Small things – Oxford Today Magazine

Tiny things can have huge effects. If in doubt, consider pathogens. Invisible and deadly tuberculosis killed off Keats, buried Burns. Thinks how terrible you feel when pillow bound you sweat and ache with flu. Consider 24 million people with AIDS; 300million infections and 3 million deaths a year from malaria, a creature which has sex, reproduces and is transmitted inside a mosquito.

In the Peter Medawar Building for Pathogen Research on South Parks Road, great minds direct their thoughts to the activities of very small creatures. Small creatures which matter profoundly to humankind. Chair of the Consortium Rodney Phillips, heads a group which aims to uncover how HIV manages to so effectively evade being killed by the immune system. He was inspired to work in this field because it matters. All of the work going on inside this building really matters which, for a biologist like me who studied how birds talk to each other, is pretty humbling. As I listen to Rodney and Karen Day and Martin Maiden talk about their research it is hard to see why anyone would study anything else.

Rodney explained the new understandings of HIV to me in a series of rapidly sketched diagrams and graphs. As I listened, everything seemed to make perfect sense, but when I come to read the papers later, it is like a foreign language, involving ‘proviral gag DNA epitope sequences’; ‘CTL escape mutants’ and ‘antilymphocytic choriomeningitis viruses’ so I go back to my notes. HIV is really good at not being killed by the immune system. That is why it is so deadly. But some people seem to be able to survive with it in their system for 10 years while others live 20. Clearly this makes an unquantifiable difference to the individuals concerned. One study undertaken by Rodney and his group is to take samples from the same individuals over a long period and see how they change.

Over a number of weeks, the virus can be seen to evolve, its genes changing, as it makes mistakes in its replication process. Immune cells kill off some of these new variants, but the constantly changing virus also means the immune system cannot keep up, so some will evade the army of immune cells. HIV also actively kills off CD4 immune cells at a rate of around 50 a year. Opportunistic infections set in and bring about the AID syndrome. Rodney starts to talk about the epidemiology of disease and then suddenly we are on drug users in the 60’s listening to Jimmy Hendrix, and shooting up, and MSM’s – men having sex with men. I ask Rodney if HIV is on the increase because people are being more promiscuous, – no he says – people have always been quite promiscuous.

Here in this building, in sparkling new, custom-designed laboratories, serious diseases lurk in test tubes in fridges. ‘Aren’t you nervous’ I ask Rodney, ‘working with all these killers?’ ‘The disease’ he says ‘doesn’t leap up off the bench and attack you’. They are blood born disease, many of which cannot survive outside the human body. But still, the class 2 diseases have X-file style containment labs to ensure they do not escape. Martin described to me the system of air movement which creates a lower pressure inside a corridor on the way into the lab. That way, when the door opens, air can only pass one way – into the lab. Staff must change their clothing and shower in and out of the lab.

Karen Day works on malaria. In Africa and Papua New Guinea (where she lived for 5 years) she has seen many people suffering, and she says there are two clear paths to try to help. One is to be a doctor and directly administer medical care, and the other is her chosen path: to research into wider solutions to controlling the disease. One past response has been to spray vast areas of land with DDT to kill off the mosquitos which transmit it, but as Karen says, this is dangerous and ineffective. The mosquitoes evolve resistance to the insecticide and very soon you are back to square one.

One aspect of her group’s research has been to take a look at what caused the parasite to emerge as a species in the first place. But how do you start off with an ill person and end up understanding the origins of malaria. And how do you go about studying something so small? First of all you have to get the disease organism. Its one thing with a sparrow or a fox, at least you can get your hands on it, but how do you collect a microrganism or a virus? In the case of malaria you may take a sample of blood by pricking the skin, or with meningitis, a swab from the back of the throat. Most parasites, die outside the body fairly quickly but Hepatitis, I am told by Emily Lyons PhD, student in Karen’s group, rather emphatically, survives really well in a plastic vial.

Then you have to go smaller: to the DNA. Malaria lurk inside human blood cells so two different washes are used, one to break the blood cell membrane and another, the parasite’s membrane. Using a series of biochemical procedures, which I am assured, are not magic, the DNA is separated from the rest of the cell contents. The amount of genetic diversity to be found between the individuals in a population gives an idea about how long it has been evolving away from a common ancestor. As time passes, DNA is replicated to allow reproduction of cells or individuals, but the process makes mistakes.

