AUTOIMMUNE DISEASE | 1990/00s
Divide and conquer
How understanding cell division and a mathematical formula influenced vaccine development and design
As scientists currently understand it, there are five main types of antibodies in humans and they each serve a unique function in defending against illness and maintaining immune balance.
The type of threat posed, along with where it occurs in the body, determines which antibody our B cells produce and send to fight the infection.
How B cells decide which antibodies to produce and put to work, was, until the mid 90s, thought to be chosen after instructions by signals received from other cells.
However, cell division research conducted by Professor Phil Hodgkins’ lab demonstrated the relationship between cell division and changes in antibody types, and that the choice of antibody was random, rather than pre-determined.
“In September 1995 I was able to move from John Curtin School of Medical Research (JCSMR) in Canberra to set up a new lab, the Immune Regulation Group at Centenary Institute thanks to a generous and competitive Fellowship from the Medical Foundation,” recalls Phil.
“One of the great features of the Centenary Institute was the quality of the education program and the very impressive cohort of students that would join the lab thanks to course coordinator, Helen Briscoe.”
What began in Canberra was leveraged in the new lab at Centenary, monitoring cell division with a precision that wasn’t previously possible and in 1996 Phil and JCSMR colleagues published the first description of division-linked differentiation by lymphocytes (B cells).
A discovery that challenged assumptions
The research revealed that as lymphocytes divide, their likelihood of switching antibody types increases with each cell division.
This challenged previous assumptions and clarified that B cells are not pre-committed to a specific antibody type; instead, switching is linked to the division cycle.
“This work gave the first clues that lymphocytes were following simple, identifiable rules and that different fates, in the same cell, such as division rate and decision to change antibody, could proceed independently.”
The knowledge that B cells follow a step-by-step plan as they divide led Phil’s team to pursue a mathematical principle to help predict the changes.
A mathematical framework
It was Amanda Gett, a PhD student in Phil’s lab at the Centenary Institute who set out to learn more about this system using the new division tracking methods.
She began with the T lymphocyte, a cell that is critical for protecting us against infections. In what Phil recalls as a ‘quite remarkable series of experiments’, Amanda established methods that allowed the team to measure times to divide and die.
“Amanda’s research enabled us to mix and match exposure to stimulation methods and show the cells were adding effects in surprisingly predictable ways. We were measuring and observing cell signal ‘calculation’”, explains Phil.
“This calculation is at the heart of all immune responses as cells decide whether a threat is dangerous and needs a response. If a response is triggered, how strong should it be, and what type of cell army needs to be created?”
Just as with B cells, the control of two different fates for T cells – division and death – seemed to be random and independent. Amanda also found that the production of different cytokines (chemical messengers), was linked to cell division, providing evidence that division, death and differentiation could be modelled as separate processes in the same cells.
In simple terms, these cells do not follow only one or two instructions; instead, they listen to multiple signals simultaneously and process them like a calculator. This combined input determines how quickly they divide and how strongly they respond, allowing the immune system to ramp up its activity when necessary.
Around this time, Stuart Tangye joined Phil’s laboratory and was able to demonstrate that the same quantitative features linking division and antibody selection were operating in human lymphocytes.
“We referred to this discovery and this new framework as the Cellular Calculus and it provided a powerful new way to understand and predict immune responses, especially in diseases, vaccines, or autoimmune conditions, and these founding concepts have been continuously improved over the subsequent years.”