Deep Reads: John Bryant reflects on a book that inspired his research

The fourth of our Deep Reads blog posts is written by John Bryant,  a Professor Emeritus of Cell and Molecular Biology at the University of Exeter, UK. In addition to his deep interest in plant DNA, John has been involved actively in Bioethics for the past 20 years. He retains a passion for the natural world in general and is very active in communicating science and bioethics to a wider public.

A colleague and I were talking about the books we had kept since our undergraduate days. As we compared our lists, both of which were relatively short, we were delighted to find one book in common: Towards an Understanding of the Mechanism of Heredity by H.L.K. Whitehouse. My colleague and I were each fortunate enough, in our respective undergraduate years at Cambridge, to ‘sit at the feet’ of the author, Harold Whitehouse, or ‘Flash’ as we affectionately called him. Needless to say, Harold was not in any way ‘Flash Harry’, rather the opposite in fact. In my third year as a student, Whitehouse gave a series of lectures on genetics that really were inspirational! They were models of clarity and of organisation. Each lecture told a story; stories that dealt with classical views of inheritance, Mendelian genetics, chromosome theory, views on the nature of genes, the functioning of DNA and so on. Evidence was discussed and evaluated, and conclusions were reached. We were brought right up-to-date.


DNA. Image from Pixabay CC BY.

In my time at university, we learnt that the lectures were based on a book (or was it the other way round?) that was soon to be published. Towards an Understanding of the Mechanism of Heredity was published after I graduated, but I can genuinely say that its contents and associated lectures pushed my career in a particular direction. I think especially of the chapters on DNA as genetic material, the genetic code, the nature of genes and operons and above all on the replication of DNA. I was, in addition to being thrilled by developments in molecular genetics, very interested in and committed to plant biochemistry. Indeed, I had already started to sound out Thomas ap Rees (who has been a major role model throughout my academic life) with a view to doing a PhD with him. But the combination of plant biochemistry and molecular genetics meant that for me, only one option was possible: I had to work with nucleic acids. Tom ap Rees was primarily known for his work on metabolic regulation which, without a doubt, would have been the direction I would have taken, had it not been for Harold Whitehouse’s lectures and book. As it happened, Tom allowed me to go where I wanted to go and I started a research career in which a major focus has been the biochemistry of plant DNA replication and its place in the cell division cycle.

But back to Towards an Understanding of the Mechanism of Heredity. As mentioned earlier, it was not published in time for me to read as an undergraduate, even though we had been exposed to its contents in lectures. PhD grants do not have much leeway for buying books and thus it was not until the second edition was published (just four years after the first) that I splashed out some of my postdoc salary to get my own copy. It is indeed a wonderful text. Look at the modesty and understatement of the title: Towards an Understanding … This contrasted greatly with the brashness and confidence of much of the molecular biology community. The book is highly readable, clear and well-organised, with each chapter devoted to a specific theme (or in Whitehouse’s terminology, theory) in genetics, dealing with the evidence and the conclusions with admirable clarity. It was a great help to me in my early years as a university teacher, with much of my teaching being at the interface between biochemistry and genetics. It is still a very good read, even though, inevitably in this field, much of it is now out-of-date.

Inspired by Towards an Understanding of the Mechanism of Heredity, my research interests led me to investigate plant DNA polymerases and other enzymes involved in plant DNA replication in my own research group. Indeed, for several years, mine was one of only four groups across the world working on these enzymes. This reinforced my interest in cell division and led me, together with Dr Dennis Francis, to set up the Cell Cycle group within the Society for Experimental Biology. The success of that group was celebrated in three days of good science at the 2013 Annual Main Meeting of the Society¹. In the meantime, working on DNA, the stuff of genes, eventually led me back to genes themselves, in looking at the regulation of genes encoding proteins involved in the initiation of DNA replication. And, just like Harold Whitehouse in his writings and lectures, I think we are approaching an understanding of these things².


Image credit: Miki Yoshihito, Flickr CC BY


We at PLOS Genetics are looking for new submissions for our Deep Reads blog series and would love to find out more about the books that have inspired you as a scientist. Have any books introduced you to a captivating new scientific concept? Or made you think about something in a completely different way? Perhaps there’s a biography of a prominent scientist that you found particularly moving. If so, please get in touch.

