RotM: Interview with Prof. Steve Winder

For our recent Researcher of the Month, we spoke to Professor Steve Winder, Professor of Molecular Cell Biology, at the Department of Biomedical Science, The University of Sheffield. His laboratory focuses on the study of dystroglycan, a protein that plays an important role in cell adhesion and signalling. His recent paper in Human Molecular Genetics speaks about the a FDA approved drug, currently being used for treating leukemia as a treatment for Duchenne Muscular Dystrophy (DMD). Here is Professor Winder telling us more about his lab's findings and how we might cure DMD in the near future. 

CTS : For the benefit of our readers, could you please tell us more about your  findings in the recent study. 
SW: Identification of a systemically acting and universal small molecule therapy for  Duchenne muscular dystrophy would be an enormous advance for this condition. Based on evidence gained from studies on mouse genetic models, we have identified tyrosine phosphorylation and degradation of β-dystroglycan as a key event in the aetiology of Duchenne muscular dystrophy. Thus, preventing tyrosine phosphorylation and degradation of β-dystroglycan presents itself as a potential therapeutic strategy. 

Using the dystrophic sapje zebrafish, we have investigated the use of tyrosine kinase and other inhibitors to treat the dystrophic symptoms in this model of Duchenne muscular dystrophy.
Dastanib or Sprycel may be used to cure Duchenne Muscular Dystrophy Image credit: Wikipedia
Molecular Structure of Dasatinib, a drug produced by Bristol-Myers Squibb and marketed as Sprycel
 
Dasatinib, a potent and specific Src tyrosine kinase inhibitor, was found to decrease the levels of β-dystroglycan phosphorylation on tyrosine and to increase the relative levels of non-phosphorylated β-dystroglycan in sapje zebrafish. Furthermore, dasatinib treatment resulted in the improved physical appearance of the sapje zebrafish musculature and increased swimming ability as measured by both duration and distance of swimming of dasatinib-treated fish compared with control animals. These data suggest great promise for pharmacological agents that prevent the phosphorylation of β-dystroglycan on tyrosine and subsequent steps in the degradation pathway as therapeutic targets for the treatment of Duchenne muscular dystrophy.

CTS: Of all Src inhibitors available, Why was dastanib chosen?
SW:We actually used the zebrafish system to screen many compounds and drugs. Dasatinib was just picked as an exemplar for publication. 

Image credit: doi: 10.1093/hmg/ddv469
Image showing significantly reduced movement in sapje fish in terms of distance covered when compared to their siblings A, results of movement tracking when compared, B, and improvement in movement when treated with dastanib, C. Image credit: Prof.Steve Winder and Human Molecular Genetics. 


CTS: Korner et al 2014 carried out a similar study with a compound called bortezomib. How different would you say is this study from theirs? 
SW: Korner et al used a mouse model of congenital muscular dystrophy(CMD) and treated it with a proteasome inhibitor, whereas we used a mouse model of DMD and a Src inhibitor. Interestingly the same group have recently shown that the same drug is not effective against a different mousemodel of the same disease.

CTS: So, would you be working on a different model of zebrafish to ensure that that your findings are reproducible?
SW: Given that we have already advanced our studies in mdx mice with some apparent success, there seems little need to go back to zebrafish at this stage.

CTS: Your lab has worked on mouse models earlier, why shift to zebrafish for this study?
SW: The mouse model demonstrated the importance of tyrosine phosphorylation in the aetiology of DMD. The shift to fish was simply for the purposes of screening many candidate compounds. Drug screening is much quicker, cheaper and easier in fish than in mice.

CTS:What happens next? Since this is an approved drug, can we skip the human trials altogether? 
SW:No, trials are still needed. Although dasatinib is approved clinically and the safety testing has been done, we will still need to demonstrate efficacy against DMD in people.

CTS: So, would your lab be involved in the clinical trials for Duchenne Muscular Dystrophy?
SW: The initial discovery is patented with us as inventors, however pharma involvement would be needed in order to obtain the drugs for the trial. The trial could be investigator led, or pharma could choose to do it. 

