Genetic predisposition to AIDS

Some people might be genetically pre-disposed to developed more severe consequences of AIDS infections, new research has found.

Writing in the journal AIDS, Stephen O'Brien and his colleagues at the National Cancer Institute, Maryland, sequenced the mitochondrial DNA from 1833 patients infected with HIV in the 1980s before anti-retroviral drugs became available.  By comparing the genetic data with the time each of the patients took to develop AIDS the team were able to identify certain genetic signatures linked to progression of the disease.  The results could be used prognostically in future to inform HIV-infected patients of their likely outcome. 

At the same time, understanding the mechanism that makes some people more susceptible than others may also help to highlight novel approaches to treatment.

14th Dec 2008

Getting personal with breast cancer treatment

It’s becoming increasingly clear that the old saying “one size fits all” doesn’t work when it comes to cancer treatment. The more scientists discover about the genetic faults that underpin different tumours, the more it’s possible to divide them into sub-types, which may in turn respond very differently to treatment.  A good example of this is the breast cancer drug Herceptin, which only works for patients whose tumours have high levels of a molecule called HER2.

Now scientists in Edinburgh funded by Cancer Research UK have made an important discovery which could help to improve tailored treatment for breast cancer. They’ve found that a genetic test that’s already used in breast cancer patients can predict whether an individual will benefit from certain drugs or not. And we could see it become standard clinical practice within a couple of years.

The drugs in question are anthracyclines, including one called epirubicin. Epirubicin as an effective drug for breast cancer, but it only works in a certain proportion of patients. But because it can cause quite bad side effects, and it doesn’t work for all patients who get it, its use in the clinic has been limited.

So Professor John Bartlett and his team looked at tumour samples from more than 2,500 women who were on clinical trials of epirubicin, to find out if they could identify genetic markers in their cancers that would predict whether they did or didn’t respond to the treatment.

In the end, they found that women who had extra copies of chromosome 17 were likely to respond to the treatment. But women with the normal number  - that’s two copies – were less likely to respond. 

And here’s where it gets interesting. This extra dosage of chromosome 17 is already known to be involved in breast cancer, because this is the region of the genome that harbour HER2. So there’s already an effective test to look for duplications of the chromosome, which is routinely used by doctors to find out if a woman will benefit from Herceptin treatment.

The team are still waiting for the results of one final clinical trial to confirm the accuracy of the test. But if all goes well, we should see this becoming clinical practice within a year or two.

14th Dec 2008

Giardia Gene Shuffling Masks Bug from Immunity

A common gut bug has evolved an ingenious strategy to outwit the immune system, helping to conceal the parasite from immune attack.

Writing in this week's Nature an Argentinian research team led by Hugo Lujan at the Catholic University at Cardoba found that Giardia lamblia, a major cause of intestinal infections worldwide, has a repertoire of 190 different coat proteins with which it can disguise itself.  The organism selects a different coat every few generations, returning the previous outfit to the genomic wardrobe to wear again in the future. 

By studying which genes were being turned on in Giardia the researchers found that the parasite uses a mechanism called RNA interference to suppress the action of the other 189 coat genes it's not using.  The bug makes short sequences of the DNA-relative RNA, which are the genetic mirror-image of the un-used coat genes.  These mirror-image RNAs lock on to their respective coat genes and prevent them from being expressed, keeping them in the closet.

Exactly how the outfit subsequently gets reshuffled to select a different coat remains a mystery, but the team suspect that chemical tags applied to the DNA, called epigenetic markers, could be responsible.  Either way, understanding this system will inevitably lead to new ways to combat the bug, which spreads via contaminated water and infects millions of people, worldwide, each year.

14th Dec 2008

Zoo life not so good for elephants

Everybody loves elephants, and they’re often a big attraction in any zoo. But some rather sad news in this week’s edition of the journal Science suggests that zoo life my not be all that good for them.

Researchers from the RSPCA, along with other colleagues, did a survey of nearly 800 elephants living in zoos, and compared them to around 3,000 elephnts who either lived wild in Amboseli National Park in Kenya, or were working with loggers in Burma.

The results of the –ahem – mammoth survey were shocking. The African elephants in the National Park lived for around 56 years, and even those that were poached or killed by humans lived and average of 36. But African elephants in zoos only made it to an average of 17.  And we know this is because adults are dying younger, and the death rates among baby and young elephants were the same across the populations.