Selected posts will be published on PLOS Biologue and should be no more than 800 words with one or two images. Entries should relate to a book (either fiction or non-fiction) with a genetics/genomics component.

Please send entries to by 20th July, 2015 and we’ll be in touch if yours is chosen.


1 See, for example

2 This understanding of science as ‘an approach to the truth’, verisimilitude, is one of the main ideas discussed by the science philosopher Michael Polyani whose work I have come to appreciate

Category: Blog, Books, Genetics, Molecular biology, Plant biology, PLOS Genetics | Tagged , , , , | 1 Comment

FASEB Conference on Genetic Recombination and Genome Rearrangements: Michael Lichten

As part of its mission to encourage engagement within the genetics community, PLOS Genetics is sponsoring a number of conferences and meetings this year. In order to raise awareness about these conferences and the researchers who attend them we are featuring a number of these conferences on Biologue.

PLOS Genetics is sponsoring the FASEB Science Research Conference on Genetic Recombination and Genome Rearrangements, to be held in Steamboat Springs, CO on July 19-24, 2015. We asked Michael Lichten, Associate Editor at PLOS Genetics, about what he is looking forward to in the upcoming meeting.

I’m Michael Lichten, Associate Editor at PLOS Genetics, PLOS Biology and PLOS ONE, and a principal investigator at the National Cancer Institute in Bethesda, MD. Co-organizer Tanya Paull (University of Texas, Austin, TX) and I are organizing the FASEB Science Research Conference on Genetic Recombination and Genome Rearrangements, to be held in Steamboat Springs, CO on July 19-24, 2015. This conference is the 16th in a conference series that for the past 30 years has been presenting cutting-edge, unpublished research on the mechanisms that maintain integrity of the genome and that ensure its faithful transmission from one generation to the next.  It’s also been a great venue for a different kind of transmission; a place where young researchers and those who are more established in the field can get together in a relaxed, informal setting to get to know one another and to exchange ideas.

Fish Creek Falls, near Steamboat Springs. One of the places where meeting participants have been known to meet informally for scientific discussions. (Image credit: Michael Lichten)

Fish Creek Falls, near Steamboat Springs. One of the places where meeting participants have been known to meet informally for scientific discussions. Image credit: Michael Lichten

The 2015 conference program includes eight plenary sessions that address a wide range of topics, including the structure and biochemistry of recombination proteins, molecular mechanisms of recombination and repair, the relationship between recombination and replication, networks that regulate recombination and repair, the chromatin and nuclear contexts in which recombination occurs, and the impact of recombination on genome stability. A similarly broad range of approaches will be included, from single-molecule analyses, structural studies, in vitro and in vivo biochemistry, live-cell imaging, to whole-genome analysis of mutations and genome rearrangements.

One of the great things about this and other FASEB conferences is the opportunity they offer to researchers at all career stages to meet and discuss science. In the 2015 meeting, we’ve included several features to promote this. Every participant will have the opportunity to present in either a platform talk or a poster session, and this year we’ve expanded the number of platform talks, so that more than one in five talks will be selected from abstracts. In addition, if space permits, we’re planning to have all posters up for the duration of the meeting, so that there will be extra time for informal discussions, in addition to formal poster sessions. There’s also a networking session (called “Meet the Experts”), scheduled for lunch and early afternoon on the second day, so that graduate students and postdocs can meet with speakers for informal discussions—but there’s also plenty of free time for even more informal conversations.

The FASEB conference on Genetic Recombination and Genome Rearrangements has always been one of my favorite meetings, because of its relatively small size (<200), pleasant environment, and high-level science. If you are interested in attending, please visit the conference website ( for more information.

Category: Genetics | Tagged , , , | Leave a comment

How it Works: the PLOS Computational Biology April Issue

Here are some highlights from April’s PLOS Computational Biology


Image Credit: Daniel Bendor

Image Credit: Daniel Bendor

How We Hear Time within Sound

How does our auditory system represent time within a sound? Daniel Bendor investigates how temporal acoustic patterns can be represented by neural activity within auditory cortex, a major hub within the brain for the perception of sound. Using a computational model, the author finds that stimulus-locked responses are generated when sound-evoked excitation is combined with strong, delayed inhibition.



