Three decades of work on Down syndrome is bringing its cause into focus
In 1866, British physician John Langdon Down described the disorder now known as Down syndrome. Despite wide-scale prenatal testing, about 1 in 800 babies in the Western world is born with this disorder. In addition to developmental disabilities, Down syndrome patients suffer from poor muscle function, diabetes and leukemia, and are at a higher risk of Alzheimer's disease.
About 50 years ago, it was discovered that people with Down syndrome have an extra copy of chromosome 21. How does an extra copy of an intact gene cause such problems? The case was far from clear-cut: Overexpression of a particular gene does not necessarily result in the overproduction of its encoded protein. In plants, for example, overexpression of genes is a widespread phenomenon that causes no harm.
Answers are beginning to emerge, thanks to the pioneering work of Prof. Yoram Groner of the Molecular Genetics Department.
In endeavoring to understand how a third copy of chromosome21 causes Down syndrome, scientists have considered two possible scenarios: One widely held "developmental instability" hypothesis suggests that the symptoms are the direct consequence of a disturbance in the chromosome balance, resulting in a disruption of homeostasis. The alternative – the gene dosage effect hypothesis – suggests that symptoms of the syndrome are caused by over-production of some or many of the proteins encoded by chromosome 21 genes, which then leads to a disturbance in the metabolic balance required for proper development and normal body function.
Groner favored the gene dosage effect hypothesis and made it his goal to prove it. The challenge he set himself was to isolate an individual gene from chromosome 21 and demonstrate that it causes known symptoms of Down syndrome. This undertaking was revolutionary in 1979: Information on chromosome 21 was marginal; no molecular tests were available to measure gene expression; and the technology for cloning genes was in its infancy.
Groner and his team found that Down syndrome patients have an abnormally high level of an enzyme called SOD1 in their blood. But was the SOD1 gene located on chromosome 21? And if so, what role did it play in the disorder? In the early 1980s, tackling these issues, which are today routine in the field of genetic research, was almost beyond the scope of conventional science.
The efforts of Groner and his colleagues led to the first ever cloning of a gene from chromosome 21 and the decoding of its DNA sequence. Groner's group created genetically modified cells (so-called transgenic cells) that produce high levels of SOD1. These transgenic cells had physical defects and excess levels of hydrogen peroxide.
One such abnormality was the cells' inability to accumulate neurotransmitters (nervous system modulators). Groner and his team revealed the molecular mechanism that causes this abnormality, tracing the defect to a special protein pump that draws neurotransmitters into the cell. This discovery provided direct evidence that the gene dosage effect of chromosome 21 causes significant physical mal-function in the cell.
How does this malfunction tie in with Down syndrome? To answer this question, Groner and his team created, for the first time, a mouse model for gene dosage: a transgenic mouse containing an SOD1 gene. These transgenic mice had high levels of SOD1 and very low levels of the neurotransmitter serotonin in their blood – close to those found in Down syndrome infants, verifying that features of Down syndrome can be attributed to the gene dosage.
Further research revealed that overexpressed SOD1 produced significantly higher amounts of hydrogen peroxide in the mice, causing defects in the pumps that draw serotonin from the blood into certain blood cells, where it normally accumulates. When this pump fails, the serotonin remains in the bloodstream, where it is broken down, leading to reduced levels of serotonin in these cells and, later, in the brains of the transgenic mice – similar to what is observed in Down syndrome patients.
The intriguing finding that increased SOD1 impairs neuro-transmitter uptake enabled Groner's team to unravel one of the long-standing puzzles in Down syndrome clinical treatment: Attempts were made in the late 1960s to raise the low blood serotonin levels in these patients, but many experienced severe seizures, bringing the studies to a halt. Why does the administration of serotonin cause spasms in infants with Down syndrome? The team were able to resolve the underlying mechanism: When the defective pumps failed to transport serotonin into the infants' blood cells, the added serotonin collected instead in the synapses – the spaces between nerve cells – bringing on the seizures.
Prof. Yoram Groner established the Weizmann Institute of Science's Molecular Genetics Department (from the former Genetics and Virology Departments), and later served as the Institute's Deputy President. Groner was recently awarded the 2008 EMET Prize for Life Sciences for, among other achievements, "his groundbreaking studies in the molecular biology of Down Syndrome, which proved the gene dosage effect theory in the trisomy of chromosome 21."
Prof. Yoram Groner's research is supported by the J & R Center for Scientific Research; the David and Fela Shapell Family Center for Genetic Disorders Research; and the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation. Prof. Groner is the incumbent of the Dr. Barnet Berris Professorial Chair of Cancer Research.