Interview with Alan Bird, MD
Dr. Alan Bird, MD is a member of the Lowy Medical Research Institute’s Board of Scientific Governors. He is Professor Emeritus at The Institute of Ophthalmology London and the Moorfields Eye Hospital. His work has had a major impact on treating blindness around the world, and he has received a number of awards and accolades for his contributions to vision science. Dr. Bird has worked with numerous fellows at Moorfields on multidisciplinary clinical research projects, including molecular genetics, cell biology, electrophysiology, psychophysics, specialized imaging, and morphology. He spent time in Africa researching River Blindness; the results of his studies changed the course of disease management. He has also studied sickle retinopathy in Jamaica, where he demonstrated the relatively benign nature of that disease. Dr. Bird has published widely, having written more than 370 papers published in peer-reviewed journals, and over 70 book chapters. We spoke about his involvement in MacTel research and the MacTel Project.
How did the MacTel Project start?
My involvement began with a meeting in Sydney [with the Lowy family]. We were asked about MacTel, and what the treatment was. There was no treatment, and no known cause. We were asked what research was going on to seek a cause. There was no significant MacTel research at that time. We were then asked: if we had funding, could we think of a research program that would give us a better understanding of the disorder? Within 15-20 minutes, we had a program roughed out – just a skeleton – as to what we might do. And of course, then the question was: why weren’t we doing it? And that was a very interesting question. I think the reason we weren’t doing it is that research is largely derivative. That is, what we do today is determined by what we did yesterday. And I suppose the answer was that we’re not doing research today on it because we weren’t doing it yesterday.
What did the vision science community know about MacTel at that time?
We understood it was a disorder that was relatively uncommon. It caused disturbance of central vision, and was very slowly progressive. We knew, particularly from the work of Don Gass, that there were blood vessels invading the outer retina, where blood vessels shouldn’t be, there was opacification of the retina and crystals occurred in the retina. But what was really thought to be important was that there were blood vessels invading the outer retina where they shouldn’t be. This was thought to be the key.
A decision was made to define the disorder clinically. A number centers were invited to join the research, to define it with equipment that wasn’t available to Don Gass and Barbara Blodi when they wrote their review describing macular telangiectasia. The centers were chosen on the basis that they were friends, and there would be free exchange of information. The centers were in Europe, the United States, and Australia. We also thought that there ought to be a laboratory research arm. At that time, we asked the researchers to investigate outer retinal vascularization. What drives blood vessels to invade the outer part of the retina? So that was the plan, and the research went really well from that time on.
The primary objectives were to understand the disorder better, to define the nature of the disorder, and in the end, to have some kind of treatment by which we could modify its course.
MacTel was thought to be very uncommon. Has it turned out to be more common than people were expecting?
It has turned out to be more common than we assumed, partly through recognizing the disease more readily. Over the course of the research, it’s been clear that the nature of the disorder is quite different than what we thought originally.
What have we learned about MacTel?
It’s been identified that there’s very dense visual loss just next to fixation. So, with one eye, if you look at something, there’s a very dense blind spot just next to what you’re looking at.
It was also identified with imaging systems that there is damage to the retina very early on. For example, there is loss of luteal pigment quite early on in the disorder. That was identified first by Frank Holz in Bonn, Germany, and he made the information available to everyone. Others in the group looked at their cases, and yes, there is a loss of luteal pigment. Sadly, not a great deal was known about how luteal pigment gets to the retina. So, although it was a very useful clinical sign, it didn’t tell us a great deal about the disorder.
Luteal pigment is in a layer of the retina that consists of photoreceptor cell axons and of Müller cells, which are glial cells that support the photoreceptor cells. So it told us at least there is something wrong either with photoreceptor cells or with Müller cells or both. It was also identified by imaging that there is a defect in the outer retina. Two dense lines in the outer retina can be seen, which are derived from photoreceptor cells and Müller cells. These lines become broken in MacTel. It was also identified that there was very good physical correspondence between the defect in the outer retinal lines and the area of visual loss. That is, one was defined very closely by the other.
So what of the blood vessels? Well, it transpired that the blood vessel changes are probably a consequence of the disorder of nerve cells and glial cells, rather than being the cause of the disorder. We had undertaken some therapeutic measures to modulate the blood vessel changes. It did indeed modulate the blood vessels to some extent, but the neurodegeneration continued.
So it turned out that the disorder had been totally redefined. It’s not a disease of blood vessels any more. It’s a disorder of nerve cells and the glial cells that support nerve activity.
This has changed our understanding of the disease in a very short period of time. What new directions does this improved understanding of MacTel offer for therapy?
