Scientific data representation

As a graduate student, one is asked to read and interpret quite a few research and review papers every week. Usually, most of the articles represent data in the form of mundane tables and histograms, which can get tedious. Recently, I read this nature review article on zoonotic diseases (diseases spread between humans and animals, for example, malaria, west nile virus infection, ebola, H1N1 flu, etc) and was really impressed by the unique and creative way the data is represented in it.

NOTE: All images and image captions copyrighted to – Bean AG, Baker ML, Stewart CR, Cowled C, Deffrasnes C, Wang LF, Lowenthal JW. Studying immunity to zoonotic diseases in the natural host – keeping it real. Nature Reviews Immunology. Published online 25 October 2013. doi: 10.1038/nri3551

Figure 1: Emergence of zoonoses. / Tombstones representing number of deaths!

Over the past century, humanity has witnessed the emergence of numerous zoonotic  infections that have resulted in varying numbers of human fatalities. Influenza viruses that originate from birds account for  an important proportion of these deaths, and recently many new zoonotic viruses that originate in bats, such as Hendra  virus, Nipah virus and severe acute respiratory syndrome (SARS) coronavirus, have caused outbreaks with high mortality  rates. Hyperlinks to World Health Organization disease report updates are provided in BOX 1. MERS, Middle East  respiratory syndrome coronavirus.
Over the past century, humanity has witnessed the emergence of numerous zoonotic
infections that have resulted in varying numbers of human fatalities. Influenza viruses that originate from birds account for an important proportion of these deaths, and recently many new zoonotic viruses that originate in bats, such as Hendra virus, Nipah virus and severe acute respiratory syndrome (SARS) coronavirus, have caused outbreaks with high mortality rates.

Figure 2: The severity of emerging infectious diseases is influenced by the host-pathogen interaction. / Organisms in the innermost circle (bats) show no sign of symptoms at all and the signs increase as one moves to the organisms in the outer circle (humans) – leading to high mortality rates. Mainly, animals in the inner blue circle are the transmission hosts. Read ‘The curious case of MERS-CoV‘ for more on MERS transmission hosts.

Many  zoonotic agents cause little or no signs of disease in their natural hosts, such as wild birds and bats, but transmission hosts  might present with disease symptoms ranging from moderate (for example, pigs infected with avian influenza virus) to  severe (for example, horses infected with Hendra virus). The terminal or spillover host can present with severe symptoms  and high mortality rates (for example, in the case of humans infected with H5N1 influenza and Hendra virus). For some of  the most recently identified emerging infectious diseases, such as H7N9 influenza and Middle East respiratory syndrome  (MERS) coronavirus, natural and transmission hosts have not been conclusively identified (indicated by a question mark).  SARS, severe acute respiratory syndrome.
Many zoonotic agents cause little or no signs of disease in their natural hosts, such as wild birds and bats, but transmission hosts might present with disease symptoms ranging from moderate (for example, pigs infected with avian influenza virus) to severe (for example, horses infected with Hendra virus). The terminal or spillover host can present with severe symptoms and high mortality rates (for example, in the case of humans infected with H5N1 influenza and Hendra virus). For some of the most recently identified emerging infectious diseases, such as H7N9 influenza and Middle East respiratory syndrome (MERS) coronavirus, natural and transmission hosts have not been conclusively identified (indicated by a question mark). SARS, severe acute respiratory syndrome.

Figure 3: The host immune response to an infection influences the disease outcome. / The difference in immune response to H5N1 in different spillover hosts.

Infection with H5N1 influenza  virus can cause very different disease outcomes in different reservoir and spillover host species. Waterfowl, such as wild  ducks, are the natural host for this virus and develop a limited inflammatory response that is associated with low levels of  cytokine expression. Intermediate hosts, including mice, pigs and ferrets, are often used to study this infection and display  mild to severe disease symptoms (depending on the H5N1 virus strain used) that are associated with increased levels of  pro-inflammatory cytokines. By contrast, spillover hosts such as chickens and humans display a rapid and strong  inflammatory response, often referred to as hypercytokinaemia (or cytokine storm) and the infection becomes systemic,  causing severe disease symptoms and high mortality rates.
Infection with H5N1 influenza virus can cause very different disease outcomes in different reservoir and spillover host species. Waterfowl, such as wild ducks, are the natural host for this virus and develop a limited inflammatory response that is associated with low levels of cytokine expression. Intermediate hosts, including mice, pigs and ferrets, are often used to study this infection and display mild to severe disease symptoms (depending on the H5N1 virus strain used) that are associated with increased levels of pro-inflammatory cytokines. By contrast, spillover hosts such as chickens and humans display a rapid and strong inflammatory response, often referred to as hypercytokinaemia (or cytokine storm) and the infection becomes systemic, causing severe disease symptoms and high mortality rates.

