Got Stripes? How the Zebrafish Got its Stripes.

 

By Sophia David

What do butterflies, snakes and fish all have in common? One answer could be that they all display colourful and spectacular skin pigmentation patterns. The zebrafish, for example, displays a beautiful and characteristic stripy pattern.

In the last decade, zebrafish, also known as Danio rerio, have emerged as an excellent model organism for studying vertebrate biology and, in particular, vertebrate development. This is due to the ease of maintaining large stocks of zebrafish, their quick development, and the transparent nature of zebrafish embryos and larvae. Luckily then, scientists wishing to study how pigment pattern formations develop already have a great model organism at their fingertips.

The zebrafish stripe pattern consists primarily of two types of pigment cell: melanophores (black pigment cells) and xanthophores (yellow pigment cells). Mutants that lack either of these types of cells do not show the stripy pattern.

Previous work by scientists from Osaka University in Japan previously showed that interactions between these two types of pigment cells are important for the development of the stripy pattern. In particular, they found that direct contact between xanthophores and melanophores causes the membrane potential of melanophore cells to change. This is called membrane depolarization. They hypothesized that the membrane depolarization of melanophores affects the movement of the cells and these movements, in turn, result in the formation of the characteristic pigment patterns.

In the study published this week in the journal PNAS, the same scientists tested and confirmed their hypothesis, and further characterized the interaction between the two types of pigment cell. They showed that the xanthophore cells reach out to touch melanophores by extending a part of their cell. These temporary projections of cells are called pseudopodia. Meanwhile, the melanophores show a repulsive response to the pseudopodia of xanthophores and move away. The xanthophores are not discouraged, however, and continue to chase the running melanophores. The authors called these “run-and-chase” movements. They believe that these movements cause the segregation of xanthophores and melanophores into distinct stripes.

The scientists further demonstrated that these run-and-chase movements are disrupted in mutant zebrafish that do not show the typical stripy patterns. For example, “jaguar” mutants have broader and fuzzier stripes. The scientists showed that the repulsive response of melanophores in jaguar zebrafish is inhibited compared to in wild-type zebrafish so essentially the melanophores cannot “run away” so quickly. This is thought to lead to the incomplete segregation of the two types of cell, resulting in broader and fuzzier stripes.

There is still much left to understand, however. The next steps are to understand the precise molecular mechanisms that occur when the two types of cells interact and how these lead to specific cell movements. Furthermore, the scientists want to understand how those mechanisms differ in the mutant zebrafish.


The Art of Manipulation

 

By Sophia David

Parasitism is the most common way of life on Earth. It occurs when two species live in close proximity to one another and while one species (the “parasite”) benefits from the relationship, the other species (the “host”) suffers. Humans are only too familiar with parasites - the common flu virus, the tapeworm and the malaria parasite are just a few examples of organisms that parasitize our own species. While these organisms benefit from us by gaining shelter and food, we, of course, gain nothing but illness.

Through thousands of years of evolving together with their host (a process known as co-evolution), parasites have learned to manipulate their hosts in remarkable ways. The most unique example I have come across is that of a bacterium called Wolbachia. This is thought to be one of the world’s most common parasites. The hosts of Wolbachia are wide-ranging; they can infect numerous species of insects, spiders and worms. Sometimes, the relationship can be beneficial to the host, in which case the relationship is one of mutualism, where both species derive benefit, rather than parasitism. More often than not, however, the relationship is parasitism.

The defining feature of these bacteria is that they are transmitted to the offspring of an infected female host through the female's eggs. Crucial to this story is that it is only female hosts that transmit Wolbachia, and not males. Instead, males are a dead-end host; once in a male host, the bacteria have nowhere to go. So, to enhance their transmission, Wolbachia would rather be in a female host than a male host. And they evolved the most fascinating mechanisms to achieve this. Like many parasites, they manipulate their host’s biology, but rather uniquely, they are able to alter their host’s reproduction in a way to favor their spread. In a paper by John Werren and colleagues from the US, the authors outline four fascinating ways in which Wolbachia can alter the reproduction of its hosts to its own advantage.