The previous therapies that we used were directed toward interfering with the blood vessels. Given that blood vessel changes are not the primary component of the disease, it’s perhaps not surprising that treatment was ineffective.
Now we have the prospect of a disorder in which we have death of photoreceptor cells (the cells that detect light) and glial cells. So, is there a therapeutic option? There is. It is known that cells die through a mechanism called apoptosis. That is, cells kill themselves because of the environment in which they live. And if you can change the environment, you can prevent or reduce cell death. It’s known that a variety of diffusible factors will modulate or reduce cell death, and the cells will continue to work. CNTF is one of these factors. Work done many years ago by Matt Levail and Roy Steinberg showed that in all the situations of cell death in the retina, the growth factor CNTF appeared to be the most effective at reducing cell death.
It was proposed that we have a treatment trial of CNTF. That is, chronic exposure of the retina to CNTF, using an implanted device that contains cells that produce CNTF over months and years. A preliminary study was undertaken to assess the safety of chronic CNTF delivery via this device. That is, is it safe to put these devices into the eyes of people with macular telangiectasia? It was shown to be safe.
On the basis of that, it was decided that we would undertake a therapeutic trial. That is, we would take a series of patients and insert the device into one eye, but not the other. We would determine whether, in the eye that has the device, the disorder evolved in a different way from the eye that does not have the device. That trial is now underway. We don’t have any definitive results yet, but we hope that within a short time we will have evidence enough to make a decision as to whether or not the treatment is effective.
The Registry and Natural History Studies have been very important for our ability to do clinical trials. Could you comment on how clinical research helped lay the foundation for the clinical trial?
The Natural History Study gave us some idea as to the rate of progression of disease, and also allowed us to find out the best way of measuring progression. It was determined that imaging structural change in the retina was a more reliable measure of progression than measures of loss of visual function.
When we decided to initiate the trial we had over 800 patients in the registry who had been seen. Thus we could recruit patients for the trial in a very short period of time. That, clearly, is a major advantage in undertaking therapeutic trials.
So the Natural History Study was a very important investment for future research, and future treatment. If alternative treatments become available, we have this large number of patients who are very well characterized, who can be recruited to therapeutic trials really quite quickly.
One question that has come up a lot is, why does MacTel specifically affect the macula? Is there something special about that part of the retina that makes it susceptible to disease?
The macula is a very special part of the retina. It’s that part of the retina that has yellow pigment, and it’s that part of the retina that we use for accurate vision. So, reading vision resides within the macula. It’s quite a small area. The photoreceptor cells appear to be different, and structurally it is unlike the rest of the retina.
What is interesting about MacTel is that when we see people with early disease, the area that is destined to be affected can be easily identified by blue light photography. We can see opacification in the area that’s well defined the central macula. The other changes, such as loss of luteal pigment, vascular proliferation, and crystal formation will start usually just temporal to the macula, in one small part of the macula. And then will spread over years to involve the whole area that was identified by blue light photography, but will never go outside that area. That highlights the question, really, as to “why the macula?”
Why is the macula susceptible to disease, and the rest of the retina remains normal? That question has not been addressed at all, as far as I’m aware.
What do we know about the macula? Well, very little. Nearly all research on the retina is undertaken on animals that do not have a macula, such as mice and rats, and occasionally other animals. The only animals that really have a fovea, apart from birds, and I’m not sure that birds are really very similar to humans, are humans and non-human primates. And so it would be important to undertake some kind of research on retinal tissue from humans and non-human primates. If a non-human primate died, that eye could be made available to research. Equally humans; if humans would donate their eyes for research, we could start to characterize the functional characteristics of the macula versus peripheral retina.
Is this applicable to disorders other than MacTel? Absolutely. There are many genetic disorders that affect the macula, only, and not the peripheral retina. Similarly, age-related macular disease affects the macula not exclusively, but primarily. And that accounts for over 50% of blind registration in North America and Western Europe. Thus identifying the functional attributes at a cellular level would help in understanding a huge number of common blinding diseases within our community.
What have been some of the highlights of working on the MacTel Project, in your view?
This research program has been extraordinarily rewarding. The disorder has been totally redefined. We know a lot about MacTel now, compared with what we knew before. It’s been very rewarding to have clinicians and scientists exchanging information freely; the program has been very successful in that regard.
We could only do this because of the financial support of the Lowy Medical Research Institute. They’ve been very generous in giving us support for this research program, which has been important to our understanding of MacTel and hopefully its treatment. The program has also been very important in ophthalmic research, in general, particularly in disorders that account for over 70% of blind registration in developed societies. I feel very lucky to have been involved in this research that may have major consequences to ophthalmic research.