The Emergence of Synaesthesia in a Neuronal Network Model via Changes in Perceptual Sensitivity and Plasticity by Oren Shriki , Yaniv Sadeh, Jamie Ward

Architecture of a general network model for studying synaesthesia.

The network consists of two interacting modalities. Each modality has a set of input neurons and a set of output neurons. There are feedforward connections within each modality but not between them. There are recurrent connections among all output neurons. The subset of recurrent connections that connect the two modalities are referred to as cross-talk interactions. The goal of the network is to optimize the representation of the combined input from both sets of input neurons, by the neurons at the combined output layer. 

For the last twenty years, theories of synaesthesia have been dominated by two general models: disinhibited feedback from multi-sensory regions to uni-sensory regions, and cross-talk theories which have emphasised the presence of atypical (and direct) structural connectivity between modalities [33]. Whereas the former explanation has tended to be favoured for explaining acquired synaesthesia, the latter has dominated explanations of developmental synaesthesia. The approach taken in our computational model represents a significant departure from this current status quo, and has generated novel insights. Our model repositions synaesthesia not as some quirk of aberrant connectivity but rather as a functional brain state that emerges, under certain conditions, as a consequence of optimising sensory information processing. In short, this model goes beyond others by offering an account not only of howsynaesthesia emerges but also of why synaesthesia emerges. It offers a unifying account of acquired and developmental forms of synaesthesia insofar as it explains how the same outcome can emerge under different conditions within the same model. 

Acquired synaesthesia is often associated with sensory deprivation due to damage to the sensory organs or pathways. Our model proposes that the same learning process that optimizes information representation naturally causes neurons in the deprived modality to enhance incoming inputs from intact modalities, leading to synaesthesia. To provide some intuition, we note that our model maximizes the output entropy of the network, which depends on two factors: one is the entropy of each single neuron, i.e. how variable the activity of single neurons is, and the other is the correlations among the neurons. Maximizing this entropy favours high single neuron entropy and low correlations among the neurons. The cross-talk connections induce correlations between the two modalities, which in general tend to reduce the output entropy. However, when one modality is deprived of input, it may be beneficial to have cross-talk connections from the intact modality to the deprived modality. The increase in the single neuron entropy due to the cross-talk connections can compensate for the higher correlations and result in a total increase of the output entropy. Loosely speaking, the deprived neurons seek for other neuronal sources of variability and enhance their connections with them. This mechanism, which emerges naturally in our computational framework, can also be useful for modelling the changes in neural representation that take place in other conditions such as phantom-limb [34]. 

Although functional accounts for acquired synaesthesia have been proposed in the past, no such comparable account has been put forward for developmental synaesthesia. Our model suggests that it arises from instability in the learning process due to high plasticity. It implies that synaesthetes have higher plasticity compared to non-synaesthetes or a relatively prolonged period of high-plasticity during childhood. Later on, as plasticity in the relevant brain areas decreases, the evolved cross-talk connections become stable. In line with this idea, whole-genome studies link some forms of synaesthesia to genes involved in plasticity, which have higher expression during early childhood [35]. Furthermore, developmental synaesthesia does not appear to be linked to sensory impairments and, if anything, is linked to increased perceptual sensitivities (notably within the concurrent modality). For instance, grapheme-colour synaesthetes show enhanced colour discrimination abilities [36]. In the proposed model, the recurrent connections within the concurrent modality amplify both its direct inputs and the ones from the inducer modality. Thus, an association between synaesthesia and increased perceptual sensitivity is an emergent property of the model, at least under certain scenarios, and it is important to explore the extent to which the presence of synaesthesia (cross-modal sensitivity) necessarily goes hand-in-hand with changes in intra-modal sensitivity. In terms of the underlying neurobiological mechanisms, the increased amplification by the recurrent interactions in our model is consistent with findings that indicate increased excitability and elevated glutamate concentration in the relevant cortical areas in synaesthetes [37, 38]. 

Traditionally, synaesthesia has not been linked to theories of learning and memory because it has been considered to reflect an innate (in its developmental form) cross-wiring of the senses. This view has been challenged on several fronts [e.g. 39, 40]. Firstly, many of the stimuli that induce synaesthesia (e.g. graphemes) are themselves learned. Secondly, for some synaesthetes the particular associations have been influenced by childhood coloured letter sets [13]. Moreover, some general cross-modal correspondences (e.g. between pitch and vertical positions) thought to reflect innate vestiges of synaesthesia have been shown to occur as statistical regularities in the environment [41]. Finally, synaesthetes (at least for grapheme-colour synaesthesia) are known to have better acquisition of new memories, and this may be related to increased plasticity during learning [32]. Future simulations of the model could use partially correlated inputs to the two modalities to model childhood exposure to coloured letter sets (they are not fully correlated given that most literacy exposure is with achromatic letters). It may well be the case that there is an interaction between learning rate (an innate parameter within the synaesthete brain) and these partial associations (in the environment), which explains why most people do not go on to develop synaesthesia after exposure to these stimuli. 

