Our 2019 magazine is now available to download if you’ve lost your glossy printed copy. Read interviews, meeting reviews and more.
At the BSCB/BSDB joint Spring meeting in Warwick last month, we announced the winner of our Science Writing Prize as Laura Hankins from the University of Oxford. You can now read her fabulous winning entry, together with a little about Laura here. Details about the competition and links to previous winners can also be found here.
Keeping Everything in Proportion: why cell size must be kept under control
Our bodies contain around 37 trillion cells that come in all shapes and sizes, from rotund fat cells to the cells that line our organs and resemble microscopic paving slabs. However, if you focus on one particular cell type, cell size is remarkably consistent across the population. This narrow distribution suggests that it is important to control the size of our cells, just as it is crucial to regulate our internal body temperature. Now, a study published in Cell may provide insights into why size seems to matter so much.
The range of sizes exhibited in a healthy population of one specific cell type is generally narrow. If, like me, you’ve ever wondered why you can’t quite reach the top shelf of the cupboard whilst others can access the biscuit stash with ease, it’s generally because those taller office mates have produced more cells, rather than grown larger ones like some human Michelin man. In fact, changes to cell size are associated with several diseases; cancer cells may be smaller than their peers. Maintaining a consistent cell size therefore seems to be important, although it is unclear why.
In the lab, it is possible to perturb cell size by preventing cells from dividing. Cell division is the process of one cell splitting to produce two daughter cells, thus allowing the population of cells to proliferate. This proliferation is the main reason that co-worker Geoff developed long enough arms to consistently swipe the custard creams. Cells usually increase in size before dividing, to ensure the two new cells inherit the sufficient cellular machinery to survive. It’s rather like lovingly preparing a toolkit for your kids when they leave home, readying them to face their first leaking roof. If you block division, either by applying drugs or by mutating proteins involved in cell cycle progression, cells may grow without being able to split in two.
A recent report published in Cell has taken advantage of this approach to investigate why regulating cell size is important . Researchers prevented yeast cells from dividing by mutating a key cell cycle protein. With the brakes on cell division applied, the cells started to swell, but were unable to divide or to initiate DNA replication. This erroneous growth led to problems; the scientists found that, once the brake was released, the now engorged cells progressed through the cell cycle slower than their smaller counterparts.
To explore why this might be happening, the team measured how the cell volume and the total protein content of these arrested cells changed as they grew. They found that, initially, protein levels increased at the same rate that cell volume did – the two processes were neck-and-neck. However, there came a point where the cells became so large that their volume was increasing faster than their protein levels. Somehow, protein production became unable to keep pace with the ballooning cell size. This could result in the dilution of the cell’s proteins, presumably affecting reaction rates. Imagine you and your friends are placed in a room, blindfolded, and have to walk silently until you find each other. You would locate each other faster in a cupboard than you would in a sports hall. Similarly, diluting proteins out in a larger cell makes them less likely to interact with their reaction partners, perhaps explaining the larger cells’ slower pace of life.
But what caused protein production rates to fall behind cell growth rate in the first place? Primarily, it was somehow due to DNA levels becoming limiting as cell volume increased. When the researchers doubled the yeast cells’ DNA content, the cells managed to grow to a larger size before the onset of protein dilution; in other words, their protein production rate was able to scale with their growth rate for a longer period of time.
This issue of scaling has been considered before. Cells are composed of several subunits called ‘organelles’, all performing different roles, including protein production. Some of these organelles are able to ‘scale’ to the size of the cell; that is, as the cell grows, the organelles also grow at a similar rate. Like the popular children’s toys that expand evenly when immersed in water, multiple parts of the cell may therefore grow proportionately. This type of growth is known as ‘isometric’. One famous example of an organelle that grows isometrically with the cell is the nucleus.
However, an increase in organelle size does not always correspond to an increase in organelle performance. Mitochondria are, of course, the organelle that launched a thousand memes, with most students knowing them as ‘the powerhouse of the cell’. There is a good reason for this accolade; mitochondria produce ATP, a molecule used as an energy source to drive many of the cell’s chemical reactions. It has been shown that the number of mitochondria increases with cell volume. However, their optimum rate of activity is only achieved in cells of an intermediate size. Similarly, this latest study has demonstrated that rate of protein production does not scale with cell size once the DNA to cytoplasm ratio becomes too low. Ultimately, there might be an optimal cell size at which this ratio is appropriate to support adequate protein production.
