All The Eyes

Article by Zac Unger

"I’m a huge retina nerd,” says Dr. Billie Beckwith-Cohen. “It has a pure aesthetic magnificence, but there is also nowhere else where you have this uninterrupted view into a piece of the brain. I mean, I love the entire eye, I love so much about it, but the retina is just obviously the best thing in the world.” While anyone who has committed their life to the study of eyes probably feels a similar sense of wonder, Dr. Beckwith-Cohen has an appreciation and understanding of the retina that goes far beyond what most optometrists and ophthalmologists can claim. Because when it comes to studying vision and treating ailments of the eye, Beckwith-Cohen doesn’t just limit herself to humans. “Raptor eyes are gorgeous,” she says. “And cat and deer eyes shine at you when you flash a light at them because they have a tapetum lucidum, which is tissue that acts like a mirror, so it makes the back of the eye look very rich and beautiful. There’s just this aesthetic magnificence to animal retinas that I never get tired of.”

Dr. Beckwith-Cohen’s academic path has been an unusual one: not too many people receive a PhD from Berkeley’s School of Optometry and Vision Science after already having received a doctorate in veterinary medicine, which she completed at the Hebrew University of Jerusalem. As both a clinician and a researcher, her work is located under the broad umbrella of “comparative ophthalmology,” which she defines as “the ability to examine, evaluate, and potentially treat all species but one: humans.” Throughout the United States there are fewer than 500 board-certified veterinary ophthalmologists. An even smaller subset of that number have both a PhD in vision science and a degree in veterinary medicine.

Now in the third year of a residency in the Department of Small Animal Clinical Sciences at Michigan State University—which after completing (and passing the boards) she’ll be able to officially call herself a comparative ophthalmologist—Dr. Beckwith-Cohen says that a big part of the appeal of her field wasn’t just her love of animals, but also the diversity of the animal kingdom and the freedom from limits and restrictions on what she could investigate. “I attended a glaucoma meeting,” she says, “and I put up a panel showing how ten different dogs can have retinas that look different from each other and yet are still, for each of them, completely normal.” While dogs and cats and horses are the most common animals that a veterinary ophthalmologist will interact with, many comparative ophthalmologists are associated with zoos and aquariums, where they can garner experience working with a wide array of species. “In our field it’s not uncommon to see publications of case reports of cataract surgery in penguins or eyelid surgery for snow leopards,” Beckwith-Cohen says.

Comparing Eyes Across Species

“It’s called ‘comparative’ because we’re supposed to know the differences between the species,” Beckwith-Cohen says. “While there are obviously resemblances and basic structural similarities between all mammalian species, there are also general ‘themes’ about how vision works in general that you can follow even all the way to insects.” While no clinician can expect to be an expert in treating every species, “you basically share the cumulative experience of everyone in the field and extrapolate it to the animal in front of you and go ahead with a compatible surgery or medical plan.” When describing the myriad challenges and opportunities in her field, Beckwith-Cohen mentions (with perhaps a small hint of envy) her colleagues in Florida, for example, who never know whether the next patient walking—or waddling, flying, slithering—through the door is going to be a crocodile or a canary.

To state the obvious, a cat is not a person, and human eyes are not the same as eyes of any other animal species. And yet, the ability to compare eyes across species has enormous practical implications for human health, the development of new treatments, and satisfying the pure scientific curiosity of understanding how vision works. Our human ancestors first evolved into a recognizable form approximately 300,000 years ago but vertebrates have been around for closer to 500 million years. “But even that is still a pretty recent development if you’re thinking in terms of the evolution of all life on Earth,” says professor of neurobiology Richard Kramer, who is affiliated with the School of Optometry and Vision Science and was Dr. Beckwith-Cohen’s thesis advisor. “So the fundamental mechanisms that you find across vertebrate species are relatively similar. And by that I mean that the cell types and the retina and how they’re arranged are preserved throughout vertebrates, and the neurotransmitters and their receptors are connected and preserved in recognizable ways.” While this might not be obvious to an ophthalmologist accustomed to working solely with people, “the difference between a mouse and a human is actually quite small on the evolutionary scale of things.”

Studying inherent similarities between species helps scientists like Beckwith-Cohen understand ocular pathologies that may overlap with humans. And actually working with animals in a clinical or research setting is critical in the development of new pharmaceuticals and treatment modalities. Figuring out which species to study is the first step. While non-human primates are the closest to humans, working with them is difficult due to cost, bio-safety concerns, and very slow breeding and long generation time. “Dogs and cats have a particular appeal,” says Beckwith- Cohen, in part because they have an eye that is similar in size and shape to our own. Canines, however, lack a fovea, the specific region in the human eye that is rich in the cone photoreceptors that play a crucial role in high-acuity vision and color detection. Despite this, “they do have a region called the area centralis that is high in photoreceptors,” says Beckwith-Cohen. “They might not be ready to read the New York Times but they do have a little area with better acuity, which gives them a regional similarity” to humans.

