...the science of studying protein folding
Have you ever had one of those really complicated pop-up books where the dinosaur leaps out of the page towards you in 3-dimensions with every tooth and scale separately attached in perfect and horrifying detail? I have, and if you're like me then you've probably also taken a peek behind the dinosaur to find out how the pop-up works. Peering between the pages like this is similar to the work that goes on in labs around the world where scientists are trying to understand the workings of one of Nature's most powerful polymers - the protein.
Proteins are massive molecules that are crucial for keeping the cells in our bodies in working order. For instance they provide the rails and the motor for microscopic cellular ‘trains’ that move biochemical cargos from one end of a cell to another, they act as molecular messengers allowing cells to communicate with each other and they package DNA so that the regions of the genome that aren’t being used are tidily coiled away. They also monitor what the cell is doing, and when something causes trouble, they get rid of it, which might even involve killing the cell. And just as the pop-up book is made from pieces of card glued to the page in the right order, proteins are made from molecular cards called amino acids, which are linked together in the right order.
If this gluing is done correctly, the protein spontaneously folds to take up its completed 3D shape. And just like opening a pop-up book, most of the time the protein folding works smoothly, but occasionally things can go wrong. A mutation in the DNA sequence coding for a certain protein can lead to the inclusion of the wrong amino acid, which is akin to inserting a wrongly shaped piece of card in the pop-up book. This causes the mature protein to go out of shape or "mis-fold", so it cannot carry out its intended role correctly. In fact an amazing 80% of human disease-causing mutations affect proteins in this way.
Proteins recognise and interact with each other according to their shape, so having the correct structure is critical for a protein to work effectively. If it fails in this role the results can be fatal. For instance some proteins do the job of killing malfunctioning cells, such as cells that have become malignant, and under these circumstances a failure in the process can mean cancer.
But while many people have been working on ways to treat diseases by correcting the function of affected proteins, my research looks at the fundamental question of how proteins fold when they are working properly. If we want to understand complicated diseases, we first need to understand how things work normally. A lot of the questions I’m asking are just the same as those you might ask about the pop-up book. What does the folded protein look like? What does the unfolded one look like? Is there a preferred order or logic to the self-assembly?
The proteins I study are 100 million times smaller than the pop-ups in a book, and a hundred times smaller than even a light microscope can see. The result is that I can't just watch what happens - instead I have to infer it by measuring other things. For example, by measuring the speed at which a protein folds and then substituting one amino acid building block for another before repeating the measurement, I can find out which parts fold first. Then, by comparing the results for similar proteins, it's possible to work out how small differences in amino acid sequence affect the way the protein folds.
At the moment, if we design a new protein we can only guess what the final shape will be – but it is the final shape that dictates what the protein can or cannot do! Making new proteins is a bit like knowing what you want the pop-up to look like, but clumsily sticking pieces of card onto the book without really understanding how the process works.
But there are ways around this: if you take a protein similar to the product you want, you can make small changes and slowly build up something useful. It's a bit like changing the pop-up dinosaur into a dragon, although making it into a Volkswagon Beetle would be much harder. My hope is that one day we will fully understand the rules of our pop-up books – not only to understand disease but also to treat it by designing protein drugs that will do exactly what we choose.
Genes for Bigger Brains
Humans have exceptionally large and complex brains. Two genes, microcephalin and ASPM, are suggested to have played a role in our cerebral evolution since mutation of either can lead to the severe clinical condition microcephaly (small brain). And studies carried out by researcher Bruce Lahn and his colleagues suggest that both genes might still be involved in the continuing evolution of human brains.
The exact DNA sequence of a gene can vary slightly from person to person due to the accumulation over time of harmless sequence changes, or mutations. This variation can be likened to the tuning of a radio station: small movements of the dial may or may not alter the quality of reception. Similarly, small DNA sequence differences (variants) may or may not alter the gene's functional ability. In terms of radio MHz variants it would be easy to tell if one of them improved the audible signal. In gene terms, however, it can be difficult to directly determine whether a particular sequence variant confers improvement.
One good indicator is if the variant has become prevalent in the human population. This would strongly suggest that the evolutionary tuning dial has found a gene variant which gives those individuals carrying it some sort of survival or reproductive advantage. This is so called "positive selection". By sequencing approximately 90 human DNA samples from a panel of ethnically diverse individuals, the Lahn group found that for both the microcephalin and ASPM genes, one predominant variant exists. To test whether, as suspected, the genes have undergone positive selection, the group calculated how likely it was that these gene variants had reached their present prevalence in the population just by chance. They found that, no matter which possible model of human demographic history they applied, given the high frequency of the variants, such a random emergence was extremely unlikely, confirming that positive selection had almost certainly taken place.
Interestingly, positive selection in both genes has been relatively recent. Divergence of anatomically modern humans is estimated to have occurred about 200,000 years ago. Using mutation rates as a kind of "molecular clock", the team determined that the prevalent microcephalin variant emerged approximately 37,000 years ago, while the prevalent ASPM variant appeared about 5,800 years ago. The group then went on to look at the global distribution of these positively-selected variants. By sequencing the versions of these genes carried by 1200 people from across the globe they found that the preferred microcephalin variant was common in all but sub-Saharan Africa, while the preferred ASPM variant was common only in Europeans and Middle-Easterners. The authors point out that emergence of the microcephalin variant coincides with archaeological estimates of the movement of humans into Europe and development of modern human behaviours, such as art and symbolism (approximately 40,000 years ago), while the emergence of the ASPM variant coincides with the development of written language and cities around 5000-6000 years ago.
Such correlations, tidy as they may be, could lead to premature and potentially controversial speculation. It is therefore important to note that so far the group has no evidence as to the possible function under positive selection. Despite this the group has already patented the tests to determine whether an individual carries the preferential variants "we just thought we should patent the genes in case sometime in the future the tests become desirable commercially" says Bruce. If Bruce's pet theory that the genes affect cognitive ability turns out to be true, these tests could raise serious social and ethical issues. But did Bruce himself test positive for the preferred variants? Perhaps wisely he has "decided to keep it a mystery for the time being". Both genes are known to regulate brain size and related studies suggest they might control cell proliferation (growth) in the developing brain. A related function such as motor control, cognition, brain size or susceptibility to neurological or psychiatric diseases is therefore possible but far from proven.
The exact DNA sequence of a gene can vary slightly from person to person due to the accumulation over time of harmless sequence changes, or mutations. This variation can be likened to the tuning of a radio station: small movements of the dial may or may not alter the quality of reception. Similarly, small DNA sequence differences (variants) may or may not alter the gene's functional ability. In terms of radio MHz variants it would be easy to tell if one of them improved the audible signal. In gene terms, however, it can be difficult to directly determine whether a particular sequence variant confers improvement.
One good indicator is if the variant has become prevalent in the human population. This would strongly suggest that the evolutionary tuning dial has found a gene variant which gives those individuals carrying it some sort of survival or reproductive advantage. This is so called "positive selection". By sequencing approximately 90 human DNA samples from a panel of ethnically diverse individuals, the Lahn group found that for both the microcephalin and ASPM genes, one predominant variant exists. To test whether, as suspected, the genes have undergone positive selection, the group calculated how likely it was that these gene variants had reached their present prevalence in the population just by chance. They found that, no matter which possible model of human demographic history they applied, given the high frequency of the variants, such a random emergence was extremely unlikely, confirming that positive selection had almost certainly taken place.
Interestingly, positive selection in both genes has been relatively recent. Divergence of anatomically modern humans is estimated to have occurred about 200,000 years ago. Using mutation rates as a kind of "molecular clock", the team determined that the prevalent microcephalin variant emerged approximately 37,000 years ago, while the prevalent ASPM variant appeared about 5,800 years ago. The group then went on to look at the global distribution of these positively-selected variants. By sequencing the versions of these genes carried by 1200 people from across the globe they found that the preferred microcephalin variant was common in all but sub-Saharan Africa, while the preferred ASPM variant was common only in Europeans and Middle-Easterners. The authors point out that emergence of the microcephalin variant coincides with archaeological estimates of the movement of humans into Europe and development of modern human behaviours, such as art and symbolism (approximately 40,000 years ago), while the emergence of the ASPM variant coincides with the development of written language and cities around 5000-6000 years ago.
Such correlations, tidy as they may be, could lead to premature and potentially controversial speculation. It is therefore important to note that so far the group has no evidence as to the possible function under positive selection. Despite this the group has already patented the tests to determine whether an individual carries the preferential variants "we just thought we should patent the genes in case sometime in the future the tests become desirable commercially" says Bruce. If Bruce's pet theory that the genes affect cognitive ability turns out to be true, these tests could raise serious social and ethical issues. But did Bruce himself test positive for the preferred variants? Perhaps wisely he has "decided to keep it a mystery for the time being". Both genes are known to regulate brain size and related studies suggest they might control cell proliferation (growth) in the developing brain. A related function such as motor control, cognition, brain size or susceptibility to neurological or psychiatric diseases is therefore possible but far from proven.
Why Don't Woodpeckers Get Brain Damage?
Beating your head against a hard surface can be a sign of frustration, yet for a woodpecker it’s a fact of life...
In the late 70's, a study carried out by Philip May, Joaquin Fuster, Jochen Haber and Ada Hirschman, using high-speed photography (capable of taking 2000 frames a second), revealed that the impact deceleration, when a woodpecker's beak travelling at 7 metres per second slams into a tree trunk, can exceed one thousand times the force of gravity (1200g).
With repeated trauma of this magnitude it's surprising that the bird's head remains attached to its body, never mind the risk of developing a severe headache, concussion or even brain damage. So why don’t they? Indeed, when other small birds accidentally fly into windows they often tumble to the ground and appear to be "knocked out" for a while before picking themselves up and fluttering off; so why should woodpeckers be any different?
The answer is that evolution has equipped them with a number of adaptations that make repeatedly banging your head against a hard surface 20 times per second slightly more tolerable.
Firstly, woodpeckers have relatively small brains which, in contrast to a human, are packed fairly tightly inside their skull cavity. This prevents the excessive movement of the brain inside the skull, which causes so-called 'contre-coup' injuries in humans. These occur when the brain bashes into the skull following a knock on the head. In other words the head stops, but the brain keeps on moving momentarily afterwards.
Secondly, unlike a human brain the surface of which is thrown into ridges and folds known as gyri to enable more grey matter to be packed in, the woodpecker’s brain has a smooth surface and, through its small size, a high surface area to weight ratio. This means that the impact force is spread over a much larger area, relatively speaking, compared with a human. Again, this minimises the applied trauma. The bird’s brain is also bathed in relatively little cerebrospinal fluid, which also helps to reduce the transmission of the shock waves to the brain surface.
Finally, and possibly most importantly, the woodpecker also makes sure that he minimises any side to side movement of his head, and this is where May and his colleague’s fast film footage comes in.
The team found a tame acorn woodpecker, which could be encouraged to perform for their camera by bashing out a few words on an old typewriter. They watched as the bird first took aim and delivered a number of "test taps" before unleashing a salvo of strikes, but always in a dead straight line.
This approach is crucial because it avoids placing rotational or sheering stresses on the nerve fibres in the brain. Humans involved in car and motorcycle accidents frequently develop the symptoms of 'diffuse axonal injury' (DAI) where sudden deceleration coupled with rotation literally twists the different parts of the brain off each other like a lid coming off a jar. By hammering in a dead straight line woody woodpecker avoids giving himself DAI, further minimising the risk of brain damage.