This optimal size may explain why cells become senescent (a state reached when older cells become unable to continue dividing as normal). These ageing cells are larger than their younger neighbours, due to accumulated errors from past cell divisions. The researchers found that old yeast cells behaved like the large ones they had artificially created. They even showed that enlarging human fibroblast cells made them more likely to become senescent and stop dividing. This raises the possibility that cells enter senescence once their size increases to suboptimal levels.
In beginning to uncover why cell size control is so important, this study raises implications for our health when this regulation goes wrong. But the key take-home? Well, always remember to keep things in proportion.
 Neurohr, Gabriel E., et al. “Excessive Cell Growth Causes Cytoplasm Dilution and Contributes to Senescence.” Cell (2019).
About the author: Having completed a BA in Biological Sciences at the University of Oxford, Laura Hankins stayed on in the city to take up a place on the Wellcome Trust’s Chromosome and Developmental Biology DPhil programme. A graduate student at Merton College, she is now in the third year of her PhD in Jordan Raff’s lab, where she is studying the process of centriole biogenesis as a model to understand how organelle growth is regulated.
Comments from our judge, Dr Jennifer Rohn (@JennyRohn) on the winner of the 2019 competition: The topic was a very abstract, hard-to-describe bit of science that was brought to life and made relevant with some beautiful writing.
Of Monsters and Genes: using AAV as a tool in the fight against childhood blindness
For many, the mundane act of tucking your child into bed at night can present as quite an ordeal. Settle them down, get them in their PJs, check the wardrobe for monsters, read a bedtime story, check for monsters again, lights out. This issue of monsters needs to be taken seriously: even with some tactically placed night-lights, and a NERF gun at the ready, sometimes darkness and the supernatural prevail and the parental bed gains an extra guest for the night. Thankfully, most of us outgrow our negative relationship with the dark, but for some children, these nights are only the beginning.
Children living with Usher syndrome never escape the darkness. For them, darkness only grows with time. Nights become blacker as they lose all ability to see below certain light levels. Those night lights and NERF guns may as well be gone as objects become harder to make out. Eventually, the darkness begins to visit them during the daytime as they see their peripheral vision close in, tendrils of blackness creeping in from every angle.
Thankfully, Usher syndrome is extremely rare, affecting approximately one in 10,000 people. In addition to the gradual onset of blindness, sufferers are also deaf from birth, which can immensely impact their abilities to learn and communicate. Usher syndrome is a genetic disease, which can be caused by a mutation in a gene called CDH23. There are currently no treatments or cures, which is leading researchers to explore some inventive approaches, such as gene therapy.
Much like changing a flat tyre on your car, the premise of gene therapy is simple: if a gene is broken, provide the cell with a new one that works. Despite this, these days it’s clear that achieving successful gene therapy is perhaps more akin to rolling a tyre down an assault course with fire pits and swinging axes and hoping that when it gets to the car, it has the manners to hop onto the axel itself.
While difficult, there are still ways to make the process of throwing genes at cells a little more elegant. For starters, targeting areas of the body that you can reach with a needle (e.g the eyes) substantially reduces the number of swinging axes our new genes come up against. Using biological tools which can stand in for qualified mechanics can also make the end switch much more possible. Enter viruses.
Viruses are fascinating objects of nature. In many cases, consisting of just some genetic information and a protein coat, viruses roam the expanses that are our bodies, seeking cells that they can hijack for their own nefarious needs. Viruses enter cells and take over their machinery, convincing them to read the viral genes as if they were the cell’s own. This means that cells are tricked into producing and assembling a new generation of viruses, each ready to head off and find their own cellular fools.
While viruses can be troublesome and, in some cases, deadly, the traits that make them great biological spies are exactly the traits that make them outstanding tools for gene therapy. By cleverly switching out some of the key genes for making viruses, and replacing them with, say, CDH23, we can in one quick motion remove the ability of the virus to cause harm and prime it for repairing our broken eye cells.
One of the more popular viruses used today is called ‘adeno-associated virus’ or ‘AAV’. AAV is a great gene therapy virus because it’s extremely safe and can infect cells that aren’t dividing – like many of the cells in our eyes. One unfortunate drawback of AAV is that it’s so tiny. Clearly, all viruses are tiny, but AAV dwarfs many of these by a long way. AAV has a genome length of just 5,000 base pairs. This means that of all those As, Gs, Cs, and Ts that code for our genes, there are only 5,000 in a line from start to finish. To put that in perspective, that’s 25x smaller than say, the chicken pox virus genome, or 600,000x smaller than the genome of humans. Unfortunately, this means that not only can you not fit many genes inside of AAV, but some genes won’t fit at all. This includes the Usher syndrome gene, CDH23, which is 10,100 base pairs long.
