The Clock Gene

This September, Jeffrey Hall, Michael Rosbash and Michael Young won the Nobel Prize for medicine for their addition to the work begun in 1971 on circadian rhythm within organisms; providing an excuse for millions of teenagers worldwide to why it is physically impossible for us to get out of bed before 11am.

Circadian rhythm is present in almost every human cell; influencing mood, metabolism, and hormone levels to name a few. The work of Hall, Rosbach and Young began with isolation of the “period gene” –per- found on the X chromosome in Drosophilia. This gene undergoes 24hour cyclical transcription forming the PER protein. PER and a second protein TIMELESS dimerise and translocate into the nucleus, inhibiting transcription factors, thus producing a negative feedback loop. The result of this is a decrease in per and timeless mRNA levels and the corresponding protein expression. In the absence of TIMELESS, the protein DOUBLETIME (also discovered by the American trio) phosphorylates PER for degradation. Hall, Rosbach and Young have shown that the stabilisation of PER by TIMELESS and DOUBLETIME results in the body clock slowing; conversely, reduced stability causes the clock to speed up.

Advanced sleep phase syndrome (ASPD) is a disorder of circadian rhythm sleep in which those affected sleep between 7pm and 4am typically. Those with ASPD have decreased stability from a PER-TIMELESS dimer, and their body clock cycles more rapidly with the deepest sleep stage peaking earlier than normal (2am). This means that the body clock control via per is aligned differently to the normal circadian rhythm. Research has shown that it is a profound problem for the elderly, not as prevalent in the young- can you see where this is going..? Dr Russel Foster from the University of Oxford had previously postulated that due to hormone levels within teenagers and young adults, PER is stabilised and the body clock slows, so the deepest sleep stage is delayed and teenagers are “programmed” to rise later. Foster’s work provided some of the first supported reasoning for teenagers’ late rising.

More damaging conditions are predicted to be linked to circadian rhythm, including the association between cancer and shift work via the decreased action of melatonin at night time. Melatonin is believed to “mop up” reactive oxygen species which induce damage to cells. On the flip side, understanding of circadian rhythm will allow optimisation of drug delivery to tie-in with other organ systems and processes. For example drugs like blood pressure drugs administered as blood pressure peaks at varying points in the circadian rhythm.

The “clock gene” is said to be inherited, leaving you in luck if you’re part of a family of early risers. Meanwhile I’m still holding out for those of us who are neither early birds, nor night owls, but fill the niche of permanently exhausted pigeon.