An interesting hypothesis that emerges from this study regards the relationship between synaesthesia and the concept of critical brain dynamics [28, 42, 43]. The goal of the learning process in our model is to find the pattern of recurrent interactions that maximizes the sensitivity of the network to changes in its external inputs. In analogy to physical systems, in which the sensitivity (often termed susceptibility) to external inputs diverges near a critical point [44], here, as the network maximizes its sensitivity, it also tends to approach a critical point [28]. This critical point represents the border between normal amplification of external inputs and a regime governed by attractor dynamics. In the context of sensory processing, the super-critical attractor phase can be thought of as hallucinations that reflect the learned pattern of interactions. A useful measure for identifying critical dynamics is the time it takes the recurrent network to reach steady-state. When close to critical points, many dynamical systems display the phenomenon of critical slowing down [28, 45]. Interestingly, in simulations of the complex model in which synaesthesia evolved, when the learning process approached the optimal pattern of interactions, the dynamics of the recurrent network became substantially slower (the number of iterations required to process each input sample until reaching steady-state was ~35000–45000 compared to ~1000–4000 in the beginning of the learning process). This observation suggests that in the proposed model networks that developed synaesthesia operate closer to a critical point compared to networks that did not develop synaesthesia. The prediction is that there may be evidence of the neural signatures of critical dynamics in synaesthetes [46, 47], particularly as synaesthesia is developing. 

In terms of its similarities to other models, our model resembles the direct cross-talk (or cross-activation) models proposed by others [48] primarily to account for developmental forms of synaesthesia. Although the model represents a direct form of cross-talk, it is an open question as to whether the model would produce similar patterns if neurons from modalities 1 and 2 were not directly connected but were themselves both connected via a third pool of neurons that receives no direct input from 1 and 2. There is some evidence for both direct and indirect types of neural architecture in synaesthesia as assessed via fMRI effective connectivity [49]. The addition of an interconnecting hub area in future modelling attempts would give the model top-down representations that could be adapted to the (Bayesian) predictive coding framework. Unlike the present (bottom-up) model, the predictive coding approach describes perception as top-down inference that is constrained and altered by sensory signals. A non-computationally explicit account of synaesthesia in terms of predictive coding has been articulated [50]. Moreover, the kinds of learning algorithms employed in our model are compatible with this approach [51]. 

The gradient-based learning rules used in this study are not local and are thus expected to reflect the long-term evolution of the system rather than mimicking the moment-by-moment dynamics of real neural circuits. In addition, the neurons in the model are described by simplified rate dynamics which do not capture the complex dynamics of real neurons. An important direction for future modelling work would be the examination of more biologically realistic networks that also optimize information representation. The scenarios for the evolution of synaesthesia described in this study are very general and we believe that similar scenarios would appear also in more realistic networks.

In summary, these computational models permit new ways of thinking about synaesthesia both in terms of causal mechanisms and in terms of optimising perceptual function. It generates non-trivial outcomes (e.g. generating monotonic mappings not found in the input characteristics) and non-trivial predictions (e.g. relating to learning, unimodal perceptual sensitivity, hallucinatory tendencies).

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Malaria parasite doesn’t pass drug immunity to its offspring

by Tina Hesman Saey

Malaria parasites (shown in blue infecting a red blood cell) can become resistant to an antimalarial drug. But the parasites can’t pass the resistance on to their offspring, a new study has found.

NIAID/Flickr (CC BY 2.0)

Malaria parasites may build up a genetic tolerance to an antimalarial drug, but they can’t spread that resistance to future generations, researchers report in the April 15 Science.

Malaria parasites can develop mutations in the cytochrome b gene that make them resistant to a drug called atovaquone, an ingredient in the antimalarial medication Malarone. Those parasites can reproduce in human or animal hosts, but the offspring have developmental defects and die in the mosquito portion of their life cycle, Christopher D. Goodman of the University of Melbourne and colleagues discovered.

The researchers tried to transmit a drug-resistant form of malaria to mice 44 times, involving 750 mosquito bites. Only one attempt succeeded, and that parasite couldn’t spread further even after seven attempts, Goodman and colleagues found.

