Monday, 30 April 2012

Patenting Genes

US Supreme Court
This recent article describes a little of the history of patenting genes and even the use of our own tissues for commercial purposes. This effectively prevents the use of a commonly-known gene sequence for a particular purpose by anyone but the patent holder, and prevents any other company designing tests for changes to that gene sequence - in other words only one company can own the test for genetic defects in a patented gene.

In the case of two genes that are known to predispose women to breast cancer (BRCA1 & 2) the patent has been under dispute on the grounds that it should not be possible to award such a patent (contending that BRCA1 & 2 are discoveries and not inventions) and is still in court awaiting an outcome. Roughly 20% of our genes are already subject to some sort of patent.

Earlier this year we outlined the coming genomics revolution that will allow us to all have our entire genome read. There are to be many benefits to all individuals knowing this information - the detection of potential threats to our health prior to any symptoms showing, the individual tailoring of drug treatment regimens to a person's genetic profile and more.

Knowing a person's genome means knowing the sequence of that persons DNA for ALL of their genes - there is a direct incompatibility between knowing a person's genome and having to run a patented test to find out the same information - the patented test would be redundant. We will not need the patented DNA tests in these cases, and costs may fall far enough to make the patented gene business uneconomic - so what is to be done?

In the immediate future we are faced with clinicians and researchers having to ignore patented gene sequences, whether or not that information is of benefit to their patient or research. They will have all of the sequence information in front of them, but will need to pay a separate company to use that information. This is an odd situation - instead of patenting providing a safeguard to inventors to allow them to continue their research (the original purpose of patenting), it may slow down research and medical treatment.

There have been several judgements released (see links above) that have gone against the use of patenting in this way, but companies with vested interests have appealed successfully. The BRCA case is set to decide the future of the use of genomic sequencing - do we sacrifice the profits of several companies in a common interest and usher in a new age of genetic information for each and every one of us? Or do we allow those companies to maximise their profits for the duration of the patents when their technology has blatantly been superceded?

Friday, 27 April 2012

Tanzania Launches Major Research into the Effects of Mycotoxins on its Population

Maize farmers spreading safe forms of Aspergillus
Mycotoxins are well known to be able to reach toxic levels in food, particularly grain and other crops that are exposed to infection by fungi such as Aspergillus while growing in the field. Once harvested and if the crop has been insufficiently dried and is then stored in large piles or in heaps in silo's then fungal growth can occur and mycotoxin contamination can quickly rise.

In developed countries this risk is closely monitored by sampling every batch of grain than comes onto the market for consumption. Strict limits are set in many countries of the world and food exceeding those limits declared unsuitable for human consumption. Unfortunately many countries do not have limits, perhaps indicating that they are as yet unable to control food imports - or perhaps they are countries were food import is not the main source of the mycotoxin problem.

In many countries in Africa most of the food eaten is provided locally by local farmers who have access to few facilities for safe storage of their produce and where the people have few alternatives to eat if a crop becomes mouldy - at this small scale it is impossible for government to monitor mycotoxin levels. It is also highly likely that these people are regularly exposed to far higher levels of mycotoxin than is set in other countries.

Tanzania has started to try to understand the extent of the effect mycotoxins have on the health of their people. This recent article outlines the health effects detected in Tanzania - these include liver cancer, impaired immune system and if the dose is large enough, death. In children there is good evidence that mycotoxins cause poor growth and development.

For some time now there has been a program of education and awareness of mycotoxin control operating in many African countries which has been successful at cutting down contamination in some areas, but there are still unacceptable levels in many areas.

The Tanzanian government is launching two new research programs:

The first project, a six-month research funded by the United States Agency for International Development (USAID) under the Feed the Future initiative, will establish the extent and spread of mycotoxin contamination of maize and cassava at the homestead and in markets, focusing on Dodoma and Manyara. 
The second initiative seeks to develop a safe and natural biocontrol technology that can effectively reduce aflatoxin contamination of maize and groundnut in the field and during storage.
There has been  signs that at least in the short term seeding crops with biocontrol strains (the same fungus - Aspergillus flavus - which does not produce toxin) reduces mycotoxin levels, but we do not know how effective that will be in the long term. At least when we get a better idea of the extent of the problem we will be able to make progress on targeting awareness.


