Holiday Lecture - 2009
“It’s critical that the immune system get this exactly right. Fail to notice a deadly virus, and you’ll get an infection and die. Get trigger happy, and the immune system could attack cells you’d rather hang onto.”
Your body’s immune system does not have the laws of mathematics on its side. Although it must protect you from an infinite number of germs, it’s equipped with a mere 20,000 genes. With nothing more to go on, it must be able to recognize and mount an attack against any virus, bacteria or parasite it encounters — most of which it has never encountered before and has no way to identify.
With the odds so clearly stacked against it, the immune system is forced to improvise. By directing immune cells known as B cells to rearrange sections of their own DNA, the body can reshuffle its genetic deck, snipping segments of code from one chromosome and reinserting them in another. This ability to cut and paste its genes allows the body to make the most of its limited DNA and gives it the genetic blueprints it needs to build a new cadre of germ-busting weapons.
The strategy works, but it’s a dangerous game. It could activate cancer-causing genes or turn the immune system against the body’s own tissues, such as your pancreas, cartilage or skin (the causes of juvenile diabetes, rheumatoid arthritis and psoriasis, respectively).
Despite its risks, the strategy has become a victim of its own success, co-opted by the very microorganisms it’s designed to fight. Trypanosomes, for instance, the parasites responsible for sleeping sickness, are able to rearrange their own DNA to disguise themselves from killer cells that have been sent after them. The cat-and-mouse game is one reason why some infections become chronic, killing their victims just as they’re on the verge of recovery.
Join Rockefeller University’s Nina Papavasiliou, a geneticist and immunologist who studies the interaction between the immune system and the ways in which pathogens can evade it, for a multimedia tour of the high-stakes battle between our bodies and the microorganisms that try to outsmart it.
The Immune System
At its most basic level, the human immune system protects us from infection. When bacteria or viruses enter our bodies, the immune system recognizes them, attacks them and prevents them from harming us. But it’s more complicated than it sounds. The various components of the immune system must be able to differentiate between harmful invaders and the body’s own cells. An overly “enthusiastic” immune system can lead to so-called autoimmune diseases, such as arthritis, diabetes, psoriasis, lupus and multiple sclerosis.
As you read this, your T cells, B cells, natural killer cells — each of the immune system’s warriors that circulate in your bloodstream — are allowing your body’s heart, brain, pancreas, joints and other tissues to exist and function without harassment or interference. Yet they still remain wary of things like parasites and the swine flu virus. It’s a delicate balance that scientists have spent decades trying to fully understand.
Seven Rockefeller labs consisting of more than 100 scientists are working at trying to understand the immune system’s intracacies. How are immune cells able to recognize pathogens that they have never seen before? How do various components of the immune system, such as B cells, T cells and natural killer cells, coordinate their efforts? What happens that allows some viruses to gain the upper hand? Why does the immune system sometimes turn on the body? The questions Rockefeller scientists are asking are relevant not only in the battle against infectious disease and the development of new antibiotics, but could also lead to strategies against cancer. By harnessing the power of the immune system, doctors hope to be able to teach it to fight off cancerous cells without the toxic side effects of radiation or chemotherapy.
Trypanosomes are microscopic unicellular protozoa that are ubiquitous parasites of insects, plants, birds, bats, fish, amphibians and mammals. They have been around for more than 300 million years. Because they have been around for so long, they and their natural hosts have evolved together to ensure their mutual survival. A few species of trypanosomes are pathogenic. Trypanosomes, and other parasites, mainly cause disease when they spread to new hosts, like humans and their domestic animals, especially recent imports into endemic areas of species that have diverged since continents separated.
We generally associate trypanosomes with diseases in Africa and South America. African trypanosomiasis is commonly known as sleeping sickness in humans and nagana (meaning ‘loss of spirit’ in the Zulu language) in cattle. Sleeping sickness, which is transmitted by the tsetse, a type of fly, and affects 300,000 people each year, causes neurological damage that eventually interrupts the sleep cycle, leading to insomnia at night and sleepiness during the day. It’s fatal if not treated. Trypanosomes also cause Chagas Disease, a chronic human infection of the heart, prevalent throughout Latin America.
Scientists study trypanosomes in order to develop vaccines and drugs to prevent or treat the diseases they cause — there are currently no vaccines and the only drugs that are effective were developed 50 years ago and are highly toxic — but also to understand why our immune systems fail to eliminate trypansomes. Trypanosomes have evolved very differently from the better-studied organisms, especially bacteria, yeast and animal cells, on which the foundations of biology have been built. Studies of some processes that operate in a more primitive fashion in trypanosomes can help us to understand how the very complex mechanisms of animal cells have evolved.
Though understudied, Rockefeller has a long tradition in trypanosome research starting with William Trager, considered the father of modern parasitology, and continuing today with George Cross, head of the Laboratory of Molecular Parasitology.
Nina Papavasiliou studies how we make antibodies and how they fight pathogens that invade our bloodstream. Even though we are born with a small number of antibody genes, we can generate up to 100 billion distinct antibodies in response to various infections during our lifetime. This is possible because our bodies mutate the DNA that produces these germ-fighting molecules. By studying this process, Dr. Papavasiliou’s research has led to a better understanding of how we, with our limited DNA, can manufacture such a diverse arsenal of weapons. Her research also aims to understand how a handful of pathogens have managed to co-opt this strategy from the immune system and beat it at its own game.
A native of Thessaloniki, Greece, Dr. Papavasiliou won a scholarship to Oberlin College, where she received her undergraduate degree in biology, with a minor in German literature, in 1992. She completed her Ph.D. in molecular immunology in 1998 at Rockefeller University. After postdoctoral studies at Yale University, Dr. Papavasiliou returned to Rockefeller as assistant professor in 2001, becoming associate professor in 2007. For her work, Dr. Papavasiliou received the Alexandrine and Alexander L. Sinsheimer Fund Scholar Award in 2005. She is a 2003 Searle Scholar and a 2002 Keck Fellow.