The research of two School of Medicine researchers and a Yale alumnus—work on the genetics of a devastating eye disorder, the capacity of stem cells to make identical copies of themselves and the decoding of the Neanderthal genome—have been recognized by the journal Science as among the top 10 scientific breakthroughs of 2006.

The journal cited two genomic studies of age-related macular degeneration (AMD) led by Josephine J. Hoh, Ph.D., associate professor of epidemiology and of ophthalmology and visual science, along with several other AMD studies, as representing significant progress against the disease, the most common cause of blindness in people over the age of 50. AMD attacks the central area of the retina known as the macula, resulting in progressive loss of vision.

In 2005, Hoh and colleagues compared the DNA of patients with AMD to those who didn’t have the disease in order to home in on genetic differences between the two groups. The team eventually linked a variant of a gene on chromosome 1 known as CFH with the milder “dry” form of AMD. Last year a group led by Hoh went on to identify a single change in a gene on chromosome 10 that leads to a significantly increased risk of developing the more aggressive “wet” form of the disease.

“Discovery of the association of CFH and AMD changed the direction of macular degeneration research,” Hoh says, adding that one of the most rewarding aspects of her work has been the collaboration it has sparked with other scientists.

Haifan Lin, Ph.D., professor of cell biology and director of the Yale Stem Cell Center, was one of four scientists whose laboratories were listed as contributing to breakthroughs in the understanding of small RNA molecules known as Piwi-interacting RNAs, or piRNAs. Lin’s lab first discovered piwi/argonaute genes, which are essential for the self-renewal of stem cells, in 1998. But it was not understood what roles these genes play in stem cell division until last year, when Lin’s group showed that Piwi/Argonaute proteins bind to piRNAs.

“Despite their tiny size, Piwi-interacting RNAs probably have important functions,” notes Lin, who describes them as “tiny, but mighty.” Now that Lin has discovered that piRNAs help cells to differentiate into many different cell types, he is trying to find out how they control gene activity inside the cell. This work may have important implications for the understanding of infertility and cancer; because of their tiny size, the molecules could also be more easily used as therapeutic molecules.

Yale Jonathan Rothberg, Ph.D., also appeared on the top 10 list. Rothberg, who received his doctorate from the university in 1991, is founder and chairman of the board of 454 Life Sciences, a Branford, Conn., company that created technology for the rapid sequencing of genomes. (The sequencer Rothberg’s company developed played a role in the discovery of piRNAs; two of the labs in Science’s top 10 list used the technology, and stem cell expert Lin is currently using it in his work.)

Rothberg and his collaborators in Germany and Croatia took the No. 2 slot on Science’s list for successfully analyzing 1 million base pairs in DNA taken from a 38,000-year-old Neanderthal fossil.

Neanderthals are the extinct hominid group most closely related to contemporary humans and believed to have diverged from humans about half a million years ago. The DNA analysis has revealed that the difference between the human and Neanderthal genome is just one base pair in 2,000.

According to Rothberg, the 454 Life Sciences team is poised to sequence the entire Neanderthal genome within two years.

“For the first time,” he says, “Neanderthal gives us a handle on understanding human intellect, one of the great mysteries left in science.”