Cir­ca­dian rhythm based on DNA

The Prince George Citizen - - FRONT PAGE -

We are crea­tures of pat­tern. We en­gage in cer­tain ac­tiv­i­ties at the same time each year. We have rhythms that run through the weeks and months of our lives. But per­haps most im­por­tantly, we have a daily cy­cle which con­trols much of what we do. Our in­ner clock helps us to ne­go­ti­ate our daily lives. It tells us when to get up, when to sleep, when to eat, and when to be most active. This cir­ca­dian rhythm pro­vides the back­ground to our lives. In­deed, ev­ery crea­ture – from the small­est mi­crobe to mighty red­woods and blue whales – has some form of in­ter­nal clock fol­low­ing a cir­ca­dian rhythm.

With modern travel, we can even see how much we de­pend on our in­ter­nal clock ver­sus our sur­round­ings. Trav­el­ling from Prince Ge­orge to Lon­don re­sults in an eight hour time shift, but de­spite the sun­light, your body will be telling you it is time to sleep. It takes days for our rhythm to shift to the new pat­tern.

We each have our own in­ter­nal pat­terns, too. Some peo­ple are able to set their rhythms so they sleep in, but can last well into the night.

Oth­ers are early birds who are up with the dawn but are in bed by 9 p.m. ev­ery night. Some peo­ple are even true night owls and can com­fort­ably stay up all night while sleep­ing dur­ing the day. But how does this in­ter­nal clock work? What makes it tick? Jeffrey C. Hall, Michael Ros­bash, and Michael W. Young were awarded this year’s No­bel Prize in Phys­i­ol­ogy or Medicine for “their dis­cov­er­ies of the molec­u­lar mech­a­nisms con­trol­ling the cir­ca­dian rhythm.”

To be clear, while the award was given to these three dis­tin­guished and de­serv­ing sci­en­tists, study­ing cir­ca­dian rhythms in all crea­tures great and small has been a sci­en­tific pur­suit which dates back cen­turies and in­volves many sci­en­tists.

But it has only been in the last 50 years or so, with the dis­cov­ery of DNA, our un­der­stand­ing of genes, the elu­ci­da­tion of the mech­a­nisms for gene tran­scrip­tion and pro­tein pro­duc­tion, and an over­all un­der­stand­ing of life at the molec­u­lar level that bio­chemists have fi­nally been able to tease out some of the fun­da­men­tal de­tails.

In par­tic­u­lar, iden­ti­fi­ca­tion of a clock gene in­volved work on fruit flies. These an­noy­ing lit­tle crea­tures are prob­a­bly some of the most well stud­ied or­gan­isms on the planet. In the 1970s, Sey­mour Ben­zer and his stu­dent Ron­ald Konopka were at­tempt­ing to iso­late the fruit fly genes rel­e­vant to cir­ca­dian rhythms.

They iso­lated three mu­tant strains of fruit flies. One with a 19 hour day, one with a 28 hour day, and one with a ran­dom cy­cle.

The re­spec­tive length of each fly’s day had pro­found im­pacts upon its bod­ily func­tions and daily life. They were able to show these changes were the re­sult of dis­rup­tion in a sin­gle gene which they named “PE­RIOD.”

In 1984, Hall, Ros­bash, and Young were suc­cess­ful in iso­lat­ing the PE­RIOD gene.

Hall and Ros­bash went on to dis­cover the pro­tein pro­duced by the gene, which they called “PER,” ac­cu­mu­lated at night and was de­graded dur­ing the day. This os­cil­la­tion in the level of PER in our cells over a 24 hour cy­cle leads to the syn­chrony of our cir­ca­dian rhythm.

Like all good re­search, an­swers al­ways lead to more ques­tions. In this case, how did this pro­tein pro­duced in the cy­to­plasm ex­ert its con­trol in the nu­cleus? Their hy­poth­e­sis was a feed­back loop in which the PER pro­tein could pre­vent its own syn­the­sis by reg­u­lat­ing the ac­tiv­ity of the PE­RIOD. That is, once enough PER has been gen­er­ated, the gene is shut off un­til the level drops to a point where it is no longer in­hibit­ing ac­tiv­ity. At this point, the gene turns on again gen­er­at­ing more PER and around and around it goes.

While tan­ta­liz­ing, the model was miss­ing pieces. In par­tic­u­lar, while PER is con­structed in the cy­to­plasm it builds up in the nu­cleus dur­ing the night. As the nu­cleus is pro­tected from the rest of the cell by a mem­brane, how was this pro­tein get­ting through the bar­rier?

In 1994, Young dis­cov­ered a sec­ond clock gene which he named “TIME­LESS” ca­pa­ble of en­cod­ing a pro­tein called “TIM.” In an el­e­gant use of bio­chem­i­cal tech­niques, he was able to show TIM binds to PER and it is the two pro­teins to­gether which en­ter the cell mem­brane to con­trol PE­RIOD.

Of course, this ex­plains the mech­a­nism of con­trol, but not the fre­quency. That is con­trolled by another gene iden­ti­fied by Young called “DOUBLETIME” which en­codes for another pro­tein known as “DBT” which de­lays the ac­cu­mu­la­tion of PER.

It is these three genes and their pro­teins work­ing in syn­chrony which give rise to our cir­ca­dian rhythms.

The up­shot of this is if you are some­one who re­ally likes to sleep late, you can blame it on your genes.

HANDOUT FILE PHOTO BY THE CHI­NESE UNIVER­SITY OF HONG KONG

Jeffrey C. Hall, Michael Ros­bash and Michael W. Young give a lec­ture in Hong Kong on Sept. 24, 2013. The three Amer­i­cans won the No­bel Prize in Phys­i­ol­ogy or Medicine on Oct. 2 for their dis­cov­ery of the ge­netic ba­sis of the cir­ca­dian rhythm.

TODD WHITCOMBE

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