Tuesday, 27 March 2012

Shedding Light on Body Clocks & Brains

Last week, on a sunny Friday afternoon I was in the basement of a UCL building performing my first public talk on my PhD and the effect of light on body clocks. This was the last session of Bite-sized lunchtime lectures this term, which allow early career researchers at UCL to talk about their research interests to the general public.

By the time I took to the stage the room had standing space only, a really successful turn-out. We even had a class of biology students from Norway! Apparently, my nerves were only noticable when I held the 96-well plate and you could see my hands shaking. Quite lucky really, as I felt like I was shaking like a leaf the entire way through.

After the presentation I got some really good questions, which I will re-type up here for everyone's benefit.

A huge thank you to the Bite-sized team for their help and feedback: Hilary, Kim, Laura and Matthew. Thank you also to Simon, who had to hear the presentation a few too many times! Thanks also to those who came and supported me.

And for those of you who missed it, or want to see it again, here it is:

0:00 Intro to talk
1:44 Chronotherapy - asthma & cancer
2:36 How body clocks work
4:35 Using light to help our body clocks
6:25 Zebrafish - development, regeneration and cancer research
7:44 My PhD research
9:40 Glowing zebrafish
10:34 Rhythms in light sensitive zebrafish brains
11:49 Conclusion

Questions - please feel free to ask more in the comments section below

As rats are nocturnal, how does testing drugs on them during the day effect them?
This is a really important point. Not all drugs are effected by time of day, but a lot of them are, and unfortunately a lot of pharmaceutical companies only test for drug effects (and side effects) during the day, which is the rat's sleeping time, not during the dark phase, when the rat's are more active. So the results are be more aligned with giving humans drugs during the night, which happens less frequently.

A few drugs have been deemed to toxic when trialled during the day, when they can be less toxic and effective during the night, and so we are losing drug candidates.

Does period3 have any other role in the zebrafish?
Period3 is a gene that signals time of day information throughout the cell, we don't know of any other role it is playing in the cell.

How did you measure gene expression, when you weren't doing the bioluminescent recording?
Good question. I mushed up the brain, to break all the cells open, and allow access to the messenger RNA molecule. This is an intermediate molecule we can measure when the gene is being expressed into protein.

We can determine how much messenger RNA is in the brain by using qPCR, quantitative polymerase chain reaction. This effectively doubles the amount of the RNA exponentially until enough can be detected, and then we can work backwards and find out how much we had to begin with.

How long can a zebrafish brain stay in culture? Will it behave in culture the same as in the body?
That's a good point. I've kept zebrafish brain regions in culture for two weeks, and the rhythms are still strong, so I think they could go for longer without any change in media. Eventually, the nutrients in the media will get used up, and the waste products will build up and so the cells will die. However, biologists can keep cells alive for decades by replenishing the media and giving the cells space to grow.

Cells and brains and other tissue cultures won't necessarily be the same in culture as they are in the body, so we try where possible to examine rhythms in both.

If light exposure during the day is so important, should schools be getting students to spend more time outside and less inside in the classroom?
Sometimes staying indoors can't be avoided, and that's why using effective lighting indoors is important. However, where possible everyone should try and spend enough time outdoors, from young people to the elderly.

How long is enough time outside?
It can vary from person to person, and on the time of year, but as a rough estimate I would aim for a couple of hours.

Is this also effective for jet lag?
Yes, light in the morning of your destination will help you synchronise to the new time zone quickly. A bike ride in the morning has been shown to be most effective, perhaps not what you really want to do to recover from a 12 hour flight, but you'll thank me later.

What does this light research mean for people with disabilities/limited vision?
The cells in the eye that are responding to this blue light are actually not the rods or cones or cells commonly associated with vision. So you can have blind people, who are visually blind, but not time blind. Their eyes can still use light to synchronise their body. Therefore, exposure to light is important for everyone including the disabled.


Enjoy this blog post? Check out my other posts from body clock related Bite-sized lunchtime talks:
Clocks make you fit, evolutionarily speaking and UCL researchers are mapping our happiness across the week

Monday, 12 March 2012

Is Daylight Savings costing us lives?

Next week, on Sunday March 25th, the clocks will spring forward an hour for Daylight Savings. Other than having an hour less in bed, and feeling a bit more sleepy in the week, can this have any other significant effect on our body clock? Can it cause you to have a heart attack?

