Scientists synthesise antibodies

This week scientists at Yale University have announced one of those game-changing achievements that could change the future of medicine. And, probably, win a Nobel prize. They have synthesized mini-antibodies that can function within the body and attack both cancer cells and disease-causing agents.

An antibody is a highly complex macro-molecule, produced by the adaptive division of the immune system. It’s a powerful bespoke weapon that will only attack a single type of bacterium, a particular strain of virus or a cancer cell with a particular genetic signature. They lock on to receptors on the surface of the pathogens and disable them. Imagine them as tiny wheel clamps that are individually designed for each new make of car that comes on the market. One of the problems with antibody production is that it is not instant. It takes the immune system several days or weeks to get its production line up to speed and in a serious disease like Ebola, the patient can die before enough antibodies are produced. Once the antibody template has been produced, it can be used more swiftly whenever the particular threat re-appears.To work on cancer cells the immune system first has to identify them as alien.

Antibodies are tiny and these new synthetic antibodies even smaller. Picture a bespoke wheel clamp on a jumbo jet. But that might make them easier to produce.

Currently there are just a few ways in which medicine can use antibodies:

Vaccines – in which the body is induced to create a new type of antibody without becoming ill. New vaccines are hard to develop.

Extracting antibodies from blood of those previously infected. This is being tried currently to treat Ebola.

Snake bite serum – produced by injecting animals with small amount of venom and then extracting antibodies from blood serum.

Monoclonal antibodies – producing an individual antibody type in the lab, using a complex biological system.

If simpler synthetic antibodies could be produced by a less laborious process than monoclonal antibodies it would open the door to a wide range of options in treating infectious diseases and cancers.

A ground breaking moment in immunology without a doubt.

http://bit.ly/13kPg4T

Ebola and the immune system

I’ve often wished the immune system had a different name. One that sounded a lot more grand and complicated. It slips easily off the tongue and gulls people into thinking that it’s no more complicated than their central heating system. And that the equivalent of a tweak of the thermostat (in the form of a pill or a foot massage) can give “it” a quick boost. When researching my book I realised that it’s a system of a very different kind – more like, say, the complexity of a city like London with its workers, businesses, buildings and transport networks.

There are two main divisions to the immune system. The emergency “innate” division kicks in the minute you have a wound. On a much slower timescale the “adaptive” division learns about all the bacteria, viruses and proteins in your environment – which to ignore and which to attack with antibodies the next time they crop up. There are many different types of immune cell (“white blood cells”) and new sub-types are discovered regularly. They produce a vast array of complex proteins called cytokines that also play a role in attacking pathogens. Part of what we mean by “immune system” is this interacting mass of cells and proteins that flow through blood and tissues during health and illness. But there is more. The permanent structures of the immune system are the bone marrow, which is the production unit for replacement immune cells, and the lymphatic system that monitors threats throughout the body.

As in cities, balance is important. You don’t need a rail system that varies its timetable unpredictably. Neither do you need an immune system that is over- or under-active. Everything has to be modulated to keep things running smoothly so as to prevent not only infection but also self-damage. Diseases associated with an over-active immune system include all the auto-immune diseases, allergies and inflammatory conditions. Toxic shock, sepsis and the cytokine storm (which can occur in pandemic flu) are more sudden and much more deadly over-reactions.

Some illnesses are not just attacked by the immune system – they directly infect immune cells and interact with them in complex ways. It’s well known that the HIV retro-virus directly attacks immune cells, using them as a base and slowly undermining their work. TB, caused by a bacterium, also infects immune cells – the ones that normally engulf and destroy bacteria entering the lungs. Ebola too infects immune cells, and progresses far more swiftly than HIV or TB. It does so by using infected immune cells to spread the virus throughout the body. Ebola is also able to damp down aspects of the immune function. But that is not all. The high fever and inflammation of the later stages of the disease are part of a massive immune over-reaction that contributes to death. 

There are various scientific initiatives attempting to tackle this unusual virus but the solutions are not simple.

