2.2.1

Bacteria, cyanobacteria and archaebacteria are prokaryotic organisms. Bacte1ia alone are probably the most common form of life on Earth. Some bacteria are pathogens and cause disease, but the great majority do no harm and many are beneficial to living organisms, for example as gut bacteria and in the cycling of nutrients in the natural world. (see Book 2 Chapter 10.2). In this section, you will mainly consider the structure and functions of bacterial cells.

The structure of bacteria

All bacterial cells have certain features in common, although these vary greatly between species.

Bacterial cell walls

All bacterial cells have a cell wall. The contents of bacterial cells are usually hypertonic to the medium around them, so water tends to move into the cells by osmosis. The cell wall prevents the cell swelling and bursting. It also maintains the shape of the bacterium and gives support and protection to the contents of the cell. All bacterial cell walls consist of a layer of peptidoglycan that is made up of many parallel polysaccharide chains with short peptide cross-linkages forming an enormous molecule with a net-like structure. Some bacteria have a capsule (or slime layer

if it is very thin and diffuse) around their cell walls. This may be formed from starch, gelatin, protein or glycolipid, and protects the bacterium from phagocytosis by white blood cells. It also covers the cell markers on the cell membrane that identify the cell. So a capsule can make it easier for a bacte1ium to be pathogenic (to cause disease) because it is not so easily identified by the immune system. This is the case for the bacteria that cause pneumonia, meningitis, tuberculosis (TB) and septicaemia. However, many capsulated bacteria do not cause disease. It seems likely that capsules evolved to help the bacteria survive very dry conditions.

Pili and flagellae

Some bacteria have from one to several hundred thread-like protein projections from their sUJface. These are called the pili ( or fimbriae) and they are found on some well-known bacteria such as Escherichia coli (E coli) and Salmonella spp. They seem to be used for attachment to a host cell and for sexual reproduction. However, they also make bacte1ia more vulnerable to virus infections, as a bacteriophage can use pili as an entry point to the cell.

Some bacteria can move themselves using flagella. These are little bigger than one of the microtubules contained in a eukaryotic flagellum and are made of a many-stranded helix of the protein flagellin. The flagellum moves the bacte1ium by rapid rotations - about 100 revolutions per second.

Cell surface membrane

The cell surface membrane in prokaryotes is similar in both structure and function to the membranes of eukaryotic cells. However, bacteria have no mitochondria, so the cell membrane is also the site of some of the respiratory enzymes. In some bacterial cells such as Bacillus sub1ilis, a common soil bacterium, the membrane shows infoldings known as mesosomes. There is still some debate about their function. Some scientists think they may be an artefact from the process of preparing the cell for an electron micrograph, others believe they are associated with enzyme activity, particularly during the separation of DNA and the formation of new cross walls during replication. It appears that other infoldings of the bacterial cell surface membrane may be used for photosynthesis by some bacterial species.

Plasmid

Some bacterial cells also contain one or more much smaller circles of DNA known as plasmids. A plasmid codes for a particular aspect of the bacterial phenotype in addition to the genetic information in the nucleoid, for example the production of a particular toxin or resistance to a particular antibiotic. Plasmids can reproduce themselves independently of the nucleoid. They can be transferred from one bacterium to another in a form of sexual reproduction using the pili.

Nucleoid

The genetic material of prokaryotic cells consists of a single length of DNA, often circular, which is not contained in a membrane-bound nucleus. However, the DNA is folded and coiled to fit into the bacterium. The area in the bacterial cell where this DNA tangle is found is known as the nucleoid. In an£. coli bacterium it takes up about half of the area of the bacterium.

70S ribosomes

The bacteria, cyanobacteria and archaebacteria have no membrane-bound organelles, but they do have ribosomes where they carry out protein synthesis. The ribosomes in bacterial cells are 7DS, smaller than the SOS ribosomes in eukaryotes. They have two subunits. The smaller is 3DS and the larger is SOS (see Section 2.1.4). They are involved in the synthesis of proteins in a similar way to eukaryotic ribosomes.

