinary Medicine & Biomedical Sciences (CVM), but also would have serious implications for a disease about which very little is known.
Creating a Model
A crucial step in finding a treatment or cure for any disorder, much less one that has been researched only intermittently, iscreating an animal model to study how the disease progresses.
“Some data exist (on hypophosphatasia) in humans, but it’s mainly cross-sectional; they may have 20 people with one specific mutation whom they saw at 10 years old, but they don’t know what happened when the child was 4,” Suva said. “All they have arepictures of them at 10 and 15 showing what they look like (with the disease).”
Their initial attempts to create a suitable animal model, with mice, proved unsuccessful, so Suva and Gaddy explored the idea of using sheep, a validated model for studying the human skeleton.
Because that large-animal model didn’t exist, Suva and Gaddy turned to the expertise of the CVM for a possible collaboration, but after visiting Texas A&M, the two decided, instead, to join the CVM faculty—Suva, as department head of Veterinary Physiology & Pharmacology (VTPP), and Gaddy, as professor of Veterinary Integrative Biosciences (VIBS)—so they could create a model without the obstacles presented by working more than 400 miles away from the CVM.
Only a year into their work, they are seeing early signs of success, effectively replicating the disease in sheep by editing the sheep genome using CRISPR technology and implanting the embryos into ewes.
The project is exciting for a number of reasons.
“We have built the first real mechanism in which you can longitudinally study how the muscle develops and then once we know why it’s weak, identify things we can do that might intervene,” Suva said. “We’ll see how the disease progresses—what happens when they’re 2 or 3 years old and how that is impacting them when they’re 6 or 7.”
Importantly, the next step will involve manufacturing a compound heterozygote, a sheep that carries exon 5 and exon 10 mutations,which happen to be the two genetic mutations carried by their granddaughter.
“With this disease, there are more than 300 mutations that have been reported; most are reported as compound heterozygotes, because the mother and father don’t know they are carriers and are not symptomatic,” Gaddy said.
While their research is still in the early stages, their work already has attracted attention—and funding; one company also has expressed interest in working to help them understand hypophosphatasia because of the human implications.
“In order to make a drug for a bone-related disease, the pharmaceutical industry requires scientists to conduct studies in rodents and a large animal before humans,” Suva said. “Now, we havea large-animal genetic model to serve as the platform for that step.”
Being at ‘Home’ with Science
Spending so much time together on such a personal project might not be possible without Suva and Gaddy’s laid-back, joking rapport, one also highlighted by a mutual reverence for one another and the individual strengths they bring to both their working and personal relationships. They work so well together, they say, because, in many ways, they see themselves as complements.
“It’s a really good combination. I have a really broad view; I know lots of stuff, but it’s not in great detail,” Suva said. “Dana is focused in particular areas; so, she can drill down into levels of information in her brain. She’s got these detailed pockets of information, like a computer.”
Those aspects of their personalities also carry over into their home lives.
“He’s the chef, and I’m happy with that because then I’ll do all the cleaning. He cooks because that’s his way to relax. For me, cooking is not relaxing; I do it because it’s necessary,” Gaddy said. “So, he can relax and cook, and I’ll be happy to relax and clean. Then I’m happy and he’s happy.”
And while many couples may cringe at the thought of working together, it’s the science that brings them together.
“I would think 75 percent of the time that we’re together there’s science involved,” Suva said.
“That’s probably a scary number, but science really intrudes in everything,” Gaddy said. “It’s not like we end each day talking science; I can guarantee we’re not that nerdy. But I do think it’s a lens through which we see life.
“I really feel bad for scientist couples who don’t work together, because they never see each other when they’re doing their own thing,” she said. “For me, working together seems much more rewarding because you can share in success; I feel what we have is hugely beneficial.”
It may help that their shared research interests allow them to work toward a common goal, especially as they address issues that have affected them personally. In addition to their granddaughter’s hypophosphatasia, both of their mothers died of bone fractures—Suva’s as the result of bone loss that stemmed from breast cancer and Gaddy’s as a result of postmenopausal osteoporosis.
“The irony of bone researchers having parents die of fractures and then to have a granddaughter with a rare bone disorder, you can’t laugh about the irony of that, really,” Suva said. “Talk about motivation.
“We’ve watched our granddaughter play tee-ball and ice skate, but she has muscle weakness. She’s 7, and she’s got four teeth left,” he said. “Only molars,” Gaddy added.
They know the challenge that lies ahead is not only in creating the phenotype that affects their granddaughter but in utilizing that information in a much broader way.
“We’re much closer to the disease than we have been in the past by working in mouse models,” Gaddy said.
“When we started, we didn’t understand anything about teeth. By the time we get to the next part, we’ll know plenty about teeth. We know about her muscle weakness; we’ve seen that,” Suva said. “We’re going to fix it; we’re going to find a way.
“Even if we don’t fix it for her, we’re going to fix it, because if she ever has a child, that could be a problem,” he said. “We have always done things to try to improve people’s lives and to better understand. This got a bit closer to the bone.”
Understanding CRISPR Technology
Trimming, changing, and replacing DNA could revolutionize modernmedicine and prevent common medical conditions.
CRISPR-Cas9 is a gene-modifying tool that targets a specific area of the genome (an organism’s full set of inheritable chromosomes), allowing researchers to cut out and insert new DNA.
The groundbreaking research, introduced in 2013, has opened the doors for monumental breakthroughs in medicine by allowing humans to repair genes responsible for diseases, or, as in the case of Texas A&M’s College of Veterinary Medicine & Biomedical Sciences’ (CVM) Drs. Larry Suva and Dana Gaddy, replicate the genetic mutations that cause hypophosphatasia—an enzyme mutation characterized by the abnormal development of bones and teeth caused by defective mineralization in the body—which will allow them to study the disorder and, hopefully, will lead to its treatment.
CRISPR, pronounced “crisper,” which stands for Clustered Regularly Interspaced Short Palindromic Repeats, has been previously researched at the CVM to fight Duchenne muscular dystrophy, or DMD—a disorder caused by a genetic mutation that deteriorates muscle as humans age—and in enhancing production traits in livestock.
W.R. Harvey contributed to this piece (The Battalion, Oct. 11, 2016).
Contact Information: Megan Palsa, Executive Director of Communications, Media & Public Relations, Texas A&M College of Veterinary Medicine & Biomedical Science; firstname.lastname@example.org; 979-862-4216; 979-421-3121 (cell)
This story originally appeared in the Spring 2018 edition of CVM Today magazine.