Eye colors: Drusen, the yellow flecks in this image of the retina, are common in people with age-related macular degeneration. These flecks are made up of proteins involved in the part of the immune system called the complement system, which has also been implicated in the disease by genetic studies.    Credit: National Eye Institute


Genome-wide association studies have generated new insight into the devastating eye disease

MIT Technology Review, May 26, 2010, by Emily Singer  –  In 2005, two genetic studies of people with age-related macular degeneration (AMD)–the most common cause of blindness in people older than 65–made a surprising discovery. Research showed that defects in a gene that is an important regulator of parts of the immune system significantly increased risk of the disease. Scientists have since identified variants in several related genes that also boost risk, and which collectively account for about 50 to 60 percent of the heritability of the disorder.

At the same time that researchers identified the harmful variation linked to AMD, Gregory Hageman, now at the University of Utah, identified a protective variant found in about 20 percent of the population. “That form is so incredibly protective that people with two copies are almost guaranteed not to develop the disease,” he says. Hageman founded Optherion, a startup based in New Haven, CT, and investigated how to translate the findings into new treatments. Optherion is now producing large quantities of an engineered version of the protein and doing preclinical safety and effectiveness testing–for example, examining whether the treatment can reduce ocular deposits in mice that lack the protein, says Colin Foster, Optherion’s president. He declined to estimate when the company will begin clinical trials of the drug.

Scientists hope that these developments will prove to be an example of the benefits that can arise from a type of genetic study called genome-wide association. The genome-wide studies of macular degeneration were among the first and perhaps the biggest success for the approach, which employs specially designed chips dotted with markers to cheaply detect hundreds of thousands of the most common variations in the human genome. While these chips have allowed scientists to cheaply scan the genomes of many patients and healthy controls, the approach has come under increasing scrutiny in the last couple of years. Even huge studies of thousands of people have failed to identify the majority of the heritability of common diseases, such as type 2 diabetes or Alzheimer’s disease.

But David Altshuler, a physician and geneticist at the Broad Institute, in Cambridge, MA, and one of the primary architects of these studies, argues that this is not the best way to measure their success. Rather than using the results to design diagnostics to predict an individual risk for developing a disease, we should use genome-wide association studies to identify new drug targets, he says. And he points toward macular degeneration as an example.

Prior to the 2005 studies, few people studying macular degeneration suspected a major role for the complement immune system, which helps to clear pathogens from the body. The link between the complement factor H gene, which is a major inhibitor of the complement immune system, and other genes to macular degeneration has allowed scientists to explore the pathology of the disease in greater molecular detail. Mice lacking the protein altogether develop kidney and eye problems. (Mice don’t have maculas, so it’s impossible to accurately mimic the disease in rodents.) Human cells expressing the mutated version of the protein have altered immune function.

Hageman, who has since left Optherion, is exploring the power of the protective protein in novel ways. Because most complement factor H protein is made in the liver, his team is examining macular degeneration in people who undergo liver transplants. “We have seen cases where people who received a liver from someone with the risk form of the protein have developed macular degeneration quickly,” he says. “And we have seen a couple of cases where someone had AMD and progression was halted after receiving a liver from someone with the protective form.” But he cautions that these cases are anecdotal; researchers need to examine many more patients to see if the effect is statistically significant.

While it’s not exactly clear how alterations in the complement factor H gene boost risk for macular degeneration, scientists theorize that the mutant protein can no longer adequately control the complement immune system, perhaps triggering it to attack healthy cells rather than the pathogens it was designed to fight. “Chronic activation of complement and chronic inability to control it probably helps to explain the age-relatedness of the disease,” says Hageman.

Anand Swaroop, a researcher at the National Eye Institute, in Bethesda, MD, points out that while the complement system is important in AMD, genome-wide association studies have implicated other genes and pathways as well. “We know that in addition to the complement system, there are three or four other pathways involved, as well as environmental factors,” says Swaroop. “Those variants are clearly as important and we have no idea what they do. I think the ultimate cure will come from targeting multiple pathways.”

