Simple Adjustment, Big Impact on Retinal Research
Originally used to spy on Russian satellites, adaptive optics can map out uncharted territory of the retina
 

Alfredo Dubra is emphatic that his findings in the open access journal Biomedical Optics Express from the Optical Society of America [news release] are the beginning of the work, not the end. By making a “simple” adjustment to the decades-old technology of adaptive optics, Dubra, a 2008 recipient of the Career Awards at the Scientific Interface, and his team increased the resolution of the cameras used to image the retina at the cellular scale, specifically resolving the full mosaic of light-sensing cells known as cones and rods for the first time.
 
The technological advance is already making an impact. For example, when a patient who had a concussion reported a blind spot in the shape of a crescent moon, a routine exam of his retina did not turn up anything out of the ordinary. But imaging with the newest technology a crescent moon-shaped area in his retina that was completely devoid of those light-sensing cones.
 
FOCUS newsletter chatted with Dr. Dubra in July 2011 while he was transitioning from his position at University of Rochester to one at the Medical College of Wisconsin where he is an assistant professor of ophthalmology and biophysics.  We discussed his recent findings and found out what drove him to become a scientist. As it turns out, Dubra has a deeply personal connection to his research, which he owes in part to a dead fish.
 
FOCUS 
 
Would you mind talking a bit about your career path?
 
DUBRA 
 
I’m a physicist. I always wanted to be a doctor, but in the first year of secondary school my biology teacher had the bad idea of dissecting a fish. I had to choose a different path that didn’t involve the morgue. 
 
I always knew to some extent I wanted to do eye research because I was born with a strong squint, like when your eyes are really crossed. Before the age of three I had already had several operations to fix it. I also had another condition that is fairly common, affecting between 1-5 percent of the population, known as amblyopia or lazy eye. Many people have one eye that is dominant over the other, but in some cases this is more extreme. That means that the weaker eye doesn’t develop connections to the brain as well, which can lead to poor or no depth perception if it goes uncorrected. To address that I used to wear an eye patch over the stronger eye to strengthen the weaker eye. I wore the patch since I was 6 months old, and I got glasses when I was one year old. Despite this, I have no depth perception, and because of it, I’m pretty clumsy at sports in which the ball comes towards me. I am also unable to enjoy any of the 3D movies that are becoming so popular. But I don’t see myself as disabled in any way. I think my experiences influenced what I chose to do research on. As a physicist you have to learn relativity, quantum mechanics and other weird things, but it was either that or the morgue and I chose the former. 
 
FOCUS
 
Tell me about your most recent paper. Technically it describes adjustments you’ve made to a design that is already in use?
 
DUBRA
 
Yes, so people have been taking pictures of the retina for several decades, centuries almost. More recently, in 1997, a former mentor of mine (David Williams) took advantage of a technique called Adaptive Optics that was originally used to look at the stars and Russian satellites.  He figured out that he could apply the same technology to look into the eye, because when you look at the retina, if you use a regular clinical camera and zoom in to a really small portion of the retina, everything appears blurry due to imperfection in the optics of the eye. By using this technology you can measure the optical blur and correct for it so that things appear sharper. 
 
This technology has been developing slowly but surely over the last 14 years. People could see the cones photoreceptors before in a handful of labs around the country, but what we did was improve the design of the instrument in an embarrassingly simple way so that you can see even smaller detail. You don’t even have to buy a single new component; you only have to fold the optical set up in a different arrangement in 3D (you can see the irony here) and that made the adaptive optics correction significantly better. When that happens, all of a sudden we can see the smallest cones in the retina that we couldn’t see before reliably and we can even see the rods too.  We don’t see every rod in every person yet, but we see well enough to start getting numbers, similar to when you have a blood test in a hospital and they tell you that you have 5,000 white blood cells per mL. Now that we can see the cells we’re trying to come up with numbers that have a clinical meaning. That’s why this is really just the beginning. 
 
FOCUS
 
Now you’re focusing on how to interpret the data?
 
DUBRA
 
Maybe I’m being pessimistic here, but the analogy I use is that the electrocardiogram was invented over 100 years ago. Even today, people are still doing research on how to read them and how to extract more information. When we go to a conference everyone says the images look great, and are ecstatic about the technological improvement, but really now we’re going to have to learn how to read them in such a way that we can come up with a number to tell Mr. Smith that you’re going to develop an eye disease, such as macular degeneration, in 5 years or so, or that you should start taking drugs to prevent irreversible vision loss. That is one of the things we hope we can do.
 
FOCUS
 
How do you think this will impact eye research?
 
DUBRA 
 
We expect to impact eye research and the quality of life for people with eye disease in four different ways. The first would be the long term goal of having one of these instruments in every clinic providing reliable, automated and easy to interpret data. The cells in the retina are post-mitotic, meaning that once the retina develops they can no longer reproduce. All you can see with current cameras are microscopic changes and by the time you can tell with confidence that you have a given eye disease, you’ve already lost tens of thousands of cells, with the subsequent irreversible vision loss. We want to be able in a few years time to tell people they’ve lost a few hundred cells so they can start treatment sooner.
 
A second and shorter term benefit relates to age related macular degeneration (AMD), which is the leading cause of blindness in the developed world. Surprisingly, it is not known yet which is the first affected cell type in this condition. We hope that by using our technology, we will be able to elucidate whether cones, rods or retinal pigment epithelial cells die first in AMD. In this way, we would be enabling researchers in both academia and industry that are trying to develop new drugs, to redirect their efforts to addressing the earlier stages of the disease. If we could do that alone, it would be fantastic. 
 
The third benefit is providing a tool for assessing the effects of new drugs with unprecedented sensitivity, thus greatly simplifying clinical trials for human use. By looking at microscopic changes to the retina in vivo would reduce the cost and accelerate drug development process. Instead of waiting to lose enough cells to see a macroscopic change in the retina that is visible with current cameras, adaptive optics systems would be able to detect changes 10 times sooner.
 
The fourth benefit relates to rare conditions, many of which affect vision in children.  Rather than waiting for donor retinas of people who have died and contributed them for research, we can use our adaptive optics instruments to study people with these rare conditions while they’re alive. We can bring them in year after year to be imaged here, contributing to the understanding of the disease.  For some of these people, through our imaging, in collaboration with Dr. Carroll’s lab, we are studying patients with a devastating condition called achromatopsia. That’s very exciting because there are some gene therapy trials that are almost ready to go and we can identify who’s a good candidate for them and who’s not. That will have a huge immediate impact in the next three years.