There are some anti-viral drugs undergoing accelerated trials but it would be surprising if they make a significant impact. The might of the pharmaceutical industry has yet to produce a range of wonder-working anti-virals for other diseases. Anti-retrovirals, used for HIV, are probably the biggest success, despite all their limitations. Vaccine development is a long and difficult road and vaccines in current development are a while away from any prospect of a  mass roll-out. The experimental biological treatment ZMapp is a product of immunological research. It’s a combination of artificially produced antibodies that lock on to specific targets on the Ebola virus, disabling it. It is to be hoped that ZMapp works, and that one day it can be produced in large enough quantities to be useful in bringing outbreaks under control. However production methods are complex involving a lot of careful work by technicians and the growth of cloned cells in laboratory conditions. This process is not at all like the factory production line that produces conventional chemical drugs. My feeling is that science is very unlikely to come up with any quick answers, with mass impact, in the next few months.

In the meantime though, simple nursing measures like infection control and putting up a drip can save lives. As Christmas looms we are asked to contribute to a wide range of charities but this year many of us will perhaps consider that paying for some nursing supplies for Ebola stricken areas is the most urgent call on our generosity.

http://www.bbc.co.uk/news/health-30217573

Immunology and Cancer

Ten years ago the author of a keynote speech on the science of immunology remarked: "The paradox of today's immunology is that tremendous progress in basic science has been matched by only a few clinical applications." At the time, he noted, a journal paper in immunology was being published every 15 minutes but little of this knowledge was translated into useful treatments for patients.

The task of trying to understand what is happening in the immune system reminds me of the Walrus and the Carpenter who wondered whether the shore could be cleared of sand: "if seven maids with seven mops swept for half a year". You could envisage those poor maids, sweeping diligently, only to discover layer beneath layer of sand. So it has been in the biological sciences with layer after layer of complexity being revealed, the deeper the scientists dig. Ten years ago only ten of the immune-based drugs known as monoclonal antibodies were in use. The list has grown rapidly since then and many of them being used to treat various forms of cancer. It has taken an astounding amount of pure research to enable these immune-based treatments to prolong lives. Herceptin is the best known example.

In the world of cancer drug development there are a two main strategies. The traditional one is to try out various chemical compounds until you find one that kills cancer cells without killing, or permanently damaging the patient. The more recent and much more sophisticated method is to pinpoint a particular cancer gene or molecular pathway, and then devise a molecule that will block the gene or disrupt the pathway. Unlike the generic weedkiller approach of chemotherapy the new drugs are very specific. They may have dangerous side effects but they are unlikely to be the ones that traditionally accompany chemotherapy: hair falling out and immune system being seriously impaired.

Some of the underpinning research is done by immunologists who are slowly starting to understand the puzzling interactions between cancers and the immune system. We have known for a long time that some immune cells can destroy cancer cells and in recent years there is increasing understanding about why they might fail to do so and how, sometimes, immune cells are deceived into promoting the spread of cancer. But the processes have to be unpicked, one molecule at a time if they are to be used by medicine.

Research published in this month's New England Journal of Medicine reveals some encouraging results for another antibody-based drug. The interesting thing about this one is that it operates directly on one of the molecular interactions between the immune system and cancer. It does not, as Science Daily implies in its headline "boost" the immune system. Instead it prevents the cancer from using one of the possible ways of defending itself against an immune attack.

The new drug was tested on 296 patients who were suffering from some of the more lethal kinds of cancer - melanoma, lung cancer and so on, who had already had other forms of treatment. The results showed that "approximately one in four to one in five patients" responded in an encouraging way. These results are exciting, given the nature of their diseases. Immunology did indeed make slow beginnings in terms of practical applications, but at last it is starting to produce benefits for patients.

  

Antonio Coutinho Immunology at the crossroads EMBO Rep. 2002 November; 3(11): 1008–1011.

Suzanne L. Topalian et al. Safety, Activity, and Immune Correlates of Anti–PD-1 Antibody in Cancer. New England Journal of Medicine, 2012 DOI

http://en.wikipedia.org/wiki/List_of_monoclonal_antibodies

http://www.sciencedaily.com/releases/2012/06/120602134835.htm