An unresolved issue however, is that the researchers noted from their photographs that their study subject also took the precaution of closing his eyes just before each strike. But whether this was to keep wood chips out, or the eyeballs in, is anyone’s guess!
In the late 70's, a study carried out by Philip May, Joaquin Fuster, Jochen Haber and Ada Hirschman, using high-speed photography (capable of taking 2000 frames a second), revealed that the impact deceleration, when a woodpecker's beak travelling at 7 metres per second slams into a tree trunk, can exceed one thousand times the force of gravity (1200g).
With repeated trauma of this magnitude it's surprising that the bird's head remains attached to its body, never mind the risk of developing a severe headache, concussion or even brain damage. So why don’t they? Indeed, when other small birds accidentally fly into windows they often tumble to the ground and appear to be "knocked out" for a while before picking themselves up and fluttering off; so why should woodpeckers be any different?
The answer is that evolution has equipped them with a number of adaptations that make repeatedly banging your head against a hard surface 20 times per second slightly more tolerable.
Firstly, woodpeckers have relatively small brains which, in contrast to a human, are packed fairly tightly inside their skull cavity. This prevents the excessive movement of the brain inside the skull, which causes so-called 'contre-coup' injuries in humans. These occur when the brain bashes into the skull following a knock on the head. In other words the head stops, but the brain keeps on moving momentarily afterwards.
Secondly, unlike a human brain the surface of which is thrown into ridges and folds known as gyri to enable more grey matter to be packed in, the woodpecker’s brain has a smooth surface and, through its small size, a high surface area to weight ratio. This means that the impact force is spread over a much larger area, relatively speaking, compared with a human. Again, this minimises the applied trauma. The bird’s brain is also bathed in relatively little cerebrospinal fluid, which also helps to reduce the transmission of the shock waves to the brain surface.
Finally, and possibly most importantly, the woodpecker also makes sure that he minimises any side to side movement of his head, and this is where May and his colleague’s fast film footage comes in.
The team found a tame acorn woodpecker, which could be encouraged to perform for their camera by bashing out a few words on an old typewriter. They watched as the bird first took aim and delivered a number of "test taps" before unleashing a salvo of strikes, but always in a dead straight line.
This approach is crucial because it avoids placing rotational or sheering stresses on the nerve fibres in the brain. Humans involved in car and motorcycle accidents frequently develop the symptoms of 'diffuse axonal injury' (DAI) where sudden deceleration coupled with rotation literally twists the different parts of the brain off each other like a lid coming off a jar. By hammering in a dead straight line woody woodpecker avoids giving himself DAI, further minimising the risk of brain damage.
An unresolved issue however, is that the researchers noted from their photographs that their study subject also took the precaution of closing his eyes just before each strike. But whether this was to keep wood chips out, or the eyeballs in, is anyone’s guess!
How The Lymphatic System Works
Our second circulatory system - past, present and future
The lymphatic system is an offshoot of the cardiovascular system and comprises lymphatic vessels, lymph nodes, lymph (the fluid they contain) and lymphocytes (immune cells). Lymphatics were first seen by Hippocrates in 400BC as vessels containing ‘white blood’, but the lymphatic system was not properly described until the 1600s, around the same time that William Harvey published his detailed description of the blood circulatory system.
Figure 1 - The lymphatic system ©St. George's, University of London
Whilst our understanding of the blood circulation progressed rapidly, the lymphatic system was regarded as a simple drainage system and largely ignored. It is only in the last 20 years that lymphatic research has really progressed. It's now clear that the lymphatic system is far more than a simple drainage network and instead comprises a complex system involved in many conditions, ranging from cancer to asthma. This article explores the essential role that the lymphatic system plays in tissue fluid regulation. A disturbance in this regulation can cause fluids to accumulate in tissues, leading to swelling or lymphoedema, a condition which presents us with many unsolved puzzles.
The essential role of the lymphatic system in tissue fluid volume regulationThe lymphatic system has several key roles including transporting fats absorbed from the gut, priming the immune system during infections bv carrying material to local lymph nodes and regulating tissue fluid volume.
Tissue fluid (also known as interstitial fluid) forms when water and proteins filter through tiny channels in the walls of small blood vessels, called capillaries, and enter the surrounding tissue.
Figure 2 - Chronic venous disease resulting in oedema. ©St George's, University of London
In general, fluids filter out of the capillary at a rate determined by pressures on either side of the wall. These pressures (‘Starling forces’) are exerted by the fluid and by protein, on both sides of the wall. All the body’s cells are bathed by 10-12 litres of interstitial fluid compared with a blood plasma volume of only 3 litres. In order to keep the volume of fluid in the interstitial compartment constant, excess interstitial fluid and large proteins must be returned to the blood stream. This process is carried out almost entirely by lymphatic vessels.
Excess interstitial fluid first drains into small, thin walled lymphatics (initial lymphatics) and then into larger lymphatics. Larger lymphatics possess valves to ensure that lymph flow is one-way and have muscular walls which can pump the interstitial fluid (now termed lymph) towards lymph nodes. Lymphocytes within lymph nodes police all fluid which passes through them and an immune response may be initiated if a foreign body is encountered (this is why our lymph nodes e.g in the neck, may swell when we are unwell). After exiting the lymph nodes, lymph empties into the blood circulation via connections to veins in the neck.
What is the difference between oedema and lymphoedema?As the lymphatic system is essential to the regulation of tissue fluid volume, any impairment is likely to lead to a build up of fluid and protein. This can manifest as swelling (oedema). Both oedema and lymphoedema manifest as swelling but the two conditions have distinct causes.
Many of us notice that our feet swell during a long haul flight and this is because the capillary filtration rate is temporarily exceeding the ability of the lymphatics to remove fluid. This however, is normal and will disappear over time. Clinical oedema is caused by a sustained excess of fluid filtering across the capillary wall. The lymphatic system will work harder to remove this excess fluid but eventually it becomes overwhelmed and fails, resulting in swelling. This excess in fluid filtration can occur as a result of a variety of conditions including: malnutrition, renal failure, heart failure and inflammation. The oedema can usually be cured if the underlying cause is identified and treated.
Figure 2 shows a patient with leg swelling caused by chronic venous disease, which is sometimes caused by deep vein thrombosis, varicose veins or chronic heart failure. This condition causes capillary filtration to be increased over a sustained period. The lymphatics are overwhelmed and this leads to an excess of interstitial fluid and oedema (swelling).
Types of LymphoedemaThere are two broad categories of lymphoedema:
Figure 3 - Milroy disease (leg swelling and associated skin changes) ©St George's, University of LondonPrimary Lymphoedema can be genetically pre-determined but can also develop later in life with no discernable cause. Primary refers to the fact that the lymphoedema is caused by an inherent defect, which may include under-development, in the lymphatic system. For example, there may be too few lymphatics or malfunctional lymphatics which do not pump properly or have faulty valves. Primary lymphoedema is relatively rare. Two examples of primary lymphoedema, in which the genetic abnormality has been identified, are:
A. Milroy disease. This involves lower leg swelling, present from birth (1 in 6000 births) (figure 3). It is caused by mutations in a gene responsible for embryonic lymphangiogenesis (lymph vessel development). As a result, lymphatics fail to develop properly, particularly in the leg.
B. Lymphoedema Distichiasis. This involves leg swelling (figure 4) and is caused by mutations in a lymphatic developmental gene called FOXC2. As a result, the valves of large lymphatics become incompetent allowing lymph to flow backwards. This impairment in lymph flow is exacerbated in the upright position as the lymph also has to work against gravity. Surprisingly, this condition is associated with a double row of eyelashes (distichiasis) (figure 5), presumably because the lymphatics and the eyelashes have a common developmental origin. The double row of eyelashes is present from birth but the lymphoedema develops only after puberty. The reason for this is unknown but hormonal changes may be a contributory factor.
Figure 4 Leg swelling in Lymphoedema distichiasis
Figure 5 Double row of eyelashes associated with lymphoedema distichiasis
Figure 6 - Lymphoedema caused by Lymphatic filariasis
Secondary lymphoedema is much more common. The word secondary refers to the fact that the lymphoedema is caused by something external to the lymphatic system.
The commonest cause of lymphoedema is lymphatic filariasis which affects approximately 90 million people worldwide, mostly in developing countries. Lymphatic filariasis is caused by a nematode worm infestation that is transmitted by mosquitoes. These worms reside in lymphatic vessels and impair lymphatic function mainly in the limbs and scrotum, causing a lymphoedema associated with hyperkeratotic elephant-like skin (Elephantiasis) (figure 6).
In Western countries, the commonest cause of lymphoedema is cancer surgery. One example is surgery for breast cancer. In the UK, around 41,000 new cases of breast cancer are diagnosed each year. (N.B Breast cancer in men does occur but it is rare – approximately 300 cases are diagnosed per year). The lymphatics are the main routes for metastases of malignant breast cancer. Axillary lymph nodes (which are the lymph nodes in the armpit which receive lymph from the breast and upper body) are usually removed during breast cancer surgery. This means that they can be examined under a microscope to determine if the cancer cells have spread. In many cases, all axillary lymph nodes are removed (there are between 30 and 50). The removal of such nodes can obstruct lymph drainage, resulting in swelling. Arm swelling is particularly common but swelling can also affect the breast and upper body.
Figure 7 - Breast cancer-related lymphoedema of the left arm ©St George's, University of London
Breast cancer-related lymphoedema (BCRL) affects approximately 25% of breast cancer patients and can be exacerbated by radiotherapy which scars tissue and disrupts lymph drainage. Most women will undergo axillary surgery as part of the breast cancer treatment and will have lymph nodes removed from the arm and approximately one quarter of these women will develop BCRL.
Clinical features and management of BCRLBreast cancer-related lymphoedema is incurable and the swelling characteristically worsens with time. The swollen arm can feel heavy and painful and the risk of infection and skin cancer is increased. BCRL is also associated with functional and psychological morbidity. Distress may be caused by clinicians whose primary focus is recurrence of the breast cancer and who may trivialise the lymphoedema because of its non-lethal nature. Some women have reported that the appearance of the arm is more distressing than living with a mastectomy. The latter can be easily hidden whereas a disfigured arm is a constant reminder of the breast cancer and a subject of curiosity to others.
Lymphoedema (unlike many cases of oedema) is incurable because underlying causes are irreversible and currently there is no drug or surgical therapies which improve lymph transport. Nevertheless, following an intensive treatment course combining Manual Lymphatic Drainage (a massage technique which encourages lymph drainage), compression bandaging (which limits the swelling) and exercise, the swelling can be reduced and controlled.
Puzzles in BCRLThe traditional and widely accepted view of BCRL is that damage to the axillary lymph nodes prevents lymph from properly draining out of the arm, much like a blocked drain, resulting in the swelling. However, this view explanation is too simplistic as it fails to fully explain certain puzzles which relate to BCRL. These include:
Why do only approximately a quarter of women who have similar breast cancer treatment develop BCRL and why not all?
Why can BCRL develop when just a single lymph node is removed and why does swelling not necessarily occur when all lymph nodes are removed?
Why can the arm seem normal for months or years after surgery and then suddenly swell for no obvious reason? (Swelling has been reported to develop as much as 20 years after surgery).