Cytoplasmic incompatibility

This sounds complicated but “cytoplasmic incompatibility” is just a way of saying that sperm from Wolbachia-infected male hosts is incompatible with eggs from females that do not harbour Wolbachia. This kind of match would produce offspring that are not infected with Wolbachia, since the bacteria can only be transmitted from the female. So Wolbachia has developed a way of manipulating the sperm of infected males so that they are only compatible with eggs that are also infected. It’s clever! The molecular mechanisms of how Wolbachia achieves this are still not properly understood though.

Parthenogenesis

Parthenogenesis is a type of asexual reproduction whereby embryos develop from eggs that have not been fertilized by sperm. While insects and other hosts of Wolbachia usually undergo sexual reproduction, parthenogenesis can also occur. Wolbachia makes use of this by ensuring only daughter progeny can be produced through parthenogenesis.

Male killing

Just as it sounds, Wolbachia are able to kill the male offspring of its hosts, usually when the embryos are developing. This gives the surviving, Wolbachia-infected females an advantage as more food and resources will be left for them.

Feminization

Even when Wolbachia is not able to kill the male embryos, it has another trick up its sleeve. By interfering with the sex-determining pathways of its host, it can cause genetic males to instead develop as females through a process known as feminization.

 

Different species and strains of Wolbachia use different combinations of these strategies to spread efficiently through host populations. Going to such extreme lengths, it is no surprise that they are among the most abundant parasites in the world.

Another characteristic of Wolbachia is that it inhibits the growth of many other microbes in its hosts. This feature, along with its remarkable ability to spread in host populations, has led to its use as a biological tool for preventing the spread of disease. One such disease is dengue fever, caused by dengue virus and transmitted by mosquitoes. The dengue virus is not able to survive inside a Wolbachia-infected mosquito. Therefore, scientists have created a strain of Wolbachia-infected mosquitoes which, when released into the environment, rapidly replace the non-infected population and prevent transmission of dengue fever. Small, pilot trials of this have worked well in Australia and larger trials are currently now taking place. In the coming years, Wolbachia could become a major, albeit slightly unusual, tool for combatting insect-borne diseases.

This post originally appeared on thetripletcode.wordpress.com


From 1 to 100,000 human genomes: the challenges faced

 

 

Sophia David

In 2003, the Human Genome Project was completed and the final version of the first human genome sequence became available as a free scientific resource. Having taken 13 years to complete, the total cost of the project was US$2.7 billion. Since then, rapid technological advancements have allowed genome sequencing costs to plummet and, just ten years later, a human genome can now be fully sequenced for less than $10,000. Moreover, the process takes just days, or even hours. Costs are expected to fall even further to just $1000 per genome within the next few years.

 

Of course, as the costs have fallen, scientists have sequenced an increasing number of genomes.  The 1000 Genomes Project, launched in 2008, has allowed scientists to characterise the variation within human genome sequences at a high resolution.

 

Remarkably, just tens years after the first human genome was sequenced, several projects are now set up with ambitions of sequencing 100,000 human genomes. One such project is the Personal Genomes Project, set up back in 2005 by George Church, a Professor of Genetics at Harvard Medical School. Although initially a US-based project, it is expanding and now also has branches in the UK and Canada. Combined, they hope to sequence 100,000 volunteers over the next ten years.  The data will be freely available for all scientists to use.

 

Meanwhile, the UK government have also pledged £100 million to sequence the genomes of 100,000 patients of the NHS (National Health Service) by the end of 2017. The data obtained from this project will be for primarily clinical use, making the UK one of the first countries to be moving genomics into the clinic on a large-scale. The UK government has set up a company called Genomics England that is responsible for undertaking this ambitious task.

 

While the translation of genomic data into useful clinical information has been slower than once expected, genome sequencing is undoubtedly impacting on medical diagnoses and treatments. For example, by examining the mutational changes within a patient’s tumour cells, clinicians are able to better characterise some cancers and consequently provide a more appropriate treatment.

 

However, the developments in genome sequencing have not come without their challenges. Currently, a major debate revolves around how open or private genomic data should be. On the one hand, sharing data is hugely important for enabling scientific discoveries. Thousands of studies have been published as a result of freely available data made by the Human Genome Project and 1000 Genomes Project. On the other hand, a whole genome sequence can reveal a large amount of information about the respective individual, as well as their family members. While such data may be published anonymously with no personal information attached, a study by scientists at MIT shower earlier this year that it is still possible to link genomic data back to the individual using Y-chromosome data and geneology websites. There are fears that genomic information linked to a specific individual could be used in malicious ways.

