Wednesday, October 29, 2014

GM Crops and the Rat Digestive Tract: Is GM Food Safe for Animals and Humans?

Global Research
by I.M. Zdziarski,  J.W. Edwards,  J.A. Carman , J.I. Haynes


The aim of this review is to examine the relationship between genetically modified (GM) crops and health, based on histopathological investigations of the digestive tract in rats. We reviewed published long-term feeding studies of crops containing one or more of three specific traits: herbicide tolerance via the EPSPS gene and insect resistance via cry1Ab or cry3Bb1 genes. These genes are commonly found in commercialised GM crops.

Our search found 21 studies for nine (19%) out of the 47 crops approved for human and/or animal consumption. We could find no studies on the other 38 (81%) approved crops.

Complete study at ScienceDirect.

Fourteen out of the 21 studies (67%) were general health assessments of the GM crop on rat health. Most of these studies (76%) were performed after the crop had been approved for human and/or animal consumption, with half of these being published at least nine years after approval. Our review also discovered an inconsistency in methodology and a lack of defined criteria for outcomes that would be considered toxicologically or pathologically significant.

In addition, there was a lack of transparency in the methods and results, which made comparisons between the studies difficult. The evidence reviewed here demonstrates an incomplete picture regarding the toxicity (and safety) of GM products consumed by humans and animals. Therefore, each GM product should be assessed on merit, with appropriate studies performed to indicate the level of safety associated with them. Detailed guidelines should be developed which will allow for the generation of comparable and reproducible studies. This will establish a foundation for evidence-based guidelines, to better determine if GM food is safe for human and animal consumption.

…. excerpts

Have enough studies been conducted to adequately state that GM crops are safe for human and animal consumption?

Genetically modified crops have been approved for human and animal consumption for nearly 20 years (Clive and Krattiger, 1996) yet the debate about their safety continues. Fifty-three crops are known to possess at least one of the genes investigated in this review (herbicide tolerance via the EPSPS gene and insect resistance via the cry1Ab or cry3Bb1 genes). Forty-seven of these crops have been approved for animal and/or human consumption, yet published toxicity studies could be found for only nine of these crops (19%) ( Table 1). Of greater concern is that for eight of these crops, publications appeared after the crop had been approved for human and/or animal consumption. We understand that other studies may exist that are commercial in confidence, but these studies are not accessible to the scientific community. Other than the few studies mentioned in the EFSA reports, where histopathological results were not reported, our review of the published literature wasn’t able to identify or locate any reported safety evaluations performed on rats on these eight crops prior to their approval. Our literature review also did not identify or locate published reports on rats for the remaining 38 crops.

The present review limited the search to only include feeding studies done on rats so that the results may be comparable. It is possible that more studies may be found if the search were to be extended to other animals. However, based on what has been found for rat studies, it is unlikely that any additional studies would involve a thorough safety investigation and a detailed report of all of the 47 approved GM crops possessing one or more of the three traits. Moreover, the rat model is the accepted OECD standard for toxicological studies of this type.

Whilst the safety of a GM crop is primarily and sometimes solely evaluated by government food regulators using the test for substantial equivalence, this is likely to be inadequate to fully assess the safety of the crop for reasons stated above. Animal feeding studies provide a more thorough method of investigating the unintended effects of the GM process or the unintended effects of ingesting GM crop components. Animal feeding studies can identify target organs as well as predict the chronic toxic effect of an ingested compound (OECD, 2008)


The evidence reviewed here demonstrates an incomplete picture regarding the toxicity (and safety) of GM crops consumed by humans and animals. The majority of studies reviewed lacked a unified approach and transparency in their methodology and results, making it impossible to properly review or repeat these studies. Furthermore, such lack of detail makes it difficult to generate evidence-based guidelines to aid in the delivery of an optimum safety assessment process for GM crops for animal and human consumption.

When considering how a better risk assessment could be done, it is important to consider systems established for other novel substances that may generate unintended effects. For example, the registration of pharmaceutical products requires an examination of both benefits and risks associated with their use and a complete assessment of those benefits and risks to establish whether the products are appropriate for general use at a range of doses. We argue that each GM crop should be assessed using similar methods, where a GM crop is tested in the form and at the rates it will be consumed by animals and people.