Prof. Steve Winder, University of Sheffield
Just a regular day at the office.
Image credit: Professor Steve Winder
CTS: Looking at the treatments in the future, isn't gene therapy a more robust answer to a genetic disease like DMD. When perfected, it holds promise of 100% recovery. Is your lab looking at gene replacement therapies as well?
SW: Whilst DMD is a monogenic disease, there are hundreds of different mutations. There is currently no single genetic therapy that is capable of correcting all the defects, and those that there are, are far from 100% perfect. Delivering these sorts of therapies to muscle remains problematic. CRISPR-Cas9 mediated gene editing would appear to be one way around that. 

However, we are not pursuing gene therapy approaches since that is not our current area of expertise.For the moment, a systemic small molecule inhibitor could be an answer. So although at present we are still working up the pharmacological approach, but ultimately a combinatorial regimen of pharmacological and genetic therapy may give greatest efficacy.

Readers interested to know about Duchenne Muscular Dystrophy would like to read our other post, Exception to the thumb rule.

If you would like to read more of these interesting stories from the world of science, subscribe to our  blog and we will send you an email every time we post something new and interesting. Alternatively, you can follow us on social media such as FacebookTwitter or Google Plus!

References:

Körner Z, Fontes-Oliveira CC, Holmberg J, Carmignac V, & Durbeej M (2014). Bortezomib partially improves laminin α2 chain-deficient muscular dystrophy. The American journal of pathology, 184 (5), 1518-28 PMID: 24631023

Körner Z, & Durbeej M (2016). Bortezomib Does Not Reduce Muscular Dystrophy in the dy2J/dy2J Mouse Model of Laminin α2 Chain-Deficient Muscular Dystrophy. PloS one, 11 (1) PMID: 26731667

Lipscomb L, Piggott RW, Emmerson T, & Winder SJ (2016). Dasatinib as a treatment for Duchenne muscular dystrophy. Human molecular genetics, 25 (2), 266-74 PMID: 26604135


Genes don't call all the shots, your environment does to.

The usage of the terms such as 'DNA' and 'genes' has exploded in recent years and is  commonly used to denote characteristics and traits in people, features of products and even as lyrics for a song. The theory of genetics that genes assign traits to individuals has been rooted so deeply into our psyche, that we fail to see the other side of the story completely. The role of the environment in shaping how our genes function is a fact that is unheard by many people and is something I would like to shed a little light on in this post.
Image credit: www.buzzle.com

The public understanding about genetics is more or less like the way people follow astrology . If the newspaper predicts that the day at work will not go well, we tend to blame the stars/ sun sign for everything that goes wrong that day. Similarly, the presumption that genes control the way we function and act, has set the tone for genes to be solely in control of everything that is happening inside our cells. However, this is not how genes work. There is a machinery that allows genes to adapt to their surroundings without actually changing the DNA sequence. These are not mutations that are stopping gene function or restarting them, these are minor changes that can increase or decrease gene expression, introduced as a result of conditions in the organisms environment. Called epigenetics, these changes are inheritable and can be passed on to future generations as well. 

In the past, there have been many studies that have shown how epigenetic changes can be brought about in genes. Methylation of DNA, role of non-coding RNA and modification of histone proteins are a few of the epigenetic methods that we have been able to unearth so far. A recent study published in Science by Daniel Simola and colleagues studied histone protein modification in carpenter ants and were able to externally amend behaviour in these ants.

Description: This image shows a Carpenter ant ...
A Carpenter ant (Camponotus ligniperda)
(Photo credit: Wikipedia)
The colony of a carpenter ant consists of a queen, her brood and several thousands of workers. We know that all worker ants are genetically the same but are given different tasks in their colonies. There is no exception in carpenter ants as well, where smaller ants or minors are assigned the task of taking care of the young and forage for food, whereas the larger ants or majors defend the colony. Using drugs that affect acetylation of histone proteins (Histone deacetylases or HDAC, the researchers saw an increase in scouting and foraging activity in minor ants. Thus, lower the acetylation, larger was foraging activity seen in the ants. Conversely, this increased foraging could be dropped by using a inhibitor of histone acetyltransferase (HATi). 

