Volume 78, Number 51
CENEAR 78 51 pp.
Bristol-Myers Squibb chemist organizes charity canoe/kayak race for research on Rett syndrome
"The pathway followed by research is like the course of the river . . . difficult, full of obstacles and challenges. And researchers are like voyagers, plying the waters of discovery."--Clark Eid
In the summer of 1999, Clark Eid and his wife, Mary Potter, took their children, Noah, then 3, and Amanda, then 7, to the headwaters of the Mississippi River in Itasca State Park in Minnesota. It was fun. The water excited Amanda, who squirmed in her father's arms to get down and wade. Eid, who is a senior research investigator in central nervous system chemistry at Bristol-Myers Squibb in Wallingford, Conn., was carrying Amanda because she has Rett syndrome --a disorder that, among many other things, makes it difficult for Amanda to walk by herself. "Amanda was thrilled by the rushing water. With my support, we awkwardly walked back into the stream," he says. And father and daughter dipped their toes in the mighty Mississippi. The experience--which seemed simple enough at the time--gave birth to the Great Mississippi River Race for Rett Syndrome. Eid explains how it happened: "Standing by the water, I soon found my hopes and dreams for Amanda's future mixing with thoughts of the river. It became clear to me that Amanda's best hope for the future would flow from Rett syndrome research."
How would Eid bring these ideas--water and research--together? He thought big--real big--and came up with the audacious idea of putting together and participating in the world's longest canoe/kayak ultramarathon. On May 5, 2001, tandem teams of paddlers--a few of them chemists--will gather at Itasca State Park to begin the race. During the following 23 or so days and nights, these teams will paddle 2,348 miles nonstop to the Gulf of Mexico--in world-record time, they hope.
Infants and children with Rett syndrome develop normally until they are between six and 18 months old. Then these children hit a wall. They stop learning new skills and gradually or suddenly lose the ability to do things that they had already learned to do--such as controlling their hands, speaking, and walking. Purposeful hand use is gradually replaced by repetitive, uncontrolled hand movements including clapping or "washing and wringing" motions. Children may also develop autistic symptoms like decreased eye contact and inattentive behavior, impaired walking and trunk movement, severe motor apraxia (the inability to plan movement), as well as breathing trouble, seizures, swallowing difficulties, and a cognitive decline. Severe scoliosis and muscle wasting often land the girls in wheelchairs.
These symptoms tend to worsen, but when the child is older, say, between two and 10 years old, the regression stops and the symptoms become relatively stable. Some improvement in communication skills may also be achieved and continue into adulthood. But many of those with Rett syndrome remain in this stage of stabilization. It is a devastating diagnosis.
The disorder is seen in every ethnic and geographic population worldwide. Although it remains underrecognized, Rett syndrome is thought to be a leading cause of progressive neurodevelopmental impairment in females. The frequency of the disorder appears to vary among different populations and geographic regions, ranging from an estimated 1 in 10,000 to 20,000 female births. There is evidence that males with the genetic mutation die before birth.
Because females are almost exclusively affected by Rett syndrome, many researchers had suggested that the disorder is caused by a mutation in a gene transmitted as an X-chromosome-linked dominant trait. However, in most females with Rett syndrome, the disorder appears to result from random--rather than inherited--sporadic changes of a particular gene. More than 99% of those affected have no history of Rett syndrome in their family.
In late September 1999, Howard Hughes Medical Institute Investigator Huda Y. Zoghbi , who is a professor of pediatrics and molecular and human genetics at Baylor College of Medicine in Houston, and colleagues reported that the great majority of Rett syndrome cases are caused by the mutation of a single gene on the X chromosome. Specifically, the genetic abnormality responsible for Rett syndrome interferes with the operation of one of the many biochemical switches that regulate how genes are expressed. The researchers found that the disorder results from the mutation of the gene that makes methyl cytosine binding protein 2 (MECP2). MECP2 is the lynchpin in one of the elaborate networks of proteins needed to switch off a group of genes.
It is speculated that in the absence of this genetic switch, certain genes fail to shut down, and excessive amounts of otherwise beneficial proteins are made. The molecular events leading to a child's decline can be explained by the overexpression of certain genes that govern the development of the nervous system. This overexpression may lead to defective maturation of the brain and nervous system.
This idea is supported by biochemical brain analyses that demonstrate reduced amounts of the neurotransmitters acetylcholine, noradrenaline, dopamine, serotonin, and glutamate in certain regions of the cerebral cortex and the basal ganglia in children with Rett syndrome. In addition, deficiency of growth factors required for the maturation of the brain and spinal cord is thought to play a role in triggering certain changes associated with the disease. "These are the questions that researchers need to address," Eid says.
Some researchers have speculated that Rett syndrome may result from mutations of mitochondrial DNA (mtDNA). However, to date, findings have not indicated a primary role for mtDNA mutations as a cause of the disorder. Further research is necessary to determine whether mitochondrial abnormalities may be the cause of Rett syndrome in some patients. "There is a possibility that a nuclear DNA mutation affects the expression of mitochondrial DNA," Eid notes.
There is no cure. Therapies to improve the quality of life for girls with Rett remain elusive. For those living with Rett syndrome, the best hope for a future free from disabilities is through continued research. Eid tells C&EN that it is vital that scientists learn about Rett syndrome. He hopes that the ultramarathon will foster communication among scientists--something money can't buy. Also, this interaction among scientists will do more to alleviate suffering in the long run than anything else, Eid says.