Gram staining and bacterial cell walls

Whilst all bacterial cell walls contain peptidoglycan, there are in fact two main types of bacterial cell wall These can be distinguished by Gram staining, a staining technique developed by Christian Gram (1853-1938) in 1884 and still in use today It is valuable because different types of bacteria are vulnerable to different types of antibiotics and one of the factors that affects their vulnerability is the type of cell wall

Before staining, bacteria are often colourless. The cell walls of Gram-positive bacteria (e.g. methicillin-resistant S1aphylococcus aureus, MRSA) have a thick layer of peptidoglycan containing chemicals such as teichoic acid within its net-like structure. The crystal violet/iodine complex in the Gram stain is trapped in the thick peptidoglycan layer and resists decolouring when the bacteria are dehydrated using alcohol. As a result it does not pick up the red safranin counterstain, leaving the positive purple/blue colour.

The cell walls of Gram-negative bacteria have a thin layer of peptidoglycan with no teichoic

acid between two layers of membrane. The outer membrane is made up of lipopolysaccharides. After the crystal violet/iodine complex is applied, the bacteria are dehydrated in ethanol. The lipopolysaccharide layer dissolves in the ethanol leaving the thin peptidoglycan layer exposed.

The crystal violet/iodine complex is washed out and the peptidoglycan takes up the red safranin counterstain, so the cells appear red.

Antibiotics and bacterial cell walls

Antibiotics are drugs that are used against bacterial pathogens. There are a number of different types of antibiotics, each working in different ways. They may work by affecting the bacterial cell walls, the cell membranes, the genetic material, the enzymes or the ribosomes. Antibiotics usually target features of bacterial cells that differ from those of eukaryotic cells, including the bacterial cell walls and the 70S ribosomes.

Different types of bacteria are sensitive to different types of antibiotics. Doctors need to know if a pathogenic bacterium is Gram-positive or Gram-negative as this will affect the choice of antibiotic used to treat the disease.

To pinpoint the actions of an antibiotic, first think about the difference between human cells and bacterial cells, and then about the differences between Gram-positive and Gram-negative bacteria.

Some antibiotics, such as beta-lactam antibiotics (penicillins and cephalosporins), inhibit the formation of the peptidoglycan layer of the bacterial cell wall. As a result they are very effective against Gram-positive bacteria, as they have a thick peptidoglycan layer on the surface of the cell, but less effective against Gram-negative bacteria, as their peptidoglycan layer is hidden and less vital to the wall structure. They don't affect human cells as they don't have a peptidogycan cell wall at all.

Glycopeptide antibiotics, such as vancomycin, are large polar molecules that cannot penetrate the outer membrane layer of Gram-negative bacteria. However, they are very effective against Gram­positive bacteria, even ones that have developed resistance to many other antibiotics.

Polypeptide antibiotics, such as polymixins, are rarely used as they can have serious side effects. They are very effective against Gram-negative bacteria because they interact with the phospholipids of the outer membrane. They do not affect Gram-positive bacteria.

Most other antibiotics affect both Gram-positive and Gram-negative bacteria because they target common processes such as protein synthesis by the ribosomes. They only target prokaryote ribosomes, not eukaryotic ones.

Alternative ways of classifying bacteria

Grouping bacteria simply by the way their cell walls do or do not take up Gram stains is of limited use in classifying the different types. Another way in which bacteria can be identified is by their shape. Some bacteria are spherical ( cocci) while the bacilli are rod-shaped. Yet others are twisted (spirilla) or comma-shaped (vibrios).

Bacteria are also sometimes grouped by their respiratory requirements. Obligate aerobes need oxygen for respiration. Facultative anaerobes use oxygen if it is available, but can manage without it. Many human pathogens fall into this group. Obligate anaerobes can only respire in the absence of oxygen - in fact oxygen will kill them.

Ke¥ definitions

A hypertonic solution is a solution with a higher concentration of solutes and lower concentration of water (solvent) than the surrounding solution.

Peptidoglycan is a large, net-like molecule found in all bacterial cell walls made up of many parallel polysaccharide chains with short peptide cross-linkages.

Pili (fimbriae) are thread-like protein projections found on the surface of some bacteria.

Bacteriophages are viruses that attack bacteria.

Flagella are many-stranded helices of the contractile protein flagellin found on some bacteria. They move the bacteria by rapid rotations.