Thursday, 26 April 2012

Newsbite: Antifungal Market Predictions 2017

Antifungals Market to 2017 - Generic Erosion of Major Polyenes, Azoles, Allylamines and Echinocandins to Slow Value Growth
GBI Research, the leading business intelligence provider has released its latest research "Antifungals Market to 2017 - Generic Erosion of Major Polyenes, Azoles, Allylamines and Echinocandins to Slow Value Growth", which provides an insight into antifungals sales and price forecasts until 2017. The report examines the global antifungal therapies, treatment usage patterns and treatment flow algorithm. In addition, the geographical distribution of antifungal therapies across the US, the top five countries in the European region and Japan are also provided in the report. The report also includes insights into the Research and Development (R&D) pipeline and the potential future blockbusters until 2017 with in-depth analysis of the top three antifungal therapeutic indications, namely aspergillosis, dermatophytosis and candidiasis. Furthermore, it also includes the market forecasts and treatment usage patterns of these three therapeutic indications. The report also explores the competitive landscape including top companies benchmarking. Finally, the key trend analysis on Mergers and Acquisitions (M&A) and licensing agreements involving antifungals therapies is also presented.
In-depth analysis of the report is based on propriety databases, primary and secondary research and in-house analysis by the GBI Research team of experts.
GBI Research analysis shows that the global antifungals market was estimated at$9.4 billion in 2010, with a Compound Annual Growth Rate (CAGR) of 2.9% during 2002 and 2010. The antifungals market is dominated by generics. GBI Research forecasts that the market will grow at a CAGR of 1.9% during 2010-2017 to $10.8 billion. The patent expiry of a number of major drugs has paved way for the entry of generics.
GBI Research analysis shows that the R&D pipeline for the antifungals market is not strong as it has become a generic market. Currently, only 38 molecules are in R&D, which indicates that antifungals R&D activity will not be very active for at least the next seven to eight years. more...

Wednesday, 25 April 2012

Fungal Infections a Threat to All Life Forms

The journal Nature is one of the most prestigious scientific journals in the world - the one many scientists working in many different fields of science aim to publish in to mark the pinnacle of their achievements. Scientific work that is published in its pages has to be the very best quality and written about the most important fields of research of the day (history of Nature articles), so when it sounds an alarm we should all listen.

Earlier in April the cover of Nature was given over, as usual, to the most important or at least most 'eye-catching' body of work in that edition. The title given to that edition was 'Fear of Fungi'.

Should we be frightened of fungi? The article highlighted was an extensive search for evidence that the numbers of infection outbreaks throughout the world involving fungi are on the increase.
We have certainly got evidence of important increases in the number of humans infected by fungi, related to increase in the use on immunosupressing therapy for a variety of illnesses but this article goes much further.

Quite large increases in reported fungal disease outbreaks were detected for both plants and animals (see below)

Examination of infectious disease trends (ProMED and HealthMap) have revealed in increase in number of fungal disease outbreaks expressed as a proportion of the total number of reported disease outbreaks from 1 to 7% in the period from 1995 to 2012. Factors causing this rise include the globalisation of trade and transportproviding a route for the introduction of new, pathogenic species into areas of the world that are relatively unprotected. Also detected is the accelerated evolution of increased virulence of pathogenic fungi caused by mixing and sexual recombination of established species with incomers.

Environmental change also has an important influence, both on the ability of the host species to resist the fungal attack and on the development of new pathogenic varients of fungi. Increased CO2 has been shown to increase rice blight for example, though other changes are known to reduce infection too. Deforestation, warmer seawater, warmer weather, widespread use of antifungal azoles in agriculture are all suspected of increasing fungal diseases in the plant, animal and human worlds.

There is much debate on how many other factors are involved in these increases but the end result is the same - aggressive fungal infection. Besides the direct effect on health, widespread damage to crops threatens our ability to feed ourselves and reduction in biodiversity presents us with problems for future generations looking for new 'genetic solutions' to multiple problems.

Increased perception of the importance of fungal disease is sorely needed to promote the means to prevent, or at least slow down, the spread of infections by multiple fungi on multiple host types. There are some attempts to achieve this internationally for specific infections e.g. The World Organisation for Animal Health (OIE) and United Nations Food and Agricultural Organization(FAO) have programs to prevent trade associatedspread of pathogens.