Cytochrome b is needed for energy generation by mitochondria. Because mitochondria are inherited from the mother, even breeding with parasites that don’t have cytochrome b mutations won’t help the parasite escape its fate. The findings suggest that other antimalarial medications that target maternally inherited organelles in the parasite may also have limited drug resistance.

Vaccinating Against Measles Could Also Protect You From Other Infectious Diseases

 by Justine Alford
Photo credit: RidvanArda via Shutterstock.

Regardless of your stance, vaccination against measles is one of the safest, most successful and cost-effective public health interventions so far in history. Prior to mass vaccination campaigns, around 4 million people in the US got measles every year, 500 of whom died, 48,000 were hospitalized, and 4,000 suffered serious brain swelling; it’s far from a trivial infection. But thanks to immunization campaigns, cases have dropped by more than 99%.

But it turns out that this jab does far more than just protect you against infection with the measles virus; it protects you from other infectious diseases. 

How? 

According to a new study, measles puts your immune system into a state of amnesia for up to 3 years after infection, leaving you vulnerable to a whole host of other potentially fatal diseases. Vaccine hesitancy therefore doesn’t just threaten community immunity against measles, but also an abundance of other microbes.

Scientists have known for some time that measles profoundly dampens the immune system, attacking cells that retain a memory of past infections. However, this was assumed to be short-term, possibly only lasting a few weeks or months. But since the introduction of mass vaccination campaigns, scientists have observed some striking effects which suggested that there is more to the story. For example, mass measles immunization in some of the world’s poorest countries has reduced overall childhood deaths by a staggering 90%. Furthermore, declines in mortality from infectious diseases after receiving the vaccine can last up until a child is 5 years old.

Although scientists aren’t sure of the exact mechanism behind this apparent protective effect, recent work on monkeys started to shed light on this mystery. After the anticipated drop in protective white blood cells following infection, their immune systems quickly bounced back within a few weeks. 

However, a large number of these new cells would have arisen from the abundance of measles-specific cells that resulted from infection. So while the immune system seemed to be replenished, the original, broad repertoire of cells could have been replaced by one almost entirely directed against measles, resulting in a so-called “immune amnesia.”

To examine this idea further, Princeton scientists began probing data on measles cases and deaths from other infectious diseases, pre- and post-mass vaccination campaigns, in three countries: the US, UK and Denmark. More specifically, they wanted to see if there were any relationships between measles cases and deaths among children.

As described in Science, they found that measles infection affected resistance to other diseases for up to 3 years. Furthermore, they found the tight relationship between measles incidence and deaths from other infectious diseases during this vulnerable period still occurred after measles vaccinations were widely used, indicating that the vaccine protects against more than just measles virus.

“In other words, reducing measles incidence appears to cause a drop in deaths from other infectious diseases due to indirect effects of measles infection on the immune system,” lead researcher Bryan Grenfell explained in a news-release.

To make the data more watertight, they also examined whooping cough data, which doesn’t suppress the immune system. This failed to turn out any links between whooping cough and mortality from non-measles infectious diseases, suggesting the finding is indeed specific to measles.

Since the study produces indirect, rather than direct, evidence for the protective effect of the measles vaccine, further studies are warranted to confirm their findings. However, the researchers are already planning on exploring potential immunological mechanisms further.

[Via Science, Science and Princeton University]

Ancient Ancestors Had More DNA Than We Do Now: Have we Devolved?

Adding to the number of unsolved mysteries regarding the ancient origins of humanity and the biology of our species, scientists have discovered that we have less DNA now than our ancient ancestors possessed. Are we de-evolving?

A study published this week in the journal Science has found that modern humans lost DNA as we evolved after our split from apes. Our ancient ancestors, early humans, possessed substantially more amounts of genetic data than we do now. This surprising discovery raises many questions, the most obvious one being: why did we lose all that genetic information? Also, what difference has the loss made?

The short answer is: we don’t know yet.

According to news website Gizmodo, the team of researchers led by Professor Evan Eichler, geneticist at the Department of Genome Sciences, University of Washington, sequenced the genomes of 236 individuals from 125 distinct populations. They found that Homo sapiens have shed approximately 40.7 million base pairs of DNA after breaking from our closest living relatives, chimpanzees, around 13 million years ago.