How Actions Influence Decision-Making

The modern view of how we make perceptual decisions is of a process of accumulating sensory evidence until reaching a threshold level of certainty. However, this evidence accumulation model neglects the contribution of action and motor processes to the choice that is made. Nathan Lepora and Giovanni Pezzulo present an explanation of how actions, encompassing behavioral strategies such as preparation and commitment, can bias decision-making processes in ways that optimize the ecological choices of animals behaving in natural environments.


How Individual Cells Contribute to the Tumor Environment

Image Credit: Wells et al.

Image Credit: Wells et al.

Over the course of tumor growth, cancer cells interact with normal cells via processes that are difficult to elucidate through experimental observation, particularly at the early stages of tumor formation. To address this, Joshua Leonard and colleagues develop a computational model of a nascent metastatic tumor (capturing salient features of known tumor-immune interactions) that faithfully recapitulates key features of existing experimental observations.


That’s how, for now..

Category: Biology, Computational biology | Tagged | Leave a comment

Restoring vision with a new optogenetic tool

Photoreceptor degeneration, and eventual blindness, affect millions worldwide. Image credit: flickr user Jenn Turner.

Photoreceptor degeneration, and eventual blindness, affect millions worldwide. Image credit: flickr user Jenn Turner.

Millions of people worldwide suffer from progressive degeneration of the eye’s photoreceptors (the light-sensing cells), leading ultimately to blindness. A recent therapeutic approach for restoring vision in blind retinas involves introducing light-sensing proteins into surviving retinal cells that normally cannot sense light, turning them into “replacement photoreceptors”. This so-called “optogenetic” method, however, has several limitations, because traditional light-sensitive proteins require extremely high light intensities, which can be harmful, and use a mechanism alien to the cells.


In a new PLOS Biology paper, Michiel van Wyk, Sonja Kleinlogel and their colleagues bring this promising technology closer to medical application by engineering a new light-sensing protein that is compatible with the cells’ own signalling mechanism but retains all the advantages of traditional optogenetic proteins: fast responsiveness and resistance to light damage (“bleaching”).


Design of Opto-mGluR6. Image credit: doi: 10.1371/journal.pbio.1002143

Design of Opto-mGluR6. Image credit: doi:10.1371/journal.pbio.1002143

This new protein, termed Opto-mGluR6, is a chimeric protein that consists of two “local” retinal proteins: the light-sensing domains of the retinal photopigment melanopsin and the signaling domain of the metabotropic glutamate receptor 6 (mGluR6). mGluR6 is a protein found in retinal ON-bipolar cells that is naturally activated by the neurotransmitter glutamate released from the photoreceptors, thereby amplifying the incoming signal.


Because ON-bipolar cells naturally receive direct input from the photoreceptors, turning the native chemically activated receptor mGluR6 into a light-activated receptor means that signaling mechanisms in the ON-bipolar cells are preserved, conferring high light-sensitivity and fast “normal” responsiveness. And using the extracellular domain of melanopsin as a “light antenna” provides resistance to bleaching: No matter how hard the protein is hit by light, the response of Opto-mGluR6 never attenuates.


To demonstrate the therapeutic potential of this new tool, the authors show that mice suffering from retinitis pigmentosa – a genetic form of retinal degeneration characterized by night blindness and progressive loss of peripheral vision – can be treated to regain daylight vision.


This new optogenetic approach could potentially be applied to the treatment of any kind of photoreceptor degeneration, including age-related macular degeneration.  Plus, the engineering of the bleach-resistant chimeric Opto-mGluR6 opens up broader possibilities for the treatment of other conditions: The mGluR6 receptor belongs to a large family of diverse signaling proteins called G-protein-coupled transmembrane receptors, which are implicated in a wide range of human disorders and are consequently prime targets for biomedical research and pharmaceutical interventions.

