There are distinct existential benefits of multicellular organisms, evidenced by the observation it independently evolved many times since the beginning of biological life itself1. However, as the applied evolutionary pressure switches from one unit (unicellularity) to multiple units (multicellularity), the mechanisms that align fitness interests of the organism changes. Where unicellular organisms only need a single division to propagate, multicellular organisms need to decide which cell divides and propagates its genes. For example, assuming genetic variation exists within the multicellular organism, one genotype of a cell may propagate at the expense of others. Consequently, the cooperation of single cells within the multicellular organism leaves room for the expansion of “cheater cells” (see Text Box 1).
| Text box 1 | The “cheater” paradigm as evolutionary force for the development of the immune system Cheater cells: any cell or combination of cells that takes advantage of another organism, to the detriment of the fitness of that organism. A bacterium represents the archetypal “non-self” example of a “cheater” in terms of immunological evolution. By taking advantage of the cooperative nature of the multicellular organism, bacteria affect the ability of the host to reproduce. Next, organisms that harbor genetic mutations that reduce the harm caused by bacteria reproduce at a higher frequency compared to the wild type organism. As a result, offspring of these mutated organisms increase in frequency of the population level in a “survival of the fittest”. The tumor cell represents the archetypal “self” example of a “cheater cell”. Somatic cells may gain proliferative advantage through the acquisition or inheritance of a series of mutations in their DNA, resulting in hyper-proliferative cells. When these cells are not removed through apoptosis or the immune system, they may outcompete neighboring cells and cause harm to the host organism. |
One way successful organisms have evolved to overcome these cheating cells is by development from one cell whose offspring stick, instead of aggregation of genotypically different cells. In this way a single cell can divide, retain its genetic composition, while eliminating the chance of cheater cells with cheating genomes. This strategy is so successful that virtually all multicellular organisms, including humans, pass the unicellular stage to ensure this first barrier against cheater cells1. Nevertheless, adaptation to a changing environment favors phenotypic variation and cellular differentiation within the multicellular organism. Multicellular organisms arising from a single cell have adapted “epigenetic prints” that allow long-term differences in use of the same genetic code, leading to different functional programs and cellular differentiation among cells. This parallel division in labor within the organism has obvious benefits over unicellular organisms that are limited to differentiate and divide labor over time in a serial manner. For example, for cell division the DNA needs to be replicated, condensed and pulled apart into two identical nuclei. During this process the DNA becomes inaccessible for RNA polymerases and transcription of mRNA is halted, preventing adaptive effector function during this period. To overcome this issue, in multicellular organisms the labor of propagation is divided at the organism level by compartmentalizing the reproductive system (only gametes ensure the propagation of genes). At this stage of evolutionary progress, selective pressure is applied to the organism level and cheater cells (either foreign or derived from somatically divided cells) may still affect the evolutionary success of the organism. We will find this Darwinian principal to be essential to the work described in this thesis, since “survival of the fittest” is the basis of many key concepts; the emergence of a hugely complex immune system, the response to invading pathogens or injected vaccines, the emergence of immune-suppressive tumors and tumor escape during treatment.
Let’s have a look how the immune system adapted to these “cheaters”.
- Grosberg, R. K. & Strathmann, R. R. The Evolution of Multicellularity: A Minor Major Transition? Annu. Rev. Ecol. Evol. Syst. 38, 621–654 (2007).
Sjoerd's thoughts on academic vaccine research 