Leading International Fungal Education  A new initiative by the Fungal Research Trust named 'Leading International Fungal Education' (LIFE) is currently running the Project LIFE competition which is the first step aimed at promoting awareness of fungal infection in the UK but aims to stimulate similar projects worldwide.

Thursday, 19 April 2012

NewsBite: Japanese Actor Dies of Aspergillosis

Shigeru Araki, lead actor in the live-action Kamen Rider Stronger series, passed away on Saturday, April 14 at 5:02 p.m. He was 63. He was admitted to a hospital in Tokyo for pneumonia symptoms but was found to have an aspergillosis infection. Aspergillosis is a lung infection caused by exposure to mold in compost, grain, and decaying vegetation more... 

Wednesday, 18 April 2012

New Antifungal Strategy: Nanotechnology

Many will know that we are in need of new classes of antifungal drugs as existing drugs tend to use similar strategies to attack fungi. Once the fungus has become resistant to one they tend to become resistant to others more quickly as the same chemical processes are targeted. The more different the target for a new drug is, the less likely that the fungus will become cross-resistant (resistant to more than one drug at a a time).

One of the latest strategies to develop a new class of antifungal medication is to use nanotechnology. At very small sizes (one billionth of a meter across) particles start to exhibit novel, useful properties - for example they become highly capable of penetrating biological membrane and disrupting them, of delivering artificial proteins that can be lethal to cancer cells and much more - all as yet in its infancy. 

An oil/water emulsion generated using nanotechnology has started to show promise as an antibiotic as it can penetrate the cell membrane and deliver a lethal dose of surfactant. This ruptures the bacterial cell and it consequently dies. A relatively recent presentation at a scientific meeting by scientists from  NanoBio Corporation shows that this strategy also works on fungi & (they claim though no evidence presented) fungal spores. Codenamed NB-002 the emulsion is shown to be effective against a range of fungi that are important in dermal (skin) infection and onychomycosis (infection of the nails)- though at this time Aspergillus data is not presented. Interestingly the suggested mode of transport of the miniscule droplets is via skin  pores and hair follicles and then lateral diffusion under the skin to the infected site - they are so small cell membranes cannot stop their movement. This technique is show to be able to deliver lethal doses of the antifungal activity and yet have little or no effect on skin.
Phase II clinical trials in humans are to begin on this revolutionary treatment soon.

Readers who browse further around the NanoBio website will find reference to the use of nanotechnology to attack bacteria infecting the airways of Cystic Fibrosis (CF) patients. This development is well under way and is undergoing clinical trials. One feature of this is to demonstrate that delicate mucus membranes are not sensitive to nanoparticles containing and they do not seem to be at least in animal studies.

It is tempting to suggest that as one type of nanoparticle is effective against fungi, and another is effective in treating respiratory infections then we may well find that we can use this technique to attack fungal infections of our lungs. The information presented for CF seems to indicate that these treatments should useful in addition to existing treatment, possibly usable at the same time for greater effect. The fungi will find it very difficult to become resistant to direct ablation of cell membranes (which is theoretically very efficient and unlikely to leave behind survivors) and all current resistant organisms will be similarly sensitive to nanoparticles as this is not a route of attack that has been tried before!

Hopefully these positive signs will lead to a new, efficient, less toxic tool that doctors will be able to use to manage fungal respiratory diseases such as aspergillosis.

Thursday, 12 April 2012

Newsbite: Antifungal Useful for Postate Cancer?

A small study suggests that men with castration-resistant prostate cancer (CRPC) that was not mediated by androgen suppression experienced better outcomes when treated with an antifungal agent, itraconazole more...

Wednesday, 11 April 2012

Soldier Insects Secrete Antifungals

Huge ant nest - a large insect community
Many communal insects form large colonies - no doubt benefiting from the advantage this gives them for defence purposes. Anyone who has sat on an ant-hill will attest to the power of the individuals sent out to guard the nest, and there are several other groups of specialised insects within an organised community - otherwise known as 'castes' - each with a particular job to do (Link). Rather like the principle of mass production 'invented' by Henry Ford 100 years ago, the development of specialised workers is a very efficient strategy to maximising production - in the case of an insect that means more insects!