Mesosomes are infoldings of the cell membrane of bacteria.

A nucleoid is the area in a bacterium where we find the single length of coiled DNA.

Plasmids are small, circular pieces of DNA that code for specific aspects of the bacterial phenotype. Gram staining is a staining technique used to distinguish types of bacteria by their cell wall.

Gram-positive bacteria are bacteria that contain teichoic acid in their cell walls and stain purple/blue with Gram staining.

Teichoic acid is a chemical found in the cell walls of Gram-positive bacteria

Gram-negative bacteria are bacteria that have no teichoic acid in their cell walls. They stain red with Gram staining.

Cocci are spherical bacteria.

Bacilli are rod-shaped bacteria.

Spirilla are bacteria with a twisted or spiral shape.

Vibrios are comma-shaped bacteria.

Obligate aerobes are organisms that need oxygen for respiration.

Facultative anaerobes are organisms that use oxygen if it is available, but can respire and survive without it.

Obligate anaerobes are organisms that can only respire in the absence of oxygen and are killed by oxygen.

2.2.2

Viruses are the smallest of all the microorganisms, and range in size from 0.02 µm to 0.3µm across, about 50 times smaller than the average bacterium. Viruses are not cells. They are arrangements of genetic material and protein that invade other living cells and take over their biochemistry to make more viruses. It is because of this reproduction and the fact that they change and evolve in an adaptive way, that they are classed as living organisms.

Viruses

Most scientists working on viruses class them as obligate intracellular parasites, meaning they can only exist and reproduce as parasites in the cells of other living organisms. Because natural viruses invade and take over living cells to reproduce, they usually all cause damage and disease of some sort. They can withstand drying and long pe1iods of storage whilst maintaining their ability to infect cells. There are very few drugs that have any effect on viruses, and those that do only work in very specific instances; for example, acyclovir can help prevent herpes (cold sores) and genital herpes.

The structure of viruses

Viruses usually have geometric shapes and similar basic structures. However, there is considerable variation in the genetic material they possess, the structure of their protein coat and whether or not they have an envelope. The protein coat or capsid is made up of simple repeating protein units known as capsorneres, arranged in different ways. Using repeating units minimises the amount of genetic material needed to code for coat production. It also makes sure that assembling the protein coat in the host cell is as simple as possible. In some viruses the genetic material and protein coat is covered by a lipid envelope, produced from the host cell. The presence of the envelope makes it easier for the viruses to pass from cell to cell, but it does make them vulnerable to substances such as ether, which will dissolve the lipid membrane.

Classifying viruses

Viruses attach to their host cells by means of specific proteins

(antigens) known as virus attachment particles (VAPs) that target proteins in the host cell surface membrane. Because they respond to particular molecules of the host cell surface, viruses are often quite specific in the tissue they attack.

Viruses are classified by their genome and their mode of replication. Viral genetic material can be DNA or RNA, and the nucleic acid is sometimes double-stranded and sometimes single. The way in which the viral genetic material is used in the host cell to make new viruses depends on which form it is in:

􀀨 DNA viruses: In these viruses the genetic material is DNA The viral DNA acts directly as a template for both new viral DNA

and for the mRNAs needed to induce synthesis of viral proteins. Examples of DNA viruses include the smallpox virus, adenoviruses, which cause colds, and some bacte1iophages (viruses which infect bacteria) for example the A Qambda) phage in fig B.

􀀨 RNA viruses: 70% of viruses have RNA as their genetic material and they are much more likely to mutate than DNA viruses. RNA viruses do not produce DNA as part of their life cycle. The majority of RNA viruses contain a single strand of RNA and are know as ssRNA viruses. Positive ssRNA viruses

(also known as positive-sense ssRNA viruses) have RNA that can act directly as mRNA and be translated at the ribosomes. Examples of plant and animal diseases caused by positive ssRNA viruses include tobacco mosaic viruses, SARS, polio and hepatitis C. Negative ssRNA viruses (also known as negative-sense ssRNA viruses) cannot be directly translated. The RNA strand must be transcribed before it is translated at the ribosomes. Examples of diseases caused by negative ssRNA viruses include measles, influenza and Ebola.