Map of the 125 populations sampled in the study and their relation to each other. (P. Sudmandt et al 2015)

The genome of modern humans now contains 3 billion base pairs of DNA (complex molecules which contain all of the information necessary to build and maintain an organism, the building blocks of life), and even then scientists are unsure how much of that number is so-called “junk DNA”—genomic data whose function, if it has any, is not understood—but they do assert that at least 27.96 million of the base pairs lost were unique.

Common relationships were traced via DNA deletions among groups of humans. The longer lines show groups with more missing DNA. (P. Sudmandt et al 2015)

Have modern humans beneficially shed superfluous DNA, or have we lost something important over the generations?

Eichler proposes that a migration out of Africa reduced the human population in new areas and played a role in the loss of DNA.

Study authors write, “the breadth of the dataset allowed us to reconstruct the structure and content of the ancestral human genome prior to human migration and subsequent gene loss.’

‘As expected, Africans were more likely to show evidence of these ancestral sequences compared to non-African populations, as the latter have experienced more population bottlenecks and thus retained less of the ancestral human diversity.” Meaning that those individuals who were more connected with Africa had retained more DNA than those who had descended from migrated populations.

MailOnline reports, “The human genome has around three billion base pairs, which reside in 23 chromosomes in the heart of almost every cell in our body. The average gene in the human genome is around 765 base pairs long, meaning humans could have lost the equivalent of up to 37,000 genes since splitting from our ape cousins.”

Adding to this mix is the historic breeding of modern humans with the now extinct Denisovans and Neanderthals. Segments of Denisovan and Neanderthal DNA can be identified now in modern populations. But Neanderthals and Denisovans had around 104,000 base pairs in their genomes that are not found in modern humans. Researchers found that Neanderthals and Denisovans were missing some ancient DNA as well, suggesting these extinct species had lost significant portions of genetic code.

“Their results showed that our ancestors shed about 15.8 million base pairs of DNA before leaving Africa. As populations spread across Earth’s continents, they jettisoned additional chunks of DNA here and there. But certain populations have also been gaining DNA, mostly through duplication events where portions of the genetic code were accidentally copied and passed on,” reports Gizmodo.

While modern humans may presume that the shedding of DNA has honed us to the peak of evolutionary perfection, science can show that not all of our changes have been beneficial. In one example, research suggests that our hands are actually more primitive than those of our chimp ancestors, despite our adaptations for the use of tools.

Chimpanzee hand, at left, and human hand, right.

This is the first time scientists have documented the loss (and gain) of large chunks of DNA in ancient populations. This genetic research may shed light on the enduring questions of how modern humans evolved and survived while other hominin died out.

Scientists still can only speculate as to what these results indicate, but as more research is done we can fill in the missing gaps of our understanding of the ancient story of humanity.

Featured Image: A DNA molecule that is methylated on both strands on the center cytosine. DNA methylation plays an important role for epigenetic gene regulation in development and cancer. (C. Bock/Wikimedia Commons)

By Liz Leafloor    

Vaccine-Preventable Outbreaks

Vaccinations are one of the of most incredible aspects of modern medicine. They can make previously lethal diseases disappear from society and save countless lives. There is, however, a chance that the vaccines work a little too well and our collective memory is too short to remember the devastating effects some of these diseases caused just a few short decades ago. Recently, for reasons that are not based on science or logic, many parents have outspokenly rejected vaccinating their children. Unfortunately, this has caused a reemergence of easily managed diseases. The Council on Foreign Relations has released an interactive map detailing the catastrophic outcome of these poor choices. 
The interactive map gives a gut-wrenching tour of global outbreaks of measles, mumps, rubella, polio, and whooping cough from 2008-2014. These diseases -- all of which are easily prevented by vaccines -- can have dire consequences. The CDC estimates that 164,000 people around the world will die from measles each year, and it is experiencing quite a resurgence in the UK. The United States has recently seen a drastic increase in whooping cough, which causes around 195,000 deaths per year. The majority of these deaths occur in impoverished regions with very little access to vaccines. In the case of developed areas like the US or UK, they shouldn’t be happening at all.
Update (10/24/2014): CFR's map has now been updated to document attacks on health care workers, which have been increasing in recent years. These attacks are indicated on the map with red triangles. Additionally, these attacks correlate with increased instance of disease, including a polio outbreak in Afghanistan. Socio-economic trends can also be seen, as incedence of measles and whooping cough are increasing in wealthier areas like the US and UK, while poorer areas indicate lacking adequate supplies and give health officials a clear idea of where efforts need to be increased.
But how did it all begin?
In 1998, Andrew Wakefield released a paper claiming to have linked the measles, mumps, and rubella (MMR) vaccine to the onset of autism. No other scientist was ever able to match Wakefield’s findings, and in the coming years, it became known that Wakefield had a financial conflict of interest. In 2010, an ethics review board found that he had falsified the data in his report, causing an immediate retraction of his original paper and revocation of his medical license. Despite the fact most scientists opposed Wakefield’s “findings” from the start, some were all too eager to jump on the anti-MMR bandwagon.

