New Research: The Evolution of Multicellularity

We are all multicellular. That is, our bodies are made up of many cells that function in a synergistic manner to create a unified whole, somewhat like how we have millions of people that function to create the ‘organism’ Canada or France. From one fertilized egg cell, we developed all the amazing coterie of cells like nerve cells, blood cells, muscle cells, etc.

Many years ago, life began as a unicellular state, like your average bacteria that lives in your gut. At some point, these unicellular organisms acquired changes that lead to a multicellular state and this was a very critical step in our evolution. With multicellularity, one can have cells that do different things like fight infection or transmit electrical signals (a necessity for cognition).

How did this transition occur? Multicellularity occurred >200 million years ago, at least 25 separate times. Scientists have found that several steps must have been needed. Firstly, the unicellular organisms must gain the ability to form simple clusters of cells. Next, the multicellular state must somehow become favored (or selected for), in comparison to the unicellular state. Finally, the cells will begin to specialize to different things within that organism.

It has long been thought that these steps will take a very long time, yet in this paper, William Ratcliffe shows that it can actually evolve in a very short time. They began with simple baker’s yeast and decided to apply pressure to evolve cell clusters. Since ten cells clustered together are heavier than one individual cell, it should settle faster in a tube due to gravity. With this premise, these scientists decided to transfer cells at the bottom of a culture to another culture, let those grow and then settle, then transfer the bottom to another culture, let them grow and settle, etc.

After 60 transfers, they found the yeast cultures were now dominated by a snowflake-like organism, with multiple cells. Moreover, these snowflake-like organisms were genetically stable; one could not detect a conversion back to a unicellular state. This argues that it had indeed evolved into a new organism. These clusters seemed to arise from an inability to separate after cell-division, rather than re-aggregation of split cells.

Even crazier, Ratcliffe found that these yeast-descendants gained classic multicellular traits. For instance, there was a juvenile phase which grew unimpeded and an adult phase which stopped growing when it reached a certain size and then released a smaller copy of themselves (see arrow on right). Since these clusters didn’t grow forever, it suggests there was some communication between the cells in this organism to arrest growth at some size, another classic multicellular trait. Even more interestingly, they found that these cells had evolved to do different things: there were cells that underwent cell suicide to release progeny.

This study is somewhat flawed however in two reasons: one they applied artificial selection pressure; it is hard to imagine alien’s spinning down yeast and then re-inoculating another culture just to evolve multicellular life on earth. Moreover, baker’s yeast evolved from a multicellular ancestor billions of years ago, so one could argue these genes for multicellularity are already present. However since yeast are not multicellular, those genes have probably been lost over the last billion years of not being used.

In conclusion, earlier in this article, I mentioned how 3 steps were needed to generate multicellularity. In this paper, Ratcliffe shows that with the appropriate selection, all three steps could occur within 60 days (or 720 generations), a remarkable discovery. This suggests that the evolution of multicellularity does not actually require a very long time. This further suggests that only a few genes may be involved. The exciting next step would be to find out exactly which genes were altered in that time period to provide clues into how multicellularity may have arisen.


Ratcliffe, WC et al. (2012) Experimental Evolution of Multicellularity. PNAS onlinePaper

General News: Nobel Prize 2011

This blog is back up and running. For a while, I put it on hold since I was busy helping teach introductory biology, but now that it is over, I am now going to return to working on articles. Many exciting things have happened since so I thought I’d write about two major events that occurred in the last four months.

First, the Nobel Prizes! The 2011 Nobel Prize in Physiology and Medicine were awarded to Bruce Beutler and Jules Hoffmann "for their discoveries concerning the activation of innate immunity" and the late Ralph Steinman, "for his discovery of the dendritic cell and its role in adaptive immunity". This is the first immunology prize since 1996, and so the immunology community is really excited!

Our species is constantly under attack by other microorganisms, which our body defends against using the complex immune system. Mammals have two arms of the immune system, the ancient innate immune response and the more recently-developed adaptive immune response. The innate immune response is the first line of defense, a non-specific response that leads to immune cell recruitment, inflammation and attack of foreign material. The second line of defense is the adaptive immune response, in which the body mounts a more effective, specific attack against the microorganism after studying it for some time. Since this takes time to develop, the innate immune response is critical for immune function.