RNA retroviruses: Retroviruses are a special type of RNA virus. They have a protein capsid and a lipid envelope. The single strand of viral RNA directs the synthesis of a special enzyme called reverse transcriptase. This goes on to make DNA molecules corresponding to the viral genome. This DNA is then incorporated into the host cell DNA and used as a template for new viral proteins and ultimately a new viral RNA genome. HIV (human immunodeficiency virus) is a retrovirus and some forms of leukaemia are also caused by this type of virus.

How viruses reproduce

Natural viruses all cause disease, and they attack every other known type of living organism. There are even viruses that attack bacteria, known as bacteriophages. We are constantly involved in a battle against the viruses that cause disease in ourselves, our animals, om crops and our environment. In order to understand how viruses cause damage to the body; and to be able to □y to target drugs effectively, it is important to understand how they reproduce in the human body

Virus 'life cycles'

Viruses only reproduce within the cells of the body They attack their host cells in a number of different ways. For example, bacteriophages inject their genome into the host cell, but the bulk of the viral material remains outside the bacterium. The viral DNA forms a circle or plasmid within the bacterium.

The viruses that infect animals get into the cells in several ways. Some types are taken into the cell by endocytosis - either with or without the envelope - and the host cell then digests the capsid, releasing the viral genetic material. Most commonly; the viral envelope fuses with the host cell surface, releasing the rest of the virus into the cell membrane. Plant viruses usually get into the plant cell using a vect01; often an insect such as an aphid, to pierce the cell wall.

DNA virus replication

Once a virus is in the host cell there are two different routes of infection:

Latency - the lysogenic pathway

Many DNA viruses are non-virulent when they first get into the host cell. They insert their DNA into the host DNA so it is replicated every time the host cell divides. This DNA inserted into the host is called a provirus. Messenger RNA is not produced from the viral DNA because one of the viral genes causes the production of a repressor protein that makes it impossible to translate the rest of the viral genetic material. The virus does not affect the host cell or make the host organism ill at this stage in the life cycle. During this period of lysogeny, when the virus is part of the reproducing host cells, the virus is said to be latent.

The lytic pathway

Sometimes the viral genetic material is replicated independently of the host DNA straight after entering the host. Matw-e viruses are made and eventually the host cell bursts, releasing large numbers of new virus particles to invade other cells. The virus is said to be virulent (disease causing) and the process of replicating and killing cells is known as the lytic pathway Under certain conditions, such as when the host is damaged, viruses in the lysogenic state are activated. The amount of repressor protein decreases and the viruses enter the lytic pathway and become virulent (see fig C).

Some types of virus have both latent and lytic stages in their life cycle, but others move straight to the lytic stage after they have infected a cell.

RNA virus replication

There are a number of different types of RNA viruses and they replicate themselves in different ways.

Positive ssRNA viruses

These are viruses that contain a single strand of RNA that is

a sense strand. It is used directly as mRNA for translation into proteins at the ribosomes. The proteins made include viral structural proteins and an RNA polymerase, which is used to replicate the viral RNA

Negative ssRNA viruses

The single strand of RNA in these viruses is an antisense strand. Before it can be used to make viral proteins and more viral RNA it must be transcribed into a sense strand. The virus imports RNA replicase, which uses free bases in the host cell to transcribe the antisense RNA strand and produce a sense strand that can be translated at the ribosomes. Once the RNA strand has been transcribed it acts as mRNA at the ribosomes and codes for viral proteins including RNA replicase. These viral proteins combine with replicated viral RNA to form new viral particles.

RNA retroviruses

Retroviruses, including the HIV virus that causes AIDS and the Rous sarcoma virus that causes cancer in chickens. have a rather different and complex life cycle. They have viral RNA as their genetic material. It cannot be used as mRNA, but is translated into DNA by the viral enzyme reverse transcriptase in the cytoplasm of the cell. This viral DNA passes into the nucleus of the host cell where it is inserted into the host DNA. Host transcriptase enzymes then make viral mRNA and new viral genome RNA.

Viruses and disease

Viruses cause disease in animals, plants and even in bacteria. They can cause the symptoms of disease by the lysis of the host cells, by causing the host cells to release their own lysosomes (see Section 2.1.4) and digest themselves from the inside or by the production of toxins that inhibit cell metabolism.