An uncommon sight: the Double Helix not in motion. [Photo by Clark Eid]
Eid began his quest by forming a team that would commit to the race. "Fortunately, fellow chemist Kurt Zimmermann shared our vision and agreed to be my racing partner," Eid says. "This was extraordinary since we were both research scientists, a fact we hope will not go unnoticed by the scientific community." The entire team--called Team Double Helix--consists of 18 members, 14 of whom are Bristol-Myers Squibb employees; nine of these are research chemists.
Current teams slated to participate are from a variety of professions, including scientists, firemen, former Olympic paddlers, and teachers. Eid believes that the length of the race, planning, and good fortune will level the playing field for all teams.
This is, of course, a charity event to help those with Rett syndrome; as such, teams will solicit donations for Rett syndrome research prior to the race. Teams will also help increase public awareness of Rett syndrome through the media by trying to beat the 1989 "Guinness Book of Records" time of Bill Perdzock and Mike Schnitzka (23 days, nine hours, and 51 minutes). Other goals of the Great Mississippi River Race include raising $1 million for Rett syndrome research, increasing the public's and the research community's awareness of this disorder, and providing hope to those facing the challenges associated with Rett syndrome.
Two months later, the Double Helixwas shaping up to be a beauty. The mold over which the craft would be constructed was completed on New Year's Day 2000. The first of many thin wood strips was fastened and the kayak began to take shape. Two intense months later, the hull and deck of the Double Helix were covered with wood. The surface was then prepared in anticipation of the next phase of construction, the marquetry that would depict 30 feet of rose vines wrapping around the slender craft.
Further symbolism was woven into the Double Helix by using materials from famous ships. The exotic woods used in the ornate compass ring, rudder catch, and hatches were left over from the reconstruction of the Amistad, another ship symbolizing liberation. "TheDouble Helix will race with a navigation console that was constructed with woods from the Calypso, echoing her spirit to venture into the unknown. A white rose inlay on the console reflects the TurboSails of the technologically advanced Alcyone," Eid says. The Calypso and the Alcyone were Jacques Cousteau's research vessels.
The Double Helix will be auctioned after the race and is expected to be put on permanent display at a children's hospital or museum. "In this way, she will continue to carry her message of hope for future generations," Eid says. All proceeds from the auction, as well as every penny from the event, will go directly into research to help find a cure for Rett syndrome. Contributions will be divided equally between the Rett Syndrome Research Foundation and the International Rett Syndrome Association's Permanent Research Fund .
Eid and Zimmermann are now in serious training to paddle down the Mississippi. They invite C&EN readers to become partners with them. To find out more about Rett syndrome, the race, theDouble Helix, or to learn how to help, go to http://www.dreamkeeper.org .
Double Helix puzzler
Two marquetry rose vines wrap around the Double Helix, the kayak Clark Eid lovingly built. This design was created from more than 2,000 pieces of 63 different wood veneers. For most people, the result is only a beautiful arrangement of flowers. However, C&EN readers are likely to appreciate that the vines represent far more than meets the eye.
"It isn't coincidental that the two rose vines spiraled around the Double Helix in a right-handed configuration. Nor is it by chance that all 120 roses were arranged into 60 pairs," Eid notes with a grin. This floral arrangement was designed to mirror a segment of double-stranded DNA. Furthermore, a special message can be deciphered from this small section of genetic code.
The key to solving this puzzle is to figure out which of the four bases a rose stands for, then to use the standard rules for transcribing and translating the resulting codons to the gene's protein product. Perhaps the most prominent clue is found within the types of woods used for the roses. Note that one rose of each pair was fashioned from Purple Heart wood. "Obviously, this must represent the bases with the most blue-shifted (hypsochromic) UV absorption: the pyrimidines thymine (T) and cytosine (C)," Eid says with tongue planted firmly in cheek.
Armed with this clue, the puzzle can now be solved--if you anticipated that the DNA segment began with the start codon ATG and ended with one of three stop codons, in this case TAA. "If this missed your attention, a further clue is found in the sepals, which are the small leaves directly below each rose. Two sepals beneath a rose stand for two hydrogen bonds, found in an adenine (A)-thymine pair, whereas three sepals represent three hydrogen bonds, or a guanine (G)-cytosine pair."
All that remains is to identify the template strand (vine) and write down the code. This vine is the one that passes between the compass and the rear cockpit, growing toward the bow in the 5' to 3' direction, of course. Since we can't picture the detail of 30 feet of rose vines in C&EN, Eid has written the code and it is printed below.
The DNA code, shown divided into clusters of three bases, or codons, is
This DNA sequence is transcribed into mRNA, resulting in the following sequence:
To "decode" the mRNA strand, begin with the first codon after the start codon, AUG. Locate the codon in any standard table of codons--one is available on the Web at http://www.cbc. med.umn.edu/~mwd/cell_www/chapter2/codon_table.html--and you'll see that it corresponds to an amino acid. Stop decoding when you reach the stop codon, UAA.
For example, the first codon after the start codon is GCC, which corresponds to alanine, abbreviated by the letter A. This is the first letter of the message; the rest of the sequence is decoded codon by codon.
[Photo by Clark Eid ]
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