Developing Treatments

Beckwith-Cohen is currently working to restore sight in a lineage of Whippets from Brazil that suffer from a visual impairment condition shared with humans. Many basic ocular diseases that are present in humans can also be observed in dogs. Keratoconjunctivitis sicca, or dry eye, for example, is an incredibly common and annoying condition estimated to affect as many as 70% of senior citizens in the United States. Dogs suffer from it as well, often presenting in a more dramatic fashion than humans with heavy discharge of mucus. The key medication for this condition—cyclosporine, often known by the brand named Restasis—was initially developed for dogs and then eventually made its way into pharmaceutical use for humans.

Far beyond drops and other topical treatments, researchers have had great success using animal models to develop novel genetic treatments. In fact, the first gene therapy ever approved by the FDA is a treatment for Leber congenital amaurosis, a condition that causes blindness. By chance, a group of Briard shepherds at the University of Pennsylvania all shared this genetic mutation. Beckwith-Cohen didn’t work on this project, but counts one of the initial researchers among her mentors. “It’s a small enough profession that I know most of the veterinary ophthalmologists who are involved with this type of research,” she says. She describes the disease as a “degeneration in the retina, a dysfunction and atrophy of the tissue that senses light.”

“With autosomal recessive conditions, if you have one affected parent and one unaffected parent,” says Beckwith-Cohen, “then the puppy is going to be normal, but if both parents are affected by the mutation, then you have only dysfunctional genes.” For the cure, then, scientists take copies of a normally functioning, non- mutated gene, and place it inside a harmless virus, which becomes the delivery mechanism for the patient. “These are viruses that do not replicate or infect additional tissues,” she says. If the virus does its job correctly, the healthy gene gets where it needs to go, eventually replacing the defective information packet with a properly functioning one. After injecting the dogs with the treatment—which eventually came to be known as Luxturna—the researchers noticed their canine patients walking around in circles, evidence that they were now able to see out of the single, treated eye. And so it was that Lancelot the Briard shepherd (and his siblings) helped scientists develop the very first commercially available gene therapy of any kind for people. “A dog isn’t like a mouse,” says Beckwith-Cohen, “and that little bit of additional closeness to humans helped the FDA trust the process enough to make the leap and approve.” Gene therapy studies for restoring vision lost to a number of other retinal diseases are currently being conducted with dogs.

While she was at Berkeley, one of the main projects Beckwith-Cohen and Kramer worked on involved attempts to restore visual function to blind mice who had lost their rods and cones because of the types of mutations that are also present in retinitis pigmentosa, the leading cause of inherited blindness in humans. “When the rods and cones die,” Kramer explains, “you have no front-end detector of light and the rest of the visual system is all dressed up with no place to go.” Their study involved trying to put back a light-triggered signal downstream from the dead rods and cones. “The mouse eye is different than the human eye,” says Kramer. “For one thing, there’s no macula. Mice have a rod-dominated retina, whereas our retinas have a lot of cones in the center. So while the structure is fundamentally different, the cell types present are very comparable, and the physiological mechanisms that are involved in diseases tend to be similar if not exactly the same.”

“But we’re not always doing our work just for ophthalmologists,” says Kramer. Any animal with an eye can help researchers understand more about the basic functional nature of vision in general. While at Berkeley, Beckwith-Cohen worked not just with mammals but with species as distinct from humans as zebrafish, a freshwater minnow that tops out at about two inches long. Specifically, she and Kramer studied the phenomenon known as lateral inhibition, a process that accentuates the ability to sense a lighter spot by making surrounding areas appear darker than they normally would. While not perfectly comparable to humans, zebrafish are excellent to work with due to the fact that they can be easily genetically manipulated, knocking in or out genes easily from one generation to the next. “We’re doing our work to understand how the retina works,” says Kramer. “It’s medically significant but that’s not its only purpose. We’re really using our curiosity to see how the nervous system works. It’s an age-old scientific question: How do we see? What enables us to detect objects in the environment?”

From Bench To Bedside

This combination of pure and applied science is what Beckwith-Cohen refers to as “bench-to-bedside” work for the way that basic foundational discoveries trickle up to therapies for animals and, eventually, humans. Someone with a similarly extensive course of training—four years of veterinary school, five years for a PhD, four more for residency, a fellowship or two along the way—could easily settle into a comfortably lucrative clinical practice performing cataract and corneal surgeries for beloved household pets. But, as Dr. Kramer describes his former student, Beckwith-Cohen has always wanted to “pursue the most modern, mechanistic, biomedical research that she can. There aren’t very many people like her who can combine hardcore science credibility with that kind of clinical veterinary skill.”

Beckwith-Cohen describes herself as a “clinician- scientist,” eager to lay her hands on actual patients but also thrilled at doing the research necessary to push vision science to new levels. “I will always be on a training continuum,” she says, learning new skills and perfecting new scientific techniques. At the end of the day, whether she’s performing microsurgery or working in a lab, what animates Beckwith-Cohen and drives her relentlessly forward is, as she describes it, “my absolute admiration for the beauty of eyes in the animal kingdom, and the amazing retina, which enables us to see.”