Can You Boost Your Memory?

On average, if you're male, your life expectancy is likely to be shorter than if you're female, and some diseases seem to affect one sex more commonly than the other. So can the humble fly tell us why? Jenny Regan explained to Chris Smith why she thinks it can...

珍妮,在研究老化,真正的东西y sticks out is that females live longer than males. In addition to this, when we did some manipulations that could extend lifespan, there are some manipulations that extend female lifespan very well but don't do anything for males. Specifically, the one that we were interested in is putting animals on a diet. This can really extend the lifespan of females but males derive much less benefit from being on a diet than females do.

Chris - So how did you pursue that?

Jenny - We used the fruit fly (drosophila). What we actually started out doing was switching sex in various tissues. To do this we took advantage of something that is particular to drosophila biology, which is that each cell individually specifies it's own sex. So we could harness this particular feature to switch sex just in specific cell types or specific tissues around the fly and we wanted to see if having a female organ in a male fly would be able to let the males get this lifespan extension that the females get in response to diet.

Chris - So what organ did you do this sex switching on?

Jenny - We looked at the liver analogue, we looked in blood, we looked in brain, and finally we looked at the gut and when we feminised the male gut and put these flies on a diet, what we saw was that the males then responded to being on a diet and their lifespan was extended.

Chris - If one studies the natural history of ageing in these flies (males versus females) and you look specifically at the gut, are there clear differences in what happens in the males and what happens in females as they age in that organ?

Jenny - Yes there is, and this is something that we did in parallel. We started to look at the guts of ageing males and ageing females and when we started out we expected that we might see males had worse guts than females because males are shorter lived than females but, actually, what we found was that male guts are really well preserved as they age and this is in real contrast to females. And when we looked at females over ageing, we saw a real spectacular decline. So we saw wounds appearing in the gut and we saw small tumours appearing in the gut as well.

Chris - Can you explain why, therefore, on the basis of your observations you see this difference between how long males live and how long females live and why calorie restriction makes a difference?

Jenny - When we looked at female guts, females who had been on a diet actually had better guts than females who had been fed a full compliment of food, and so those restricted diet females had fewer small tumours and few wounds in their guts so it looked like they were really better off from being on a diet. So, we started to understand that perhaps this difference that people observed for the last few decades, might be explained by the fact that the guts respond very differently, i.e. the males don't really get much of a benefit from being on a diet, whereas the females do.

Chris - What is it about the female biology that means that their gut benefits in this way that the males don't?

珍妮的女性,他们真的蛋马基nes, especially towards the earlier part of their lifespan they're laying hundreds of eggs a day, so it's really important for them to be able to get as much nutrition from food as possible. And some related studies recently have shown that females can grow their guts spectacularly when they're required to do so by the demands of egg production so it seems that females have more of a reason to have active stem cells in their gut. It also is true that females, when their guts are challenged by an infection, their guts responds much more than males in the sense that they repair their gut faster or they switch on stem cells to actively divide more than males do and we think this is probably the root of the difference we see in the male.

Chris - It's not that their gut lets them down, it's something else that's making them age and die prematurely compared with the females, and if you sorted out the guts in the females, they would live even longer?

Jenny - Yes, absolutely. For females, the gut and the deterioration of the gut is really important, but for the males it looks like something else is important and we think that this could be they don't respond as well to microbial challenge. So this could be something which is more of an issue for males than it is for females.

Origami, the ancient art of paper folding, is popular all over the world as a way ofrelaxing or expressing creativity. But a new type of origami which is making waves in science celebrates its 10th anniversary this year - Georgia Mills has the story...

Georgia - Scientists in Cambridge are currently using origami to make structures which could change the face of drug delivery. There's just one twist - it's not paper they're using...

Kerstin - We are assembling DNA into arbitrary two and three dimensional shapes on the nanoscale. So we are literally building with the building blocks of nature, so to speak.