Among those leading the charge against vaccines is Jenny McCarthy, the Playboy Bunny-turned-pseudoscience advocate. McCarthy began speaking out against vaccines in 2007, as she believed they caused her son’s autism. Based on her son’s symptoms, some believe the boy actually has Landau-Kleffner syndrome. She has written a few books (including one with a foreword by Wakefield himself) continually claiming that vaccines cause autism and that she cured her son’s disorder with alternative treatment, without a shred of credible medical evidence. In the face of a possible misdiagnosis and absolutely no scientific evidence to support the claim that vaccines cause autism, she remains unchanged in her opinion. Unfortunately, her celebrity status has given her a platform to use anecdotal (not scientific) evidence to urge parents against vaccines.

Of course, absolutely nothing is without risk and there can be side effects from vaccines, but those are incredibly rare. Some people are unable to be vaccinated due to allergies or other medical conditions. This makes it altogether more important for those who can get vaccinated to do so, creating a herd immunity for our most vulnerable members of society.

The full version of the map is available on CFR’s website.

First Complete Mapping Of Human Proteome Discovers 193 New Proteins

May 29, 2014 | by Janet Fang

Photo credit: Catalog of human proteins / H. Hahne, TUM

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In separate papers published this week, two independent teams have drafted the first maps of the human proteome -- which charts all of the proteins that make up a person. And both teams discovered that proteins do come from “noncoding” DNA sequences. 

The proteome is an important complement to the genome and transcriptome, and together they create a more complete resource for researching health and diseases. While genes determine many of our characteristics, they’re able to do that by providing instructions for making proteins. So these draft maps -- which you can think of as the Human Genome Project for proteins -- consist of profiles of proteins expressed in all sorts of different human cell types. Both drafts were generated using mass spectrometry. 

One of the teams, led by Akhilesh Pandey from Johns Hopkins University, identified and annotated proteins encoded by 17,294 genes – that accounts for around 84 percent of all the genes in the human genome that are predicted to encode proteins (that number is estimated at 19,629, if you’re curious). The team extracted proteins from samples of 30 different tissues, then used enzymes to cut them into small pieces called peptides. They ran the peptides through a series of instruments to identify and measure their relative abundance. 

They also discovered 193 novel proteins that come from regions of the genome that haven't been predicted to code for proteins. Within the genome, there are stretches of DNA whose sequences don’t follow a conventional protein-coding gene pattern – these have been labeled as noncoding. “The fact that 193 of the proteins came from DNA sequences predicted to be noncoding means that we don’t fully understand how cells read DNA, because clearly those sequences do code for proteins,” Pandey explains in a news release. 

The other team, led by Bernhard Kuster of Technische Universität München (TUM) in Germany, assembled protein evidence for over 18,000 genes (or 92 percent of the entire proteome) by compiling raw mass spec data from databases and other analyses that were already available. These include a core of 10,000–12,000 proteins expressed in several different tissues, and to fill in the gaps, they generated their own mass spec data by analyzing 60 human tissues, 13 body fluids, and 147 cancer cell lines. 

Like the Hopkins team, they also found evidence of translation from DNA regions that were not thought to be translated. This includes more than 400 translated long, intergenic non-coding RNAs (lincRNAs). "While we have a good idea of what the genome looks like, we didn't know how many of those potentially 20,000 protein-coding genes would actually make protein," Kuster tells BBC. The team also identified protein markers that may pre

dict an individual’s resistance or sensitivity to drugs for diseases like cancer.

“You can think of the human body as a huge library where each protein is a book,” Pandey says. “The difficulty is that we don’t have a comprehensive catalog that gives us the titles of the available books and where to find them.” Now it looks like we’ve got two first drafts of that comprehensive catalog. Each group has built a publicly accessible, interactive database of their datasets: Human Proteome Map and ProteomicsDB. 

Although they had seen each other's work at conferences, both Pandey and Kuster tell BBC they had "no idea" they were headed towards publishing simultaneously. And now they share a Nature cover. "We never saw this as a race to be first," Kuster says. "My interpretation is that when the time is right, somebody's going to just do it. And perhaps two people are going to do it!" Here's the human body map of protein expression. 