Whilst this provides for an effective general approach, there are additional issues for assessing GM crops that need to be taken into account. For example, the process of developing GM crops may generate unintended effects. Furthermore, the plant developed is a novel entity with genes, regulatory sequences and proteins that interact in complex ways. Therefore, the resultant plant should be assessed as a whole so that any pleiotropic effects can also be assessed. As a result, long-term animal feeding studies should be included in risk assessments of GM crops, together with thorough histopathological investigations using a variety of methods to better detect subtle changes or the beginning or presence of pathologies. Such robust and detailed studies will then make it possible to put evidence-based guidelines in place, which will substantially help to determine the safety of GM crops for human and animal consumption


Tuesday, October 21, 2014

Ebola 2014 is Mutating as Fast as Seasonal Flu

Operon Labs


The current Ebola 2014 virus is mutating at a similar rate to seasonal flu (Influenza A). This means the current Ebola outbreak has a very high intrinsic rate of viral mutation. The bottom line is that the Ebola virus is changing rapidly, and in the intermediate to long term (3 months to 24 months), Ebola has the potential to evolve.

We cannot predict exactly what the Ebola virus will look like in 24 months. There is an inherent stochastic randomness to viral evolution which makes predictions on future viral strains difficult, if not impossible. One basic tenet we can rely on is this: Viruses tend to maximize their infectivity (basic reproduction number) within their biological constraints (Nowak, 2006).

These evolutionary constraints can be extremely complex, and can include trade-offs between virulence and infectivity, conditions of superinfection, host population dynamics, and even outbreak control measures.

One of the few statements we can make with confidence that the Ebola genome is changing at a specific rate, which is explained below.

Ebola Mutation Rate:

Analysis of the available research suggests that the Ebola 2014 virus is currently mutating at a rate 200% to 300% higher than historically observed (Gire, 2014).

Ebola Genome Substitution Rates (Gire, 2014)

Furthermore, the Ebola-2014 virus's mutation rate of 2.0 x 10−³ subs/site/year is nearly identical to Influenza A's mutation rate of 1.8 x 10−³ subs/site/year (Jenkins, 2002). This means Ebola 2014 is mutating as fast as seasonal flu.

Disclaimer: This paper contains no evidence (for or against) alternate modes of transmission for Ebola, nor is this paper postulating that genetic changes have impacted EVD clinical presentation (although evidence for this has started to emerge). This paper is simply demonstrating what appears to be a rapid rate of evolution in the Ebola 2014 Virus. Many recent Ebola viral mutations have been synonymous mutations, some have been in intergenic regions, while others are non-synonymous substitutions in protein-coding regions. All have unknown impact at the present time. Such questions should be the subject of future scientific research. This article simply points out that Ebola in 2014 is undergoing rapid mutation and adaptation. The future implications of Ebola's rapid evolution are unclear.
We chose to compare Ebola-2014 to Influenza A (Seasonal Flu) because Influenza is one of the fastest-mutating viruses (Jenkins, 2002). Unlike chickenpox (VZV), which people usually only contract once per lifetime, Influenza can infect a single individual many times repeatedly over the years. One of the reasons Influenza is able to re-infect humans each year is because the Influenza's high mutation rate allows the virus to generate 'escape mutants'. Escape mutants are Influenza viruses which are no longer recognized by human immune systems. Each winter presents us with a new mutated strain of the Influenza virus. Rapid mutation is beneficial to Influenza genetic fitness (in regards to antigenic regions), because it allows a 'new' Influenza virus to circulate year after year.

The benefit of a high mutation rate in Ebola 2014 is different -- the genetic changes in Ebola-2014 allow for rapid exploration of the entire fitness landscape in a brand new host -- humans. We need to be aware that the Ebola-2014 virus is undergoing rapid adaptation.

Ebola in Zoonotic Reservoir: Viral Genome adapted to Fruit Bats. (Green)
Ebola in Human Hosts: Viral Genome adapted to Humans. (Red)
Ebola Genotype will move Green -> Red during serial passage through Humans.

Until the Ebola outbreak is brought under control, the Ebola-2014 virus will continue to seed and adapt in its growing pool of West African human hosts. We need to consider that as the weeks and months go on, the rapidly-changing Ebola-2014 virus will undergo repeated export from the West African region to countries around the world.

As new Ebola cases grow in West Africa and elsewhere, we are effectively conducting 'serial passage' experiments of Ebola-2014 through human hosts. The repeated passage of Ebola-2014 through humans is exerting selection pressure on the Ebola-2014 virus to adapt to our species (instead of fruit bats). The introduction of Ebola-2014 into a large pool of West African human hosts (coupled with the complex dynamics of evolutionary selection pressure) may allow the Ebola-2014 virus to become more transmissible as the months go on, particularly in the absence of effective control interventions.