Category: Biology, Blog, Disease, Neuroscience, PLOS Biology | 3 Comments

Stressed to Death: Overcoming Drug Resistance in Malaria Parasites

Artemisinin (public domain, via Wikimedia Commons)

Artemisinin (public domain, via Wikimedia Commons)

In recent decades the burden of malaria has greatly decreased. This is the result of both successful public health initiatives and widespread use of antimalarial therapeutics. Artemisinins are a family of drugs that have been incredibly effective against Plasmodium falciparum – the parasite that causes most cases of malaria – and are the foundation of antimalarial treatment worldwide. Unfortunately, strains of P. falciparum that are resistant to artemisinins have emerged and are spreading in South East Asia.


Containing and eliminating resistant parasites before they spread is critically important, and in a new research article published in PLOS Biology by Con Dogovski, Stanley C. Xie, Nectarios Klonis, and Leann Tilley at the University of Melbourne, working with colleagues from Thailand, Singapore and the USA, have identified two ways to overcome artemisinin resistance. They also develop a model, which can be used in clinical settings to predict whether a parasite has become resistant to artemisinins, providing a powerful tool to improve detection and treatment of malaria.


Plasmodium falciparum gametocyte among human blood cells

Plasmodium falciparum gametocyte surrounded by human blood cells (image credit: CDC).

Their research begins with determining how artemisinins kill P. falciparum. They found that normal parasites, when treated with artemisinins, exhibit the signs of cellular stress. When cells are stressed (and these can be any type of cell, from single-celled yeast, to parasites, to the cells that comprise your body), their proteins are often damaged. Stressed cells halt the production of new proteins and break down the damaged proteins, in a process known as the stress response. In the presence of a little stress, the stress response is able to prevent the cell from being inundated with damaged proteins, but in the face of a lot of stress, the stress response will be overwhelmed and the cells will die. What Dogovski, Xie, and colleagues found was that drug-resistant parasites resistant had a better stress response than sensitive parasites, which allowed them to tolerate and survive the stress-inducing artemisinin treatment.


The researchers identified two means to overcome the drug-resistant parasites’ increased stress tolerance. First, they blocked the way that cells degrade damaged proteins. Damaged proteins are broken down by a complex known as the proteasome. By treating drug-resistant parasites with artemisinins and a proteasome inhibitor they were able to stress the parasite and prevent its ability to protect itself from damaged proteins. Artemisinins and proteasome inhibitors, which are used in some cancer therapies, acted synergistically to kill the resistant parasites.


The second way they found to defeat drug resistance was to simply extend artemisinin treatment. Artemisinin treatment is usually only three days long, but the work presented in this article suggests that extending the treatment to 4 days, or splitting the doses, is effective at overcoming resistance. This concurs with research that recently found in an area with prevalent artemisinin-resistance that extending treatment to 6 days from 3 days was 97.7% effective at treating infections.


The WHO, in their Global Plan for Artemisinin Resistance Containment, states that “There is a finite window of opportunity to contain artemisinin resistance. If the current foci of artemisinin-resistant parasites are not contained or eliminated, the costs, both human and financial, could be great”. The research of Professor Tilley and colleagues makes an important step towards preventing the spread of drug resistance by identifying treatments that can kill resistant parasites.

Dogovski, C., Xie, S., Burgio, G., Bridgford, J., Mok, S., McCaw, J., Chotivanich, K., Kenny, S., Gnädig, N., Straimer, J., Bozdech, Z., Fidock, D., Simpson, J., Dondorp, A., Foote, S., Klonis, N., & Tilley, L. (2015). Targeting the Cell Stress Response of Plasmodium falciparum to Overcome Artemisinin Resistance PLOS Biology, 13 (4) DOI: 10.1371/journal.pbio.1002132

Category: Biology, Cell biology, Disease, Infectious disease, Microbiology, PLOS Biology, Research | 2 Comments

Help us choose the PLOS Comp Biol Tenth Anniversary T-shirt!

In June 2015 PLOS Computational Biology will be ten years old, and as part of our celebrations, we’d like you to help us pick the image for our official tenth anniversary t-shirt from these past PLOS CB designs:


T-shirt 1




























What’s your favourite? Click the survey link below to submit your vote:

Or simply tweet us (@PLOSCB) or email us ( with the letter of your favourite design by Monday 4th May. Get voting!