Viral infections are often specific to particular tissues. For example, adenoviruses. which cause colds, affect the tissues of the respiratory tract, but do not damage the cells of the brain or the intestine. This specificity seems to be due to the presence or absence of cell markers on the surface of host cells. Each type of cell has its own recognition markers and different types of virus can only bind to particular markers. The presence or absence of these markers can even affect whether a group of living organisms is vulnerable to attack by viruses at all. For example. the angiosperms (flowering plants) are vulnerable to viral diseases, but the gymnosperms (conifers and their relatives) are not.

Viruses are well-known for causing diseases like flu, measles, AIDS and Ebola. Research also shows that in some cases they play a role in the development of cancers. Certain animal cancers have been clearly linked to viral infection, and in humans there seems to be a link in certain specific cases. For example, the human papilloma virus responsible for warts on the skin, including genital warts, has been linked with the occurrence of pre­cancerous and cancerous changes in the cells of the cervix, and there is now a vaccine against it.

2.2.3 Controlling Viral Infections

As you have seen, the lifecycle of a virus involves the destruction of host cells. As a result of this direct damage, and the response of the host body to infection, viruses usually cause disease in the organisms they infect.

The spread of viral diseases

Viral diseases are spread in many different ways. The key feature is that material carrying viruses from an infected animal or plant comes into contact with vulnerable tissues in another uninfected organism. So, viruses may be spread through infected mucus, droplets of saliva, infected blood or faeces, or simple contact between infected organisms. International travel means that diseases that would once have just caused local outbreaks can now rapidly spread all over the world. Different viral diseases are spread in different ways. For example:

• Foot-and-mouth disease is a serious disease of cloven-hoofed animals such as cattle. It severely weakens adult animals and kills a high percentage of young animals. It is spread through body secretions, such as milk and semen, and transmitted in the breath and the faeces of infected animals. Healthy animals can pick up the virus from contaminated pens, food, water, contact with diseased animals and even from infected meat and animal products if they are eaten.

􀀓 Ebola is a severe viral illness caused by the Ebola virus. It is often fatal, especially if the symptoms are untreated. It is an animal disease that spreads to humans through the faeces, urine, blood and meat of infected animals. It then spreads easily from person to person by the direct contact of the skin or mucous membranes of a healthy person with blood, faeces and other body secretions of an infected person, or even bedding and surfaces contaminated with fluids from an infected person.

Treating viral diseases

As you have seen, bacte1ial diseases can be treated with antibiotics. The drugs affect the bacterial cells in one way or another (see Section 2.2.1). Viruses, however, are not living cells in the conventional sense. Scientists have not yet developed drugs that can affect the virus particles themselves. Instead, antiviral treatments target virus replication. There are a number of different ways in which they can work. They can:

target the receptors by which viruses recognise their host cells

• target the enzymes that help to translate or replicate the viral DNA or RNA

• inhibit the protease enzymes that enable new virus particles to bud from host membranes.

So far, scientists have not been able to cure viral diseases, but they have reduced the time a person is sick (see fig A) and can delay the development of symptoms after infection (e.g. the cocktail of antiretroviral drugs used to treat HIV/ AIDS)

fig A The impact of antiviral medication on the duration of influenza.

Preventing viral disease

Some viral diseases, such as the common cold, are relatively mild and have a very low mortality rate. Others, however, are very serious. During 1918-19 an outbreak of influenza killed up to six times more people than the whole First World Wa[ Foot-and­mouth disease has an almost 100% mortality rate in young stock.

In the 2001 UK epidemic of foot-and-mouth disease there was no treatment available and no tests to reliably identify infected animals before they showed symptoms. So all of the cloven-hoofed animals on infected farms were destroyed and burned to try and prevent the spread of the virus to other farms in the area. Over 6 million animals were killed. Veterinary scientists are working on developing sensitive tests to identify infected animals so that control of the disease may be possible in the future without this extensive culling. The mortality rate of humans infected with Ebola varies but can be very high with 25-90% of people infected with the disease dying. Mortality depends on the strain of the virus, the health of the infected person and the speed with which they get support and health care. The average mortality rate is around 50%.