The findings [here and here] were published in Nature this week. 

[Johns Hopkins, TUM via The Scientist, BBC]

Images: H. Hahne, TUM

Microorganisms From Earth Could Survive On Mars

 by Justine Alford

Photo credit: University of Arkansas. Test tubes containing methanogens, water, nutrients and sand.

The prospect of finding life on another planet is certainly a thrilling one. Over the years, scientists have tried to theorize how life started on our own planet in order to predict how life could begin in other habitable planets. In particular, researchers have been interested in microbes living in “extreme” environments since some of these are thought represent some of the oldest forms of life on Earth. These ancient and highly specialized organisms, called “extremophiles”, are thought to be able to grow pretty quickly in harsh conditions and are therefore an attractive candidate for the existence of life on other planets.

In line with this, researchers from the University of Arkansas have been investigating extremophilic organisms and exposing them to Mars-like conditions to see how they fare. In particular, they wanted to see if two species of methanogens could withstand Martian freeze-thaw cycles.

Methanogens are microorganisms within the domain archaea which is a domain distinct from bacteria. They’re actually responsible for the methane in the belches of ruminants and the flatulence of humans. Methanogens are methane producing anaerobic organisms, some of which use hydrogen to reduce carbon dioxide into methane. Because these organisms are anaerobic and non-photosynthetic, some scientists believe that they could be an ideal candidate for life on Mars; in particular, it is thought they could exist in sub-surface environments.

In order to test their survivability in Mars-like conditions, scientists exposed M. formicicum and M. wolfeii to Martian freeze-thaw cycles that are far below the ideal growth temperature of these organisms (37^oC and 55^oC, respectively). These organisms are in fact both thermophiles, which are extremophilic organisms that thrive at relatively high temperatures. The scientists found that both species survived the Mars-like temperature ranges in the laboratory.

“The low temperature on Mars inhibited their growth, but they survived,” said Rebecca Mickol, one of the researchers involved in the study, in a news-release. “Once they got back to a warm temperature, they were able to grow and metabolize again. I wanted to see if these cold temperatures would kill them, or if they were able to survive and adapt.”

According to Mickol, the temperature of Mars can range from between -90^oC and 27^oC in just one Martian day. “If any life were to exist on Mars right now, it would at least have to survive that temperature range. The survival of these two methanogen species exposed to long-term freeze/thaw cycles suggests methanogens could potentially inhabit the subsurface of Mars,” she added.

Back in 2004, methane was discovered in the atmosphere of Mars. Lead researcher of this study Timothy Kral believes it is possible that methanogens are the source of this methane, and has been studying the ability of these organisms to withstand Mars-like conditions since the ‘90s.

Of course, just because these organisms can survive these dramatic temperature ranges, this does not necessarily mean that methanogens can survive on Mars. It’s a little more complicated than that. It isn’t clear whether the researchers also replicated other conditions found on Mars besides these temperatures. But it's a very interesting study that certainly demonstrates the capability of these organisms to survive some of the harsh conditions found on Mars. 

Semi-Synthetic Organism Uses New DNA Bases

 by Lisa Winter

Photo credit: schulergd

Life, on the most basic level, is incredibly simple in theory yet vastly complex in practice.

DNA is made out of only four nucleic acids: adenine which pairs with thymine, and cytosine which pairs with guanine. For simplicity’s sake, these molecules are typically referred to by just their first letter. A set of three ‘letters’ is known as a codon, which is how DNA is read.

There are 64 possible codons that code for one of 20 standard amino acids (though three are used for punctuation purposes) for eukaryotes. The order in which the amino acids are put in the chain will determine the shape, structure, and function of all the different proteins created.

If all of that diversity can stem from only 4 nucleic acids, what would happen if new ‘letters’ were introduced to the genetic alphabet?

Recent research led by Floyd Romesberg of The Scripps Research Institute leads us one step closer as his team has created a plasmid with a novel pair of nucleic acids known as d5SICS and dNaM in the sequence and introduced it into E. coli bacteria.

Though this has been shown possible in a test tube, this is the first time it has been accomplished in an organism. The details of the research have been described in Nature.

Before anyone gets worried that this new DNA data is going to take over the world or some such nonsense, don’t get too ahead of yourself. Since these molecules aren’t found in natural cells, the ingredients to make them aren’t readily available in cells either.

The researchers were able to make this breakthrough by utilizing a triphosphate transporter found in microalgae that was capable of dealing with these new additions.

