Stripping Down Science (6 page)

To keep time, the nerve cells that make up the suprachiasmatic nucleus use the molecular equivalent of a genetic domino effect. A linked series of genes turn each other on and off sequentially, taking about 24 hours to complete the cycle, altering the electrical activity of the cells as they go. The nerve cells then transmit this activity to other parts of the nervous system to control how awake we are and the levels of certain hormones circulating in the blood. This, in turn, controls our pattern of sleeping and waking, which is called the circadian rhythm.

Historically, researchers thought that the suprachiasmatic nucleus was the only clock the body had, but more recently that idea has been radically revised. Scientists now know that every cell in the body, with few
exceptions, is running the same genetic clock, so every organ and every tissue also knows the time. The difference is that these clocks function as slaves to the master clock in the suprachiasmatic nucleus. They're continuously updated by signals carried by hormones that circulate in the bloodstream, including one called cortisol.

Doctors and scientists now realise how important the body clock is to health and disease. Some drugs, like cancer chemotherapies, work best when given at certain times of the day, stem cell transplants can have different outcomes depending upon when they are given, and mental illnesses, including depression, schizophrenia and some dementias are often associated with poor sleep and tend to improve if the sleep– wake cycle is fixed.

There are also metabolic consequences of disrupting the body's normal timekeeping. People who work night shifts are at higher risk of high blood pressure, strokes and heart disease and, amongst females, the risk of
breast cancer increases. Researchers are currently trying to find out why this happens and one way to do this is to put volunteers into sleep experiments. One recent study was carried out by Harvard researcher Frank Scheer and his colleagues.
²⁰

They placed 10 volunteers in a sleep study environment where they were denied access to watches or clocks and, unknown to the participants, the ‘days' were made 28 hours long. This meant that over the 10-day course of the study the participants' body clocks were progressively shifted until they were completely out of phase (equivalent to 12 hours jet lag), and then back into phase with their normal sleep–wake cycles. Throughout the study period, the team collected urine and blood samples and monitored the subjects' blood pressures, metabolic rate and sleep quality to see how this affected the physiology of the participants.

The results were dramatic: levels of the
anti-appetite hormone leptin fell by 17%, with the most pronounced drop at the 12-hour out-of-phase point, the glucose levels of the subjects were 6% higher and their insulin levels 22% higher. The average blood pressure was 3% higher, and the ‘sleep efficiency' of the subjects was significantly lower – 67% versus 84% normally. Levels of the stress hormone cortisol, which should peak in the morning and fall during the day, were also reversed, leading to a surge in cortisol at the time when the subjects should have been going to sleep.

This shows that there are genuine and significant metabolic and biochemical effects associated with body clock disruption. And as Frank Scheer and his colleagues point out, discovering what causes these changes will help researchers to come up with effective ‘countermeasures' to minimise the health impacts of shift work.

Chimpanzees carry the direct viral ancestor of HIV, the human AIDS (acquired immune deficiency syndrome) virus. This chimp version is called SIV (simian immunodeficiency virus) and is very similar to HIV except that, strangely, scientists have always claimed that, unlike untreated HIV in a human, SIV-infected chimpanzees don't develop an AIDS-like illness and instead, infected animals live alongside the virus without getting sick.

But new research, carried out in the African bush, has found that this claim is actually a microbiological myth and that chimp numbers in the wild – which are already dangerously low – are taking a significant beating at the hands of this virus. Brandon Keele, from the University of Alabama, Birmingham,
²¹
made the discovery when he carried out a long-term study on three free-living chimp communities in the Gombe National Park in Tanzania.

Together with colleagues, he collected over 200 urine and 1100 faecal specimens from more than 90 chimps during a nine-year period. These samples were then used to look for antibodies as well as the genetic material of chimpanzee SIV. The team were also able to use genetic fingerprinting technology to identify and follow the progress of individual animals during the full nine years of the study. The results were strikingly at odds with the prevailing view that SIV is a relatively benign infection for chimpanzees.

Infected animals, they found, had between 10 and 16 times the mortality rate compared with uninfected chimps. Females carrying the virus were also less likely to produce offspring and, of those that did, the babies had much higher infant mortality rates compared with uninfected mothers and frequently picked up the infection through their mother's breast milk, mirroring the breastfeeding risk seen amongst HIV-infected humans.

The team also witnessed nine ‘new' SIV infections amongst the animals they were following during the study and, by genetically sequencing the viruses involved, found that, just as in humans, most new cases arise through
infection passing from individuals that have only recently been infected themselves. This is because when chimps first acquire the virus, they initially develop very high blood levels of the agent, making them much more likely to transmit SIV to other individuals during this early phase of the infection. The same is also true of humans infected with HIV. The team were also able to carry out post-mortems on some of the chimps that died during the study. One animal they examined showed chronic muscle wasting and shrinkage of the liver, multiple abscesses in the abdomen and depletion of the key CD4 immune cells targeted by the virus. Tissue samples obtained from other animals also showed similar parallels with human AIDS, including the loss of white blood cells from the spleen.