The scientists behind a recent study published in Cell have valiantly taken this problem on. They reason that if a gene won’t fit into a virus’s shell, then why not chop it into pieces? Imagine a family of very tall people all trying to fit into the same Mini. If there’s not enough legroom to go around, it makes much more sense to take separate cars. In the same vein, researchers took the CDH23 gene, and placed it into three separate AAV vectors.
The key to making this work was finding a way to get the three gene pieces to assemble back together again once inside the cell. This involved flanking each gene piece with special ‘recombinogenic’ and ‘splicing’ sequences. The recombinogenic sequences are used for the sticking; like two Velcro pads at either end of a piece of fabric, the cell uses these sequences to assemble the gene into one. However, this leaves rough sequences in the middle of the gene, making it impossible to read. This is where the splice sites come in. These sequences tell the cell to chop out the intervening recombination parts, much like instructing someone to diligently sew together the Velcroed fabrics, leaving one uninterrupted, readable sequence.
The researchers showed that when these viruses were injected into the retinas of mice with the CDH23 mutation, levels of full-length CDH23 protein were shown to increase. Unfortunately, this system cannot show whether the increase is enough to reverse any of the effects of the disease.
This research hopefully provides some light at the end of the tunnel for children suffering from Usher’s. Maybe one day, AAV will be just another weapon in the fight against monsters in the dark.
About the Author: Alex Binks (@binknabel) is a final year PhD student at the University of Glasgow, currently completing the remainder of his studies on a secondment at Imperial College London, supervised by Prof Iain McNeish. Alex’s research revolves around oncolytic (“cancer-killing”) viruses and how the mechanisms of killing that these viruses employ can impact the immune system. Outside of the lab, Alex enjoys finding ways to engage the public with his science via articles and videos.
Comments from our judge on the 2018 competition: Our judge, Jenny Rohn, was impressed with the high quality of the entries this year. After a difficult decision, the prize went to Alex Binks, a PhD student from the University of Glasgow, for his essay entitled Of Monsters and Genes: using AAV as a tool in the fight against childhood blindness.
“Alex engages the reader straight away with a humorous sketch about how kids are afraid of the dark and what parents have to do to mitigate night terrors at bedtime,” Jenny says. “But then the tone shifts dramatically as he paints a haunting picture of what life is like for patients with Usher syndrome, ‘tendrils of blackness creeping in from every angle’ “.
The essay was also packed full of creative and humorous analogies to aid in comprehension of the science: gene therapy was likened to changing a flat tyre – in an assault course with fire pits and swinging axes – whereas packing a segmented genome into a virus particle was like trying to get a family of very tall people into a Mini. And along with the best essays, Alex’s piece ended full circle, echoing those monsters under the bed from the beginning.
Although not taking the prize, Jenny chuckled quite a bit over an essay about gingival scarring by Chris Smith, a PhD student from Barts and the London School of Medicine and Dentistry, which was penned entirely in rhyming couplets. Her favourite line? “Let’s examine the role of saliva/Strip it down like Lady Godiva”.
Many thanks to everyone who entered this year.
Did you guess what it was? Whether you were at the 2019 Spring Meeting in Warwick or not, you may not be able to guess the identity of the sample that produced this year’s first-prize winning image! All is now revealed: you can find out about the winning images and their creators here.
Thanks, as ever, to everyone who entered and supported this competition.
. New type of regional meeting run by PhD students and postdocs on careers and networking
. Scientific discussions can be part of the programme as long as the primary theme is career development
. Limited to £500 for ~0.5 day activity
. Preferable if BSCB members from more than 1 university are involved in running each meeting
. The meeting should be open to students and postdocs from across the UK
Prior to applying, we encourage potential applicants to contact the BSCB student and postdoc representatives (Joyce Yu, email@example.com and Gautam Dey, firstname.lastname@example.org to discuss their proposal.)
Exciting news for our members with artistic and literary talents! The deadlines for the BSCB Image Competition and Science Writing Prize will both be 20th February 2019. Both have generous cash prizes.