Why can certain parts of the arm be more swollen than other parts which may have no swelling at all? For example, sometimes the whole arm can be swollen whilst the hand is spared of swelling (figure 8) even though the hand and arm lymph drains to the same lymph nodes.
Current research into BCRL aims to solve these puzzles in the hope that management of the condition will improve and the swelling may be minimised or even prevented. Unless more can be understood about the mechanisms which cause the swelling, this incurable and debilitating condition is likely to remain a significant problem.
Figure 8: Left panel shows breast cancer-related lymphoedema of the arm and hand. Right panel shows breast cancer-related lymphoedema of the arm but no hand swelling.
The Louisiana Wetlands: An Introduction
Science Tales from the Red Stick.
A growing human presence interrupts the natural beauty and vastness of Louisiana’s coastline. Beyond the wetlands and outside the bayous are oil platforms and it seems everywhere there are warning markers of underground oil pipes. Still, the most dramatic change these wetlands are undergoing is the inundation of saltwater and the loss of land. Since the early 1930s, it is estimated that Louisiana has lost almost 5,000 square kilometers of wetlands. In fact, some say an area the size of a tennis court disappears every thirteen seconds. The wetlands are turning into water.
A wetland can be defined in many ways but most definitions include three distinguishing features: water, either at the surface or within the root zone, soil conditions unique to this wet environment, and vegetation known as hydrophytes that is adapted to these conditions. Wetlands can be fresh or salt water and in Louisiana there are both and they're equally in danger of disappearing.
According to the United States Geological Survey (USGS) and the Louisiana Department of Fish and Wildlife (LDWF) Louisiana has about 3,560 square kilometers of fresh water wetland and 6,600 square kilometers of tidal (salt water) wetland. That’s an area equivalent to two states of Rhode Island or almost 14 Isle of Mans. Wetlands include landscape features you are familiar with such as marshes, bogs, and swamps.
The wetlands I grew up with were small. You could easily walk across them and you could always see the edge. This is not the case in Louisiana. Here the wetlands stretch to the horizon. They are dotted with small fishing camps and telephone poles that sit at weird angles due to the shifting ground. Often flooded roads and abandoned houses blot the landscape. Despite this I had only to spend a single day out there accompanying two scientists on their monthly monitoring trip to Barataria Bay southwest of New Orleans, to be hooked.
We loaded our small boat early in the morning and headed to the southern most sampling station closest to the Gulf of Mexico. The plan was to work our way north collecting water samples for phytoplankton (microscopic plants), zooplankton (microscopic animals) and bacteria counts, nutrient analyses, and other water characteristics (temperature, salinity, dissolved oxygen, light attenuation). Regular monitoring is part of larger effort to understand the changes occurring along Louisiana’s coastline.
On this day, we wound our way up and down narrow passages surprising fish and sneaking up on alligators. The sky was grey and ominous. Because it is so flat you can see thunderstorms well in the distance - the rain and lightening drumming the water. Twin storms merged into one and chased us all the way to our last sampling station. From there, we headed into a bayou. A bayou is a secondary extension of a larger waterway – in this case – the Mississippi River. Thick with dark green vegetation and monstrous plants, this bayou had a prehistoric and deeply wild feel. Alligator eyes rose just above the surface and brilliant blue horse flies, the size of small birds, buzzed overhead. The water was slow moving and brown, hiding whatever it was that might be waiting underneath. What the bayou’s future holds is more readily detectable.
The coast of Louisiana is a deltaic system built of sediment transported from all over the United States by the Mississippi River. The Mississippi River drains 41% of the contiguous states of the US and is fed by the Missouri, Arkansas, and Ohio Rivers. The river carries this sediment load to the coast where it settles out and forms sediment lobes or land. Typically, as silt and clay clog the natural path of the river, it switches course finding a more direct and quicker route to the coast. This process is called delta switching and it occurs approximately once every one thousand years.
But as the population grew, and with the establishment of the Port of New Orleans, it became necessary to control the Mississippi River. Levees were constructed to maintain its path and the natural delta switching that occurred for thousands of years was interrupted. Gone then was the sediment distribution and ultimately the land building. Now the Gulf of Mexico can encroach, un-impeded by the River. Sometimes wetlands can keep up with sea level rise through sediment trapping and soil building but not here. These factors combine with land subsidence, the compaction of sediment, to augment the drowning of these wetlands. While subsidence can be a natural geologic process, human activities may also be the cause. Fluid (i.e. oil, gas, groundwater) extraction from underneath the marshes and/or artificial drainage systems have been blamed for high rates of subsidence in Louisiana. The final straw is shipping channels that have been cut and the pipelines that have been laid beneath the marshes. While this has increased navigation abilities it has also allowed saltwater inundation of the many freshwater marshes. For example, the cypress forests that once characterized this area are quickly vanishing because they cannot tolerate saltwater.
The disappearance of these wetlands has innumerable consequences. The coastal landscape is an important habitat for animals and migrating birds while the marsh provides an essential nursery ground for fish. According to Louisiana State University’s Agricultural Center, 95% of commercial fish landings for the Gulf of Mexico depend on the coastal wetlands and 25% of all seafood consumed in the US originates from Louisiana. The bountiful harvest of oysters and crawfish (crayfish) that once drove the local economy is threatened too. Many people have relocated or constructed their houses on stilts to protect them from the encroaching water. On a national scale almost 30% of the oil and gas consumed in the US passes through ports and pipes of South Louisiana. But without these wetlands more than 48,000 km of pipelines would be exposed to open water and waves. On an even larger scale, hurricanes that have struck Louisiana have even provoked increases in global oil prices.
But I am most interested in the loss of wetlands for another reason. Wetlands are areas rich in organic matter and can be important areas for nutrient cycling. Specifically, I am interested in the cycling of nitrogen and a process called denitrification. Denitrification is bacterial process that converts usable forms of nitrogen to unusable forms. It is therefore a natural cleansing process which can remove man-made nitrogen (such as fertilisers) from the environment. As the water from the Mississippi River drains the US it not only brings sediment for land building but high concentrations of nutrients (such as nitrates and phosphates). Most of these nutrients originate from agricultural practices high in the watershed. When the nutrients reach the coast they can stimulate the growth of phytoplankton which can be good for the growing fish. But, like all things, too many nutrients and too much phytoplankton growth can lead to negative consequences. Most notably in this case, when the phytoplankton die they sink to the bottom and decompose, which leads to the water becoming oxygen depleted, killing shellfish and finfish. One striking example of this is the Dead Zone in the Gulf of Mexico. The Dead Zone is a 13,000 - 21,000 square km area of oxygen-depleted water devoid of most forms of life. While many factors contribute to its size and duration, the high concentration of nutrients entering from the Mississippi River is thought to be the main cause.
So here is our dilemma – how do we build land and yet decrease the amount of nutrients entering the Gulf of Mexico? The answer may just lie in sustaining healthy wetlands. One option is to allow more water from the Mississippi River to be directed into the wetlands. By doing this, as it flowed to the coast the river would once again distribute sediment and the wetland might act like a giant filter and remove contaminating nitrogen. Working with colleagues here at LSU I hope to improve our understanding of how much nutrient cycling can occur in these systems and how these processes might change with temperature and water flow.
Beauty-wise, Louisiana’s coast rivals the icecaps of the Antarctic, the rolling waves of the Pacific and the tropical beaches of the Caribbean. But protecting these wetlands is about more than preserving a magnificent landscape. We should all feel a great sense of urgency to guard a culture, an economy, and a natural wonder teeming with life...
References:- Mitsch, W.J. and Gosselink, J.G. (1993). Wetlands. Van Nostrand Reinhold, New York, N.Y.- Dunne, M. (2005). America’s Wetland: Louisiana’s vanishing coast. Louisiana State University Press. Baton Rouge, LA
Bio-plastics:
Turning Wheat And Potatoes into Plastics
The science of how "taters" can become Tupperware
In the past, fields of wheat and rows of potatoes were seldom destined for anything more than a rumbling tummy. But bio-products have come a long way since people first branched out into weaving hemp into clothes and pulping papyrus into scrolls. Today the line between Mother Nature and man made has never been more blurred. Animals are re-engineered into living drug factories, crops fuel our cars and now plants are increasingly being repackaged as the epitome of the synthetic world – plastic. Wheat, maize, vegetable oils, sugar beet and even the trusty spud are finding new life as water bottles, car fuel lines and laptops.
Wheat, maize, vegetable oils, sugar beet and even the trusty spud are finding new life as water bottles, car fuel lines and laptops.
Bio-plastics harness the natural structures found in crops or trees, such as slightly modified forms of the chains of sugars in starch or cellulose, that share the ability to be easily reshaped that has made conventional oil based plastics so useful. Bio-materials scientists are also constantly tweaking these natural structures to try and better replicate the durability and flexibility of conventional plastics.Global business is now turning to bio-plastics for an increasing number of applications, as consumers and governments demand cleaner alternatives to petroleum based technologies and their reckless production of the greenhouse gas CO2.
Worldwide players, such as DuPont and Toyota Motor Corp, are making vast investments in new technologies and processing plants with the hope of cornering a multi-billion pound industry.
The "BC" at Bangor University in North Wales has 18-years experience of working with large companies and Non-Governmental Organisations (NGOs) to find sustainable and viable bio-based alternatives to man-made materials.
BC director Paul Fowler points out that “practically anything that you can find as polyethene you can find as a bio-plastic. You are talking about a whole range of everyday products - cups, combs and wrappers, everything you can think of is out there. There are inroads being made all the time - on the one hand there is research into trying to get biological alternatives to replicate the properties of conventional plastics and on the other hand people are looking at the natural properties of these plants and trying to find an application for them. Most of the manufacture is happening in the US and continental Europe. The UK is a producer of wheat starch and biotimber but the only major bioplastic producer is Innovia Films in Cumbria, which produces cellulose films.”
Innovia Films has an annual turnover of £400m, employing 1,200 people worldwide and producing more than 120,000 tonnes of film – used in packaging to protect food. Japan is also forging ahead, from the leading role in bioplastic production played by Toyota to its recent passing of a triumvirate of laws pushing forward environmental initiatives.In South Korea too there is a rapid drive to replace conventional plastic packaging with polylactic acid bio-plastics.
Fowler says bio-plastics also offer an opportunity to get a double return for the energy used in their manufacture – first as a useful item and secondly as a fuel source. “My view is that we should burn them at the end of their life to recover energy, which could be then used to produce new materials,” he said. “In the first instance you have a valuable resource can use, be it as packaging or a shopping bag, and then you are also getting some energy back at the end of it. The biggest advantage of such bio-materials is the reduction of CO2 emissions in their production over petrochemical-based plastics.”
He also suggests that burning bio-plastics would also avoid the problems caused by them breaking down and producing methane, which is 25-times more potent as a greenhouse gas than CO2.
The BC is currently looking at developing naturally-derived alternatives to phthalates, which are plasticisers added to PVCs to make them more flexible in products such as electrical cable flex. It follows concerns that phthalates are metabolised in the body into substances that can mimic the body's own hormones, including those concerned with fertility. The centre is also developing bio-resins, natural alternatives to synthetic resins such as phenol and formaldehyde.