"When we stopped the flow of the unnatural triphosphate building blocks into the cells, the replacement of d5SICS-dNaM with natural base pairs was very nicely correlated with the cell replication itself—there didn't seem to be other factors excising the unnatural base pairs from the DNA," lead author Denis Malyshev said in a press release. "An important thing to note is that these two breakthroughs also provide control over the system. Our new bases can only get into the cell if we turn on the 'base transporter' protein. Without this transporter or when new bases are not provided, the cell will revert back to A, T, G, C, and the d5SICS and dNaM will disappear from the genome."

While these new molecules work well during DNA replication, the next steps in the research will be to manipulate RNA so they can be integrated into the synthesis of new unnatural proteins. This could be used for information storage as well as a new family of nanomaterials

Scientists Believe They Have Explained The Great Flu Outbreak Of 1918

by Stephen Luntz

Photo credit: US Naval Centre. This scene of mass hospitalization in Dartmouth from the 1918 flu epidemic was repeated all around the world

A paper claims to have solved on of the most important puzzles in infectious disease research: what made the 1918 influenza pandemic so lethal?

“Ever since the great flu pandemic of 1918 it has been a mystery where that virus came from and why it was so severe,” says Professor Michael Worobey of the University of Arizona. Between 50 and 100 million people died from the outbreak dubbed “the Spanish flu”, several times more than World War I, yet history books generally relegate it to a footnote.

While most of those who die from normal flu outbreaks are the very young or the elderly the 1918 outbreak was different – the heaviest death toll was among young adults, including those that had been in good health beforehand.

Interest is more than historical. There is little reason to doubt that a similar strain could return, and while modern medical technology would limit the death toll, no healthcare system in the world could cope with the volume of patients struck down in such a short period. Moreover, airtravel would likely see the disease cross the globe far faster than in an era when circumnavigating the world in 80 days was still the benchmark for speed.

The reason we still lack a universal flu vaccine is that the virus is always scrambling the hemagglutinin and neuraminidase proteins on its surface. "Imagine a soccer ball studded with lollipops," said Worobey. "The candy part of the lollipop is the globular part of the HA protein, and that is by far the most potent part of the flu virus against which our immune system can make antibodies. If antibodies cover all the lollipop heads, the virus can't even infect you." A different sort of lollipop, but with the same type of stick, will still attract antibodies that won't prevent infection but may slow the development of the virus “which protects you from severe disease and death," Worobey said.

Once infected or inoculated our body produces defenses against a particular combination, but these are of little or no use against a different form. The 1918 version has been labeled H1N1. Other versions of H1N1 have appeared since – the so called “swine flu” epidemic of 2009 was treated with such alarm because it was also H1N1 - but none have been so lethal.

Worobey compared samples from different H1N1 outbreaks to try to find the origins of the 1918 catastrophe. He thought this might settle debate between the two competing theories – a jump from birds or the reshuffling of genes between existing human and swine varieties. Instead in the Proceedings of the National Academy of Sciences he proposes a third option in which a human flu virus with the H1 protein in circulation for 10-15 years gained the N1 genes from a version infecting birds. He believes previous researchers have missed this because after 1922 a slightly different form of H1 displaced the one responsible for the 1918 outbreak, and scientists have been examining the wrong one until samples taken during the original outbreak were found.

"It sounds like a modest little detail, but it may be the missing piece of the puzzle," Worobey said. "Once you have that clue, many other lines of evidence that have been around since 1918 fall into place." 

It has previously been suggested that the reason people over 35 were less likely to die in the 1918 epidemic might be because they had been exposed to a form of flu with some similarity to the epidemic of that year; the same lollipop stick in Worobey's analogy. While the common features might not have been enough to stop them getting sick the immune system would have had just enough recognition to save their lives. Worobey endorses this, suggesting widespread exposure to either H1 or N1 in childhood would explain the relatively low death rate among the elderly from the pandemic.

However, Worobey also turns the idea on its head by proposing exposure to a very different version of the flu virus primed the immune system to misread epidemic version. The finger of suspicion is pointed at an H3N8 virus common between 1889 and 1900. Tens of millions of people would have been exposed to this virus in childhood and recovered, but Worobey said, “A person with an antibody arsenal directed against the H3 protein would not have fared well when faced with flu viruses studded with H1 protein. And we believe that that mismatch may have resulted in the heightened mortality in the age group that happened to be in their late 20s during the 1918 pandemic." 

Of course people could have been infected by both the H3 and the H1 versions at different times, but essential to Worobey's thesis is the idea that the first infection has the most impact in terms of the antibodies produced, what some researchers have called “original antigenic sin”. Even if they were infected by an H1 version in the early years of the century, those whose first exposure was to H3N8 were vulnerable.

