Interview with Paul Bernstein, MD, PhD

Dr. Paul Bernstein is a Professor at the University of Utah, School of Medicine, in the Department of Ophthalmology.  Dr. Bernstein is a Lowy Medical Research Institute extramural investigator and clinical researcher.  He has been instrumental to MacTel genetics research; recruiting families with MacTel to participate in the MacTel Project.  In the laboratory, his research focuses on macular pigment.  Changes in macular pigment distribution are among the first clinical signs of MacTel.  In this interview, we discuss both his clinical and laboratory work.


How long have you been involved with the MacTel project?

I’ve been an active member of the MacTel Project for about eight years now.  I work on macular pigments from the basic science side, and from the clinical side running clinical studies on macular pigments.  I’m also very involved in studying the genetics of MacTel.

You bring in families with MacTel from the Intermountain West region to participate in the MacTel Project.  Why is studying families, in addition to individuals, so important to this project?

It’s very important to try to understand the underlying causes of MacTel.  That will allow us to develop rational treatments for the disease.  We have a lot of evidence that MacTel is, in part, a genetically mediated disease.  We realized early on that siblings and other first degree relatives such as parent-child pairs, were affected more often expected based on the frequency of MacTel in the general population. This means that there is likely to be a gene or genes involved in mediating the risk of Macular Telangiectasia type 2.

MacTel is not a simple genetic disease like Stargardt disease, or retinitis pigmentosa.  Such diseases have high penetrance and they follow very classically in the genes.  The genetic inheritance of MacTel is a little difficult to study because the disease has a late onset. People typically are not affected until they are at least 40 years old.  The disease also seems to have variable penetrance, which means that there may be people who have genes associated with MacTel that never develop the disease.  By studying families we can get large groups of individuals with shared genes, and try to find genes in those groups that are associated with disease.  Utah became the focus for the genetics studies because we have some of the largest families in the United States, and they are often close-knit, so it’s easier to assemble large families.  We also have large databases, such as the Utah population database, which can give us additional information about these families.

If a person has MacTel, how likely is it that other members of their family also have the disease?

In my experience approximately 20-30% of a MacTel patient’s first degree relatives over age 40 (siblings, parents) are also affected.  If this were a classically dominant disease we would expect to see as many as 50% of first degree relatives affected, so MacTel not a completely penetrant disease. It’s highly significant that we find a relatively high rate of this disease within families.  Other studies have found a slightly lower rate; around 10% of first degree relatives affected.  In either case, it’s certainly higher than the incidence of MacTel in the general population.  I think we’re finding a higher level here in Utah because we’re looking very carefully.  We now know some of the earliest clinical signs that may be missed, especially if a person reports no symptoms.  This allows us to diagnose and find family members with MacTel much earlier.

Have you diagnosed MacTel in asymptomatic family members of people who are affected?

Yes.  There have been a number of cases in which family members have no complaints at all; they have 20/20 vision.  But when we look carefully at the retina, we see some of the earliest signs of MacTel in those individuals.  We may see abnormal blood vessels, clumps of pigmentation, or changes in macular pigment.  We also have found that by using optical coherence tomography, which allows us to look at a cross-section of the retina, we can find early changes, such as little cysts or holes in the structure of the retina.  These are also some of the earliest signs. So, indeed, we are able to diagnose very mild cases in which the people have no current symptoms. And they may be such mild cases that the individuals may never develop problems, or they may become symptomatic 5-10 years down the road.

What symptoms typically bring people who don’t yet know they have MacTel into the clinic for diagnosis?

The initial complaints of patients are problems with reading, and some blurring of vision. Or they may notice that when they are reading there are letters missing, or even words. These are the main complaints that patients have.  The changes can be very subtle.  Later on, as the disease progresses, patients may have a drop in visual acuity, and they may no longer be correctable to 20/20 vision.  If they drop to 20/40 they may have difficulty passing a driving test.  Those are some of the most common complaints people have.  Previously, when retinal physicians were not as attuned to MacTel, the diagnosis would often be missed.  The diagnosis could often take years to be made.

You mentioned earlier in this interview that you’ve been using the Utah Population Database to piece together larger families.  How has that resource assisted you?

The Utah Population Database is a list of family pedigrees and documented relationships between a large number of people who live in the intermountain west, particularly in Utah and Arizona.  There are over 7 million people in this database, going back hundreds of years.  Utah has the only database like this in the entire United States. The only similar ones we are aware of are in other countries, like Iceland, and they are much smaller than the size of this current database.