THE ROAD TO INNATE IMMUNITY
Insects have a relatively short lifespan, so it doesn’t seem apparent that they require a powerful immune system to fight pathogens, yet insects are highly resistant to microbial infection. Yet early inquiries into understanding how this happened lead nowhere, because it turns out insects are unlike humans in that they do not have an adaptive immune response. The first glimpse into this mystery occurred in 1981, when Hans Boman discovered that moths induced the antimicrobial peptides Cecropin and Attacin. By the 90s, several genes encoding these antimicrobial compounds were identified in the Drosophila genome. Yet no one understood what was turning on expression of these antimicrobials, a process that Beutler and Hoffmann coined “the black box.”

They explored the promoters of these antimicrobial genes and found they contained binding sites for something similar to the mammalian NF-kB (discovered by Nobel laureate David Baltimore - from MIT!), which has been linked to immune system activation. Previous work by the Nobel laureate Nusslein-Volhard had found a critical development pathway that set up the axes for dorsoventral establishment, the Toll pathway that ended in Dorsal, a NF-kB-like molecule. Through a long line meandering experiments and wrong leads, Dr Hoffmann eventually discovered a mutant, Toll which was highly susceptible to fungal and bacterial infections, for the first time proving that Toll was somewhat essential in immune responses.

In a parallel line of research, septic shock is a debilitating syndrome that causes multiple-organ failure at the end-stage of a bacterial infection. It was recognized that this was induced by a molecule common to most bacterial cells, LPS. Dr Beutler wanted to try to find the receptor that could bind LPS, so they soon discovered that mice resistant to LPS had a mutation in a gene similar to the Toll gene of the fruit fly. They demonstrated that LPS-binding to the Toll receptor activated inflammation, and when the doses were very high, the organ systems in the body would go into inflammation overload and cause septic shock.

Thus, in the grand picture of things, Bruce Beutler and Jules Hoffmann discovered a set of receptors that we now call the pattern-recognition receptors, which recognize a set of molecules that are broadly found in microorganisms but not humans. They demonstrated that it was a very ancient pathway, conserved from flies to humans. Moreover, in later work, they picked apart the pathway, allowing the development of drugs that can target the innate immune response. Indeed the fundamentalness of this pathway is indeed one reason why these two have been awarded Science's Highest Award.


THE ROAD TO DENDRITIC CELLS AND THE ADAPTIVE IMMUNE RESPONSE
One characteristic of the immune system is its incredible diversity of cells; in fact when Dr Steinmann first entered the field in 1970, it was known as God (for generation of diversity). At the time, clonal selection theory suggested that there was an infinite variety of cells in the immune system, each which recognized one antigen. Binding to a specific antigen caused one specific clone to multiply thousand-fold and promote an immune response against that antigen. This hypothesis was further enriched when Nobelist Susumu Tonegawa (also MIT ) demonstrated that the great diversity of clones was generated through genetic recombination. Yet one problem with the theory was that injection of antigens into animals did not always generate an immune response, an idea which would have critical impacts on vaccine generation.

In 1973, Steinman found that purifications of lymphocytes (mixtures of B and T cells) could not produce antibodies unless they were supplemented with “accessory cells.” Looking under the microscope, he explored the accessory cells and found the usual culprits (macrophages) but also, a weird stellate elongated cell, which he named the dendritic cells. Further studies revealed he only needed to mix 1 dendritic cell per 100 lymphocytes to induce strong clonal selection.

We now know that dendritic cells are the critical link between the innate and adaptive immune response. The innate immune response (which half this year’s Nobel is awarded for ) turns on these dendritic cells, which then go on to activate T cells for priming the adaptive immune response. Indeed, these cells have been so influential that pharmaceutical companies are now trying to develop vaccines using dendritic cells as well as treatments for allergies.

However, it is with great sadness that Dr Ralph Steinman passed away on Friday Sept 30, 3 days shy of him finding out about his Nobel Prize. Dr Steinman was a consummate scientist of the highest caliber and many colleagues value his contributions greatly. In one of his essays, he recalls Palade’s quote “For a scientist, it is a unique experience to live through a period in which his field of endeavor comes to bloom—to be witness to those rare moments when the dawn of understanding finally descends upon what appeared to be confusion only a while ago—to listen to the sound of darkness crumbling.” And indeed Dr Steinman helped clear the darkness.


REFERENCES:
Beutler's Discovery of TLRs
Hoffmann's Discovery of TLRs
Steinman's Discovery of Dendritic Cells