Viral diseases like these can be devastating. Because there are no antiviral drugs against most viral infections, disease control focuses on vaccination and reducing the spread of viruses.

Vaccinations

Vaccination plays a major role in the prevention of disease outbreaks. When you are vaccinated against a disease you become immune to it and so will not become infected should you encounter it. Ideally, everyone is vaccinated against serious diseases that may affect them. If an epidemic breaks out and the population is not vaccinated, there is a rush to deliver vaccines to everyone who is not already infected. Usually health care workers, the very young and the elderly are vaccinated first. Unfortunately we have not yet developed fully-tested vaccines against some of the worst viral diseases, such as HIV/ AIDS and Ebola. You will learn more about vaccination if you continue to study A level Biology

Disease control

Understanding the cause of a disease and how it is spread means we can work to control it. Disease control is particularly important when an epidemic occurs. An epidemic is when the levels of people with a particular disease are much higher than expected over a given period of time. When there is a vaccine available, this is the time for mass vaccination of vulnerable people, alongside measures to prevent the spread of disease. In diseases where no vaccine is available, controlling the spread of the disease is key

Identifying the pathogen early and putting control measures

in place can make all the difference to the numbers of people affected (see fig C)

There are a number of different ways of controlling the spread of a disease. Some are relevant to all diseases, some are only used in more extreme diseases such as Ebola. They include:

• Rapid identification of disease: For example, in West Africa in 2014, it was some time before the Ebola was recognised and effective testing regimes put in place. If the disease is bacterial, it must be identified and an effective antibiotic used.

• Nursing in isolation: This is used for serious infections such

as Ebola and C. difficile only It is readily available in countries such as the UK but sealed isolation units are rarely available in developing countries such as those in West Africa. This lack of health infrastructure makes it difficult to isolate people affected by diseases such as Ebola. When ill people are cared for within their families the virus spreads easily Simple units nursing all infected patients together can help.

Preventing transmission from one individual to another: Simple measures such as regular hand washing, hand washing before and after every contact with patients by health workers and families, care in handling body fluids and wastes, careful disposal of infected bodily wastes, and frequent disinfecting of surfaces and people are key Body fluids are very infectious in Ebola cases and good hygiene is vital.

• Sterilising or disposing of equipment and bedding after use: One of the main transmission routes for Ebola at the beginning of the epidemic was through unsterilized needles used in an antenatal clinic.

• The wearing of protective clothing by health workers: When dealing with dangerous and highly infectious viruses such as Ebola, health workers should wear facemasks, gowns, gloves, and goggles to protect the eyes. The slightest contact of infected material with the eyes is enough to lead to infection. The gloves should be washed and disinfected before removal and then the hands washed as well.

• lndentifying contacts: People who have been in contact with infected people need to be monitored so that they can be treated and/ or isolated rapidly if they show signs of disease.

In the twenty-first century, in countries such as the UK, we expect to be able to take some medicine and get better if we feel unwell. In an epidemic caused by a virus this isn't always possible due to limited treatment options. If the epidemic is of a potential killer disease, such as flu or Ebola, the pressure to find an effective treatment or vaccine is very high.

The development of new medicines

The development of a new medicine or vaccine takes up to 10 years, involves many different scientists and doctors, and costs millions of pounds. Initial ideas for potential drugs come from a wide range of sources including genome analysis of pathogens, computer modelling, clinical compound banks and medicinal plants. These chemicals have to go through thorough research and testing on cell and tissue cultures, safety analyses and molecular modifications. This is followed by animal testing to ensure the compound works in a whole organism and is safe. This is then followed by three phases of human testing to further ensure safety and that the drug works well. This goes along with complex regulation and licensing procedures until finally, a new drug may reach the doctor's surgery. This process is summarised in fig D.

Speeding up the process

When an epidemic develops, some of the final stages of the testing of a new medicine or vaccine may be speeded up to try and save lives and prevent the spread of a deadly disease. Here are two examples.