I think it is really important to represent scientific data in a simple, straightforward and an efficient fashion. Many researchers disregard this fact and don’t acknowledge it well enough.  A really good diagram or data representation is one which contains all important facts or information required to infer the purpose of the diagram itself. One must be able to simply look at it to make interpretations and get the general idea without having to go too much into the depth of long procedures and discussions in the paper. (Sometimes exceptions exists w.r.t. the kind of paper & data, of course.)

Understanding sexual parasitism and cannibalism

The mating ritual of the deep-sea anglerfish is one of the most bizarre in the animal kingdom. The female anglerfish are larger, reaching a length of around 10 centimeters, and the male fish are just a fraction of this and can be more than ten times smaller. These peculiar (read ugly) looking creatures live at a depth of 1 to 3 kilometers in the ocean.  In the darkest depths of the waters where food is scarce, finding a mate is problematic. It is estimated that 80% of the females never encounter a male in their lifetime (which is around 30 years). These fish have adopted a way as to resolve the issue of nutrient and mate acquisition through evolution.

Female deep-sea anglerfish with attached male. Photo: Dr. Theodore W. Pietsch, University of Washington
Female deep-sea anglerfish with fused male (circle). Photo: Dr. Theodore W. Pietsch, University of Washington

The larger female anglerfish release chemical factors known as pheromones into the water for the males to find them. Upon finding her, the male bites onto her skin (the ultimate love bite in the animal kingdom, if you ask me) and gets fused to her permanently! His internal organs degenerates – except for the gonads which are used to impregnate the female – and he now survives solely on the female’s blood vessels to acquire nutrients. He never has to hunt for food in his life. The female can fuse with multiple males (around 6 to 8) ensuring a fresh supply of sperm throughout her life! The males are reduced to a mere small lump of tissue on the female’s skin.

While the anglerfish’s mating ritual serves as a classic case of sexual parasitism, another interesting and even bizarre reproductive behavior is seen in Australian redback spiders, in which the males are consumed (yes, eaten!) by the females during copulation. A male redback spider performs a somersault behavior during sperm transfer and positions it’s abdomen on top of the female’s jaws. The female starts to feed on the male during the duration of copulation. One may ask, why would the male spider want to risk his life and sacrifice himself? The answer is simple: survival of the species through increased reproductive success.

A female Australian redback spider. Photo: Toby Hudson on Wiki Commons

A female Australian redback spider. Photo: Toby Hudson on Wiki Commons

Darwin in 1871, wrote The Descent of Man, and Selection in Relation to Sex, where he proposed sexual selection to explain how some traits evolve to give an advantage in the struggle for reproduction, but reduce the probability of survival. This is exactly what happens in Australian redback spiders. Sexual cannibalism is favored by selection because the cannibalized male spiders receive two paternity advantages. Through a series of behavioral experiments, Maydianne C. B. Andrade found that cannibalized males copulated for longer periods of time during which more eggs are fertilized (advantage #1). After consuming their first male, females reject subsequent males for copulation. This increases the paternity of the first male since the female only produces his off-springs and reduces the probability of her mating with a second male (advantage #2). This explains why sexual cannibalism is in fact, an adaptive strategy for male redback spiders since it increases their reproductive value.

These wild mating rituals of certain creatures may seem strange and even outrageous at first. However, one can appreciate these reproductive strategies when they’re understood in the light of evolution.

Two new drugs for Hepatitis C

Recently, two new oral drugs were considered for approval for Hepatitis C – a viral infection caused by Hepatitis C Virus (HCV) that affects liver cells and ultimately causes liver failure and/ or hepatocellular carcinoma due to chronic condition. One may not have heard much about the Hep C disease, but it is more common than HIV. WHO has estimated that around 150 million people around the world are chronically infected with HCV and more than 350,000 people die every year from Hep C related liver diseases. So far, smallpox is the only viral disease of humans that has been completely eradicated from the planet due to the success of vaccination strategies using live attenuated vaccinia viruses. No vaccine is available against HCV owing to the high mutation rates of it’s positive single stranded RNA genome.

Current treatment for Hep C involves injecting interferon- a class of cytokines which induces an antiviral state in the infected cells and enhances the immune system. It is given in combination with ribavirin, which is a nucleoside analog. Being a prodrug, ribavirin is activated inside the cell and inhibits viral replication by interfering with viral RNA synthesis and viral mRNA capping. However, simeprevir and sofosbuvir – the newly approved oral medications, are meant to directly interfere with HCV’s ability to replicate and make proteins when taken along with ribavirin. In a phase II trial, about 78% of patients infected with HCV were cured with a combination of sofosbuvir and ribavirin without the need of interferon. This is not a new strategy when it comes to antiviral drug treatments. Similar kinds of “drug cocktails” are used to treat HIV infection as a part of Highly Active Antiretroviral Treatment therapy.