Eye shade: Scientists hope that new compounds that make the eye less sensitive to light will slow the buildup of yellow spots–called drusen–seen here in the center of this retinal image from a patient with macular degeneration.     Credit: National Eye Institute


Dampening a light-sensing reaction in the eye might slow a common cause of blindness

MIT Technology Review, by Emily Singer  –  Molecules designed to slow the production of toxic byproducts in the eye by making it less sensitive to light are now being tested in patients with macular degeneration, the leading cause of blindness in people age 50 and older. If successful, the compounds would provide a much needed therapy for the disease, which affects more than 15 million people in the United States.

In macular degeneration, cells in the center of the eye, called the macula, deteriorate. A handful of new treatments for the more severe form of the disease, known as wet AMD, have been approved in recent years. But no treatments are yet available for the dry form, which accounts for about 90 percent of cases. Some dry cases ultimately progress to the wet form, which accounts for a large part of AMD-related blindness. “If you can treat dry AMD, you can kill two birds with one stone,” both reducing early symptoms and preventing progression to the wet form, says Paul Sieving, director of the National Eye Institute, in Bethesda, MD.

While scientists are still trying to understand the causes of AMD–age is the biggest risk factor, with genetics and lifestyle factors also playing a role–a growing pool of evidence suggests that the build up of specific compounds in the eye can hasten the cellular damage that underlies the disease. These compounds accumulate in the photoreceptors–cells in the retina that detect light–during normal eye function as the light-sensitive pigments in these cells change conformation in response to photons.

One form of the photopigment, a derivative of vitamin A, is highly reactive and leaks into nearby tissue called the retinal pigment epithelium. “Over time we think these compounds are a burden for the retinal pigment epithelium, which is essential for the healthy function of the photoreceptors,” says Janet Sparrow, director of the Retinal Cell Biology Laboratory at Columbia University, in New York. “In age-related macular degeneration, particularly the dry form, these cells die, and the photoreceptors follow.”

While this reaction is vital for sight, researchers believe that slowing the cycle in the subset of photoreceptors responsible for night vision, known as rods, could slow damage without having a large impact on daytime vision. (Preliminary results suggest it can affect dark-adaptation–when our eyes adjust to low-light conditions.) “During the daytime, the rods are spinning like crazy, wasting vitamin A for no good use,” says Ryo Kubota, an ophthalmologist and founder of Acucela, a Seattle-based startup that is developing treatments for macular degeneration. “It’s like a CCD camera pointed at the sun.”

One compound developed by Acucela that is in clinical trials inhibits the enzyme that converts the photopigment in photoreceptors from one form to another. This process happens only in the eye, allowing the drug to be administered systemically without affecting other tissue, says Kubota. The company has finished initial safety testing in humans and plans to begin a clinical trial assessing the compound’s effectiveness in patients with late-stage dry macular degeneration in a few weeks. Kubota also aims to test the compound in diabetic retinopathy and Stargardt disease, a rare, genetically inherited form of macular degeneration.

A second drug that acts by a slightly different mechanism is being evaluated for macular degeneration by Sirion Therapeutics, a Florida-based pharmaceutical company. The compound is a synthetic vitamin A derivative that is thought to reduce toxin buildup by binding to one of the proteins involved in the reaction. According to preliminary results from tests of the drug in patients with late-stage dry macular degeneration, it can slow the scarring that is characteristic of the disease by 45 percent. However, scientists won’t know if the results are statistically significant until completion of the study next year. Because no treatments had been approved for dry AMD, in 2009, the U.S. Food and Drug Administration fast-tracked the drug, speeding the review process.




Molecular Sunglasses for Macular Degeneration

Eye sight: White dots a patient’s retina (top) are early signs of disease. In the image below these spots are identified automatically.             Credit: Ken Tobin


Web-connected cameras may help doctors detect a common eye disease


MIT Technology Review, May 2010, by Arlene Weintraub  –  Of all the complications of diabetes, few are as devastating as diabetic retinopathy, a progressive eye disease that causes blurred vision and in some patients, blindness. By the time most patients recognize something’s wrong, it’s often too late for them to be treated effectively. As a result, diabetes is the leading cause of vision loss among adults over 20. More than 12,000 new cases of blindness each year are caused by diabetic retinopathy, according to the National Institutes of Health.