 

Scientists at the Personal Genome Project are only too aware of this dilemma and have devised their own solution. They state on their website that, “We feel the most ethical and practical solution to this dilemma is to turn the privacy problem on its head and collaborate with individuals who are willing to share their data publicly with the understanding that re-identification is possible.”

 

Thus, data produced by the Personal Genome Project will be freely available to everyone. However, in order to take part in the study, participants must pass tests to prove that they fully understand the risks of having their genomic information shared with the world before taking part.

 

Meanwhile, genome sequence data from NHS patients will not be publicly available and instead be stored inside the NHS firewall. It will be linked to patient records for clinical use, and anonymised data will also be available in a restricted place for scientists to use for research purposes.

 

Another potential problem that arises from the analysis of genomic data regards how incidental or secondary findings are managed. These could occur when a genome sequence is used to answer a particular question about a patient’s health but something unrelated and unexpected arises. While incidental findings are nothing new in medicine, the risks of such occurrences in genomics are probably higher than most areas of medicine. Earlier this year, the American College of Medical Genetics and Genomics released their recommendations on incidental findings that occur through genome sequencing. They suggest that all labs performing clinical sequencing should test for well-studied mutations in 57 genes that have a strong association with disease. These include BRCA1 and BRCA2 mutations that are linked to hereditary breast and ovarian cancers. They believe that people should not be able to opt out of knowing these results unless they refuse clinical sequencing.

 

There is also the risk that genomic information could actually cause harm to patients through misdiagnoses, or that clinicians or scientists could fail to identify clinical useful genetic variants.  However, it is likely that these risks will diminish as more genomes are sequenced and clinicians and scientists gain experience in the application of genomic data to medicine.

 

Finally, one of the great challenges may lie in managing expectations. While the last decade has seen remarkable progress in genomics, the application of genomics to medicine will be a much longer road. Politicians must understand that they will not see a quick return on their investment and patients offered genome sequencing should not always expect a straightforward cure. And lastly, clinicians and scientists should not expect to see medicine transformed overnight by genomics.


The Accidental Pathogen

 

Sophia David

The Bellevue-Stratford Hotel, Philadelphia - the site of the first outbreak of Legionella. Credit: Historic American Buildings Survey, Library of Congress.
The Bellevue-Stratford Hotel, Philadelphia - the site of the first outbreak of Legionella. Credit: Historic American Buildings Survey, Library of Congress.

In July 1976, two thousand American Legionnaires’, or war veterans, gathered at the annual three-day convention of the American Legion at the Bellevue-Stratford Hotel in Philadelphia, Pennsylvania. On returning home, dozens were struck down by a mysterious illness. 147 people were hospitalized with a severe form of pneumonia and 29 people died. When it was noticed that all the cases had attended the same convention, the US Centers for Disease Control and Prevention (CDC) launched an emergency investigation that attracted huge media attention. The elusive killer quickly became known as Legionnaires’ disease.

Six months later, a new type of bacteria called Legionella was finally discovered, and was found to be multiplying in the cooling tower of the Philadelphia hotel’s air conditioning system. It had spread through the entire building and was transmitted to the unwitting Legionnaires’ through aerosols in the air.

Since its discovery 36 years ago, Legionella has caused thousands of outbreaks throughout the world, as well as sporadic cases of Legionnaires’ disease. It causes up to 18,000 hospitalisations annually in the US alone and, alarmingly, strikes with up to a 30% mortality rate. Unsurprisingly then, this once mysterious bacterium has been subjected to much scientific research over the last four decades and it is now also the subject of my PhD.

 

Having learned that the first recorded outbreak of Legionella was caused by a contaminated air-conditioning system, you may not be surprised to hear that Legionnaires’ disease is a man-made problem. This Gram-negative ϒ-Proteobacterium is found ubiquitously in natural aquatic environments; up to 80% freshwater habitats are home to Legionella bacteria. However, the construction of man-made water systems such as cooling towers, swimming pools and hot tubs have now also provided wonderful environments in which Legionella can flourish and replicate to high numbers. It is from these man-made sources, and not natural environments, that people become infected with Legionella. This explains why Legionella is a recently emerged pathogen, despite its probable existence in the natural environment for thousands of years.