Diagram showing behavioral differences in major and minor carpenter ants when treated with HATi and HDACs.
Image credit: Simola et al., 2016. doi:10.1126/science.aac6633
Using this information, the researchers were able to induce foraging behaviour in major ants (who are built to defend and protect) and retain them for up to 50 days of age. This goes to show that even though these ants are genetically programmed to carry out a certain task, their behaviour can be modified using external factors. Since a large number of these proteins and enzymes are common among insects and even vertebrates, it is safe to assume that such epigenetic change in behaviour can be brought about in vertebrates as well. 

The study also found that there is a window of opportunity, where epigenetic changes can result in behaviour modification and there is a lot of work to be done to understand this window, right from why it exists, how it functions to why it closes as the animal matures. Nevertheless, the study manages to show that genes are not in complete control and your environment has say too. 

If you liked reading this post, you might also like our other post about cells not being ruled by genes.

If you would like to read more of these interesting stories from the world of science, subscribe to our  blog and we will send you an email every time we post something new and interesting. Alternatively, you can follow us on social media such as FacebookTwitter or Google Plus!

Reference: 

Simola DF, Graham RJ, Brady CM, Enzmann BL, Desplan C, Ray A, Zwiebel LJ, Bonasio R, Reinberg D, Liebig J, & Berger SL (2016). Epigenetic (re)programming of caste-specific behavior in the ant Camponotus floridanus. Science (New York, N.Y.), 351 (6268) PMID: 26722000

Do pets really like to play?

Isn't it strange where cats and kittens will f...
Isn't it strange where cats and kittens will find to sleep and play? (Photo credit: Wikipedia)
I have cats at home, I love cats, and am a self proclaimed animal activist, who loves her quadruped counterpart than watching humans play. But the idea of play I have come to believe is not universal. When I do catch a trail of ants, or the occasional team of ants scouting the place for left over cat food, I can’t help but think that they are probably having a fun time looking around, and contrary to popular scientific belief, I do think they kinda like to waste time goofing around, when the food is right there in front of them. But then again, that is my opinion, which has no scientific evidence, and need not be taken seriously.

So, if you have cats at home or are fortunate enough to have seen cats playing you would see that it greatly resembles their hunting behaviour. It wouldn’t be wrong to say that play hones the kittens hunting skills so that they grow up to become mean killing machines. And that is definitely true, after I saw one of my kittens take down a very testy fly, that came swarming into the house (might I bring to your notice, it was one of those huge flies that make the buzzing sound- not the regular house fly variety that is small). In what was very much play behaviour; the kitten took down, what may not be big and mighty- but definitely faster and much more agile than my naive kitten. The reward was, the dead fly that she happily gobbled and went to her perch for a celebratory groom session. Much like the felines, canines too start young. If you have a dog at home, you know just too well, that when the forelegs are extended and the rump is in the air, your dog is in the mood to play. 

Dog playing GIF. Source: www.giphy.com
A common occurrence in every house that has a dog
So why do they animals engage in play?

Probably, because they have too much time on hand. Like toddlers who run around the house whole day, our pets are animal toddlers who don’t seem to have much to do, which is why they keep playing. But contrary to my belief, this is far from the truth. This “Play Bow”- as researchers  and behaviorists call it is not just restricted to the urban landscape.


Play behaviour is not only seen in our house kitten, but  in larger kittens- I mean cats as well. One thing is for certain that this play behaviour seems to be common with, most animals, and one can safely presume, is evolutionary. So could it be, keeping my theory in mind, that animals in the wild, also, like their more docile counter parts in our homes, have a lot of time to kill in the wild as well?

Researchers have observed that this behaviour tends to manifest itself, when resources are at a high, life, in other words, is comfortable, and non  threatening- no impending doom situation, and when the animal is completely bored (yes you read it right,  bored). Much like small children, when animals are bored, and have nothing better to do, they indulge in play, as simple as that. In fact it was during one of these ‘whether to call it play or not behavior’ that Jaak Pankseep, a neuroscientist found out that rats actually laughed. He observed that his lab rats produced this high pitch sound only when they were at play.