An ophthalmologist and a scientist from the Department of Energy’s Oak Ridge National Laboratories in Tennessee believe they can help doctors detect diabetic retinopathy long before the disease wreaks havoc on their patients’ vision. Their startup company, Automated Medical Diagnostics (AMDx), has developed software that can detect the early signs of diabetic retinopathy by comparing digital photos of a patient’s retina to images that represent various stages of diabetic eye disease. AMDx’s founders believe their technology will enable all health workers–even those who are not trained in eye care–to take retinal scans of any patient, zap them over the Internet to AMDx’s servers, and get a diagnosis back before the patient leaves the office. “We’re trying to show we can be as accurate as a trained ophthalmologist,” says Ken Tobin, AMDx co-founder and division director of measurement science and systems engineering at Oak Ridge.

AMDx’s technology was inspired by a system that Oak Ridge scientists originally developed to help semiconductor manufacturers analyze defects in computer chips. Their software essentially teaches computers a technique called “content-based image retrieval.” The system can take a single image of a chip and then sort through giant databases of other images to find similar visual patterns–a process that some chipmakers now use to spot problems and improve manufacturing methods.

In 2005, Tobin met Edward Chaum, an ophthalmologist and professor at the University of Tennessee’s Hamilton Eye Institute in Memphis. “Less than half of diabetics are screened in any given year for retinopathy, despite the fact that they are told they need regular eye exams,” Chaum says. Many patients don’t have health insurance, he says, or they just don’t want the hassle of traveling to see yet another specialist. But Chaum and Tobin realized that if primary care doctors could do basic eye screenings on diabetic patients, they might catch many more cases of retinopathy than are being detected today.

The retina is particularly well suited to content-based image retrieval, Tobin says. Unlike other types of medical images, such as brain scans and mammograms–which are highly variable and require multiple images to create a three-dimensional effect–the retina is virtually two-dimensional and similar from one photo to another. That makes it easier for the technology to detect lesions, leaky blood vessels, swelling, and other abnormalities on the retina that can be early signs of disease. Chaum and Tobin spent five years developing algorithms that can extract information from retinal images and screen it against a database of more than 20,000 photos. AMDx doesn’t produce diagnoses but rather alerts doctors to patients who need to be referred to specialists for more in-depth testing, diagnoses and treatments.

AMDx is currently testing its system in a handful of clinics in Mississippi and Tennessee. Training doctors is easy, Chaum says, because the cameras have features like auto-focus, and they don’t require that the patients’ eyes be dilated. The photos are sent over the Internet to AMDx’s servers and automatically compared to images in its database. Chaum then checks each result manually–a process that takes about 90 seconds per case, he says.

AMDx’s goal is to ultimately turn over the entire job to its computers, but for now it must rely on Chaum’s review. That’s because some insurers–most notably Medicare and Medicaid–will only reimburse physicians for eye screenings after an ophthalmologist examines the results. Chaum and Tobin are collecting data, with the goal of proving to both regulators and insurers that their computers are as effective as Chaum at detecting disease. “The computers can handle thousands of reports a day. The bottleneck is me signing off on them,” Chaum admits.

Efforts to remotely diagnose eye diseases have been tried on a limited basis by the Veterans Administration hospitals and other institutions. Some ophthalmologists believe that if the idea catches on, they’ll be able to treat many more cases of diabetic retinopathy than they can today. “If you can teach a clinician to recognize changes in the eye, you can teach a computer to do it,” says Barrett Katz, an ophthalmologist and professor at Montefiore Medical Center and the Albert Einstein College of Medicine in the Bronx, NY. “It doesn’t take an ophthalmologist to gather these images–if anyone could do it, that would be a major step forward.”

Tobin and Chaum are on the hunt for venture capital to fund AMDx’s expansion. They hope the current focus on health reform will give them a boost, because the ongoing debate is drawing attention to the need for improving the efficiency of the health care system. “It’s not that we can’t treat diabetic retinopathy,” Chaum says. “It’s that we’re inefficient in how we screen for it.”