The high mutation rate we see in Ebola-2014 reflects its ability to rapidly explore the fitness landscape. The ability of Ebola to undergo rapid genome substitutions and SNPs, coupled with genetic recombination, will allow 'survival of the fittest' in Ebola-2014 genetic variants (on both the intra-host and inter-host levels). New Ebola sub-clades are created with each passing month (there are already four sub-clades as of August 2014). New Ebola genetic variants are created with each new infection, though most are selected against. Rapid adaptation emerges from the high intrinsic Ebola-2014 mutation rate, coupled with the virus's ability to undergo RNA recombination during superinfection.

Molecular dating of the Ebola-2014 outbreak (Gire, 2014). 
Probability distributions for both 2014 divergence events are overlaid above. 

This phylogenetic tree is based on 99 Ebola viral genomes deep-sequenced from 78 distinct patients in Sierra Leone (Gire, 2014). We can see in the figure above that there are at least four Ebola genetic clusters (or sub-clades) based on phylogenetic analysis: These Ebola clusters are called GN, SL1, SL2, and SL3 by Gire et al. The key takeaway is that even prior to July 2014, the current Ebola outbreak had already accumulated significant genetic diversity. Furthermore, the dominant circulating Ebola variants have changed over time. Up to four different Ebola-2014 viral sub-clades (groups of genetically related Ebola isolates) have circulated between humans since the onset of the 2014 Ebola outbreak.

As the number of people affected by the 2014 Ebola outbreak has grown, so has the number of Ebola unique viral mutations and unique viral genetic lineages. We can expect Ebola 2014 viral lineages to grow as some function f(i) proportional to the number of people infected with Ebola.

Ebola-2014: Acquisition of genetic variation over time (Gire, 2014).
Fifty mutational events (short dashes) and 29 new viral lineages (long dashes) were observed.

The diagram above suggests that as the Ebola-infected host pool grows, so does the number of unique Ebola viral lineages (Gire, 2014). This implies that Ebola acquires genetic diversity as it infects more people, particularly if the virus undergoes recombination during superinfection (Niman, 2007). The growing number of new Ebola viral lineages will undergo natural selection for some 'optimum' balance of virulence, infectivity, tissue tropism, immune suppression, and other parameters which maximize the reproductive fitness of the Ebola virus in humans. What that final virus might eventually look like 2 years from now is anyone's guess. But the explosion of genetic variation suggests that the Ebola virus will become more difficult to contain as time goes on, which is why early action is important.

The idea that the Ebola-2014 Virus jumped species, but is now somehow 'static' or 'frozen in time' is a mistake. The Ebola-2014 virus is undergoing a period of rapid adaptation in human hosts, as evidenced by the Ebola RNA sequences deposited in Genbank, and the studies referenced with this article. Hopefully, interventions (like contact tracing) will be able to stop Ebola-2014 before the virus optimizes its genotype.

RNA Virus Mutation Rates - image not available

These are two scenarios to outline what may happen in the future. The critical variable determining the global outcome of Ebola is the response in West Africa, not the response in the United States.

Best Case Scenario:

WHO immediately deploys contact-tracing teams on the ground in West Africa. The US Military is deployed as well, and constructs hospitals sufficient to care for the sick. The hospitals are staffed by qualified (read: well trained) caregivers. Teams on the ground track down and care for Ebola-infected patients across West Africa, distributing self-treatment kits, food, medicine, and expertise. An effort is made to involve local authorities and community leaders. These efforts cause measurable reductions in the basic reproduction number of the virus by the end of 2014.  
Within 3 months to 9 months, the outbreak in West Africa peaks, levels-off, and begins to fade. The Ebola virus never has the opportunity to acquire any significant mutations, due to its limited host pool. Ebola is fully under control by early 2015. Sporadic cases in other countries are dealt with by treatment and contact tracing. By Q4 2015, multiple Ebola vaccines and drugs are in the pipeline limiting the overall threat Ebola poses. 
Worst Case Scenario: 
The international response is perpetually behind the curve. Every response action is 8 to 12 weeks too late. Statistics from the WHO become volatile and are unreliable as the lack of deployed personnel make hard numbers impossible to pin down. By 2015 the number of infections is in the hundreds of thousands in West Africa. The West African region exports 'asymptomatic infectives' which go undetected by basic screening. These individuals 'seed' outbreaks in other countries. 
 As more people become infected, a significant mutation arises that allows for a longer asymptomatic but infectious period, increasing the R-0. Globally, cases continue to double every 16 days, contact tracing infrastructure outside the West becomes saturated, and hospitals are overrun. By early-to-mid 2015, the global pool of Ebola-infected patients are in the millions, mainly centered in West Africa and Southeast Asia with multiple strains of varying virulence. A sudden change in the outbreak epidemiology caused by a recombinant Ebola strain causes confusion about how to respond. Efforts at developing treatments/vaccines become logistically complex and ineffective. 