Category: Uncategorized | 1 Comment

Tumor evolution and microbial forensics: the PLOS Comp Biol March Issue

Here are some highlights from March’s PLOS Computational Biology


Spatial Heterogeneity in Drug Concentrations

Image Credit: Fu et al.

Schematic section view of an “onion-structured” solid tumor with the nearest blood vessel located in the centre. Image Credit: Fu et al.

Acquired resistance is one of the major barriers to successful cancer therapy. There is increasing evidence that the tumor microenvironment influences cell sensitivity to drugs and thus mediates the evolution of resistance during treatment. Feng Fu and colleagues use mathematical models to investigate the effect of drug heterogeneity on the probability of escape from treatment and the time to resistance, and the results provide new insights into understanding why cancers tend to quickly become resistant.


Evolution and Phenotypic Selection of Cancer Stem Cells

Image Credit: Enderling

Cells of different organs at different ages have an intrinsic set of kinetics that dictates their behaviour. After transformation into cancer cells, these kinetics – that determine initial cell and tumour population progression dynamics – will be inherited. However, due to subsequent genetic mutation, cancer cell kinetics can change, and favourable alterations that increase cellular fitness will manifest themselves and accelerate tumor progression. Heiko Enderling and colleagues present a computational model of cancer stem cell evolution during tumor growth.


Microbial Forensics

Can the cellular state and environmental conditions of an organism be inferred from its gene expression signature? To investigate this question, Ilias Tagkopoulos and colleagues create an extensive normalized gene expression compendium for the bacterium Escherichia coli, and then construct an ensemble method to predict environmental and cellular state. Functional analysis of the most informative genes provides mechanistic insights and palpable hypotheses regarding their role in each environmental or genetic context.

Category: Biology, Cancer, Cell biology, Microbiology, PLOS Computational Biology, Uncategorized | Tagged , , , | 1 Comment

Deep Reads: Daisy Hessenberger’s evolving perspective on Gerald Durrell’s books

Our third Deep Reads blog post, ‘Deep Reads: Daisy Hessenberger’s evolving perspective on Gerald Durrell’s books’, was written by Daisy Hessenberger, who has recently completed her PhD at the University of Cambridge. Her main scientific interest has always been evolution, and during her PhD she investigated the occurrence of extreme hybrid traits. On the topic of her research, she says: “I worked with a delightful unicellular Green algae (Chlamydominas reinhardii). After getting different strains to mate, I compared the genetics and epigenetics of the hybrids.” Besides science, her interests lie in travelling, cooking, and writing whatever comes to her mind.

One thing has always fascinated me: how did the process of evolution lead to the incredible biodiversity we find in our world? It’s this question that drives me to research the epigenetic component of the formation of hybrid traits, the black box of evolution. But my initial curiosity into evolution and species diversity was born when I read Gerald Durrell’s books.

The first of his books that I read, Catch me a Colobus, describing the first of many collection trips that Gerald took to Africa, opened up my young mind to the breadth of complexity and environments found in our world. I also got my first taste of the impact human society has on animal conservation. The second, My Family and Other Animals, taught me that biodiversity could be found closer to home, and that even an aspiring 10-year-old naturalist could make some profound (and often amusing) discoveries. He recounts countless hours spent observing animal behaviour, from the fights involved in the courtship of tortoises to the differing levels of care provided by sparrow fathers.


A Colobus Monkey. Image from: Pixabay.

Whether they were some of Gerald Durrell’s more amusing books (cue chasing escaped tapirs in Menagerie Manor), or more academic in nature (such as The Stationary Ark – a collection of essays on how to ethically run a zoo), I was always captivated by the diversity of animals and behaviours that he documented. Be it describing the inhabitants of his garden or his adventures on the many collection and TV trips around the world, these books portray the glory of the natural world and why we must protect it.

As I learnt more about the environment and conservation at school, I reread The Stationary Ark and Gerald Durrell’s own account of setting up his zoo in Jersey, A Zoo in my Luggage; except this time I questioned the need for zoos and the accompanying ethical issues with a more critical eye. The more serious messages in his novels became apparent to me and it was this realization that steered me from wanting to go to veterinary school to studying evolutionary biology. The joy of a young naturalist turned into the drive of a young scientist. As I progressed through my academic career, at each and every stage of my development I found myself rereading those books with a new perspective.