Testing the FDA: Pathway Genomics, a startup that sells a genetic testing kit to consumers over the Internet, garnered regulatory attention when it announced plans to sell the test at Walgreens.     Credit: Pathway Genomics


Questions arise over several companies’ plans for over-the-counter genetic tests

MIT Technology Review, May 26, 2010, by Arlene Weintraub  –  On May 19, the U.S. House of Representatives Committee on Energy and Commerce sent a toughly worded letter to three CEOs, including James Plante of San Diego-based Pathway Genomics. Pathway was preparing to sell an over-the-counter genetic-testing kit at Walgreens. The product, called Genetic Health Report, purported to test for more than 70 health issues, including predispositions to Alzheimer’s, breast cancer, and diabetes. But the committee’s questions prompted Walgreens to postpone its plans to sell Genetic Health Report.

The committee’s action could mark a crackdown on companies that sell genetic tests directly to consumers. The tests–which use saliva samples–have been sold, mostly over the Internet, with little interference from authorities, including the U.S. Food and Drug Administration. But some experts in law and genetics say Walgreens’s plan to stock the tests on shelves may have made enough of a splash to change all that. “We could see a demand for more transparency from these companies, so consumers can clearly see what they’re testing for, and what the evidence is” for the legitimacy of the results, says Daniel Vorhaus, attorney at Robinson, Bradshaw & Hinson in Charlotte, NC, and editor of the firm’s Genomics and Life Sciences blog.

The committee is demanding that consumer genetic-testing companies provide documents that describe the accuracy of the tests, and how the analysis of the results takes into account such factors as age, gender, and geographic location. Less than two weeks before the committee mailed its letters, the FDA sent a letter to Pathway requesting that Plante justify Genetic Health Report’s lack of FDA approval.

An FDA spokesman said in an e-mail that the other two companies that were contacted by the House committee–23andMe and Navigenics–had also been asked to defend their lack of FDA clearance: “This type of communication is often an initial step to open discussions with companies to clarify the FDA’s role in regulating their products and it’s also a step to gather more information about the products themselves.”

The three companies contacted by the House committee declined to comment for this story, though all released public statements expressing their willingness to cooperate with the investigations. “Pathway is in compliance with currently applicable regulations and guidelines for our laboratory and the services we offer to our customers,” said a company statement.

As it stands, the regulations governing genetic tests are a bit muddy. Pathway’s statement says the company has a certification known as Clinical Laboratory Improvement Amendments (CLIA), a federal certification that merely establishes quality standards for the laboratories that perform the tests.

But should the FDA be more vigilant? Most genetic tests–including those given by doctors–are subject to the FDA’s medical-device regulations. There are three classes of medical devices, each requiring an increasing degree of regulatory control. Depending on the nature of the test and what reagents are used to produce the results, the consumer genetic tests may or may not require premarket approval, though they must include a disclaimer stating that they have not been cleared by the FDA. The agency’s discussions with Pathway and its rivals may result in more such cautionary language being displayed prominently on packaging and consumer leaflets.

Some genetics experts believe consumers need even more comprehensive information about the limitations of genetic testing. They point out that scientists have not yet decoded the genetic causes of most diseases and many uncertainties surround genetic testing.Take BRCA1 and BRCA2, for example. While mutations in these genes have been linked to breast cancer, less than 10 percent of women who develop the disease actually test positive for the genes. For other diseases, such as Alzheimer’s, very few genes have been linked to the illnesses, and it’s unclear how important those genes are in the diseases. So genetic tests might create unwarranted fear in some patients, says Hope Northrup, director of the Division of Medical Genetics in the Department of Pediatrics at the University of Texas Medical School at Houston.

Edward McCabe, codirector of the Center for Society and Genetics at the University of California at Los Angeles, believes consumers who buy genetic tests–either online or on store shelves–should be instructed on exactly what each result can accurately predict and what it can’t. The FDA should have the authority to vet the tests, as well as the information that comes with them, he says. “Otherwise inappropriate health-care decisions could be made.”