Looking at Asian elephants, the team found the same thing. The logging elephants in Burma made it to an average of 42 years old, compared with Asian elephants in zoos that lived to an average of just 19.  But in this case, most of the difference was due to higher death rates among newborn baby elephants in zoos, rather than adults dying younger.  The researchers think this my be due to traumatic events while the babies are still in the womb, as Asian elephants that are born wild but then captured for zoos live longer on average than those born in captivity.

So what’s causing the difference? The RSPCA believe that zoo life causes the elephants stress and obesity, which affects their lifespan. And diseases such as herpes, and tuberculosis, as well as lameness and infertility play a part.  The researchers also point the finger at the stress that happens when animals are transferred between zoos – especially when this involves separating mothers and calves.

Although it’s causing controversy in the world of zookeepers, this study highlights the fact that more needs to be done for the welfare of zoo elephants. And maybe we should ask if they should be kept in zoos at all.

14th Dec 2008

Paws for thought - dogs demonstrate envy!

Scientists have found that just like humans and other primates, dogs get jealous too!

The Austrian team paired up pooches and asked the dogs to hold out a paw on demand from the handlers.  One of the dogs was given a treat whenever it cooperated, the other dog went unrewarded.  Quite quickly the un-treated dogs detected the inequality and refused to cooperate further.  That this was down to jealousy was suggested by the fact that when the dogs were tested on their own - i.e. without a second dog being rewarded alongside them - they continued to cooperate despite the absence of any treat.

"This shows that dogs have the same basic brain programming for inequity that we do," says study author Friedericke Range, "although it is probably better developed in higher animals like primates that also gauge the size rather than just the sheer physical presences of a reward."

The team suggest that the result is an evolutionary mechanism for fostering cooperation between pack and social animals like dogs, wolves and monkeys.  "When you see that someone doing the same work as you is getting more reward it makes sense to refuse to cooperate until equality is restored," says Range.

14th Dec 2008

Catching New Viruses

Chris - Hello, Bob.

Bob - Hello, there.

Chris - Welcome to the Naked Scientists. Tell us what happened with this case. Tell us about this history.

Bob - Well this is a travel agent, a 36-year-old lady who worked in Lusaka. Unfortunately shortly after she got ill – you know the beginning of diseases is always milder than what comes later – she went from Lusaka down to a wedding in South Africa and then went back because there was some confusion as to about whether she actually picked up the infection in South Africa or Lusaka.

Chris - What were the symptoms she was complaining of?

Bob - Initially, I mean with any of these things if you’re talking about Ebola or severe diseases, people start off with non-specific pain. The same way flu starts with headache and muscle pain and just not feeling well and fever and rigour. That was how she started. She was taking pills for headache and that sort of thing. She went down to the wedding in South Africa and she returned on Sunday evening. From the Monday she was feeling extremely ill and couldn’t go back to work at all. She saw several doctors in town and by the Friday she was medically evacuated to South Africa and the following day she died.

Chris - What was the cause of death?

Bob - At that stage what normally happens is that people who are extremely ill, whether it be Ebola or anything else, the infection’s really similar to anything with bacterial infection or so-called septicaemia. It could be meningococcal septicaemia so a very similar picture. Clinically the clinicians do the right thing. They pump them full of antibiotics to save their life but the trouble is then if you do a blood culture to diagnose the illness you’re not going to find the answer because there’s always antibiotics. People die of one illness like that in every city every day. They have this septicaemia and so there was nothing that was deemed to be unusual about it. She was deemed to be a bacterial septicaemia and she died and no results were obtained.

Chris - So how did you find out it was something unusual?

Bob - It was only some days later, two weeks later, when a paramedic who’d flown down in the air ambulance with her came down with the same symptoms and was also medically evacuated. People put two and two together and realised there was something unusual and that’s often the case. Talking about emerging diseases earlier in this programme, quite often people can have an emerging disease and a one-off like that you don’t notice. It’s only with accumulated evidence. When the second person came down and that person developed the same symptoms and it happened to be at the same hospital a day later. The physician recognised this looked identical to the first one.

Chris - Can you tell us what the actual organism was that they were suffering from and where it came from?