格鲁吉亚——这是Kerstin Goepfrich谁工作啊n this technique at the Cavendish Lab in Cambridge and she kindly agreed to show me around. But first, I wanted to know why anyone would want to use DNA to build with...

Kerstin - What makes DNA a good building structure is, first of all, it's availability. It's safe to use, you get it everywhere; it's very cheap and it's very easy to process; it's quite stable and we can programme it's assembly and that's, of course, the big plus. You can programme assembly with near atomic precision. So how do you fold a piece of DNA?

Let me take out a piece of velcro tape actually, because I really like to use that for illustration. So imagine, you had a long piece of velcro tape which is basically a long single strand of DNA - it's very floppy. But now, imagine you had a short piece of DNA (a short piece of velcro tape) which matches the long one at one side and say at a distant end. By doing that, you can pull the long piece together and now you've got something like a loop just made from velcro tape. Now with many short pieces of velcro tape you could, essentially, fold the long piece up into any shape and here this is a bit, broken, but you will see you can make a flower or a clove by attaching a few pieces of velcro tape together and this is exactly how DNA origami works. You take a long single strand of DNA and fold it up using short pieces, which we call staples.

格鲁吉亚——形成DNA的四个字母(A、T、Gand C), they like to stick to one another. G always stick to C and A always sticks to T, and these are known as the base pairs. So if you use this knowledge, you can design sections of the DNA strand that will always like to stick to one another and this would make the DNA automatically fold up on itself which can be used to build any structure you like. So, if I wanted to fold some DNA into the origami classic shape of a crane, how would I go about it?

Kerstin - Today you just go online, you download a programme which is actually available for free and this programme is just a 3D drawing software so you literally draw the shape you want. So, you can literally draw a single strand of DNA and then it appears in the 3D view...

Georgia - Once Kirsten has drawn the right shape, she sends off the specifications to a company who then synthesise the DNA with the right pattern of base pairs needed. They then send it back to her in a small white box which can then be processed in the lab...

Kirsten - This is the DNA room and, as you can see, it's not very exciting. There are lots of fridges and freezers, which we use to store the DNA, and I will go to one of those now and I'll show you the little box in which the DNA comes...

让我看看…在这里。在每一个wells here we've got one DNA sequence and now we can take a pipette and we would use this pipette to mix all the difference sequences together, essentially...

Georgia - This is like no pipette I've ever seen.

Kirsten - Oh, this has 12 tips so that you don't have to do them one by one, we just get 12 at the same time.

Georgia - You're so busy here you need 12 in 1 pipettes?

Kirsten - Yes. We don't have a pipetting robot yet! So, once we've mixed all the bits and pieces of DNA together, we put them in a small tube like this one here and then we put them into this machine, which looks fancy, but all it is an oven. It's called a 'thermocycler' but it just heats the DNA up, cools it down slowly and then as it cools down it forms the predesigned shape.

Georgia - Why does heating it up and cooling it down help the individual strands form into whatever shape you've made?

Kirsten - You just give it a bit of energy so that when the DNA is already coiled up a bit it can straighten out and by cooling it down, you allow the DNA double helices to form.

Georgia - After seeing the lab I was satisfied I knew roughly how to make a DNA crane. What I wasn't clear on was why anyone would want to do this...

柯尔斯顿——这是一个很好的例子which might seem like art and a scientist playing around can be transformed into something real and into something which does have applications in the real world. So, it is simply a way of assembling atoms with near atomic precision and, in my lab, we're using DNA origami to make small channels or pipes which can punch holes into membranes and into the envelope which surrounds the cell, and we are doing that because 50% of the drugs that we currently use target channels in cells. So just imagine what you could do if you could could create artificial channels exactly the way you want them.

Georgia - So it will be a way of drug delivery?

Kirsten - It could be a way of drug delivery. It could be a way of simply understanding the process which is really fundamental in biology, namely the way cells communicate.