 

This electron micrograph depicts an amoeba, Hartmannella vermiformis (orange) as it entraps a Legionella pneumophila bacterium (green) with an extended pseudopod. Credit: Dr. Barry S. Fields, CDC.
This electron micrograph depicts an amoeba, Hartmannella vermiformis (orange) as it entraps a Legionella pneumophila bacterium (green) with an extended pseudopod. Credit: Dr. Barry S. Fields, CDC.

As well as being a man-made problem, Legionella is also an “accidental” pathogen. Infecting humans is not part of its natural life cycle. Instead, Legionella survives naturally in the environment by infecting single-celled protozoal organisms such as amoebae. The bacteria replicate to high numbers inside protozoal cells before bursting out, killing the host in the process. Each bacterium is then ready to infect a new cell and the cycle continues.  On the other hand, human infection is actually detrimental to Legionella because once it is inside a human lung, it has no way out again. We are a dead-end host. Yet, despite its non-intent, Legionella can still infect humans because of the high similarity between its natural protozoal hosts and a class of immune cells in the human lung called alveolar macrophages. Both of these types of cell are phagocytes, meaning that they can engulf, or “phagocytose”, surrounding material such as bacteria or debris. In its natural environment, Legionella has evolved to hijack this phagocytosis process and use it as a means to gain entry into the host cell. And because the phagocytosis mechanism is not too different in human macrophages, if we happen to breathe in contaminated aerosols, Legionella can “accidentally” infect human cells too.

 


Cancer Is Contagious?

Sophia David

Most people know cancer as an aggressive yet non-infectious disease that fortunately is not passed from one person to another. There are, of course, infectious agents such as human papillomavirus virus (HPV) that can lead to cancer in some individuals, but barring these cases, we know you can’t “catch” cancer from another individual. However, evidence obtained in recent years challenges this paradigm. Here, I will discuss two fascinating examples of truly “transmissible” cancers in the natural world: one that occurs in Tasmanian devils and the other in dogs. I will then briefly consider the implications of this research for our own species– is it possible for human cancers to become transmissible?

 

During a person’s lifetime, cells will divide a staggering ten thousand million million times. This provides a lot of opportunities for mistakes to happen and thus somatic mutations do occur. Usually these are repaired or destroyed by tumor suppressor genes such as p53 or BRCA1 and do not cause major problems. However, if mutations occur in genes that regulate the cell division process, and such mutations accumulate, cancer can be the result.

 

As we know it, a cancerous clone of cells that arises in an individual remains restricted to this individual. These clones are often self-destructive by causing the death of their host. However, two types of cancer have overcome this constraint of existing only within one host and, remarkably, have acquired the ability to spread between different individuals. In this way, cancer clones can exist long after the death of the individual that gave rise to them.

 

The first known transmissible cancer is Devil facial tumor disease (DFTD), which plagues the Tasmanian devil population. Until about 500 years ago, Tasmanian devils inhabited all of Australia but hunting caused a massive decline in their population, which is now highly fragmented and restricted to Tasmania. To exacerbate this decline, DFTD was first reported in 1996 and is a highly virulent disease that causes tumors around the mouth and face of the animals. The disease has been killing large numbers of devils through starvation and there are fears that, at the current rate of population decline, Tasmanian devils will be extinct within 20 years.

 

When scientists searched for clues as to what is causing DFTD, the obvious culprit was a cancer-causing virus that is sweeping through the population. It came as a great surprise when, in 2006, a study was published in Nature which reported that no virus or other infectious agent is involved. Instead, the scientists reported that it is the cancer itself that is transmissible.

 

The authors had studied the karyotype (the number and appearance of chromosomes) of tumor cells from different individuals. Normally, Tasmanian devils have 14 chromosomes, including the X and Y chromosomes. However, all the tumor cells possessed the same karyotype, containing only 13 chromosomes with identical rearrangements. This provided strong evidence that the tumor cells arose in one individual and spread through the population.

 

Later, another study published in Science looked at the genetic sequences of tumor cells taken from different individuals. The authors found that the sequences were all highly related, as well as distinct from the normal devil sequences. miRNA expression profiling also showed that the tumor cells are very similar to brain cells, in particular Schwann cells, suggesting that the cells are of neural origin.