The implication of the Ebola 2014 mutation rate is this: A single Ebola mutation doesn't necessarily mean the virus will become 'airborne', or that the virus has altered tissue tropism, or that the virus spreads more easily. But a high intrinsic rate of Ebola mutation means that such changes may become possible in the future. If the number of people infected grows into the hundreds of thousands, or even low millions, then the probability of a significant 'constellation' of accumulated Ebola mutations with phenotypic impact becomes more likely. The problem is that accumulated Ebola mutations will scale with the size of the population infected. Conversely, in a small population, such Ebola mutations are not likely to have a significant impact. It's a bit like the virus is buying lottery tickets... The more lottery tickets the Ebola virus 'buys', the more chances it has to 'win'.

Next Steps: 

The general consensus in the scientific and epidemiological community is immediate intervention in West Africa is necessary in order to avoid taking the risky outcomes possible in a 'worst case' scenario. A suitable response would need to include airlifting self-treatment kits with thermometers, the distribution of life-saving drugs, the construction of Ebola treatment centers, hospital staffing, contact tracing teams, and so forth. A robust international response must happen soon in order to ensure that the current situation with the Ebola outbreak remains a 'best case' outcome.


[1] Genomic surveillance elucidates Ebola virus origin and transmission during the 2014 outbreak. (Gire et al, 2014).

[2] Rates of Molecular Evolution in RNA Viruses: A Quantitative Phylogenetic Analysis. (Jenkins et al, 2002).

[3] Isolates of Zaire ebolavirus from wild apes reveal genetic lineage and recombinants. (Wittman et al, 2007).!po=17.8571 

[4] Ebola Recombination: Recombinomics Commentary. (Niman, 2007).

[5] Evolutionary Dynamics: Exploring the Equations of Life. (Nowak, 2006).

CDC Plans To Route Future U.S. Ebola Patients To Specially Trained Hospitals

Huffington Post

In the event that another person in the United States tests positive for Ebola, they could be re-routed to one of a handful of hospitals that are specifically equipped and trained to deal with deadly viruses like Ebola, confirmed Centers for Disease Control and Prevention director Dr. Tom Frieden during a press conference on Oct. 20.

"There’s a need for specialized centers when there is a patient with confirmed Ebola, or a number of patients if that were to happen in the future,” said Frieden, though he did not specify which hospitals would be among the designated group. "We need to increase the margin of safety.”

So far during this outbreak, only four hospitals across the United States have experience treating Ebola patients: Nebraska Medicine, Emory University Hospital, the National Institutes of Health Clinical Center and Texas Health Presbyterian Hospital Dallas.

"There are many hospitals in the country that are already in the process of becoming proficient in care of patients with Ebola,” said Frieden. "We’re focusing first on Dallas, where they’ve been dealing with Ebola, and in case there are additional cases that arise there, they’ll be ready to care for them."

In addition to announcing the hospital plan, Frieden also confirmed significant changes to safety protocol for U.S. health workers who are caring for Ebola patients. The changes were reached by consensus among “all people in the U.S. with experience with Ebola,” as well as Doctors Without Borders (MSF).

The changes include: rigorous and repeated training of the donning and doffing of personal protective equipment (PPE), to the point that the steps become “ritualized," no skin exposure when PPE is worn, and a trained hospital staff monitor that oversees health workers putting on and removing PPE.

The CDC also now recommends that health workers wear a respirator -- either an N95 respirator or powered air purifying respirator (PAPR) -- while with the patient in his or her isolation unit. This doesn’t mean that the virus is airborne, Frieden explained, but that procedures that are undertaken in the U.S., like intubation or suctioning -- procedures that require close contact with the nose and mouth of patients -- may pose a higher risk to health workers than the supportive care measures conducted in West Africa.