 There is however a drawback to living in a large community. Once an infection enters the community it can rapidly sweep through the nest killing vast numbers - after all, the occupants of an insect nest are closely related and thus have similar ability to fight off infection. Once it has begin it is difficult to stop.

 A recent paper suggests that insect communities also have an answer to fungal contamination. Thrips are communal insects that have specialised soldiers to guard the colony. It has always been suggested that the large forelimbs of these soldiers offers a physical advantage to them as they fight off invaders, but the authors of this paper suggest that the advantage may not be as big as we thought - when large limbed individuals were matched against smaller limbed thrips they tended to do just as well in a fight!

This begs the question - what are the larger limbs for then? Tests show that the soldier insects can secret antifungal compounds whereas smaller limbed castes cannot. Perhaps then remarkably the main job of a soldier is to fight of fungal invaders rather than larger foe?

This theory is not yet universally accepted but it serves to illustrate the degree of threat fungi exert even on the smallest of creatures, and the extent to which even they have to go to hold fungi at bay.

Tuesday, 10 April 2012

Honey Bees Self Medicate Against Fungal Infection

Propolis in a hive
Aspergillus is frequently found in bee hives along with several other fungal genus'. Some of those fungi are known to be pathogens of the bee, some in cooperation with virus' that have been suspected of causing the recent collapse of honey bee numbers in many countries of the world (Colony Collapse Disorder). Some fungi (Ascosphaera - a close relative of Aspergillus) seem to exist only in association with honey bees and can also cause disease in the bee hive (Chalkbrood) - so how do bees prevent infection wiping out a hive?

A recent paper gives us a clue. Some plants secrete substances that have an antifungal activity and bees collect these substances to form a waxy chemical called Propolis. They line their hives with this substance - so do they do this to ward off infection? The authors of the paper show that the bees collect more Propolis when the hive is infected with Ascophaera and remove mouldy objects from the hive more frequently - they are actively controlling the extent of fungal infection. Furthermore they didn't do this when infected with a non-pathogenic strain of fungus so this activity seems to be in response to fungi that are capable of causing them harm.

This information is economically useful. Bee keepers traditionally cultivate hives that are low in Propolis, so perhaps here we have a way to help keepers reduce fungal infection of their hives, and thus reduce the effect of  Colony Collapse Disorder. Needless to say the commercial value of honey bees is huge as many food crops are pollinated by bees.

Tuesday, 3 April 2012

Severe Photosensitivity in Children Taking Voriconazole

It is well documented that there are many differences between adults and children that have to be taken in for account when considering giving them medicines, and antifungal medication is no different.  Doctors have to be very careful in administering drugs to children, especially so when the medication is not often used in that context.
Children have a different metabolism compared with adults and this means that they can be very variable in the dose they have to take in order to maintain sufficient levels of the antifungal in their blood for it to be effective.

Voriconazole is a relatively new antifungal so relatively little is known about how it is metabolised in children, though the most recent information suggests that the dose level needs to be relatively high for best effect. In adults voriconazole can be difficult to use as it has nonlinear kinetics (also see talk given to patients by Caroline Moore) which means that a given dose can give very different levels in the blood of different patients in an unpredictable way. Individual patients have to be checked to ensure blood levels are sufficient, sometimes several times. The situation in children is just as difficult, if not more so.

Adding to the problems can be other medication that the patients may be taking and interactions with antifungals are quite common (Antifungal Interactions database).

This recent paper describes two cases of children who were immunocompromised by intensive chemotherapy during treatment for cancer. As a precaution against fungal infection these children were given voriconazole and in line with recommendations it was at a dose higher than that normally recommended. Both children developed severe photosensitivity despite the levels of voriconazole in their blood never reaching that which would cause toxicity in adults. An earlier study of voriconazole side effects in children showed no such problem.

The authors speculate that factors other than voriconazole (photosensitivity is a well known side effect of voriconazole in adults) could also have been important in the development of this side effect e.g. they lived in a sunshine-rich country, they were taking other medications that might have contributed in addition to their young age. However caution is strongly recommended when giving voriconazole in all cases similar to this.

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