Whether prior infection by the H3N8 virus was better than nothing remains unclear. On the one hand, island populations that may never have encountered flu at all experienced death rates higher than anything seen in urban areas. On the other,in places with good health records there is an extraordinary match in the death rates between those people who would have been exposed to H3N8 as their first dose of flu and the proportion who died (see chart below),

Worobey found support from recent outbreaks to back his theory up. In recent years The H5N1 virus has been much more likely to kill people born after 1968 than before. On the other hand, H7N9 is lethal to those born earlier, particularly in the late 1940s. He attributes this to each group having been exposed to a particular virus when young that offered some protection against one of the recent strains, but not against the other.

The good news here is that much of the population has now been immunized against numerous strains of flu. While these might not be enough to stop people getting sick from a novel version, it should keep the death rates down if we experience something as potentially devastating as the 1918 outbreak again. Further research on the way specific hemagglutinin and neuraminidase match up might help us design vaccines that would offer widespread partial protection to cover all options for future pandemics.

A Ghost of Evolution: The Curious Case of the Avocado, Which Should Be Extinct But Still Exists

by Maria Popova

“Even after thirteen thousand years, avocado is clueless that the great mammals are gone.”

In any market economy, it’s common sense that as soon as the consumer for a certain product ceases to exist, the product itself becomes moot and soon vanishes from stores. In nature, however — or market ecology, if you will — that need not necessarily be the case. In the altogether fascinating

The Ghosts of Evolution: Nonsensical Fruit, Missing Partners, and Other Ecological Anachronisms (public library), popular science writer and evolutionary biology champion Connie Barlow builds on the work of renowned ecologists Dan Janzen and Paul Martin, who in 1982 published a provocative paper arguing that many of the fruits and nuts found in Central American forests today evolved to be eaten by animals that have been extinct for thousands of years. Barlow explores the curious anachronistic existence of these species, ranging from papayas to persimmons to ginkgo biloba, and even coffee.

But as an avid aficionado of the avocado, I was especially taken with its particular story: Since fruits propagate by seeds, their progeny doesn’t grow far from the tree, as the proverb goes; their only chance of spreading their seeds across the land, then, are the animals who eat the fruit, along with its seeds, then “plant” those elsewhere when they poop.

The avocado’s abnormally giant seed presents anything from a severe digestive hazard to a death sentence for contemporary earthly species but, apparently, avocados coevolved with ground sloths and were originally eaten by gomphothere — elephant-like creatures that lived during the Miocene and Pliocene, between 12 million and 1.6 million years ago, who happily reaped the fruit with their hefty trunks, crunched them with their massive teeth, and passed the seeds comfortably through their oversized digestive tract.

Relic of a ghost: An avocado fruit and seed paired with the tooth of its missing partner in evolution, the gomothophere Cuvieronius.

The problem, of course, is that gomphothere no longer roam the Earth — and yet avocados still exist. Barlow writes:

Avocado’s strategy for propagation made a great deal of sense throughout the long life of its lineage — until the present moment. Even after thirteen thousand years, avocado is clueless that the great mammals are gone. For the avocado, gomphothere and ground sloths are still real possibilities. Pulp thieves like us reap the benefits. Homo Sapiens will continue to mold the traits of the few species of genus Persea it prefers. Ultimately, however, wild breeds will devolve less grandiose fruits, or else follow their animal partners into extinction.

In this fascinating short video for PBS, Joe Hanson of It’s Okay To Be Smart explains the avocado’s curious fate, along with those of its brethren of ecological anachronism:

Read more about this time warp of evolutionary biology in Barlow’s The Ghosts of Evolution.

Another International Darwin Day!

Posted by xdhaas on 12 February 2014

Posted in: Awareness Day. Tagged: charles darwin, Darwin, evolution, International Darwin Day, natural selection. Leave a Comment

International Darwin Day is here again, celebrating the birth of Charles Darwin!  The man, as I’m sure all of you know, is the person that came forth with the then-hypothesis (now scientific theory!) of evolution by natural selection. 

This concept was a breakthrough in understanding the world, not only in how things came to be but also how things will continue to adapt. 

It is the foundation of biology and an understanding of it is fundamental to life today, especially in the agricultural and pharmaceutical fields.  You can check out the basics of evolution in my What Is Evolution? post. 

You can also check out Darwin’s work here: The Complete Work of Charles Darwin Online

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International Darwin Day!
In "charles darwin"

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