What types of bioplastic are there?The common types of bio-plastics are based on cellulose, starch, polylactic acid (PLA), poly-3-hydroxybutyrate (PHB), and polyamide 11 (PA11). Cellulose-based plastics are usually produced from wood pulp and used to make film-based products such as wrappers and to seal in freshness in ready-made meals.Thermoplastic starch is the most important and widely used bioplastic, accounting for about 50pc of the bio-plastics market. Pure starch’s ability to absorb humidity has led to it being widely used for the production of drug capsules in the pharmaceutical sector. Plasticisers, such as sorbitol and glycerine are added to make it more flexible and produce a range of different characteristics. It is commmonly derived from crops such as potatoes or maize.
FOMA(TM) N701iECO phone made of PLA bioplastics reinforced with kenaf fibres developed by NEC, UNITIKA and NTTDoCoMo © Paul FowlerPLA is a transparent plastic whose characteristics resemble common petrochemical-based plastics such as polyethylene and polpropylene. It can be processed on equipment that already exists for the production of conventional plastics. PLA is produced from the fermentation of starch from crops, most commonly corn starch or sugarcane in the US, into lactic acid that is then polymerised. Its blends are used in a wide range of applications including computer and mobile phone casings, foil, biodegradable medical implants, moulds, tins, cups, bottles and other packaging.PHB is very similar to poylpropylene, which is used in a wide variety of fields including packaging, ropes, bank notes and car parts. It is a transparent film, which is also biodegradable. Interest in PHB is currently very high with companies worldwide aiming to expand their current production capacity. There are estimates that this could lead to a price reduction below five euros per kilogram but this would still be four times the market price of polyethylene in February 2007. The South American sugar industry has commited to producing PHB on an industrial scale.PA 11 is derived from vegetable oil and is known under the tradename Rislan. It is prized for its thermal reistance that makes it valued for use in car fuel lines, pneumatic air brake tubing, electrical anti-termite cable sheathing and oil and gas flexible pipes and control fluid umbilicals. These are often reinforced with fibres from the kenaf plant, a member of the hibiscus family traditionally used to make paper, to increase heat resistance and durability.At the cutting edge of bioplastic technology lie polyhydroxyalkanoate (PHA) materials. These are derived from the conversion of natural sugars and oils using microbes. They can be processed into a number of materials including moulded goods, fibre and film and are biodegradable and have even been used as water resistant coatings.
What are the benefits of bio-plastics?
- Reduced CO2 emissions. One metric ton of bio-plastics generates between 0.8 and 3.2 fewer metric tons of carbon dioxide than one metric ton of petroleum-based plastics. Electronic giant Sony uses PLA in several of its smaller components, including one of its new walkmans, but in future hopes to use PLA-based polymers to reduce its carbon dioxide emissions by 20pc and non-renewable resource input by 55pc compared to oil-based ABS.- Rising oil pricesDespite currently costing more to produce than conventional plastics bio-plastics are becoming more viable with increasing and instability in oil prices, which are in turn triggering spikes in conventional plastic costs, illustrated in a sharp upturn two years ago. Dwindling oil supplies means that man will eventually be forced to turn to a sustainable basis for plastics.
- WasteBio-plastics reduce the amount of toxic run-off generated by the oil-based alternatives but also are more commonly biodegradable. The US’s second largest biopolymer producer Metabolix, of Cambridge, Massachusetts, claims that its plastics are biodegradable in composting bins, wetlands and the oceans. On the flip side not all bio-plastics are biodegradable and there are a growing number of conventional plastics that can naturally break down. The downside of their biodegradability is the methane that can be released as the bio-plastics decompose is a powerful greenhouse gas.- Benefit to rural economyPrices of crops, such as maize, have risen sharply in the wake of global interest in the production of biofuels and bio-plastics, as countries across the world look for alternatives to oil to safeguard the environment and provide energy security.- Enhanced properties In some fields engineered bio-plastics are now beating oil-based alternatives at their own game. Multinational materials giant Arkema has produced a form of Rislan PA11 that is being used in Europe and Brazil in fuel lines to carry biofuels as it is better able to withstand the corrosive effects of biofuels than oil-based alternatives such as polyamide 12. Rislan is widely used in oilfield applications as well as automotive brake lines. Elsewhere innovations in PA11 production are helping increase car passenger safety and reduce the risk of accidents by inhibiting spark ignition in the fuel lines. US car giant General Motors has replaced its non-conductive fuel-pump modules for new North American car models as it felt it was the best material for the job. In the US chemical multinational DuPont says it has developed a bioplastic derived from corn sugar that has superior stiffness and strength to its naturally based competitors. Global electronics corporation NEC has produced a kenaf-reinforced laptop casing, made of 90pc PLA, which helps reduce overheating by conducting heat better than stainless steel coupled with high temperature resistance and increased strength. Who are the flagwavers?Bio-plastics are not being produced by a group of hippies brewing up in their garage. Some of the world’s largest companies including multi-billion dollar chemicals company DuPont, car manufacturer Toyota, UK-based Innovia, US food processing behemoth Cargill and electronics giants NEC and Fujitsu are pouring money into driving the technology and production forward. NEC and its partners Unitika and NTT DoCoMo produce mobile phone and laptop casings based on plant-derived bio-plastics, mostly PLA. NEC plans to expand its green credentials by substituting more than 10pc of the oil-based plastics in its electronic products with bio-plastics by 2010.Toyota Motor Corp uses mainly PLA bio-plastics, derived from sweet potatoes corn and sugar beet, reinforced with kenaf to produce components for its cars such as the Prius and Lexus. It hopes to grow its bio-plastics division into a four billion yen business by 2020 and capture two thirds of the global market for petroleum free plastics. Fujitsu introduced its FMV BIBLO notebook PC series two years ago, which it has manufactured using a material called Ecodear, a combination of 50 pc PLA and an oil-based plastic. Fujitsu is now developing a castor oil derived PA 11 plastic with Arkema, which is more flexible and will help expand its use of bio-plastics in notebook computers. The material can withstand repeated bending thanks to scientists weakening the interaction of the chain molecule in PA 11 and relaxing the stereoregularity of their organisation. The improved durability means its prototypes of PC cover components consist of 60-80 percent of the new bioplastic, an unprecedented achievement to date. Fujitsu is also using high density fillers to increase strength and extend its use into notebook covers and other applications requiring high impact resistance. The new material is expected to cut carbon dioxide emissions by 42pc compared to oil-based nylon 6/6.DuPont in particular is continuing to expand the market for bio-plastics and plans to continue to offer hybrid bio/conventional plastic materials until the market matures, which could eventually cost less than the oil-based alternatives. DuPont has teamed up with sugar giant Tate & Lyle to build the world’s largest aerobic fermentation plant in Loudon in Tennessee in the US for the production of bio-PDO, with a capacity of 45,000 metric tonnes a year.The largest commercial producer of bioplastic in the US is NatureWorks, owned by Cargill. The company’s plant in Blair, Nebraska uses corn sugar to produce PLA plastics packaging material and its own Ingeo-brand fibres.
What lies ahead?With US President George Bush’s recent pledge to produce 35 billion gallons of renewable and alternative fuel by 2017 - driving the price of maize up 60pc in the past two months - the farmer’s field is fast turning into a high tech bio-battleground.
Mr. Fowler warns that the still fledgling industry will have to fight for space and commercial viability as millions of hectares are given over to corn, rapeseed and sugarbeet for bio-fuel production. "There is a real tension between the use of agriculture for fodd versus plastics and other non-food uses and this whole move to produce new fuels," he said. Whereas only two years ago plant materials were at the cheap end of the market and bio-products such as straw had little value, now it is really much more costly. There would have to be a step change in the extent of the production to match oil-based plastics. The amount of bioplastics produced worldwide is less than 200,000 tonnes a year; contrast that with the more than 30 million tonnes of oil-based plastics. You can see we have a long way to go before they replace conventional plastics".
The science of how "taters" can become Tupperware
In the past, fields of wheat and rows of potatoes were seldom destined for anything more than a rumbling tummy. But bio-products have come a long way since people first branched out into weaving hemp into clothes and pulping papyrus into scrolls. Today the line between Mother Nature and man made has never been more blurred. Animals are re-engineered into living drug factories, crops fuel our cars and now plants are increasingly being repackaged as the epitome of the synthetic world – plastic. Wheat, maize, vegetable oils, sugar beet and even the trusty spud are finding new life as water bottles, car fuel lines and laptops.
Wheat, maize, vegetable oils, sugar beet and even the trusty spud are finding new life as water bottles, car fuel lines and laptops.
Bio-plastics harness the natural structures found in crops or trees, such as slightly modified forms of the chains of sugars in starch or cellulose, that share the ability to be easily reshaped that has made conventional oil based plastics so useful. Bio-materials scientists are also constantly tweaking these natural structures to try and better replicate the durability and flexibility of conventional plastics.Global business is now turning to bio-plastics for an increasing number of applications, as consumers and governments demand cleaner alternatives to petroleum based technologies and their reckless production of the greenhouse gas CO2.
Worldwide players, such as DuPont and Toyota Motor Corp, are making vast investments in new technologies and processing plants with the hope of cornering a multi-billion pound industry.
The "BC" at Bangor University in North Wales has 18-years experience of working with large companies and Non-Governmental Organisations (NGOs) to find sustainable and viable bio-based alternatives to man-made materials.
BC director Paul Fowler points out that “practically anything that you can find as polyethene you can find as a bio-plastic. You are talking about a whole range of everyday products - cups, combs and wrappers, everything you can think of is out there. There are inroads being made all the time - on the one hand there is research into trying to get biological alternatives to replicate the properties of conventional plastics and on the other hand people are looking at the natural properties of these plants and trying to find an application for them. Most of the manufacture is happening in the US and continental Europe. The UK is a producer of wheat starch and biotimber but the only major bioplastic producer is Innovia Films in Cumbria, which produces cellulose films.”
Innovia Films has an annual turnover of £400m, employing 1,200 people worldwide and producing more than 120,000 tonnes of film – used in packaging to protect food. Japan is also forging ahead, from the leading role in bioplastic production played by Toyota to its recent passing of a triumvirate of laws pushing forward environmental initiatives.In South Korea too there is a rapid drive to replace conventional plastic packaging with polylactic acid bio-plastics.
Fowler says bio-plastics also offer an opportunity to get a double return for the energy used in their manufacture – first as a useful item and secondly as a fuel source. “My view is that we should burn them at the end of their life to recover energy, which could be then used to produce new materials,” he said. “In the first instance you have a valuable resource can use, be it as packaging or a shopping bag, and then you are also getting some energy back at the end of it. The biggest advantage of such bio-materials is the reduction of CO2 emissions in their production over petrochemical-based plastics.”
He also suggests that burning bio-plastics would also avoid the problems caused by them breaking down and producing methane, which is 25-times more potent as a greenhouse gas than CO2.
The BC is currently looking at developing naturally-derived alternatives to phthalates, which are plasticisers added to PVCs to make them more flexible in products such as electrical cable flex. It follows concerns that phthalates are metabolised in the body into substances that can mimic the body's own hormones, including those concerned with fertility. The centre is also developing bio-resins, natural alternatives to synthetic resins such as phenol and formaldehyde.