Bob - Well this whole group of organisms are known to be associated with rodents. They cause chronic infection in rats and mice of various species. Each of these viruses tends to be associated with a particular rat or rodent species.

Chris - How do you think the lady got it from the rat?

Bob - That’s a big question yet to be answered. One of the things is there was a lot of confusion initially. Did she become sick in Zambia or South Africa? We believe it was Zambia and one of the things that has been suggested is an increase in wheat farming. It’s not that is just more has been planted per acreage because the price has gone up. That’s the sort of thing that happens in nature with human intervention, that we create a bonus situation for rats and mice. With all this wheat around them, grain crops, there’s a population explosion. Maybe that had something to do with it because she lived on the edge of town and indeed worked on the edge of town.

Chris - Can you tell us briefly what can you do about this in the future and what’s the likelihood of it recurring?

Bob - Well, I suspect it will recur and suggest that we will be better geared-up next time to recognise it. I think even in Zambia the physicians are really good at knowing what to look for.

December 2008

Does a mint make your mouth cold?

Does a mint actually make your mouth cold? And for that matter does chilli make it hot? We try and find out.

What you need

What to Do

What may Happen

You should find that adding a mint to your mouth doesn't make your mouth any colder, in fact we found it made Ben's mouth a few tenths of a degree warmer.

Similarly the tabasco sauce doesn't make your mouth any warmer, we actually found that Ben's mouth got about 1.3°C colder!

And as for the mint and the tabasco - apparently it starts off feeling hot, and then you get waves of hot and cold sensations and eventually it just feels hot.  Ben says it is a very strange, but perculiarly addictive experience.

What is going on?

As the results should suggest, you just feel the change in temperature it is not a real effect.  You feel temperature with two different sets of nerve cells.  One set called TRP-V1 will detect increases in temperature and TRP-M8 will detect decreases.

When the temperature decreases the TRP-M8 neurons will open sodium gates, allowing positive sodium ions to move into the cell and potassium to flow out, this creates a voltage which sends a signal along the thin tail of the nerve cell towards your brain.  Similarly when the TRP-V1 cells heat up they also send a signal.

In the mint there is a molecule called menthol.  This has the effect of fooling the nerve cell into opening the sodium gates on the cold sensing neurons and triggering a sensation of coldness.  In the chilli there is a chemical called capsacin which has the same effect on the TRP-V1 nerves, creating the sensation of heat with no actual change in temperature.

We found a slight change in actual temperature in the opposite direction to your sensation.  This could easily be a fluke and it should be tested by more repetition.  But it could be an example of your body detecting that your mouth is cold, so it rushes blood in to warm it up, and vice versa.

It is hard to tell exactly what is going on with both the mint and chilli at the same time, without a lot more research.  But it would appear that the chilli acts much more quickly than the menthol, and it somewhat confuses your sensory systems to feel something both hot and cold at the same time.

If you want to find out more try reading our article 'Does a Hot Mint Still Taste Cold?'

Written by Dave Ansell

The Origins of HIV

Chris - When did HIV first pop up in humans?

Mike - Well this study that we recently published we used some archival samples. We went into a time machine back to 1960 and sequenced a variant of HIV from that time period. From that vantage point it became possible to home in on when we think the pandemic strain first started circulating in humans. It’s pretty early. The virus may be celebrating its hundredth anniversary in humans. Our best guess is about 1908 + or – 20 years.

Chris - First of all, let’s take a look at how you came by these samples. What was the work that led up to being able to say I’ve got samples from 1960?

Mike - Actually it kind of traces back to last time we talked four years ago. It was regarding some work I’d done collecting virus samples from chimpanzees in the Congo so that’s one way you can go about investigating the origins of the virus. You can look at the modern counterparts in the reservoir species. At that time, actually even before that, I started thinking about ways that you could get at it. The obvious thing was to try to get human samples that go really far back in time and the state of the situation at that time was we had one little glimpse. A fragmentary sequence from one HIV patient from 1959 and then there was no sequence at all until the late 1970s, early 80s.

Chris - That 1959 sample was a blood sample that someone had luckily stored in a freezer for years, wasn’t it?