This is open to all of our members. This year, we would like particularly to encourage entries that show cells outside tissues and sub-cellular structures. Details of how to enter, image resolution, file types and the rules and regulations can be found here.
Science Writing Prize
The science writing prize is open to student and postdoctoral members only. More information can be found here.
If you don’t want to enter either competition yourself, but know someone who might be in with a chance, then please spread the word! The competitions are for members only, but brand new members are welcome to enter. Find out how to join the BSCB here!
For the second medal announcement this week, we are pleased to reveal Prof. Eugenia Piddini from the University of Bristol as the 2019 winner of the BSCB Hooke Medal. Read all about her work here.
The BSCB is delighted to announce that the winner of the Women in Cell Biology Medal for 2019 is Dr Pleasantine Mill from the MRC Human Genetics Unit, University of Edinburgh. You can read more here.
Breaking the unbreakable: Solving the problems of plastics and plants
We are addicted to plastics. They are used for everything, from food packaging to smart phones. But when we are done with them, they hang around for a long time, taking decades to decompose.
These hardy plastics aren’t just creating litter in cities and filling up landfills. They are harmful to wildlife, especially in the sea where animals can become entangled in the plastic or mistake it for food. The harm of a single piece of plastic can be long lasting since it takes so long to degrade. A striking example of this is the Great Pacific garbage patch which has formed from small bits of floating plastic that break into smaller and smaller pieces but haven’t fully degraded. Researchers have described ocean water taken from there as looking like a “snow globe” of plastic chips (1). Though we are developing biodegradable plastics and recycling is on the rise, there is still the question of what to do with the built up waste.
One way to solve this problem is by taking a cue from nature. Plants also developed an incredibly sturdy material many hundreds of millions of years ago. When plants evolved from water-based organisms to living on land, they had many new problems to adapt to: drying out in the air, withstanding UV from sunlight, and counteracting gravity. To be able to grow upwards, they evolved a new material – lignin. Lignin becomes embedded in the wall that surrounds plant cells and gives it rigidity, and is held together by strong bonds so it resists degradation. At the time lignin evolved, no living thing could break it apart. So why aren’t we surrounded by piles of un-decomposed trees?
We have bacteria and fungi to thank for that. Specifically, the kinds that have counter-evolved to break lignin apart. Mostly this job is done by the fungus, white rot. Cells make proteins called enzymes that can help bring molecules together or break them apart. For example, it is the enzyme lactase that breaks down the lactose in milk we drink into parts we can absorb for energy. Similarly, it was useful for fungi to be able to break lignin apart to get at the food stored in plants. Under this strong selection pressure, a fungus with an enzyme that could even partially break lignin apart would get more food and thrive. Every change that appeared that was a small step towards improving this enzyme would be an advantage for the fungus. Eventually, they evolved a special type of peroxidase enzymes that are particularly good at using reactive chemicals to attack the lignin structure.
So, plants invented an indestructible material and then fungi figured out how to digest it – can we do the same with plastics? Even though there is currently no known organism that can efficiently break down plastic, there are ways to search for ones that do. Scientists test already known bacteria and fungi for their ability to degrade plastic. They also try to find new candidates by sifting through organisms found around slowly degrading plastic to pinpoint which one is actually responsible for breaking the plastic apart.
There have been plastic-degrading bacteria and fungi found in this way, but they are nowhere near as efficient as the white-rot fungus is at breaking down lignin. This is probably because of the short amount of time organisms have had adapt to this new material, similar to how fungal enzymes had to evolve from less efficient enzymes. There was a lag of many millions of years between the evolution of lignin and the evolution of organisms able to degrade it thoroughly and quickly.
We do not have this kind of time. So, scientists can speed up the process by directed evolution. While natural evolution depends on random mutations popping up, in directed evolution we can actively create small differences in enzymes that could make them better, and then directly test these slightly different enzymes for their ability to degrade plastic.
With this type of biotechnology, we can use the cells of organisms around us as a resource and learn lessons from their evolutionary history. By harnessing the ingenuity of natural systems we can solve our plastic problem.
1. Kaiser, J. “The Dirt on Ocean Garbage Patches.” Science 328.5985 (2010): 1506. Web.
About The Author: Marcia is a final year PhD student at the University of Cambridge with Angeleen Fleming and Roger Keynes in the Department of Physiology, Development and Neuroscience. She is studying how the vertebral column develops using zebrafish as a model system and is broadly interested in evolution and development.