At an undergraduate level, I learnt about cultural inheritance and epigenetics, both inherited separately to the underlying DNA code. My mind reeled; the network that evolution worked on had grown even more complex. Given this personal paradigm shift, I questioned the enchanting behaviour captured in Gerald Durrell’s words. The megapode bird (also known as the incubator bird) incubates its eggs underground and keeps them at the correct temperature using fermentation of vegetation. To keep the temperature stable, the male measures the temperature with his beak or tongue (scientists are yet to confirm which) and adjusts the structure of the nest as needed. How had this adaptation evolved? Could culture or epigenetics play a role? I decided to aim my academic career at understanding how such a plethora of variation could have evolved.

Now at a graduate level, I’ve had the opportunity to try to answer some of my questions, drawn from some of Gerald Durrell’s writings. Specifically, I’m researching the potential effect that small RNAs could have on hybrid phenotypes in a unicellular alga. With the results I hope to establish a firmer understanding of how these intriguing molecules can affect the evolution of hybrid traits. I am still seeking answers to many of my questions and will do so for some time. As I approach the next stage of my scientific career, I’m sure that new discoveries will lead me to reread Gerald Durrell’s books in a new light. As science advances faster and faster, it’s important not to forget tomes of natural history, as their descriptiveness can remind us of our initial inspiration and put into context the importance of our work. Taken even further, with many species of plants and animals under threat, there is no guarantee that the biodiversity which so inspired Gerald Durrell will always be around to comment on, and we may eventually have to rely on his words alone.


A megapode bird. Image credit: Vicki Nunn

We at PLOS Genetics are looking for new submissions for our Deep Reads blog series and would love to find out more about the books that have inspired you as a scientist. Have any books introduced you to a captivating new scientific concept? Or made you think about something in a completely different way? Perhaps there’s a biography of a prominent scientist that you found particularly moving. If so, please get in touch.

Selected posts will be published on PLOS Biologue and should be no more than 800 words with one or two images. Entries should relate to a book (either fiction or non-fiction) with a genetics/genomics component.

Please send entries to by 1st June, 2015 and we’ll be in touch if yours is chosen.

Category: Uncategorized | Leave a comment

Any Questions about our Data Policy?

by PLOS Biology, PLOS Genetics and PLOS Computational Biology

Publication is the end of one journey, but the beginning of another (longer) one, where the ideas and the underlying data that shaped them take on a life of their own. As part of our commitment to fostering scientific progress through scholarly communication, we’re hoping to ensure the more lasting utility of published research down the line.

As we’ve discussed before, an open access paper is enhanced enormously if it’s directly linked to the openly available data from which it was constructed.  Data availability enables replication, reanalysis, new analysis, interpretation, or inclusion into meta-analyses, and facilitates reproducibility of research.

With this in mind, we updated our data access policy in March 2014, and we’ve been listening closely to the discussions that ensued. Researchers across different subject areas have raised questions about our policy and how it applies to their work.  This has helped us gain a deeper awareness of those areas in the policy that needed clarification and elaboration, as well as a deeper appreciation of the challenges associated with information scarcity.

In the hope of addressing these, we’ve released an expanded set of FAQs across each of our journal sites.  These include:

  • more detail on specific data types (sensitive data, big data, etc.)
  • general information on data deposition
  • more detail on PLOS’ submission requirements for data

We’ve also re-organized the information to accommodate the expanded content. While we hope this will give you a more accessible up-front information source, we also encourage you to send any more specific inquiries to respective journals. And as this is an ongoing process, we’ll add to the FAQs over time to continue to provide better support for the data access policy. As always, we welcome feedback (data[at]plos[dot]org).


Category: Advocacy, Data, Open access, PLOS Biology, Policy, Publishing, Research | 1 Comment

Understanding Images: Golden Retrievers Contribute to Cancer Research

This continues our series of blog posts from PLOS Genetics about our monthly issue images. Author Kerstin Lindblad-Toh discusses February’s issue image from Tonomura et al

Author: Kerstin Lindblad-TOH, Professor Uppsala University, Co-Director SciLifeLab Sweden and Director of Vertebrate Genome Biology, Broad Institute of MIT and Harvard.