The Utah Population Database has helped us build larger families from affected individuals who visit our clinic.  We can collect groups of patients who seem to be the only ones affected in their immediate families, and submit those 10-30 people, to the Utah Population Database.  People working with the database can look through our list of individuals and create family trees of people who don’t even know that they are related.

We have had a number of very remarkable “hits,” or successes, with this approach.  In a group of, for example, 10 patients, we might be told that three of them are actually related to each other as fourth cousins.  Most of us don’t know who our fourth cousins are.  This allows us to trace families back to founders who lived hundreds of years ago, and to build up new and larger families.  Larger families can be very helpful for the genetics researchers who do whole genome and whole exome sequencing to try to get at the gene or genes underlying MacTel.  We think this is a unique and very powerful way of approaching a genetic problem in a complex and somewhat rare disease like MacTel.

You are a clinician-scientist, which means that you see patients in the clinic and you also run a laboratory.  In your lab, you study macular pigment distribution in the eye.  What is the function of macular pigment in the eye? 

Macular pigments are the reason the macula is called the macula lutea, or the “yellow spot.”  These are nutritional factors, specifically lutein and zeaxanthin, which we get from eating fruits and vegetables.  They are concentrated right in the center of the eye.  We have quite a bit of evidence that macular pigments are protective against oxidative damage to the retina, and are very important in a number of diseases, specifically age-related macular degeneration.  They seem to protect against light-induced damage to the retina and they help preserve visual function until much later in life.

Macular pigment deposition in a healthy retina peaks right at the center, appearing as a yellow spot.  About 5-10 years ago, we realized that when we imaged the MacTel retina we found a very unique change in the macular pigment.  Instead of a central dot, there is actually a donut-like ring of macular pigment in the MacTel eye. This is one of the earliest signs of Macular Telangiectasia, and is one of the earliest tests we do for MacTel in diagnosing patients. From a clinical standpoint, it’s very important just to see this ring of yellow pigmentation.

The work in my laboratory is dedicated to macular pigment biochemistry, or understanding at a molecular level how these pigments work in the eye.  One of the things we have focused on are the macular pigment binding proteins, which are responsible for pigment uptake into the retina.  We have discovered several such binding proteins.  We think that the early changes to macular pigment distribution in MacTel occur because the proteins are in the wrong position in the retina, resulting in the ring.  We don’t understand why this happens, but we are trying to figure out the underlying cause.

We, and others, have seen if we can correct this problem.  We’ve looked at whether taking supplements containing lutein or zeaxanthin might fill in the doughnut-shaped hole that is absent of macular pigment in the MacTel retina. The study I did used zeaxanthin supplements.  We found that giving supplements made the ring more intense, but it never filled in the hole.  Some of my patients taking supplements did feel that their vision improved.  Dietary supplementation is not high-risk, but the benefits are very subtle.  We still need to understand more biochemistry to get a more rational intervention against this disease.

Studying macular pigment and binding proteins is important not just for MacTel, but for understanding basic biology of the eye.

Yes, it’s very important for age-related macular degeneration, as well.  In other projects in my laboratory we know that the macular pigment is found even at birth. So it may also be important for the development of the retina.  It truly is a nutrient that’s important throughout the lifespan.

What are some of the high-priority questions to be answered about macular pigment, especially in regards to MacTel?

The highest priority question we are trying to understand is where these pigments are in the retina.  They could be in Müller cells, or in photoreceptors.  Müller cells are the first cell type affected in MacTel, and are important support cells in the retina.  Photoreceptors – rods and cones in the macula – are affected later in the disease.  The macular pigment, we think, is particularly good at protecting the rods and cones of the macula.  On the other hand, the Müller cells are also important to the health of the retina.  We are trying to settle the controversy:  in which cell is the macular pigment?  Through the courtesy of the Lowy Medical Research Institute and some other private foundations, we will soon have specialized microscopes to really get at some of these questions from a molecular level.  We will be able to discover where the binding proteins are, where the macular pigments are, and how macular pigment abnormalities cause degeneration of the retina.

One of the ways that we do this is by studying eyes donated by MacTel patients.  Eye donation is very important to our research, and some patients with MacTel have graciously agreed to donate their eyes after death.  We’ve had a few key donations of these eyes, which we study in my laboratory and in other laboratories.  That’s one of the key ways that we will help solve this disease; by having these rare, but very important, eyes to work on.