The FDA and Congress are unlikely to outlaw the marketing of genetic tests to consumers altogether, most experts believe. But Vorhaus predicts they will put pressure on the U.S. Federal Trade Commission to monitor the messages that these companies are giving to consumers.

In any case, the fact that these agencies are paying attention to genetic testing could be enough to change how Pathway, Walgreens, and other companies communicate the value of their products to consumers. “Shine a bright light on the industry,” Vorhaus says, “and you’ll get the industry to monitor itself.”

By S. James Gates Jr.

“The reason we are doing this with urgency is because it’s connected to our country’s future economy.” John Consoli/University of Maryland

Is science education broken in the United States? And if so, how should the country fix it? A working group of the President’s Council of Advisors on Science and Technology (PCAST) has been investigating these long-standing questions and is expected to issue a report on its policy recommendations this month. Science News Contributing Editor Alexandra Witze spoke with the working group’s cochair, physicist S. James Gates Jr. of the University of Maryland in College Park. Gates also serves on the Board of Trustees of Society for Science & the Public, the parent organization of Science News.

What is the outlook for U.S. science education?

If you look at U.S. performance on various international metrics, depending on which one you use, we come out something like 24th or 25th in the world. A lot of people might argue: “Well, who cares? It’s just science.” The only problem with that theory is we’re moving into a time in the development of the world economy when innovation and the formation of novel approaches will clearly come from countries best situated to create a population that can innovate in science and technology.

We’re not doing this because we want to make more scientists. The reason we are doing this with urgency is because it’s connected to our country’s future economy.

The Obama administration has announced a number of science education initiatives. Will they do enough?

I think the true test is yet to come. Does one put one’s money where one’s mouth is? To some substantial degree, this administration has stepped up to the plate with its increased support of science. On the other hand, we have heard concerns about sustainability of this commitment in light of current economic constraints.

How is PCAST approaching its deliberations about science education?

We’re trying to be mindful of the tremendous number of efforts that have gone before; there are at least 40 to 50 such reports that one could list. We have found discussions in the literature all the way back to the ’60s where people were raising issues of science and technology education.

When I look at the country’s current crisis with regard to STEM [science, technology, engineering and mathematics] education, this is in fact the third such crisis.

The first one was World War II in my opinion. If you look at the way this nation prosecuted the war successfully, it was because the United States innovated at a level far beyond its competition.

Crisis two in my opinion was the launch of Sputnik. Once again there was a public resolution. You create NASA, our space program, and we successfully get men on the moon by 1969.

In this third STEM crisis, what we really need to do is start thinking in light of our previous experience. What might be policy structures that could bring to bear the kind of transformational and long-term vision to allow our nation to progress to higher levels of performance?

How do we do that?

My [PCAST working group] cochair [Eric Lander of the Broad Institute of MIT and Harvard in Cambridge, Mass.,] says the problem is that we in this nation do not have the structures that have allowed us to get inside the innovation cycle in education in the way that we have in scientific research.

One way to look at this problem is to look at education as a system to be engineered and to ask how one might do this. What I’ve been looking for is maps between how research works in this country and how education works in this country. In particular I have been struck by the fact that there is nothing like DARPA [the Defense Advanced Research Projects Agency] for education. You need something like that in the system to drive innovation like we haven’t seen.

Previous education has been mostly about the delivery of facts; you wanted people to remember and manipulate facts. But one thing that’s different now is in a world that has a Web [and] access to information at your fingertips, the memory of facts won’t be that important. What’s going to be important is the capability of people to marshal those facts to solve the kinds of problems they’re engaged in.

Are you optimistic about the country’s future in science education?

I’m optimistic in the long term. There’s lots of evidence that this country solves difficult problems, especially if you give us enough time. In the short term, I’m afraid it’s going to be very painful. I fear that we may not be able to impress upon the larger society quickly enough that the issues around science, technology, engineering and mathematics are not tied to just those fields — that in fact this is the basis for our wealth formation. If we can’t get that message out quickly enough, the nation’s not going to respond quickly enough.