The genes change slightly, and it is on these differences that natural selection acts, favouring some mistakes while annihilating others. The good mistakes which improve survival will become more common in the population. However, some sections of DNA are ignored by natural selection. The introns are sections of genes, of DNA, which are not coding for any proteins, that is they have no function in the body and come along for the evolutionary ride. These sections of DNA are really useful to Karen and her group for they accumulate mistakes at a certain rate with being selected for or against. Comparing the introns of malaria parasites from one person with that from the next will give you an idea of how diverse the population is – and how old it is.

Throughout the labs in the Medawar building are clever machines which sit on the desk tops looking smug. Their job is to make the very small things these people study, bigger so that they can see them. They ‘amplify’ the DNA using a recipe of base pairs, of DNA constituent parts. Then the interesting introns can be examined by sequencing. Listening to Emily patiently describe these GSCE level biological processes of forming DNA from base pairs and proteins from amino acids I am suddenly struck by what a miracle life is. How such minute processes can lead to the unbounded complexity of living organisms. How a bit of DNA can encode for the colour of a leopard’s fur or make you sleepy or hungry or in love. How a bit of DNA which keeps changing can rob someone of their life. Most of the genetic diversity in malaria represent ways in which the disease organism is adapted to drug therapy and immune avoidance suggesting that it is engaged in an evolutionary arms race with us, its host.

Adding a mathematical model called coalescent theory, to the orchestra of biological research procedures, Karen’s group in Oxford along with her colleagues in Harvard have established malaria’s relationship with human prehistory. That the introns have enough diversity to represent around 3-7000 years of evolution but not much more. The different types of malaria emerged as human pathogens, from a single ancestor, around six thousand years ago. At the same period, people began slash and burn agriculture in the rainforests of Africa, gathered together in larger numbers and provided pools of standing water on fields- perfect homes for mosquito babies. Thus malaria is as young as human agriculture, and we helped it on its way.

Martin Maiden is the man to ask about meningitis. Like Karen, he is taking a studious look at the natural history of the microscopic creatures which cause the disease. Meningococcus is a strange bacterium, existing in a completely harmless form in the noses of around six million people in Britain, and causing only around 2-3000 cases of disease a year. But when it does, the media goes mad, as it often strikes in universities or colleges affecting young people or babies. Research has tended to focus, understandably on swabs and bacterial clones taken from people who are dead or ill. This means that we understand only a small and rather exceptional subpopulation. It is rather like examining the psyches of murderers to understand the brains of all humans.

The bacterium exists in hundred of different types, of which only a dozen are liable to enter the bloodstream and cause disease. Meningococcus has around 13 different carbohydrate coatings, most of which the immune system spots and kills but around five seem able to avoid detection. Two types in particular cause the disease and while one can be vaccinated against, the other cannot. Martin is concerned that vaccinating against one may allow the other (for which there is no vaccine) to take its place in the ecosystem which is the human population. This is no small matter.

In 1999 the political decision was taken to inoculate all members of the UK population under the age of 18 years against . Following Dobson’s announcement in July 1999, Martin wrote a very persuasive grant proposal because the Wellcome Trust came up with a million pounds to allow him to research into the effects of these inoculations within six weeks. The vaccinations and the study started in November. Martin is excited about this unique opportunity to see how a disease organism reacts to vaccination. They swabbed 16,000 16 year olds before they were vaccinated and will do the same afterwards. Towns from Glasgow to Plymouth are involved.

These data come up with lots of samples which are bar coded so that almost all of the work is handleable by computers. The samples are fed through a microtitre plates 96 at a time. The first results are with the journal, The Lancet and as Martin is waiting for their response, he won’t tell me what they have found. He looks pretty pleased though. This is joined up research from nurses taking swabs from people’s throats to sequencing DNA on computer benches to phylogenetic analysis by computer software to theoretical modelling.

And that is what the Peter Medawar centre is all about: bringing together biologists from different corners of this vast discipline. There is something functional, practical, serious about the centre. The PhD students and post grads have a sense of professionalism, perhaps a bit more stress than elsewhere in academia. As Rodney put it, the problem of infectious disease is not going away. And how do you possibly sustain giving 50 tablets a week to 24 million people with AIDS? Research says Rodney is difficult and laborious so you may as well work on something that’s going to make big a big hit: big changes to stop the small things devastating so many human lives.