 

However, we know that cancers are not usually transmitted between individuals. A physical mode of transfer would be required and, in any case, foreign cells would normally be rejected by an individual’s immune system.  It turns out that devils have overcome both of these barriers. Firstly, Tasmanian devils are extremely aggressive animals, and fights between individuals can leave severe wounds on the head and face. During fighting, it is believed that cancerous cells can be released from ulcerated oral tumors and transmitted into the facial wounds of another devil. Secondly, the decline in devil numbers and resultant inbreeding has led to a population with extremely low genetic diversity. A lack of major histocompatibility complex (MHC) variation means that the DFTD cells are not always recognized as foreign by the immune system, a factor further facilitating cancer transmission.

 

The second known example of a transmissible cancer is one that contrasts with DFTD in a number of ways. It is called Canine Transmissible Venereal Tumor (CTVT) disease, and occurs in all breeds of dogs throughout the world but at a low frequency. Unlike DFTD, which is transmitted through fighting, CTVT disease is transmitted through sexual contact. The tumors grow as small nodules on sexual organs.

 

It is clear that CTVT disease is a better-adapted clone than DFTD. It exhibits very low virulence, a necessary condition for sexual transmission, and normally regresses without any treatment. This is in contrast to the highly virulent cancerous clone in devils, which could wipe out the entire population of devils leading to its own destruction. The likely reason for this difference between the two diseases is that CTVT disease is much older. CTVT disease is thought to have originated up to 65,000 years ago, possibly in a dog/wolf ancestor, giving the cellular clone a long period of time to adapt to its host. On the other hand, DFTD is thought to have arisen up to only 20 years ago, leaving little time for adaptation. So scientists are hopeful that, if the devil population survives, DFTD will also become less virulent over time.

 

An interesting question is, of course, should humans be worried about transmissible cancers? Unsurprisingly, there is very little evidence on this topic due to the unethical nature of potential experiments. However, there have been very occasional reports of transmission events. For example, one study in 1996 reported the accidental transmission of a malignant sarcoma from a patient by a surgeon when he injured his hand during an operation.  However, it is believed that such cases are extremely rare and that the risk of transmissible cancers is very low due to the high genetic diversity within human populations.

 

 


5 Ways to Make the Most Out of Your Grad School Experience

Welcome to grad school, you are on your way to adding 3 magical letters at the end of your name. As we'd like y'all to start well-informed and be prepared, our brilliant contributors share their wisdom and best advice on making the most our of your grad school (and beyond) experience!

That's our top 5:

  1. Run while you still can! Just kidding....
  2. Learn new things and learn all the time and it will all come together at the end, we promise!
  3. Take a careful look of the PI personality and lab's dynamics when choosing a lab.
  4. Keep it balanced, as in stay healthy!
  5. Diversify your experience at the bench and beyond it.

Now read on:Read more


Brain Bot

Mapping the Human Brain - the Challenges Faced

Sophia David

The human brain is made up of billions of neurons that communicate with each other via trillions of connections. Together, they make up a network of unimaginable intricacy. Perhaps it is not surprising then, given this complexity, that things frequently go wrong within the brain. Approximately 1 in 4 people suffer from a diagnosable mental health disorder within any given year and as many as five million Americans now live with Alzheimer’s disease.

Unfortunately, drugs to treat brain disorders have been slow to materialize. Many large pharmaceutical companies have withdrawn their research on mental health diseases due to the length of time it takes these drugs to be developed and the high failure associated with them. Essentially, to big pharma, the field is unattractive and economically not viable.

Our inability to Read more


Shining Light on Microbial Dark Matter

Sophia David

Microorganisms are the most abundant and diverse cellular life forms on the planet. Unfortunately though, we have only been able to culture a small subset of microbial species in the laboratory. These represent just a tiny fraction of the environmental diversity. Furthermore, we have only been able to sequence the genomes of organisms that we can culture. Our knowledge of microorganisms is therefore highly biased towards cultivated bacteria and archaea that almost certainly do not represent the full environmental diversity.

Research published two weeks ago in Nature by a team led by Tanja Woyke from the DOE Joint Genome Institute in California has attempted to address this issue. The researchers used an emerging technique Read more


First Fluorescent Protein Identified in Vertebrates

Sophia David

A novel fluorescent protein discovered in Japanese eels may offer superior experimental advantages and clinical applications

In the early 1960s, researchers investigating the bioluminescent properties of the Aequorea victoria jellyfish discovered a protein that has since revolutionized experimental biology. The protein is, of course, green fluorescent protein (GFP).Read more