This is also true with Porbeagle sharks, which are studied at the ReefQuest Center for Shark research. These sharks observed at the Cornish Coast, showed repetitive behaviour, rolling while swimming and interaction with manmade and natural objects. In fact many sport fishers are well aware of the curiosity of these guys. The mere repetitive nature of the actions was a hint that this was a frivolous activity that didn’t lead to any attainable goal- or in other words – play. (You might want to go Reef Quest Research Centre website to read more about these fascinating fish). Among fish, it is not just the Porbeagle sharks that have a frivolous nature, cichlids have also been observed to keep themselves entertained in aquariums found playing with the thermometers in the tank.


 Here is a great video to show you how playful they can get.





If that amazes you, wait till you hear this. For all those who believe that reptiles are the quintessential cold blooded species, think again. Researchers have observed that when the environment is stress free, Monitor lizards engage in what can only be called – an identity crisis, where these huge lizards have engaged in shaking shoes, and even retrieving soda can like dog often do. Even salt water crocodiles and turtles have shown to love playing with a tethered ball (Burghart 2014).

Which brings me to the primary question, were those ants I was staring at, playing? And how exactly do you know if what they were doing constituted as play. While identifying play behaviour may be easy in mammals, who is to say that the same behaviour constitutes as play in insects? It is a growing consensus in the scientific community, that the older definition of play may not be universal enough to describe what constitutes as play (say we encounter aliens who just want to play and be friendly and we stand guarded with our guns).

Our inherent need to humanize things and for this matter even play, and what we deem as play, which is in turn representative of what we do as play, does not constitute play. 

Too much? Well, this is why Burghardt, put forth a new definition of play which said- "play is repetitive, may not seem to have any function, and is indulged in when the animal is most relaxed and in a low stress environment"

To know that we (as in first, human and then mammals) presumed to have had the exclusive right to play, is both astonishing and humbling. We are now coming to learn that we (citizens of earth) are not very different from each other. Who knows someone might (or already has) discovered that plants have a way with play as well. So the answer to my question, probably YES, what those ants were doing may just have been goofy good old school ant fun play, before going back inside their tiny hole to get the others to pick the food up.

For now, I’m comfortable with that.

Citation: 

Burghardt, G. (2014). A Brief Glimpse at the Long Evolutionary History of Play Animal Behavior and Cognition, 2 (2) DOI: 10.12966/abc.05.01.2014

Cure for Psoriasis - a possiblity

English: Psoriasis
Psoriasis (Photo credit: Wikipedia)
WebMD defines psoriasis as a "baffling and persistent skin disorder." With no real cure and treatment methods that have side effects, psoriasis can be a daunting condition to handle. Although, it is not a life threatening condition, it does reduce the quality of life and according to WHO estimates, affects more than 140 million people on the planet. Drugs, currently, in the market are primarily aimed at suppressing the immune system in general. So, although, symptoms reduce, the body is not putting up its best defense and the patient is prone to secondary infections. However, a promising study published in Science Translational Medicine might just enable us to treat psoriasis and not just symptomatically. But to understand this, we first need to look into what really happens in psoriasis.

Psoriasis involves the abnormal production of skin cells due to a cascade of inflammatory responses which are triggered by Tumor Necrosis Factor (TNF) and Interleukin-22 (IL-22). These cytokines (cellular chemical signals) are responsible for the inflammation (redness of the skin) seen in early stages of the condition and sets the tone for disease progression. Greater the trigger greater would be the cellular response and thus, severe the condition in the patient. Treatments of psoriasis with topical ointments or medications usually begins at an elevated level of inflammation, which basically means that the treatment is lagging far behind the cause of the condition. It is no surprise then that psoriasis cannot be cured and is only treated symptomatically.


Psoriasis inflammatory pathway: Image credit: www.clinsci.org
Role of cytokines in development of psoriasis. TNF and IL-22, the major contributors are marked in RED

What we really need is a method to counter this inflammation soon after it is initiated. Luckily, the human body works on something called a feedback mechanism. To every event in the body, there is a response in the form of a chemical (enzyme, hormone, cytokine etc.) released and for every release there is a built mechanism to counter it and negate the effect. The cycle continues till a normal equilibrium is reached and stays so until another trigger sets it in motion. Cytokines  IL-4 and IL-10, contribute largely to this feedback mechanism which can help in reducing the inflammation but in psoriasis patients, the feedback mechanism is somewhat faulty and cannot keep the inflammation in check. The solution to this problem does not lie in developing new drugs or combinations thereof, but in tackling the root issue of producing the anti-inflammatory molecules such as IL-4 and IL-10. 

