In the words of the award citation: “In a mammal, all cells have the same DNA sequence. However, cells involved in different functions express distinct subsets of genes. These different expression patterns are stabilized through epigenetic marks, of which DNA methylation was the first to be discovered and characterized. DNA methylation marks are inherited as cells divide, and in some cases inherited across generations.”

His work on methylation would later lead Bird to a discovery which could prove game-changing in the neurosciences domain. He found that by correcting defects in a protein associated with a severe form of autism known as Rett syndrome, the symptoms of the condition disappeared in mice. “This is the first time that a neurological disease has been reversed in an experimental context, and offers hope that this approach can be translated into the clinic,” the citation continues.

This result, obtained in 2007, has refocused research efforts on this congenital condition, which affects girls – one in every 10,000 – and causes severe mental retardation and the progressive and persistent loss of cognitive and motor skills. Bird has since combined his basic research with an active involvement in the quest “to do in humans what we have done in mice,” he explained after hearing of the award. “I used to be quite content with myself just pursuing knowledge. But to see that your research can have such practical relevance in people’s lives adds a new dimension, and makes the whole thing more exciting and engaging,” he observed during the same conversation, after stating his gratitude for the jury’s decision.

Importance in cancer and aging

Epigenetic changes in the genome occur naturally during embryonic development and throughout life. They are also the mechanism through which the environment acts on our genes – smoking, for instance, affects DNA methylation. So understanding how these changes happen is a vital first step in order to understand diseases like Rett syndrome, and clarify the ways in which lifestyle and environmental factors influence cancer.

“DNA methylation is organized in a pattern, which is slightly different in each cell. And in the case of cancer cells, we know that these patterns are really messed up,” Bird explains. “Although the relationship between DNA methylation and cancer is not fully understood, it seems pretty clear that certain genes in the tumor cell that depend on the absence of methylation become methylated and are shut down in consequence, which facilitates the development of cancer.”

By the late seventies, scientists knew a relationship existed between methylation and gene activation, but not how it worked. Bird obtained the first ever DNA methylation map, demarcating the regions where the process unfolds.

New hope for Rett syndrome

Bird not only revealed the precise form of organization of “the regions within the genome marked by DNA methylation,” the jury remarks, but also “identified proteins that read the DNA methylation signals, mutation of which leads to human diseases.”

His discovery of the MeCP2 protein that detects methylation signals in the genome occurred in the early nineties, before the human genome was sequenced. It was therefore a “huge surprise”, Bird now recalls, for himself and everyone, when he was able to show, at the end of that decade, that it was a mutation in this protein that causes Rett syndrome.

Even more remarkable was his achievement in reversing the disorder in an animal model. In 2001, Bird switched research tack and created a mouse with the Rett syndrome genetic defect, presenting all the symptoms of the disease. In 2007, he found a way to activate the correct protein in these laboratory animals, and the symptoms disappeared.

“We didn’t expect it because it was assumed that once you have a neurological disorder, you have it forever. We thought we might, with luck, delay the animals’ death or perhaps alleviate some of the symptoms,” Bird reflects. “But what we got was a clear result, a spectacular improvement. It was one of those Eureka moments.”

The new laureate explained at the award announcement event that his experiment to treat mice with Rett syndrome started from the fact that the disease is not accompanied by the death of neurons, so it was theoretically possible to restore them to a fully functional state. This characteristic is shared by fragile X syndrome, another disabling hereditary disorder.

“We are still far from finding a cure for these diseases, but our work provides a proof of concept that has got a lot of other research groups involved in the search for therapies.”

Bird admits to feeling pressurized by the thought of people waiting for a cure and “frustrated” at the failure, so far, to replicate his results in human subjects. He also warns that “we cannot be sure” if the same cure will work in humans. Nevertheless, the hope felt by many families is not, in his view, unfounded: “The parents know it will take time, that their own daughters might not benefit from the advances. But they also know that there are lots of labs around the world working on Rett syndrome, and that wasn’t true before.”

Biomedicine jury

The jury in this category was chaired by Angelika Schnieke, Chair of Livestock Technology in the Department of Animal Science at Technische Universität München (TUM) (Germany). The secretary was Óscar Marín, Research Professor in the Department of Developmental Neurobiology at the Instituto de Neurociencias de Alicante, a joint center of CSIC and Miguel Hernández University (Spain). Remaining members were Dario Alessi, Director of the Protein Phosphorylation Unit, a Medical Research Council unit in the College of Life Sciences at the University of Dundee (United Kingdom); Mariano Barbacid, leader of the Experimental Oncology Group at the Spanish National Cancer Research Centre (CNIO); Robin Lovell-Badge, Head of the Division of Stem Cell Biology and Developmental Genetics at the MRC National Institute for Medical Research (United Kingdom); Ursula Ravens, Head of the Department of Pharmacology and Toxicology in the Carl Gustav Carus Medical School of Technische Universität Dresden (TU Dresden) (Germany); and Bruce Whitelaw, Head of the Developmental Biology Division at The Roslin Institute, a basic and translational research center belonging to the University of Edinburgh (United Kingdom).