What types of bioplastic are there?The common types of bio-plastics are based on cellulose, starch, polylactic acid (PLA), poly-3-hydroxybutyrate (PHB), and polyamide 11 (PA11). Cellulose-based plastics are usually produced from wood pulp and used to make film-based products such as wrappers and to seal in freshness in ready-made meals.Thermoplastic starch is the most important and widely used bioplastic, accounting for about 50pc of the bio-plastics market. Pure starch’s ability to absorb humidity has led to it being widely used for the production of drug capsules in the pharmaceutical sector. Plasticisers, such as sorbitol and glycerine are added to make it more flexible and produce a range of different characteristics. It is commmonly derived from crops such as potatoes or maize.
FOMA(TM) N701iECO phone made of PLA bioplastics reinforced with kenaf fibres developed by NEC, UNITIKA and NTTDoCoMo © Paul FowlerPLA is a transparent plastic whose characteristics resemble common petrochemical-based plastics such as polyethylene and polpropylene. It can be processed on equipment that already exists for the production of conventional plastics. PLA is produced from the fermentation of starch from crops, most commonly corn starch or sugarcane in the US, into lactic acid that is then polymerised. Its blends are used in a wide range of applications including computer and mobile phone casings, foil, biodegradable medical implants, moulds, tins, cups, bottles and other packaging.PHB is very similar to poylpropylene, which is used in a wide variety of fields including packaging, ropes, bank notes and car parts. It is a transparent film, which is also biodegradable. Interest in PHB is currently very high with companies worldwide aiming to expand their current production capacity. There are estimates that this could lead to a price reduction below five euros per kilogram but this would still be four times the market price of polyethylene in February 2007. The South American sugar industry has commited to producing PHB on an industrial scale.PA 11 is derived from vegetable oil and is known under the tradename Rislan. It is prized for its thermal reistance that makes it valued for use in car fuel lines, pneumatic air brake tubing, electrical anti-termite cable sheathing and oil and gas flexible pipes and control fluid umbilicals. These are often reinforced with fibres from the kenaf plant, a member of the hibiscus family traditionally used to make paper, to increase heat resistance and durability.At the cutting edge of bioplastic technology lie polyhydroxyalkanoate (PHA) materials. These are derived from the conversion of natural sugars and oils using microbes. They can be processed into a number of materials including moulded goods, fibre and film and are biodegradable and have even been used as water resistant coatings.
What are the benefits of bio-plastics?
- Reduced CO2 emissions. One metric ton of bio-plastics generates between 0.8 and 3.2 fewer metric tons of carbon dioxide than one metric ton of petroleum-based plastics. Electronic giant Sony uses PLA in several of its smaller components, including one of its new walkmans, but in future hopes to use PLA-based polymers to reduce its carbon dioxide emissions by 20pc and non-renewable resource input by 55pc compared to oil-based ABS.- Rising oil pricesDespite currently costing more to produce than conventional plastics bio-plastics are becoming more viable with increasing and instability in oil prices, which are in turn triggering spikes in conventional plastic costs, illustrated in a sharp upturn two years ago. Dwindling oil supplies means that man will eventually be forced to turn to a sustainable basis for plastics.
- WasteBio-plastics reduce the amount of toxic run-off generated by the oil-based alternatives but also are more commonly biodegradable. The US’s second largest biopolymer producer Metabolix, of Cambridge, Massachusetts, claims that its plastics are biodegradable in composting bins, wetlands and the oceans. On the flip side not all bio-plastics are biodegradable and there are a growing number of conventional plastics that can naturally break down. The downside of their biodegradability is the methane that can be released as the bio-plastics decompose is a powerful greenhouse gas.- Benefit to rural economyPrices of crops, such as maize, have risen sharply in the wake of global interest in the production of biofuels and bio-plastics, as countries across the world look for alternatives to oil to safeguard the environment and provide energy security.- Enhanced properties In some fields engineered bio-plastics are now beating oil-based alternatives at their own game. Multinational materials giant Arkema has produced a form of Rislan PA11 that is being used in Europe and Brazil in fuel lines to carry biofuels as it is better able to withstand the corrosive effects of biofuels than oil-based alternatives such as polyamide 12. Rislan is widely used in oilfield applications as well as automotive brake lines. Elsewhere innovations in PA11 production are helping increase car passenger safety and reduce the risk of accidents by inhibiting spark ignition in the fuel lines. US car giant General Motors has replaced its non-conductive fuel-pump modules for new North American car models as it felt it was the best material for the job. In the US chemical multinational DuPont says it has developed a bioplastic derived from corn sugar that has superior stiffness and strength to its naturally based competitors. Global electronics corporation NEC has produced a kenaf-reinforced laptop casing, made of 90pc PLA, which helps reduce overheating by conducting heat better than stainless steel coupled with high temperature resistance and increased strength. Who are the flagwavers?Bio-plastics are not being produced by a group of hippies brewing up in their garage. Some of the world’s largest companies including multi-billion dollar chemicals company DuPont, car manufacturer Toyota, UK-based Innovia, US food processing behemoth Cargill and electronics giants NEC and Fujitsu are pouring money into driving the technology and production forward. NEC and its partners Unitika and NTT DoCoMo produce mobile phone and laptop casings based on plant-derived bio-plastics, mostly PLA. NEC plans to expand its green credentials by substituting more than 10pc of the oil-based plastics in its electronic products with bio-plastics by 2010.Toyota Motor Corp uses mainly PLA bio-plastics, derived from sweet potatoes corn and sugar beet, reinforced with kenaf to produce components for its cars such as the Prius and Lexus. It hopes to grow its bio-plastics division into a four billion yen business by 2020 and capture two thirds of the global market for petroleum free plastics. Fujitsu introduced its FMV BIBLO notebook PC series two years ago, which it has manufactured using a material called Ecodear, a combination of 50 pc PLA and an oil-based plastic. Fujitsu is now developing a castor oil derived PA 11 plastic with Arkema, which is more flexible and will help expand its use of bio-plastics in notebook computers. The material can withstand repeated bending thanks to scientists weakening the interaction of the chain molecule in PA 11 and relaxing the stereoregularity of their organisation. The improved durability means its prototypes of PC cover components consist of 60-80 percent of the new bioplastic, an unprecedented achievement to date. Fujitsu is also using high density fillers to increase strength and extend its use into notebook covers and other applications requiring high impact resistance. The new material is expected to cut carbon dioxide emissions by 42pc compared to oil-based nylon 6/6.DuPont in particular is continuing to expand the market for bio-plastics and plans to continue to offer hybrid bio/conventional plastic materials until the market matures, which could eventually cost less than the oil-based alternatives. DuPont has teamed up with sugar giant Tate & Lyle to build the world’s largest aerobic fermentation plant in Loudon in Tennessee in the US for the production of bio-PDO, with a capacity of 45,000 metric tonnes a year.The largest commercial producer of bioplastic in the US is NatureWorks, owned by Cargill. The company’s plant in Blair, Nebraska uses corn sugar to produce PLA plastics packaging material and its own Ingeo-brand fibres.
What lies ahead?With US President George Bush’s recent pledge to produce 35 billion gallons of renewable and alternative fuel by 2017 - driving the price of maize up 60pc in the past two months - the farmer’s field is fast turning into a high tech bio-battleground.
Mr. Fowler warns that the still fledgling industry will have to fight for space and commercial viability as millions of hectares are given over to corn, rapeseed and sugarbeet for bio-fuel production. "There is a real tension between the use of agriculture for fodd versus plastics and other non-food uses and this whole move to produce new fuels," he said. Whereas only two years ago plant materials were at the cheap end of the market and bio-products such as straw had little value, now it is really much more costly. There would have to be a step change in the extent of the production to match oil-based plastics. The amount of bioplastics produced worldwide is less than 200,000 tonnes a year; contrast that with the more than 30 million tonnes of oil-based plastics. You can see we have a long way to go before they replace conventional plastics".
The Science of HIV & AIDS in the UK
The biology and impact of the world's worst pandemic
In the UK the plight of AIDS today gets much less attention from the public and the media than it did back in the 1980’s and early 1990’s. This often leads to the misconception that AIDS is no longer a problem in this country; in reality, the increasing prevalence of HIV in the UK proves that this is simply not true.
Worldwide, accepted definitions, facts and figures on HIV and AIDS include:
Acquired immune deficiency syndrome (AIDS) is a collection of symptoms and infections that result from specific damage to the immune system by the human immunodeficiency virus (HIV).
HIV is transmitted through the direct contact of a mucous membrane, or the bloodstream, with a bodily fluid containing HIV.
The late stage of the condition leaves individuals prone to opportunistic infections and tumours.
Whilst antiretroviral treatments for AIDS and HIV exist to reduce the mortality and morbidity of HIV infection to date there is no known cure; even access to these antiretroviral treatments is not routine in all countries.
Researchers believe that sometime in the 1930’s a form of simian immunodeficiency virus jumped to humans who butchered or ate chimpanzee bush meat in the Democratic Republic of Congo. The virus became HIV-1, the most widespread form found today.
The world’s first known case of AIDS has been traced to a sample of blood plasma from a man who died in 1959. During the 1970’s HIV continued to spread undetected around the world and hence the pandemic began. Today an estimated 40 million people are living with HIV worldwide.
As of January 2006, the Joint United Nations Programme on HIV/AIDS and the World Health Organization estimate that AIDS has killed more than 25 million people since it was first recognised on June 5th, 1981.
The stigma associated with HIV/AIDS is severe and extends to providers and volunteers involved with the care of HIV infected patients. AIDS exerts its toll also on societies, devastating their economies, decimating their labour forces and orphaning children.
Thus, it is one of the most destructive pandemics in recorded history, surpassing even the Black Death. By 2015 it is estimated that 60 million people will have died of AIDS.
In 2004 the global spending on AIDS was $6.1b. Estimated global AIDS spending required in 2007 for prevention and care is $20b. Less than 3% of all money spent on AIDS goes towards developing a vaccine for the disease.
In February 2007 a study published in the Lancet showed that male circumcision could dramatically reduce the risk of HIV infection. The randomised control trial showed that circumcised men were 60% less likely to pick up HIV. This means that if all of the 2.5 million men in KwaZulu-Natal province had been circumcised, 37,000 new HIV infections could have been prevented in 2007 alone.
The history of HIV / AIDS in the UKThe first recognised case of AIDS in the UK was recorded in December 1981, when doctors at Brompton Hospital in London reported the case of a 49 year old homosexual man who had died ten days post referral. He was suffering from a rare infection that almost always occurs in individuals with severely weakened immune systems. Doctors believed that the condition might be linked to similar cases that had been occurring amongst gay men in the US.
Throughout the 1980’s the number of newly diagnosed HIV infections per year in the UK rose steadily. The figure plateaued during the 1990’s, averaging about 3,000 cases per year, but then increased dramatically after 1999. By 2005, the annual number of newly diagnosed infections was more than 7,500, and an estimated 63,500 people over 15 years of age were living with HIV in the UK, 20,100 (32%) of whom were believed to be unaware of having been infected. Since the pandemic began there have been 17,161 known UK HIV deaths.