Competing interests: Kerstin Lindblad-Toh is an author of the article discussed in this blog.

Golden retrievers carry risk haplotypes predisposing to two different cancers. Image credit: Mike Lappin

Golden retrievers carry risk haplotypes predisposing to two different cancers. Image credit: Mike Lappin

Cancer is a common disease in both humans and dogs, affecting as many as 50% of individuals in both species. Finding genes and mutations affecting both disease onset and progression would allow for a better understanding of disease mechanisms, and the potential for more accurate diagnosis and treatment guidance. In this issue of PLOS Genetics, we identify two new loci associated with two canine cancers and provide insights into their role in the disease mechanisms.


Human and dog cancers similar in type, but more easily mapped in dogs

Dogs and humans suffer from many of the same cancers, including lymphoma, breast cancer, melanoma, bone cancer, and hemangiosarcoma. Some cancers are common in both species, including breast cancers and lymphoma, whereas others such as osteosarcoma and angiosarcoma/hemangiosarcoma are common in dogs but relatively rare in humans. The rarity of these cancers in humans can make them hard to study. Purebred dog breeds are an attractive model for these rare cancers because the breed structure contributes not only to an enrichment for specific cancers in certain breeds, but also to making the gene mapping process more efficient. While in humans thousands or tens of thousands of samples are needed for genome-wide association mapping, in dogs complex diseases such as cancers can be mapped with only a few hundred patients and controls.


Lymphoma and hemangiosarcoma both coupled to reduced T-cell activation

Our study mapped lymphoma and hemangiosarcoma in purebred golden retrievers. Surprisingly, both diseases mapped to two loci on chromosome 5, together accounting for ~20% of the risk for these diseases in golden retrievers. The loci contained several genes, but no mutations changing the protein sequence were found to correlate with the genetic variants associated with the cancer risk. Instead, expression analysis of B-cell lymphomas showed that the two loci affected the expression of multiple genes. One identified risk locus down-regulates several nearby genes including TRPC6, a Ca2+-channel involved in T-cell activation. The second risk locus overlaps the vesicle transport and release gene STX8, but changes the expression of >100 genes spread across the genome. Many of these genes are involved in activating immune cells, particularly T-cells. Thus, the disease mechanism for B-cell lymphoma and hemangiosarcoma appears to act through a dysregulation of the T-cell mediated immune response to the tumor.


Implications of findings

The findings from this study have potential benefits for both human and canine cancer patients. While further work is necessary to identify additional risk factors contributing to the risk for lymphoma and hemangiosarcoma in golden retrievers and other breeds, there is an opportunity to use the current findings to help cancer patients. Since dogs are patients receiving clinical care just like humans, there is a need for both genetic tests that allow the assessment of disease predisposition and diagnosis, as well as the potential for more personalized treatment options based on genetic risk factors. We are therefore examining how these canine inherited risk factors affect the clinical picture, tumor mutations and treatment outcomes for our canine patients, with the hope of developing better disease regimens. Importantly, these cancers have sufficient similarity to their respective human cancers that the same genes and pathways identified in the dog are likely to play a role also in the human cancer.  Therefore, clinical trials in dogs showing correlations between genetic risk factors and treatment outcomes could also inform human cancer treatment.
Tonomura, N., Elvers, I., Thomas, R., Megquier, K., Turner-Maier, J., Howald, C., Sarver, A., Swofford, R., Frantz, A., Ito, D., Mauceli, E., Arendt, M., Noh, H., Koltookian, M., Biagi, T., Fryc, S., Williams, C., Avery, A., Kim, J., Barber, L., Burgess, K., Lander, E., Karlsson, E., Azuma, C., Modiano, J., Breen, M., & Lindblad-Toh, K. (2015). Genome-wide Association Study Identifies Shared Risk Loci Common to Two Malignancies in Golden Retrievers PLOS Genetics, 11 (2) DOI: 10.1371/journal.pgen.1004922

Category: Biology, Blog, Cancer, Community, Genetics, Image, PLOS Genetics | Tagged , , , , , , , , , , , , | Leave a comment