Mike - Exactly, it was something that was collected for other reasons. It was genetic research to do with malaria but someone had the foresight to save those samples. Central African blood samples that go back that far in time are hard to find. I think most people just kind of gave up. They thought when we got the 1959 one we’re not going to find any more, that this is all we have. What I thought about was are there other kinds of samples that aren’t in freezers and aren’t so delicate? I turned to paraffin embedded, wax tissue specimens, biopsies and autopsy specimens. They’re routinely taken in hospitals and clinics around the world and put in a cellar and archived. It turns out it’s kind of painstaking but you can get gene sequences out of these things.

Chris - Who happened to have some of the right sorts of paraffin-embedded tissue you could study?

Mike - The one that yielded this sample from 1960 was actually stored in Kinshasa, the capital of the Congo at the University of Kinshasa. What i did for quite a few years actually was just put out feelers and do some work and talk to a lot of old Belgian scientists and physicians who had connections who had either done work in the Congo back in the day or knew people who did. Eventually turned up many old samples like this and, like I said, they were samples that had sat in Kinshasa all this time that yielded this sequence.

Chris - So you go to old human tissue, you go to 40+ years ago and you can find HIV in that. What does that tell you about where HIV came from and how do you wind back the genetic clock to find out when it first popped up in humans?

Mike - The first thing that tells us is you can compare the 1960 Kinshasa sequence to the 1959 Kinshasa sequence. It’s like having a human genome, it’s great and tells you lots of things. As soon as you have a chimp genome to compare against it there’s a whole lot of other things you can tell by comparing. Once we have these two viruses side by side we could see that they were pretty surprisingly divergent. Even at that early date in 1960 a direct comparison of that early sequence indicated these things had spent a long time evolving away from their common ancestor: decades and decades. The other thing that we could do now is plug those early sequences into a more sophisticated analysis using more that 100 sequences worldwide. They really helped calibrate the molecular clock of these viruses and allowed us to estimate with a lot of precision when the virus started spreading in humans. Like I said, it’s many decades before 1960.

Chris - but something must have happened 100 years ago in that part of Africa to make that HIV appear. The closest relative  of HIV is SIV: the virus which you find in chimpanzees. What was going on in that part of Africa that meant this chimpanzee virus got into people?

Mike - This is one of the coolest things about the finding. There are all sorts of SIVs from different primates that are circulating out there. The big question is if these things have been around why didn’t they cross in earlier or later? Why now, at this point? When we matched up the timing of these genetic analyses of the viruses against what was happening in that epicentral region of Africa for me it was a surprise. I didn’t realise how little urbanisation there was in the region until that time. Basically, in the whole area around southeast Cameroon where we think the chimp virus produced the pandemic strain of AIDS entered humans there were basically no cities at the turn of the 19^th century. It wasn’t until that time that places like Kinshasa were established as colonial administrative trading centres.

Chris - So you think it was people moving in and establishing cities that got the thing going?

Mike - I think it’s almost too much of a coincidence to dismiss that what I think happened was, HIV is a fairly poorly transmitted virus human-to-humans. You have to set the stage for it to survive and create a chain of transmission otherwise viruses entering from chimps might get into one or two people but then die out.

Chris - So what do you think happened?

Mike - Well, with the advent of cities in the region cities make life a lot easier for HIV. They bring people into high densities. You often have high-risk behaviours like prostitution that facilitate the movement of the virus from person to person. We talk about this magic number of viruses: a basic reproductive number of one. This means a virus which your average infected person infects one other person will persist in the population. If it’s below that number it will become extinct. The advent of urbanisation may have pushed that magic number above one for HIV.

Chris - Briefly, I think one of the other things to mention might be people immunising people. When they set up cities weren’t they exploring vaccines in those early days? Could that also have been how it happened because people weren’t so rigorous with sterilising needles as we are now?

 Mike - It’s definitely one of the things that have been discussed as a possible player in the establishment of the virus. My thinking is if you actually look at the timing of those events people like Preston Marx have talked about the spread of disposable needles. That’s actually in a large part after the timing that we’re pointing to. The bulk of the transmission of the virus in sub-Saharan Africa today is through sexual transmission. I don’t see any reason to think that the establishment of the virus had things to do with things like dirty needles. They probably play a minor role in transmission but I don’t think they’re the key.