The genes. 

For most part of the past 100 odd years that we have known about genes and genetic diseases, we have thought of them as incurable. But recent advancements in gene therapy have provided promising results in alleviating patients of their genetic conditions. Success stories of clinical trials for genetic treatments of Hemophilia, Leber Congenital amaurosis and a few other conditions have increased our confidence in treating genetic conditions and paved way for future therapies. 

But it is not so straight forward either. So far, gene therapies have focused on diseases caused by the loss of function of single gene. Hemophilia B for example. Caused by defects in gene for Factor IX clotting factor. Deliver copies of Factor IX into the patient and some amount of factor IX can be produced, leading to reduction in spontaneous bleeding. 

But for the condition like psoriasis, there is no absent component. There is no recognized faulty gene. All we know is that a couple of cytokines are triggered and present in excess concentrations. What is needed is a system which can detect not one but two molecules at the same time. Computer scientists call this an AND gate and use it regularly to get certain outputs in computing/ electronics. A simple example for this would be working of a microwave. A microwave works if you press the Start button AND if the door is closed. It basically means that the system responds (Q) if both signals A and B  (as shown in the figure) are present at the same time.
AND Gate

Researchers at the Department of Biosystems Science and Engineering, ETH Zurich led by Martin Fussenegger, were successful in creating a cellular gene circuit which responds like an AND gate. They injected this gene circuitry in mice in specialized cellular capsules and used a special drug so that the mice produced TNF and IL-22. The gene circuit then responded in the presence of these two cytokines and instructed the cells to produce IL-4 and IL-10 to reduce the inflammation. Mice which did not have the gene circuitry did not show reductions in the level of inflammation. The gene circuitry enables the mice to respond at the early stage, at the cellular level, way before the symptoms appear on the skin.

The cure for psoriasis may still be far away but research findings such as these are harbingers of hope for many other inflammatory diseases as well. In the future, treatments could include injecting gene circuits that can do much more than detect one or two markers alone and this is good news for patients of cancer too.

If you would like to read more of these interesting stories from the world of science, subscribe to our  blog and we will send you an email every time we post something new and interesting. Alternatively, you can follow us on social media such as FacebookTwitter or Google Plus!

Reference: 

Schukur L, Geering B, Charpin-El Hamri G, & Fussenegger M (2015). Implantable synthetic cytokine converter cells with AND-gate logic treat experimental psoriasis. Science translational medicine, 7 (318) PMID: 26676608

Salamanders helping us heal fractures faster

Salamander : Image source: www.wildlife.state.nh.us

Salamanders are best known for their ability to regrow their amputated limbs. While regrowing limbs in humans might sound like science fiction for now, the canonical Wnt signalling pathway, which allows salamanders to regrow their limbs, plays an important role in maintenance of our body and also during the process of healing. 

Recent research has shown that the Canonical Wnt pathway can be stimulated to promote faster healing of fractures. My story on this was published recently in Health Section of The Wire. 

Read the complete story here

Harvesting dinosaurs from Ghost Ranch [Video]

Tyrannosaurus rex, Palais de la Découverte, Paris
Tyrannosaurus rex, Palais de la Découverte, Paris (Photo credit: Wikipedia)
Once in a while, we come across a news story of paleontologists finding a dinosaur fossil in some part of the world. The significance of the fossil is then explained and the news story is buried into the depths of our mind to be excavated out the next time, there is a similar news story.

But there is a lot more than happens between discoveries, which is left out of the story but if you would like to witness it, you could simply visit, the Ghost Ranch in New Mexico, a hot bed for finding dinosaur fossils.

In this episode of the Shelf Life, you can see how dinosaur fossils are excavated and prepared to be brought back to the American Natural History Museum to be added to their vast collection and studied some day.





Excavations in Ghost Ranch began in the year 1928 and continue to this day.