Georgia - As well as potential medical applications, the technique has also be used to build tiny basic computers and also nanoscale rulers. And, while paper origami is hundreds of years old, DNA origami celebrates it's tenth birthday this year. So new possibilities for applications are still being dreamt up and, as far as Kirsten is concerned, the sky's the limit.

Kirsten - I think one day origami might even save a life which is what paper origami artist Robert Lange once said. One day I hope the same may be true for DNA origami in a way.

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How we form memories is a complicated system as many different things can disturbthe process, from drug use to emotional state. But there's one thing that we now know is critically important for memory, and that is sleep. Connie Orbach went to meet Dr Matt Jones in Bristol to find out more...

Connie - It sounds quite other worldly doesn't it? Well actually, this is the sound of our brain's orchestra. It's the patterns of activity of different parts of our brains as we sleep, whirring away, organising, filing, sorting our memories and it was recorded by Dr Matt Jones' team at the University of Bristol...

马特-好的,睡眠很有趣的东西,因为我们10d to equate it, of course, with rest but, in fact, parts of the brain are more active during sleep than they are during wakefulness. In particular, a part of the brain called the hippocampus, which is a central hub for integrating learning and memory, becomes very active during certain phases of sleep. As you probably know, human sleep is subdivided into non-REM (non-rapid eye movement) sleep, sometimes called slow wave sleep and REM (rapid eye movement) sleep, and these different phases are associated with different types (patterns) of hippocampal activity. Now the hippocampus is activated during wakefulness, so neurons in the hippocampus, for example, code information about new places that we visit and is then reactivated during subsequent sleep when those neurons that encoded new memories come to life again. So you replay your waking experience whilst you're offline during sleep and it's this process which is thought to support the strengthening of memories, the sourcing of memories: kind of sorting the wheat from the chaff - which things we need to remember, which things are less important and can, therefore, afford to forget.

Connie - Wow. So parts of the hippocampus are being activated specifically by location as we're moving around and then, as we sleep, we're literally replaying that in exactly the same order of brain cell activation, as it was in the day?

Matt - That's right. We're replaying those patterns of activity that encoded new memories during the day but we're doing it at a different time scale. So, in fact, the patterns of activity that are replayed during sleep are replayed on a compressed time scale (about 10 times faster than they were during wakefulness), and that short time scale activity is thought to be important for driving changes in the strength of connections between brain cells that cooperatively encode these memories. Now we know it's important for memory function because, if you disrupt that replay activity, then you slow formation of memories.

Connie - So is that all that's happening at this level of hippocampus play cells or is there more than that?

马特-所以,不一个神经元,而不是大脑结构island and the hippocampus has to share all this information it's laying down memory with other parts of the brain. For example, certain parts of our environment might be particularly rewarding. So, if you wander down a new corridor and stumble upon a big pile of chocolates and think woohoo!, then dopamine signalling in the midbrain, for example, is activated and that dopamine signaling is also replayed during subsequent sleep in a way that coordinates with the hippocampus. That might, for example, enable the brain selectively strengthen particularly important memories about chocolate. Similarly, we know that over time as memories mature, then they're integrated into other parts of the brain beyond the hippocampus into the neocortex, for example. So the neocortex is important for storing memories long term and that integration of memories across the hippocampal system and the neocortical system is supported by coordinated activity during sleep. We suspect that the way the brain deals with this is to brain waves or neural oscillations as a kind of clocking mechanism to coordinate activity. The brainwaves are acting almost like the conductor of an orchestra so the hippocampus, when we're asleep, doesn't necessarily know when to do its stuff and the neocortex is being told when to do its stuff by external stimuli. So instead, we have this internal conductor mechanism (these slow waves), which modulate the time of the hippocampal activity and the timing of the cortical activity and, therefore, bring the two into line allowing the hippocampus to tune in to the neocortex and vise versa.