The CDC has faced increased scrutiny and criticism over their recommended safety protocols after Texas Health nurses Nina Pham and Amber Joy Vinson contracted Ebola from Thomas Eric Duncan, the first person to be diagnosed with the virus in the U.S. Pham was later transferred to NIH Clinical Center for Ebola treatment, while Vinson was transferred to Emory University Hospital. These changes are in a response to Pham and Vinson’s positive diagnoses, said Frieden.

“We may never know exactly how [transmission] happened, but the bottom line is that the guidelines didn’t work for that hospital,” said Frieden. “Dallas shows that taking care of Ebola is hard.”

Ebola Cases Rise Sharply in Western Sierra Leone

ABC News


After emerging months ago in eastern Sierra Leone, Ebola is now hitting the western edges of the country where the capital is located with dozens of people falling sick each day, the government said Tuesday. So many people are dying that removing bodies is reportedly a problem.

Forty-nine confirmed cases of Ebola emerged in just one day, Monday, in two Ebola zones in and around the capital, the National Ebola Response Center, or NERC, said. Lawmaker Claude Kamanda who represents a western area said more than 20 deaths are being reported daily.

Kamanda told the local Politico newspaper that authorities are experiencing challenges collecting corpses from both quarantined and non-quarantined homes.

Authorities say the uncontrolled movement of people from the interior to Waterloo which is the gateway to Freetown, the capital, has fueled the increase of Ebola cases in the west. There is a strong feeling that people are violating the quarantines elsewhere and coming to Freetown through Waterloo.

There are 851 total confirmed Ebola cases in the two zones, called Western Area Urban and Western Area Rural, the NERC said. In numbers of cases, they may soon surpass a former epicenter of the outbreak in the country, the eastern districts of Kenema and Kailahun where there have been a total of 1,012 confirmed cases.

No new cases were reported Monday in Kenema and Kailahun but a World Health Organization spokeswoman said it is too early to declare that the epidemic has burned itself out in the east.

"There was a drop in new cases in Kenema and Kailahun and fingers were crossed but there has been a bit of a flare up thanks to a couple of unsafe burials," said Margaret Harris, WHO's spokeswoman in Sierra Leone. "So it's too early to say we have a real decline ... definitely too early to say it's been beaten there."

A local newspaper suggested Tuesday that authorities quarantine Waterloo. The World Food Program over the weekend delivered emergency food rations to people there.

"The growing fear has left the public with no choice but to call on the Government for Waterloo to be quarantined as was done to other places including Kailahun, Kenema, Bombali, Port Loko and Moyamba Districts," the Exclusive newspaper said.

Many residents of the capital note that Ebola has followed the same route across the country as rebels who in 1991 started a savage war in Kailahun district. The war ended in Freetown a decade later where the final battle was fought. Now the enemy is a disease, and the president is putting in place a more military-style response.

President Ernest Bai Koroma last week appointed Defense Minister Alfred Palo Conteh as CEO of the National Ebola Response Center, whose headquarters are being placed at the former War Crimes Tribunal for Sierra Leone in the west end of Freetown together with the United Nations Mission for Ebola Emergency Response.

The West African nations of Sierra Leone, Liberia and Guinea — where the outbreak first emerged 10 months ago — have been hit hard by Ebola with more than 4,500 deaths, according to WHO estimates. A few cases have also emerged in the United States and Spain.

In Guinea on Tuesday, hundreds of residents in the Conakry suburban neighborhood of Kaporo Rail protested the construction of an Ebola treatment center nearby.

"We don't want the hospital here. They want to infect our neighborhood," said Binta Sow, the spokesman of the group. Kaporo Rail has a thriving market for ice cream and milk that employs hundreds of women and youth. There were worries this could harm the local economy.

"No one will buy anything here if they erect the center," said a local ice cream vendor.

On Tuesday the East African nation of Rwanda was singling out travelers from the U.S. and Spain for special screening. A Rwandan Ministry of Health document says all passengers from the U.S. and Spain will have their temperatures taken upon arrival. If the passenger has a fever he or she is denied entry. If there is no fever, the visitors still must report their health condition daily to authorities.

The U.S. Embassy in Rwanda on Tuesday urged Americans who may have a fever or who have traveled to Ebola countries "to weigh carefully whether travel to Rwanda at this time is prudent."

"Please note neither the Department of State's Bureau of Consular Affairs nor the U.S. Embassy have authority over quarantine issues and cannot prevent a U.S. citizen from being quarantined should local health authorities require it," the embassy said.

No Ebola cases have emerged in Rwanda.