In an interview with Nature, pharmacologist Raymond Schinazi of Emory University said “This is the first time in the history of humankind that we have a cure for a viral disease”. This statement may seem too far fetched considering the nature of the virus and it’s ability to reside in the cells for many years causing no external symptoms. Also, there is always the case of emergence of drug resistant strains due to highly mutable viral genomes. Antiviral drug treatment studies take extremely long periods of time to evaluate the outcome across the globe. However, an advantage for HCV treatment efforts is that the virus has no animal reservoirs and is transmitted between people only through contaminated blood. Increased and improved blood screening techniques can prevent transmission of the virus among populations.

The Curious Case of MERS-CoV

MERS - Coronavirus - has a crown-like appearance when viewed under an electron microscope. Credit: NIAID on Flickr
MERS – Coronavirus – has a crown-like appearance when viewed under an electron microscope. Credit: NIAID on Flickr

A couple of days back, I briefly spoke about the theories surrounding the origin of MERS-coronavirus on twitter and got interesting responses like “Batman!” during the discussion. (Let us not eliminate this possibility entirely, okay?) Middle Eastern Respiratory Syndrome, which was first reported in Saudi Arabia in September 2012 1, is similar to SARS, and causes severe respiratory illness with symptoms of cough, fever, and shortness of breath including acute renal failure which ultimately results in death of the infected individuals in fifty percent of the cases. So far, 150 cases have been reported by CDC 2, which include 64 deaths (most affected countries being Saudi Arabia, United Arab Emirates, Jordan and Qatar). What’s interesting is the quest to find the origin of the virus and it’s mode of transmission.

Since most viruses are harbored and transmitted by animals, a team of scientists first suspected the most plausible animal in the Middle-East that could’ve sheltered this virus – camels! Antibodies against MERS-CoV (and not the virus itself) were found in some retired racing camels in Oman 3. The specificity of the antibodies against MERS were tested positive in every single camel but none of the animals had antibodies against SARS. These false positive results further raises questions about camels being the original animal reservoir of the virus .

Bats are the next key suspect because viruses related to MERS are found in several bats species. More specifically, SARS-CoV comes from bats. These mammals are also the reservoir for Nipah virus, Hendra virus, Rabies virus, Ebola virus, and Marburg virus – all of which belong to other families. Not surprisingly, Columbia University virologist Dr. W Ian Lipkin found a 187-nucleotide RNA fragment in the feces of an Egyptian tomb bat that exactly matched the corresponding sequence in MERS-CoV 4 that was isolated from one of the victims. A possible theory is that humans may have been infected with the virus by coming in contact with bats’ feces during encroachment of old abandoned buildings, which serve as a natural habitat for tomb bats. However, Dr. Lipkin does not think that the bats could’ve infected humans directly 5.  Here’s where the camels from Oman come into picture, by acting as an intermediate host for the virus. The virus could’ve been transmitted to camels through the bats’ droppings. Humans and camels posses a close relationship in the Middle-East where the animals of burden, used for their meat and milk, are imported from other countries. An alternate possible explanation is that the virus might have originated in bats from one of these countries, hitchhiked on the exported camels and spread in the Middle-East.

Given only the small sampling of camels and bats in these countries so far, one can speculate the existence of other hosts for the virus. Perhaps there are other missing links in the chain of transmission. Other bats & wildlife species and domestic animals for CoV infection, and their link to humans must be investigated. It is a situation of race against time for scientists when a new virus emerges faster than our understanding.

SOURCES:

  1. Zaki AM, van Boheemen S, Bestebroer TM, Osterhaus AD, Fouchier RA. 2012. Isolation of a novel coronavirus from a man with pneumonia in Saudi Arabia.  The New England Journal of Medicine. 367: 1814 – 1820
  2. MERS webpage on CDC – http://www.cdc.gov/coronavirus/mers/
  3. PubMed Health News Article – http://www.ncbi.nlm.nih.gov/pubmedhealth/behindtheheadlines/news/2013-08-09-camels-may-be-source-of-mers-virus-transmission/
  4. Memish ZA, Mishra N, Olival KJ, Fagbo SF, Kapoor V, Epstein JH, et al. Middle East respiratory syndrome coronavirus in bats, Saudi Arabia. Emerging Infectious Diseases. Vol 19. November 2013
  5. Dr. Ian Lipkin for Science – http://news.sciencemag.org/health/2013/08/bat-out-hell-egyptian-tomb-bat-may-harbor-mers-virus