Connie - In the day, we're processing information and our brain cells in the hippocampus are firing, dependent on specific things that are happening. At night, we're then recoding that at a quicker pace to give us a strong memory and that's happening whilst we're asleep. But on top of all of that are our hippocampus needs to go talking to other parts of the brain to link all of these bits of information and, in order for it to know when to do that, we've got these huge ripples of brainwave activity which are giving it a second by second, like a conductor coordination, telling it where to go.

Matt - That's exactly right... yes.

Connie - Wow! That sounds incredibly complicated but amazing. It sounds really awe inspiring, I think, is probably where I want to go with that.

Awe inspiring indeed. I just can't get over the complicated patterns of activity that are happening through our brains all the time. It's so much more than I can even... take in. Maybe I should be giving sleep a bit more credit.

Unless you have been under a rock for the past few years you may have notice anincreasing obsession with Apps that promise to "train your brain" with a series of different task. These Apps usually come with a price tag but are they worth shelling out for? Dr Adam Hampshire from Imperial College London joined Georgia Mills to explain what these apps aim to do...

Adam - Researchers have been working on a variety of approaches to cognitive training that are being applied in these sorts of apps. Now one of the most popular areas of research focuses on trying to increase what psychologists refer to as working memory capacity. This is essentially how much information a person can actively hold and process in mind. So the idea there is that through exercises capacity could be increase, rather like if you slop more RAM into your computer. Now there are simple and complex variants on this theme, for example, one might be asked to hold sequences of numbers, images, or spatial locations in mind across some delay. So, I make say to you, for example, repeat the sequence 1893574. In more complex working memory training, there may be distracting stimuli or multiple different tasks that a person has to try and perform at the same time. Now, as you practice and get good at the task, you get better at it and the difficulty level is increased. So the idea is it's a little bit like going to the gym and upping the level.

Georgia - I've had a go at a couple of these games myself and they're quite fun but is there any evidence that they actually do anything?

Adam - Well, that's actually a very controversial question. So a major problem is that there are many poorly validated products out there on the market. Now the aim with that type of training is exercise and improve core working memory capacity but, of course, anyone can practice and get good at a specific task - that's just learning. If it's going to be useful, the training really needs to lead general improvements that extend beyond the training task itself and for the most part, the products that are out there and are available haven't really been validated properly in that latter respect. I've got a bit of a unique perspective on this question actually, because I've been involved in research that show positive and null findings.

For example, a few years back I was involved in one study in which we tried to cognitively train around about 11,000 individuals using the type of training that was being made commercially available and we found participants got good at the train task but they showed no generalised improvements whatsoever. However, subsequently, when we we tracked and trained older adults using the same tests, we found that there were generalised improvements and this data was published just last year. So to my mind, that study's actually some of the best evidence to date that cognitive training can sometimes have generalised benefits. A sort of take home message there really is that certain forms of cognitive training may help certain populations but that said, training in young healthy adults, it might just not work. But, on the other hand, it may perhaps be possible to try and slow memory decline in older adults. That area is really very active in research at the moment.

Georgia - So to sum up, these games for someone like me, I might do a sudoku every single day - I'm going to get super, super good at sudoku but my memory and my maths and things like that - I'm not going to see an improvement, but you have found this kind of improvement in some select proportions of the population. So, should be spending my time just playing a fun computer game instead?

Adam - Well that's actually quite an interesting question in itself. So I've run a number of studies where I've just screened large scale cohorts from the general population and, funnily enough, I found that individuals who say they do brain training, presumably with commercial packages, show no advantage whatsoever. Individuals who say they play normal computer games tend to be a little bit better in terms of their working memory and reasoning ability. So, of course, that's just a large scale cross section cohort study. We can't infer cause and effect relationships from that type of data but it's quite interesting. It all goes against the zeitgeist that brain training is good and other computer games are perhaps somehow bad. I think it's a promising area of research at any rate.