The science bit...HIV is a retrovirus, meaning that it uses a chemical relative of DNA, called RNA (ribonucleic acid), as its genetic material. It primarily attacks components of the human immune system, including T lymphocytes and other white blood cells that carry "CD4" receptors on their surfaces. HIV enters its target cells by binding to both the CD4 molecule and a chemokine "co-receptor", of which there are two forms, CCR5 and CXCR4. Once inside the cell the virus makes a DNA copy of its genome and then uses an enzyme it carries with it, called integrase, to insert this copy into the cell’s own DNA. Either immediately, or after a period of dormancy known as latency, the virus then hijacks the cell and turns it into a virus factory. The newly produced viruses leave the infected cell, destroying it in the process, and move on to invade other CD4+ cells, which are mainly T lymphocytes. These are the cellular linchpins that help to marshall the other components of the body's immune system. As their numbers dwindle the ability of the body to mount an effective immune response to combat other invaders, including bacteria, viruses and fungi, is progressively weakened. This means that HIV kills by slowly destroying the immune system and leaving the infected individual vulnerable to infection by so called "low grade" or opportunistic bugs.
What is the natural history of HIV infection? What are the symptoms?Most infections with HIV are initially "silent", meaning that a person may not notice that anything is wrong. Then, several weeks after infection, patients often develop a "seroconversion illness", which characteristically includes flu-like symptoms, lymphadenopathy (swollen lymph glands), fevers, loss of appetite and weight, diarrhoea and general lethargy and malaise. During this time infected individuals have very high levels of virus in the bloodstream (10 million viruses per millilitre of blood is not uncommon). The reason for this very high viral load is that the virus is able to replicate (grow) largely unchecked because the immune system has yet to mount an effective suppressive response, including the production of antibodies that can mop up viral particles. As a result the number of CD4+ T cells can fall to very low levels at this time, and the patient is highly infectious.
But then the immune system kicks in, and the virus largely retreats, hiding within lymphoid tissues and replicating only very slowly. The levels of virus in the blood stream become much lower, the patient is less infectious and feels well. Untreated, an infected individual usually remains "healthy" like this for 5 to 15 years.
Structure of the human immunodeficiency virus (HIV) viral particle.
However, the body’s immune system only has a limited ability to control HIV. The virus makes mistakes when it copies its genetic code. Roughly once in every 10,000 genetic letters that are copied the virus introduces the wrong genetic base. Since the genome contains about 9000 bases in total, almost every genome copied will contain an error. The result is that these genetic mistakes alter the appearance of the virus and so make it harder for the immune system to recognise and keep up, because it is trying to hit a moving target. Eventually, through this progressive shape-shifting, the virus takes on a form that the immune system cannot respond to, and at this point the pace of the infection begins to accelerate and the number of CD4+ T cells begins to fall.
When the CD4 count falls below a critical threshold (400 per microlitre of blood) the body is no longer able to defend itself. At this point an HIV-infected individual is said to have AIDS, and patients usually begin to develop opportunistic infections caused by organisms that would not normally affect healthy people. These include mycobaterial infections (caused by bacteria related to tuberculosis), the lung infection PCP (pneumocystis carinii pneumonia), oral and genital thrush, complications of CMV (cytomegalovirus), chronic diarrhoea and weight loss, toxoplasmosis, meningitis, dementia, and polyomavirus (JC virus), which is associated with a disease of the brain's white matter known as PML (progressive multifocal leucoencephalopathy). At this point patients are often prescribed prophylactic drugs to help ward off some of these infections including co-trimoxazole, which can slow down the progression of PCP.
Without treatment the median survival time after developing AIDS is only about 9 months. However, the rate of clinical disease progression varies widely between individuals from 2 weeks to 20 years. Many factors affect this rate of progression, including age, quality of health care and the presence of co-existing infections. An individual's genetic make-up also plays an important role because it's now becoming clear that some people are resistant to certain strains of HIV and although they become infected they do not seem to develop AIDS, or they do so only extremely slowly. There are even people who seem to be totally immune to infection with the virus. They carry a mutated cell surface marker called CCR5-delta-32, which prevents HIV from locking onto and invading their cells. Scientists hope that understanding what makes these people able to resist the virus may hold the key to future therapies to block infection amongst susceptible individuals.
TreatmentWhilst the number of people living with HIV is rising each year, the number of HIV infections that progress to AIDS has dropped dramatically since 1996. This is primarily the result of anti-retroviral therapies, which are available to slow the progress of the virus. These target essential components of the viral replication cycle and include reverse transciptase (RT) inhibitors, which interfere with the way the virus makes a complementary "cDNA" copy of its RNA genome, and protease inhibitors, which prevent the virus from cutting up the raw materials it needs to form new viral particles.
There are two types of drugs that block RT; these are known as nucleoside and non-nucleoside RT inhibitors. The nucleoside RT inhibitors are structurally very similar to normal DNA bases, but they lack a critical chemical group required to enable a DNA chain to grow. So when the viral RT inserts one of these altered bases into the copy that it's making of its genetic code, it can't finish the job because it cannot add the next genetic letter. An example of this type of agent is the drug AZT or zidovudine (azidothymidine). The non-nucleoside RT inhibitors, which include drugs like efavirenz and nevirapine, work slightly differently. They target the RT enzyme itself and bind to it, distorting its shape so that it cannot work properly. This stops the virus from replicating.
Protease inhibitors (PIs) only emerged more recently. They work by blocking the action of a protein-cutting enyzme carried by HIV, which is critical to the virus being able to assemble new infectious particles. If this enzyme is prevented from doing its job the virus cannot escape from the infected cell. An example of the PIs includes saquinavir, which is famous for being one of the first drugs produced by building a computer model of the shape of the viral enzyme and then designing a drug specifically to block it.
There are also agents known as fusion inhibitors, which are a newer type of drug that work by stopping HIV from binding with the CD4 receptors that it uses to enter cells. One being evaluated at the moment is called efurvatide.
Doctors have also recently been testing a new agent called raltegravir, which is an "integrase inhibitor". This prevents the virus from inserting a copy of its genetic material into the host cell genome. In a recent trial published in the Lancet doctors randomly allocated 179 patients with end-stage HIV / AIDS to receive either the active drug or a placebo. After 6 months the patients receiving raltegravir showed a 98% drop in the levels of virus in the bloodstream, compared with only 45% in the placebo group. The next step will be to test raltegravir in combination with other HAART regimen drugs in healthier patients who are not approaching the end-stages of their disease. It may make a considerable difference to the rate of disease progression.
So there are lots of drugs with which we can now combat HIV; but there's a problem. Because the virus frequently makes mistakes when it copies its genetic material it rapidly develops forms of the virus that are resistant to the action of these drugs. To slow down the rate at which this happens, rather than use them singly, a cocktail of drugs is used, often one from each of the three classes (nucleoside RT inhibitors, non-nucleoside RT inhibitors and protease inhibitors). This is known as HAART or Highly Active Antiretroviral Therapy (HAART) and it has dramatically reduced the evolution of viral resistance and prolonged the time during which an HIV-infected individual remains healthy and symptom free. However, it's worth emphasising that, whilst drugs help to control the spread of HIV to uninfected cells, unfortunately there is no treatment available at present that can eradicate HIV once integrated into a host.
Side effects...This means that individuals using HAART have to take medication every day for the rest of their lives, and this often causes severe side effects. When individuals first start treatment they may suffer headaches, hypertension or general malaise (feeling unwell), although these usually improve or disappear with time. Other side effects can include diarrhoea, nausea, fatigue, anaemia, lipodystrophy, skin problems, neuropathy, mitochondrial toxicity, dyslipidaemia and bone problems. Whilst most people who take anti-HIV medications have some side effects it must not be assumed that everyone gets every side effect that has ever been written down.
Another problem with combating HIV is that a number of different strains of the virus can arise due to differences in selection pressures as the virus encounters different individuals, different drugs and different routes of spread. This can result in resistance to multiple anti-retrovirals and frequently occurs through a process called recombination. It occurs because each HIV virion carries two complete RNA genomic strands, meaning that homologous recombination can occur when a cell is coinfected with two different but related strains. The two strains may then exchange genetic material, including drug resistance traits. The process of recombination also therefore poses theoretical problems for the development of a safe vaccine against HIV.
The situation is also made worse by the fact that increasing numbers of patients are found to be carrying resistant forms of the virus at diagnosis, even before any drug therapy has been administered. Indeed, in 2004 an estimated 9% of new HIV diagnoses were found to be drug resistant strains, presumably acquired from individuals who had already received treatment. If patients then acquire additional strains of the virus with different resistance profiles the process of recombination can yield multiply-resistant viruses. In a case described recently in the Lancet this resulted in an individual producing a strain of the virus that was resistant to every available anti-retroviral agent. The patient in question also progressed to AIDS and died within six months of becoming infected.
The main ways HIV is transmitted in the UKThe three main transmission routes of HIV are sexual contact, exposure to infected body fluids or tissues and from mother to foetus or child during the perinatal period. It is possible to find HIV in the saliva, tears and urine of infected individuals but there are no recorded cases of infection by these secretions and the risk of infection is negligible. Breast milk, however, is known to be a significant risk factor for mother to child transmission of HIV. Studies have shown that if no anti-infection precautions are taken then 15-20% of new born babies will be infected, but if they are also breast-fed this proportion rises to over 50%. As a result HIV-positive mothers are advised not to breastfeed their babies.
A reported 754 HIV-infected children had been born in the UK to infected mothers as of the end of December 2006. Aware of the increasing risk posed by HIV to newborns and care-workers, in 1999 the UK Government introduced routine antenatal testing for HIV amongst all pregnant women. In those found to be positive, the use of antiretroviral treatment can greatly reduce the chances of a mother passing the infection to her baby. Since 1996 the increased use of such treatment has caused the rate of mother-to-child transmission to fall substantially.
Early media coverage of AIDS in the UK focused on injecting drug users. During the early 1980’s it was a big problem, but in 1986 needle exchanges began to operate across the UK, providing clean needles and giving drug users information and support. These schemes were largely effective in reducing the prevalence of HIV among certain members of this population. However, while they account for a small proportion of people living with HIV in the UK, the prevalence of HIV among injecting drug users has risen significantly in recent years (from 1:110, in 2002, to 1:62, in 2006). This rise has been attributed to an increase in the use of drugs outside of London where needle exchange schemes and information about HIV are harder to access.
Government policy in the UKAccording to the latest Government legislation, NHS treatment for HIV is free to everyone who is living in the UK legally. This means that people who are living in the UK without due authority (such as illegal immigrants and failed asylum seekers) must pay for any HIV treatment they receive.
This measure aimed to tackle health tourism, the process whereby people migrate to a country in order to take advantage of better healthcare services there. However, denial of treatment to people in these situations can effectively be a death sentence, especially if they are then deported to countries where no treatment is available.
There are certain 'notifiable diseases', for which a person will always receive treatment in the UK regardless of their legal status, in order to prevent the rapid spread of epidemics. HIV, however is not on the notifiable diseases list. If a woman has no legal right to be in the UK then she will only receive medication to stop her baby being born HIV positive if doctors decide it is an 'emergency'.
Financial costs to the UK health system
The cost of managing a patient with HIV is around £16,000 a year.
The total cost of treatment and care in 2002/03 was estimated to be £345m.
In 2000 it was estimated that the average lifetime treatment cost for an HIV positive person was between £135k and £181k.
Why is HIV / AIDS still on the increase in the UK?There is currently no vaccine or cure for HIV or AIDS. The only known methods of prevention are based on avoiding exposure to the virus, male circumcision which is discussed below, and antiretroviral treatment administered directly after a highly significant exposure. This is known as post exposure prophylaxis (PEP) and comprises a 4 week drug schedule, the side effects of which are very unpleasant.