Research published this year has looked at the effect of Daylight Savings on the number of people suffering acute myocardial infarctions (heart attacks) in Sweden [1].

Blood pressure is a component of the body clock, dipping low at night naturally. Heart attacks are far more likely to occur in the morning when your blood pressure is rising. Can altering the timing of the body clock by just one hour have such a profound effect on your heart as to cause a heart attack?

Heart attacks are linked to the body clock, being more likely to occur in the morning  © Grewlike

In 2008 the group showed that in the week following the transition into Daylight Savings the number of people going into hospital with heart attacks did increase [2]. In that study they analysed hospital admissions over 19 years, comparing the fortnight before with the fortnight afterwards.

In their latest study they repeated the analysis on data collected from 2007 from 74 hospitals, covering 95% of the coronary care admissions in Sweden. This data was more detailed, so they could find out who were more at risk.

As well as age and gender, there was information on other heart attack indicators such as cholesterol levels, BMI, smoking history, diabetes, high blood pressure, history of heart problems, other heart attacks etc.

When they analysed this new data, they observed the overall increase in heart attacks again. There were higher rates of heart attacks in the week following Daylight Savings. The increase measured was smaller than the first study, however still significant (and therefore still a risk).

More heart attacks occur in the week after entering Daylight Savings Time (DST) in the Spring © Janszky, 2008 

Those at higher risk in this Spring week included all those on preventative medication, including aspirin, calcium channel blockers and statins.

Remarkably, those who had a high cholesterol and high triglyceride (fat) levels seemed to have less heart attacks. This was unexpected, but the researchers point out that they have no information on the sleeping and activity levels of this group.

It could be those who are protected in this week are more sedentary, sleep more, and become less sleep deprived than the rest of the population. Further information on the link between sleep, the body clock and heart attacks could determine what advice can be given to those vulnerable of having a heart attack.

With 1.5 billion people (close to a fifth of the world's population) being influenced by Daylight Savings, a small increase in the number of heart attacks can have large ramifications. Governments, scientists and society really need to investigate their motives for having daylight savings.

In the meanwhile, take it easy next week!

Enjoy this blog post? Check out: Double Summertime: Double trouble? and Using time of day to reduce heart damage in breast cancer treatment

[1] Janszky, I., et al. (2012). Daylight saving time shifts and incidence of acute myocardial infarction - Swedish Register of Information and Knowledge About Swedish Heart Intensive Care Admissions (RIKS-HIA). Sleep medicine. Elsevier B.V. doi:10.1016/j.sleep.2011.07.019

[2] Janszky, I., & Ljung, R. (2008). Shifts to and from daylight saving time and incidence of myocardial infarction. The New England Journal of Medicine, 359(18), 1966-8. doi:10.1056/NEJMc0807104

Friday, 9 March 2012

ADHD: Sleep and Body Clocks

Over 50% of adult attention deficit hyperactivity disorder (ADHD) sufferers report on-going sleep trouble, with 27% of suffers fitting the criteria for chronic insomnia [1]. In the past few years several studies have looked at the relationship between sleep, the body clock and ADHD. Does ADHD cause sleep problems? What can be done to help?

There are many ways to monitor rhythms in human body clocks. We can look at an individual's sleeping patterns, their hormone levels, and even their genes. We've already mentioned that sleeping problems are significantly linked to ADHD, but as we examine these other body clock markers we can see how deep the problem lies.

Cortisol, the stress hormone, is released at higher intensities in the night (see post on asthma). In ADHD patients whilst they maintain a daily rhythm in cortisol, the peak shifts to later in the day, effecting their sleep at night.

The rhythm in cortisol occurs later in ADHD patients (C) Baird et al 2011

Some of the clock genes, which are used to signal time of day information throughout all the cells in the body, were also found to not be functioning at all in the ADHD patients tested [2].

All this evidence combined shows that it is not just sleep that is a problem with ADHD, but there are underlying issues with a dysfunctional body clock. In fact, the more severe ADHD rating a patient had, the weaker their body clock rhythms were.

Melatonin is a hormone that is released at night, induces sleepiness, and communicates time of day information around the body. Melatonin is produced much later in chronic insomniac ADHD sufferers who stay awake at night.