So, far from being a walk in the Gombe National Park, SIV is a serious and often fatal infection for Africa's chimpanzees. Apart from overturning an inaccurate dogma, this research also helps to highlight an important future avenue of research: chimps with SIV seem to develop the disease in the same way we do, but other primate species with their own forms of SIV do not. If scientists can track down which viral or host
factors are responsible for the progression of the disease in some species but not others, it might be possible to uncover new ways to combat the virus in both humans and our next nearest relative.

FACT BOX

HIV biology

HIV/AIDS is, without doubt, the worst pandemic that humankind has ever faced. Researchers estimate that about 25 million people have already died of the disease and that about 35 million people are currently carrying it. In 2008, there were more than 7000 new HIV infections every day – one every 12 seconds.

Untreated, HIV slowly destroys the immune system by attacking key white blood cells that carry a marker on their surfaces known as CD4. When the supply of these cells is exhausted, which occurs after about 10 years on average, the infected person develops AIDS – and becomes vulnerable to a range of
lethal infections caused by a host of different microbes ranging from viruses and bacteria to fungi and amoebae.

Scientists suspect that HIV ‘jumped' into humans about 100 years ago, following close contact between a person – perhaps a hunter or a butcher preparing bush meat – and the blood of a chimp carrying SIV. Because humans and chimpanzees are so genetically alike, the SIV in the chimp is thought to have managed to infect the exposed human and then mutate within them to become the human AIDS virus. We know that HIV has jumped into humans in this way at least twice, because there are actually two types of HIV in circulation, HIV-1, which came from chimpanzee SIV, and a rarer form, largely confined to West Africa and called HIV-2, which came from a different primate species called a sooty mangabey.

When HIV infects an individual, it first has to break through the body's main defence, the skin. For this reason, sex, needle sharing and the use of contaminated blood products are the main ways in which the virus is passed on.
In the case of sexual transmission, researchers have discovered recently that the virus triggers the cells that make up the surface layers of the genital tract, and other mucous membranes, to part company with each other, creating HIV-sized chinks in the body's immunological armour. This allows the virus to penetrate and infect the susceptible immune cells that sit in the tissue below. Once inside these cells, the virus inserts a copy of its genetic material into the DNA of the cell. This is then used as a template to produce thousands of new virus particles which bud off to infect other cells around the body.

Part of the reason why HIV is so difficult to treat is that the virus uses as its genetic material a chemical relative of DNA called RNA. But unlike DNA, which contains two strands of information, one the mirror image – and effectively a back up – of the other, RNA contains just one single strand. With nothing to check the message against, the virus makes multiple genetic spelling mistakes when it copies itself, introducing mutations that can
alter the appearance, virulence and drug-resistance profile of the virus.

To get around this problem, doctors now prescribe cocktails of different drugs which target the virus from several different biochemical directions at the same time. This approach, known as HAART (highly active anti-retroviral therapy) slows down the rate at which resistant mutants appear, helping patients to remain healthier for longer. But drug therapy is only a temporary solution and, owing to cost, one which is available only to a minority of those who are infected. Instead, what the world sorely needs is an effective AIDS vaccine.

So far this has proved impossible to achieve. One of the reasons for this is that to block HIV, the body needs to be able to produce antibodies capable of neutralising the viral velcro employed by HIV to lock onto and invade CD4 immune cells. But the virus keeps this part of its structure concealed beneath a meshwork of sugar molecules and only reveals its hand in the final moments as
it infects a cell, making it very difficult for the immune system to intervene.

That said, scientists have found recently that some people can make antibodies capable of blocking this part of the virus, suggesting that if a vaccine can be produced to allow everyone to make these antibodies, then we may finally be looking at a way to stop the 7000 new cases of HIV that are being diagnosed daily.

In the meantime, apart from sending out clear safe-sex messages, a number of other anti-AIDS strategies are being investigated. One study carried out recently in South Africa by Salim Abdool Karim and his colleagues at the University of KwaZulu-Natal, Durban,
²²
showed that a gel impregnated with the anti-HIV drug tenofovir and applied vaginally before and after sex reduced the rate of new HIV infections amongst the women using the gel by up to 50%.

Also, amongst men, researchers have shown convincingly that being circumcised can have
an equally powerful protective effect; several studies have confirmed that circumcision cuts the HIV infection rate by over 60% in males who undergo the procedure. Removing the foreskin is probably protective because it reduces the mucosal surface area through which infection can occur and also leads to the virus becoming deactivated more quickly because there are fewer warm, wet recesses in which it can lurk.