Another reason people are still dying of AIDS is due to many being diagnosed with HIV at a late stage of infection. In 2005 more than one third of adults diagnosed with HIV had a CD4 count lower than the recommended threshold for starting treatment. At this stage treatment is much less likely to work. This late diagnosis is alarmingly common, highlighting the need for greater awareness and for people to access testing services as soon as possible if they think they may have been exposed to HIV.
What is next?Billions of pounds are spent every year worldwide on caring for and treating individuals with HIV/AIDS and on resources to prevent further spreading of the virus. However, ultimately it is a cure that is required to combat this pandemic. A vaccine to prevent HIV infection, as an alternative method to current therapies, may still be many years away. Not only might such a vaccine have to prime antibodies to attack HIV (the way most vaccines work) but it might also need to increase T cell production. Vaccine trials have been undertaken in South Africa, Kenya, the USA and Thailand, though most have yet to yield promising results. Controversial vaccines made from the blood of HIV carriers have been tested in Nigeria and Thailand. Other developing avenues for treatment of HIV positive individuals include gene therapy, targeted radiation therapy and nanotube technology to block the invasion of HIV into target cells. In April 2007 researchers even identified a component naturally present in human blood (a protein derived from alpha-1-antitrypsin) that can block HIV entry into cells.
In the absence of a vaccine researchers have turned to other approaches to try to combat the virus. A promising discovery, confirmed earlier in 2007, was that male circumcision can dramatically reduce, by 60%, the chances of acquiring HIV. The first clues that circumcision might be beneficial in halting the spread of HIV came after researchers noticed much lower prevalences of HIV infection amongst communities in which males were routinely circumcised. This hypothesis was tested recently in a series of randomised control trials in which HIV-negative volunteers seeking the procedure were randomly assigned either to undergo circumcision immediately or to wait for a period of time first. The patients were then followed up with regular HIV tests. The trial had to be stopped prematurely on ethical grounds when a large excess of HIV cases were found in the group of individuals asked to wait before undergoing the procedure. Scientists think that the foreskin represents a significant portal of entry for the virus because it is relatively enriched in cell types targeted by HIV, it provides an environment in which the virus can persist for an extended period thus maximising the risk of infection, and the mucosa of the foreskin can develop tiny fissures during intercourse and these facilitate viral entry and infection.
In response to these findings, the WHO / UNAIDS have recommended that it should be considered as an effective preventative measure. According to Kevin de Cock, director of the World Health Organisation's AIDS department, "This is an extraordinary development...Circumcision is the most potent intervention in HIV prevention that has been described". And according to Marie-Louise Newell of the University of KwaZulu-Natal in South Africa and Till Barnighausen of the Harvard School of Public Health "if all of the 2.5 million men in KwaZulu-Natal province had been circumcised, 37,000 new infections could have been prevented in 2007".
But none of these strategies can be effective without education, particularly about safe sex. One in ten girls aged 16-19 in the UK is infected with chlamydia, which can only have been acquired through unsafe sex. This is clear evidence that large numbers of young people are placing themselves at direct risk of HIV, probably because they are from a generation who never saw the "grim reaper" television adverts of the 1980s when AIDS first hit the headlines. HIV is a very real threat and still very much a life sentence. Unless people can be made aware of this then the problem will only continue to get worse.
In the UK the plight of AIDS today gets much less attention from the public and the media than it did back in the 1980’s and early 1990’s. This often leads to the misconception that AIDS is no longer a problem in this country; in reality, the increasing prevalence of HIV in the UK proves that this is simply not true.
Worldwide, accepted definitions, facts and figures on HIV and AIDS include:
Acquired immune deficiency syndrome (AIDS) is a collection of symptoms and infections that result from specific damage to the immune system by the human immunodeficiency virus (HIV).
HIV is transmitted through the direct contact of a mucous membrane, or the bloodstream, with a bodily fluid containing HIV.
The late stage of the condition leaves individuals prone to opportunistic infections and tumours.
Whilst antiretroviral treatments for AIDS and HIV exist to reduce the mortality and morbidity of HIV infection to date there is no known cure; even access to these antiretroviral treatments is not routine in all countries.
Researchers believe that sometime in the 1930’s a form of simian immunodeficiency virus jumped to humans who butchered or ate chimpanzee bush meat in the Democratic Republic of Congo. The virus became HIV-1, the most widespread form found today.
The world’s first known case of AIDS has been traced to a sample of blood plasma from a man who died in 1959. During the 1970’s HIV continued to spread undetected around the world and hence the pandemic began. Today an estimated 40 million people are living with HIV worldwide.
As of January 2006, the Joint United Nations Programme on HIV/AIDS and the World Health Organization estimate that AIDS has killed more than 25 million people since it was first recognised on June 5th, 1981.
The stigma associated with HIV/AIDS is severe and extends to providers and volunteers involved with the care of HIV infected patients. AIDS exerts its toll also on societies, devastating their economies, decimating their labour forces and orphaning children.
Thus, it is one of the most destructive pandemics in recorded history, surpassing even the Black Death. By 2015 it is estimated that 60 million people will have died of AIDS.
In 2004 the global spending on AIDS was $6.1b. Estimated global AIDS spending required in 2007 for prevention and care is $20b. Less than 3% of all money spent on AIDS goes towards developing a vaccine for the disease.
In February 2007 a study published in the Lancet showed that male circumcision could dramatically reduce the risk of HIV infection. The randomised control trial showed that circumcised men were 60% less likely to pick up HIV. This means that if all of the 2.5 million men in KwaZulu-Natal province had been circumcised, 37,000 new HIV infections could have been prevented in 2007 alone.
The history of HIV / AIDS in the UKThe first recognised case of AIDS in the UK was recorded in December 1981, when doctors at Brompton Hospital in London reported the case of a 49 year old homosexual man who had died ten days post referral. He was suffering from a rare infection that almost always occurs in individuals with severely weakened immune systems. Doctors believed that the condition might be linked to similar cases that had been occurring amongst gay men in the US.
Throughout the 1980’s the number of newly diagnosed HIV infections per year in the UK rose steadily. The figure plateaued during the 1990’s, averaging about 3,000 cases per year, but then increased dramatically after 1999. By 2005, the annual number of newly diagnosed infections was more than 7,500, and an estimated 63,500 people over 15 years of age were living with HIV in the UK, 20,100 (32%) of whom were believed to be unaware of having been infected. Since the pandemic began there have been 17,161 known UK HIV deaths.
The science bit...HIV is a retrovirus, meaning that it uses a chemical relative of DNA, called RNA (ribonucleic acid), as its genetic material. It primarily attacks components of the human immune system, including T lymphocytes and other white blood cells that carry "CD4" receptors on their surfaces. HIV enters its target cells by binding to both the CD4 molecule and a chemokine "co-receptor", of which there are two forms, CCR5 and CXCR4. Once inside the cell the virus makes a DNA copy of its genome and then uses an enzyme it carries with it, called integrase, to insert this copy into the cell’s own DNA. Either immediately, or after a period of dormancy known as latency, the virus then hijacks the cell and turns it into a virus factory. The newly produced viruses leave the infected cell, destroying it in the process, and move on to invade other CD4+ cells, which are mainly T lymphocytes. These are the cellular linchpins that help to marshall the other components of the body's immune system. As their numbers dwindle the ability of the body to mount an effective immune response to combat other invaders, including bacteria, viruses and fungi, is progressively weakened. This means that HIV kills by slowly destroying the immune system and leaving the infected individual vulnerable to infection by so called "low grade" or opportunistic bugs.
What is the natural history of HIV infection? What are the symptoms?Most infections with HIV are initially "silent", meaning that a person may not notice that anything is wrong. Then, several weeks after infection, patients often develop a "seroconversion illness", which characteristically includes flu-like symptoms, lymphadenopathy (swollen lymph glands), fevers, loss of appetite and weight, diarrhoea and general lethargy and malaise. During this time infected individuals have very high levels of virus in the bloodstream (10 million viruses per millilitre of blood is not uncommon). The reason for this very high viral load is that the virus is able to replicate (grow) largely unchecked because the immune system has yet to mount an effective suppressive response, including the production of antibodies that can mop up viral particles. As a result the number of CD4+ T cells can fall to very low levels at this time, and the patient is highly infectious.
But then the immune system kicks in, and the virus largely retreats, hiding within lymphoid tissues and replicating only very slowly. The levels of virus in the blood stream become much lower, the patient is less infectious and feels well. Untreated, an infected individual usually remains "healthy" like this for 5 to 15 years.
Structure of the human immunodeficiency virus (HIV) viral particle.
However, the body’s immune system only has a limited ability to control HIV. The virus makes mistakes when it copies its genetic code. Roughly once in every 10,000 genetic letters that are copied the virus introduces the wrong genetic base. Since the genome contains about 9000 bases in total, almost every genome copied will contain an error. The result is that these genetic mistakes alter the appearance of the virus and so make it harder for the immune system to recognise and keep up, because it is trying to hit a moving target. Eventually, through this progressive shape-shifting, the virus takes on a form that the immune system cannot respond to, and at this point the pace of the infection begins to accelerate and the number of CD4+ T cells begins to fall.
When the CD4 count falls below a critical threshold (400 per microlitre of blood) the body is no longer able to defend itself. At this point an HIV-infected individual is said to have AIDS, and patients usually begin to develop opportunistic infections caused by organisms that would not normally affect healthy people. These include mycobaterial infections (caused by bacteria related to tuberculosis), the lung infection PCP (pneumocystis carinii pneumonia), oral and genital thrush, complications of CMV (cytomegalovirus), chronic diarrhoea and weight loss, toxoplasmosis, meningitis, dementia, and polyomavirus (JC virus), which is associated with a disease of the brain's white matter known as PML (progressive multifocal leucoencephalopathy). At this point patients are often prescribed prophylactic drugs to help ward off some of these infections including co-trimoxazole, which can slow down the progression of PCP.
Without treatment the median survival time after developing AIDS is only about 9 months. However, the rate of clinical disease progression varies widely between individuals from 2 weeks to 20 years. Many factors affect this rate of progression, including age, quality of health care and the presence of co-existing infections. An individual's genetic make-up also plays an important role because it's now becoming clear that some people are resistant to certain strains of HIV and although they become infected they do not seem to develop AIDS, or they do so only extremely slowly. There are even people who seem to be totally immune to infection with the virus. They carry a mutated cell surface marker called CCR5-delta-32, which prevents HIV from locking onto and invading their cells. Scientists hope that understanding what makes these people able to resist the virus may hold the key to future therapies to block infection amongst susceptible individuals.
TreatmentWhilst the number of people living with HIV is rising each year, the number of HIV infections that progress to AIDS has dropped dramatically since 1996. This is primarily the result of anti-retroviral therapies, which are available to slow the progress of the virus. These target essential components of the viral replication cycle and include reverse transciptase (RT) inhibitors, which interfere with the way the virus makes a complementary "cDNA" copy of its RNA genome, and protease inhibitors, which prevent the virus from cutting up the raw materials it needs to form new viral particles.