Luckily, melatonin can be taken as a pill (it is often used to help overcome jet-lag). When taken at the correct dosage and time of day, melatonin can fix broken body clocks and improve sleep patterns.

Melatonin, a sleep-inducing hormone, is being used in trials to treat insomnia in ADHD (C) 

A few small trials have reported significant benefits in using melatonin to treat insomnia in ADHD sufferers. In one trial with approx 100 children, after 3 years, 88% recorded improved sleep at night. They were also able to perform better during the day, both mentally and physically [3].

Daily melatonin intake led to no serious side effects in this trial. However, only 9% could stop the melatonin treatment without reverting back to suffering insomnia, so the treatment needs to be continued long term.

Parents' responses after a 3 year follow up when using melatonin to treat ADHD (C) Hoebert 2009 

Melatonin is one method to realign a person's internal body clock to the external day, and is showing positive benefits in ADHD sufferers day to day lives. With the amounting evidence of the relationship between ADHD and a broken body clock there will hopefully be trials conducted in adult ADHD patients and more treatments available.

Please note, I am not a medical doctor and cannot advise ADHD patients on melatonin treatment. However I would love to hear from you if you have ADHD and sleep problems. Please write in the comments box below.

Enjoy this blog post? You may want to check out Nocturnal Asthma or Around the Clock Doc.

[1] Coogan, A N. et al (2012). Adult attention deficit hyperactivity disorder: translating research into practice. Attention deficit and hyperactivity disorders, 41-51. doi:10.1007/s12402-012-0073-7

[2] Baird AL, et al (2011) Adult attention-deficit hyperactivity disorder is associated with alterations in circadian rhythms at the behavioural, endocrine and molecular levels. Mol Psychiatr. doi:10.1038/mp.2011.149

[3] Hoebert M, et al (2009) Long-term follow-up of melatonin treatment in children with ADHD and chronic sleep onset insomnia. J Pineal Res 47(1):1–7. doi:10.1111/j.1600-079X.2009.00681.x

Thursday, 1 March 2012

Sleepless Bees

Human babies need a lot of sleep, but as they grow older their body clocks and sleeping habits will change. Other animals also change their body clocks with age. One extreme example is the Honey Bee, Apis mellifera.

The phrase "busy as a bee" is truly deserved in these youngsters. At only 3 days old the infertile females are put to work as "nurse" bees. They feed larvae and are active around the clock without any sleep - for 9 days!

Brains of nurse and forager honey bees were examined for daily rhythms in gene expression (C) Goshzilla Dann, 2008

The infertile honey bee females go through several roles in their lifetime. At 11 days the nurse bees will mature into different worker roles in the hive. At 3 weeks old they become "foragers" with highly rhythmic behaviour: pollen hunting during the day and sleeping at night.

A recent study has looked at the genetics behind the body clocks of the honey bee [1]. They compared the levels of gene expression in the non-rhythmic nurses with the rhythmic foragers. Were there any rhythms remaining in the nurses?

Nurse bees work around the clock without sleep for 9 days (C) Max

The genetic analysis showed that whilst 4% of genes were rhythmic in the foragers brains, only 1.5% were in nurses. Genes in the visual system and the core clock genes did not oscillate in the nurses. However, there were genes involved in energy metabolism that remained rhythmic.

When nurses were taken away from their hive and isolated, they became diurnally rhythmic, being more active during the day. This suggests that their working-around-the-clock behaviour is in part due to their hive environment or association with other bees. However, there are still some underlying rhythms in the nurses that aren't lost even when their behaviour is arrhythmic.

When the nurse bees grow older they take on different roles, as foragers they are highly rhythmic (C) JR Guillaumin

The honey bee represents a useful animal to understand how body clocks can change with age. Like cavefish they show how a body clock can tick quietly in the background. However, I won't be attempting to stay awake for 9 days straight to test this directly!

Enjoy this post? You might also like Old Fruit Flies and Broken Body Clocks and Young or old: who can stay awake better at the wheel?

[1] Rodriguez-Zas, S. L., et al. (2012). Microarray analysis of natural socially regulated plasticity in circadian rhythms of honey bees. Journal of Biological Rhythms, 27(1), 12-24. doi:10.1177/0748730411431404