December 2008

Hotspots for Emerging Disease

Kate - Emerging infectious diseases are diseases that have basically increased in incidence, impact or range, newly-evolved like multi drug-resistant TB or malaria or entered the human population for the first time like SARS or Ebola or HIV/AIDS.

Meera - What exactly are the factors that cause these diseases to emerge in the first place?

Kate - It's usually because there's a change in the transgression dynamics between and within host populations. You have populations of humans,wildlife and domestic animals all interacting. Changes which change those dynamics between these populations and within host populations cause these diseases to enter the human population for the first time.

Meera - What are the actual changes that happen?

Kate - It could be increase in intensification of agriculture. You get more contact between domestic animals and humans. It could be going to ranges of wild animals that people didn't do before because of bush meat hunting. You're exposed to a different disease. Diseases and pathogens don't want to kill their host because they're evolving with them. It's when you get a change in these transmission dynamics and suddenly it's new for the pathogen. That's where it causes the problem because pathogens don't actually want you to die because they're living in you.

Meera - When it comes to emerging infectious diseases there are obviously lots of different types. What are the factors that influence these different types?

Kate - We thought originally about emerging infectious diseases all as one thing. Then it because obvious that there were different drivers for the different things. We cut it up into broadly different types: drug-resistant emerging infectious diseases like drug-resistant TB, vector-borne diseases such as malaria and then we thought about zoonotic. This is diseases from wildlife that entered the human population such as Ebola, AIDS or SARS. Those are the broad categories that we use.

Meera - So what were the different drivers for the different disease playing more crucial roles in them?

Kate - Human population density is absolutely critical for predicting the probability of an emerging infectious disease because you've got more people, more chance of infection. For drug resistant ones human growth is actually more important. The rate of population growth is more important or, for example, zoonotic pathogens we were finding that human population density is really important but the other driver that was equally important was the distribution of possible hosts. In this case we used wildlife biodiversity.

Meera - Earlier this year you managed to create this map that basically showed hotspots on a global scale of where these diseases are occurring more often.

Kate - We took a really innovative, multi-disciplinary approach. I study broad-scale, by diversity pattern so I'm not an epidemiologist at all. I was working with people who were but the problem with the field as it stood before we tried to do this is that people were looking at single diseases and not taking a really broad-scale approach to think well, what are the processes behind those patterns?What we did was we tried to think about an emerging infectious disease and not just the disease but the event. The first time in space and time that that pathogen entered the human population. We tried to model the human event because we wanted to work out what were the factors that were affecting that event happening. Maybe we could predict that event in the future.

Meera - Are there particular examples of diseases that you managed to think about the factors for then?

Kate - Yeah so we tried to do this in a general approach. A few examples would be Nipah/Hendra virus in Malaysia. This is a zoonotic, a disease from wildlife. What happened was an intensification of pig farming in the region and so people put pigs natural forest for the first time and there was an interaction between the bats and the pigs in the forest. The pigs were eating fruit that the bats had eaten. Bats have Nipah virus naturally and they cope with it in their populations. Pigs, however, have never been exposed to that. The humans which were handling the pigs had never been exposed either. You had an emerging infectious disease event of this really nasty disease.

Meera - Is it safe to say that we're moving closer and closer to animals, it's causing a big change in the emergence of these diseases?

Kate - That's a really good question. That's what we were trying to try and answer. Our first result coming out of this huge database was that the incidence of emerging infectious diseases has actually increased over time. What we then did was plot it spatially. Normally in my biodiversity studies you find a lot more biodiversity, a lot more things, in the tropics. Now with emerging infectious disease events the opposite is true. You get more in the north and more in the south. We were thinking that possibly that shows you that biology is important but there are other socio-economic factors involved that we needed to model. Quite frighteningly since 1940 the hotspots of diseases have been in the really big capital cities of the world: London, New York and Tokyo. Maybe one possible explanation is that you put more money into antibiotics and you're getting a lot more emergence of these diseases which are drug-resistant. The other interesting factor was that if you look at the zoonotic patterns, they're affected by human population density but also the density of other wildlife in the region which makes perfect sense really. It's not just that you've got high population densities of humans or wildlife. It's the interaction of those two things. In a way it gives added value to preserving wild areas, to keeping them wild. We're preventing horrible emerging infectious diseases coming and entering the human populations.

December 2008