There are two types of drugs that block RT; these are known as nucleoside and non-nucleoside RT inhibitors. The nucleoside RT inhibitors are structurally very similar to normal DNA bases, but they lack a critical chemical group required to enable a DNA chain to grow. So when the viral RT inserts one of these altered bases into the copy that it's making of its genetic code, it can't finish the job because it cannot add the next genetic letter. An example of this type of agent is the drug AZT or zidovudine (azidothymidine). The non-nucleoside RT inhibitors, which include drugs like efavirenz and nevirapine, work slightly differently. They target the RT enzyme itself and bind to it, distorting its shape so that it cannot work properly. This stops the virus from replicating.
Protease inhibitors (PIs) only emerged more recently. They work by blocking the action of a protein-cutting enyzme carried by HIV, which is critical to the virus being able to assemble new infectious particles. If this enzyme is prevented from doing its job the virus cannot escape from the infected cell. An example of the PIs includes saquinavir, which is famous for being one of the first drugs produced by building a computer model of the shape of the viral enzyme and then designing a drug specifically to block it.
There are also agents known as fusion inhibitors, which are a newer type of drug that work by stopping HIV from binding with the CD4 receptors that it uses to enter cells. One being evaluated at the moment is called efurvatide.
Doctors have also recently been testing a new agent called raltegravir, which is an "integrase inhibitor". This prevents the virus from inserting a copy of its genetic material into the host cell genome. In a recent trial published in the Lancet doctors randomly allocated 179 patients with end-stage HIV / AIDS to receive either the active drug or a placebo. After 6 months the patients receiving raltegravir showed a 98% drop in the levels of virus in the bloodstream, compared with only 45% in the placebo group. The next step will be to test raltegravir in combination with other HAART regimen drugs in healthier patients who are not approaching the end-stages of their disease. It may make a considerable difference to the rate of disease progression.
So there are lots of drugs with which we can now combat HIV; but there's a problem. Because the virus frequently makes mistakes when it copies its genetic material it rapidly develops forms of the virus that are resistant to the action of these drugs. To slow down the rate at which this happens, rather than use them singly, a cocktail of drugs is used, often one from each of the three classes (nucleoside RT inhibitors, non-nucleoside RT inhibitors and protease inhibitors). This is known as HAART or Highly Active Antiretroviral Therapy (HAART) and it has dramatically reduced the evolution of viral resistance and prolonged the time during which an HIV-infected individual remains healthy and symptom free. However, it's worth emphasising that, whilst drugs help to control the spread of HIV to uninfected cells, unfortunately there is no treatment available at present that can eradicate HIV once integrated into a host.
Side effects...This means that individuals using HAART have to take medication every day for the rest of their lives, and this often causes severe side effects. When individuals first start treatment they may suffer headaches, hypertension or general malaise (feeling unwell), although these usually improve or disappear with time. Other side effects can include diarrhoea, nausea, fatigue, anaemia, lipodystrophy, skin problems, neuropathy, mitochondrial toxicity, dyslipidaemia and bone problems. Whilst most people who take anti-HIV medications have some side effects it must not be assumed that everyone gets every side effect that has ever been written down.
Another problem with combating HIV is that a number of different strains of the virus can arise due to differences in selection pressures as the virus encounters different individuals, different drugs and different routes of spread. This can result in resistance to multiple anti-retrovirals and frequently occurs through a process called recombination. It occurs because each HIV virion carries two complete RNA genomic strands, meaning that homologous recombination can occur when a cell is coinfected with two different but related strains. The two strains may then exchange genetic material, including drug resistance traits. The process of recombination also therefore poses theoretical problems for the development of a safe vaccine against HIV.
The situation is also made worse by the fact that increasing numbers of patients are found to be carrying resistant forms of the virus at diagnosis, even before any drug therapy has been administered. Indeed, in 2004 an estimated 9% of new HIV diagnoses were found to be drug resistant strains, presumably acquired from individuals who had already received treatment. If patients then acquire additional strains of the virus with different resistance profiles the process of recombination can yield multiply-resistant viruses. In a case described recently in the Lancet this resulted in an individual producing a strain of the virus that was resistant to every available anti-retroviral agent. The patient in question also progressed to AIDS and died within six months of becoming infected.
The main ways HIV is transmitted in the UKThe three main transmission routes of HIV are sexual contact, exposure to infected body fluids or tissues and from mother to foetus or child during the perinatal period. It is possible to find HIV in the saliva, tears and urine of infected individuals but there are no recorded cases of infection by these secretions and the risk of infection is negligible. Breast milk, however, is known to be a significant risk factor for mother to child transmission of HIV. Studies have shown that if no anti-infection precautions are taken then 15-20% of new born babies will be infected, but if they are also breast-fed this proportion rises to over 50%. As a result HIV-positive mothers are advised not to breastfeed their babies.
A reported 754 HIV-infected children had been born in the UK to infected mothers as of the end of December 2006. Aware of the increasing risk posed by HIV to newborns and care-workers, in 1999 the UK Government introduced routine antenatal testing for HIV amongst all pregnant women. In those found to be positive, the use of antiretroviral treatment can greatly reduce the chances of a mother passing the infection to her baby. Since 1996 the increased use of such treatment has caused the rate of mother-to-child transmission to fall substantially.
Early media coverage of AIDS in the UK focused on injecting drug users. During the early 1980’s it was a big problem, but in 1986 needle exchanges began to operate across the UK, providing clean needles and giving drug users information and support. These schemes were largely effective in reducing the prevalence of HIV among certain members of this population. However, while they account for a small proportion of people living with HIV in the UK, the prevalence of HIV among injecting drug users has risen significantly in recent years (from 1:110, in 2002, to 1:62, in 2006). This rise has been attributed to an increase in the use of drugs outside of London where needle exchange schemes and information about HIV are harder to access.
Government policy in the UKAccording to the latest Government legislation, NHS treatment for HIV is free to everyone who is living in the UK legally. This means that people who are living in the UK without due authority (such as illegal immigrants and failed asylum seekers) must pay for any HIV treatment they receive.
This measure aimed to tackle health tourism, the process whereby people migrate to a country in order to take advantage of better healthcare services there. However, denial of treatment to people in these situations can effectively be a death sentence, especially if they are then deported to countries where no treatment is available.
There are certain 'notifiable diseases', for which a person will always receive treatment in the UK regardless of their legal status, in order to prevent the rapid spread of epidemics. HIV, however is not on the notifiable diseases list. If a woman has no legal right to be in the UK then she will only receive medication to stop her baby being born HIV positive if doctors decide it is an 'emergency'.
Financial costs to the UK health system
The cost of managing a patient with HIV is around £16,000 a year.
The total cost of treatment and care in 2002/03 was estimated to be £345m.
In 2000 it was estimated that the average lifetime treatment cost for an HIV positive person was between £135k and £181k.
Why is HIV / AIDS still on the increase in the UK?There is currently no vaccine or cure for HIV or AIDS. The only known methods of prevention are based on avoiding exposure to the virus, male circumcision which is discussed below, and antiretroviral treatment administered directly after a highly significant exposure. This is known as post exposure prophylaxis (PEP) and comprises a 4 week drug schedule, the side effects of which are very unpleasant.
Another reason people are still dying of AIDS is due to many being diagnosed with HIV at a late stage of infection. In 2005 more than one third of adults diagnosed with HIV had a CD4 count lower than the recommended threshold for starting treatment. At this stage treatment is much less likely to work. This late diagnosis is alarmingly common, highlighting the need for greater awareness and for people to access testing services as soon as possible if they think they may have been exposed to HIV.
What is next?Billions of pounds are spent every year worldwide on caring for and treating individuals with HIV/AIDS and on resources to prevent further spreading of the virus. However, ultimately it is a cure that is required to combat this pandemic. A vaccine to prevent HIV infection, as an alternative method to current therapies, may still be many years away. Not only might such a vaccine have to prime antibodies to attack HIV (the way most vaccines work) but it might also need to increase T cell production. Vaccine trials have been undertaken in South Africa, Kenya, the USA and Thailand, though most have yet to yield promising results. Controversial vaccines made from the blood of HIV carriers have been tested in Nigeria and Thailand. Other developing avenues for treatment of HIV positive individuals include gene therapy, targeted radiation therapy and nanotube technology to block the invasion of HIV into target cells. In April 2007 researchers even identified a component naturally present in human blood (a protein derived from alpha-1-antitrypsin) that can block HIV entry into cells.
In the absence of a vaccine researchers have turned to other approaches to try to combat the virus. A promising discovery, confirmed earlier in 2007, was that male circumcision can dramatically reduce, by 60%, the chances of acquiring HIV. The first clues that circumcision might be beneficial in halting the spread of HIV came after researchers noticed much lower prevalences of HIV infection amongst communities in which males were routinely circumcised. This hypothesis was tested recently in a series of randomised control trials in which HIV-negative volunteers seeking the procedure were randomly assigned either to undergo circumcision immediately or to wait for a period of time first. The patients were then followed up with regular HIV tests. The trial had to be stopped prematurely on ethical grounds when a large excess of HIV cases were found in the group of individuals asked to wait before undergoing the procedure. Scientists think that the foreskin represents a significant portal of entry for the virus because it is relatively enriched in cell types targeted by HIV, it provides an environment in which the virus can persist for an extended period thus maximising the risk of infection, and the mucosa of the foreskin can develop tiny fissures during intercourse and these facilitate viral entry and infection.
In response to these findings, the WHO / UNAIDS have recommended that it should be considered as an effective preventative measure. According to Kevin de Cock, director of the World Health Organisation's AIDS department, "This is an extraordinary development...Circumcision is the most potent intervention in HIV prevention that has been described". And according to Marie-Louise Newell of the University of KwaZulu-Natal in South Africa and Till Barnighausen of the Harvard School of Public Health "if all of the 2.5 million men in KwaZulu-Natal province had been circumcised, 37,000 new infections could have been prevented in 2007".
But none of these strategies can be effective without education, particularly about safe sex. One in ten girls aged 16-19 in the UK is infected with chlamydia, which can only have been acquired through unsafe sex. This is clear evidence that large numbers of young people are placing themselves at direct risk of HIV, probably because they are from a generation who never saw the "grim reaper" television adverts of the 1980s when AIDS first hit the headlines. HIV is a very real threat and still very much a life sentence. Unless people can be made aware of this then the problem will only continue to get worse.
New Drug Hits Hiv Where it Hurts
New drug hits AIDS where it hurts - A new drug is now entering trials which aims to boost the arsenal of agents with which we can combat HIV. Arriving on the scene 25 years after the first cases of HIV were diagnosed, PA-457, as the new agent is currently known, targets a totally new component of the viral life cycle. It's being developed by Panacos Pharmaceuticals in Maryland, US, and works by preventing the virus from "maturing" and budding successfully from an infected cell. The latest research on the agent, published in the Journal of Virology, shows that it disrupts the formation of a viral structure referred to as the capsid, which is essentially a protein flask which contains the viral genetic material. PA-457 interferes with the production of the capsid, leading to the formation of a defective virus particle which is disabled and unable to infect other cells. A small trial of the agent conducted in August 2005 showed that when administered in isolation it reduced levels of virus tenfold in the blood of patients. But the new study will look at how PA-457 performs alongside traditional anti-retroviral drug therapy. 48 patients, whose existing anti-HIV drug regimens are failing, will also receive either the new agent or a placebo. Panacos Pharmaceutical's Graham Allaway cautions that the agent will not reach the market until at least 2009, but this represents a large step forward in the form of a totally new way to tackle HIV.
Monday, December 24, 2007
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