In 2006 a new strain of HSN! flu (known as bird flu) caused a global pandemic. A vaccine against the new strain was produced very quickly, fast-tracked using existing techniques and technology for producing annual flu vaccines and put through basic clinical trials. They were to be used for health workers if the pandemic hit the UK. The Medical Research Council said they expected the vaccines would give some, if not total, protection whilst a better vaccine was developed. In addition, antiviral medicines such as Tami flu™ and Relenza TM were stockpiled in spite of concerns that there was incomplete data about their effectiveness. These concerns were raised again when the drugs were used in the 2009 swine flu epidemic and the Cochrane Collaboration, which carries out systematic analysis of the published data on medicines, has since stated that these drugs have not been proven to reduce hospitalisations and serious complication from influenza. You will learn more about influenza in Book 2.

The first case of Ebola in this outbreak occurred in late 2013 in West Africa. However, it took until mid-2014 for the world beyond Africa to recognise the size and severity of the outbreak of disease and the speed with which it was spreading. Once the severity of the outbreak was recognised, the World Health Organisation (WHO) and pharmaceutical companies around the world looked for ways to fast-track drugs and vaccines that were already in development and had passed many of the development stages, but which had not completed human trials. In this situation there are two challenges: to make sure the drugs are safe and effective and also to ramp up production to be able to make enough of the medicine or vaccine for it to be useful. Potential treatments included:

ZMapp™, an expe1imental drug produced after long-term studies of people who had survived Ebola in previous less-widespread outbreaks. Scientists had genetically modified tobacco plants to produce three antibodies that seem to be associated with surviving the disease. In trials it was effective in treating monkeys, but had not been tried on people. Tiny amounts of the drug were available and used to treat 7 people including African, American, Spanish and British health workers who developed Ebola. Some recovered, but some of the seven died, as you would expect with a disease with around 50% mortality. Scientists are tlying to produce more of the substance to run bigger trials on more people.

Vaccines: Several companies had vaccines in trials that are being fast-tracked for use against Ebola. They are making many doses of the vaccine so that if they are safe to use in humans, many health workers and then people living in epidemic areas can be vaccinated.

Other pharmaceutical companies are supporting the work of companies with drugs and vaccines closest to completion, and are also developing other drugs against the virus itself.

Ethical implications

Historically, doctors and scientists tried out new medicines on themselves, their families or their patients with little or no testing or trials. Today it would be considered completely unethical under normal circumstances to give anyone a medicine or vaccine that had not been through the full process of testing and approval. However, in severe epidemics or pandemics, with thousands of lives at risk, decisions may be made to use drugs that are only part way through the full testing process. Most often this involves drugs that have not completed human trials. Although the media will report these as 'untested', they have in fact already undergone a minimum of five years testing and development, and often will be part way though human trials.

There are a number of factors that have to be evaluated when considering whether a drug should be fast-tracked for use in an epidemic. These include:

the severity of the disease

• the availability of any other treatments for the disease

• the effectiveness of standard disease control measures in halting the spread of the disease

• transparency about the process and informed consent of those given the treatment

• freedom of choice over participation

• involvement of the affected community - community consent for treatment can be more valuable than individual consent

collection of clear clinical data from the use of new medicines in this situation so an on-going assessment of the safety and efficacy of the drug or vaccine can be made.

Reasons against using untested drugs include:

• Some people simply feel that it is not ethical under any circumstances to use drugs that have not completed full human trials.

• If an untested drug produces unexpected side effects it can make the situation worse

• Deciding who gets the drug or vaccine can be difficult. For example, in a situation such as the Ebola epidemic, local people might feel they were being used as guinea pigs for Western medicine if they are given the medicine, but might feel resentful if only health workers are treated.

• Informed consent is an issue as it depends on a level of education to understand the drug and how it works and

also clarity of thought. People who are dying may grasp at straws but their relatives may then blame the treatment for an inevitable death.

• Issues of trust between individuals or communities and health workers, especially if supplies of a new drug are limited.

In any epidemic situation, the ethical implications of using a fast-tracked and relatively untested drug have to be evaluated

at national and international levels. In the US, the Federal Drug Agency decided that an antiviral called peramivir that had not completed testing could be used intravenously in seriously ill patients in the 2009 HIN! flu epidemic. The WHO recently decided that ZMapp™, which had had no human trials, could be used in the Ebola epidemic in Western Africa and that at least two vaccines could also be fast-tracked through the process for use. The effectiveness of these interventions is yet to be seen, and only then can a full evaluation be made.