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.”
How AI is reinventing what computers are
Three key ways artificial intelligence is changing what it means to compute.
These weird virtual creatures evolve their bodies to solve problems
They show how intelligence and body plans are closely linked—and could unlock AI for robots.
We reviewed three at-home covid tests. The results were mixed.
Over-the-counter coronavirus tests are finally available in the US. Some are more accurate and easier to use than others.
A horrifying new AI app swaps women into porn videos with a click
Deepfake researchers have long feared the day this would arrive.
Get the latest updates from
MIT Technology Review
Discover special offers, top stories, upcoming events, and more.