by Piyush Nanda
figures by Corena Loeb

Around 600 million years ago, single-celled life transitioned to multicellular life forms, begetting a paradigm shift in the definition of life on earth. This was an event so remarkable in earth’s timeline that it would set the stage for the evolution of complex organisms, from sponges to the human body we each reside in. These complex life forms eventually gained biological functions that allowed them to perform tasks far beyond the capacity of individual cells, from banging flintstones to spark a fire to inventing the internet and sending cameras to probe the deepest corners of the universe. There still remain standing questions as to why this evolution occured in the first place: What would have been the primitive benefits of being multicellular? How did evolution manage to select for the vast biodiversity that earth harbors? What underlying principles can inform us of how we descended from unicellular organisms? Researchers around the world have already hit the road to find answers to these questions. Combining biology, physics, and mathematics, researchers have uncovered a few possibilities for how multicellularity could have evolved and been steadily maintained through millions of years. 

Why study the evolution of multicellularity?

The human body functions as the result of a complex network of interactions. Our cells not only communicate with each other, but with the microbes that inhabit our body. When uninvited guests like SARS-CoV-2 enter and attack the social fabric that ties our cells together, the immune system attacks them in defense. The COVID-19 pandemic has exposed the fragility of the human body, causing the loss of around 5 million lives, despite modern medicine and technology. Therefore, gaining a deeper understanding of how cellular interactions maintain complex organisms is not just a question for basic science, quenching inquisitive minds as to our evolutionary origin—it could also inform biomedical science of the mechanisms that keep organisms multicellular and the disruptions that trigger diseases. Another prominent example in this context is cancer: a disease in which “cheater” cancer cells prioritize their own proliferation and growth over maintaining the social structure of the human body. Broadly, carcinogenesis can be considered as a reversal from an ordered and cooperative multicellular state amongst cells in the body to a dysregulated one.

How do we study the evolution of multicellularity?

Fossil records are an excellent snapshot of our evolutionary history, but unfortunately don’t elucidate mechanisms that might have played a role. Therefore, we are dependent on experimental science and ingenious thinking to reconstruct such evolutionary events. There are currently two ways of getting closer to the answers: i) Find and study unicellular organisms that are in the process of uniting and forming multicellular structures, and ii) Use artificial evolution and synthetic biology to produce multicellular structures from unicellular organisms. 

What scenarios could have compelled the selection of multicellular organisms? 

While scientists have proposed many putative selection pressures that could have given rise to the evolution of multicellularity, we will focus on three convincing scenarios: i) Resource bartering, ii) Stress protecting, and iii) Division of labor (Figure 1). 

Figure 1. Three scenarios that may have given rise to multicellularity: i) Resource bartering: In this scenario, different cell types specialize in producing different resources for the survival of the whole multicellular system. ii) Stress protection: Peripheral cells shield internal cells from external chemical or physical stress allowing the whole multicellular system to survive. iii) Division of labor: Different cell types specialize in different tasks allowing the whole multicellular system to navigate and assimilate nutrients.

i) Resource bartering: Cells are remarkably good at making a spectrum of chemical compounds from simple molecules like glucose or carbon dioxide. These compounds can range from the ethanol in alcoholic beverages to the antibiotics we take. However, for a single cell to produce multiple things may be too much of a responsibility. Therefore, it is possible that two cells arrived at a so-called “agreement” to exchange metabolic goods in proportionate amounts—kind of like the barter system of the 1800s. This pair of cells would have outcompeted any other cells that attempted to produce all goods on their own. This is a clear example of how cellular unison and subsequent cooperation would have led to their evolutionary commitment to stay together, eventually leading to multicellular features. 

ii) Stress protection: Present-day multicellular creatures like you might be reading this article from the comfort of their couch, but the environment wasn’t as considerate to our prehistoric unicellular ancestors. From the lens of a unicellular organism, the world is a torturous place where they have the potential to be subjected to high salinity, toxic chemicals leaching from rocks, or years of starvation followed by fugitive nutrient conditions. One strategy to persist throughout these stressors may have been to cluster together and protect each other from external chemicals. If this happened multiple times in evolutionary history, mechanisms allowing the participating cells to stay together may have been naturally selected for. 

iii) Division of labor: While resource bartering is considered the exchange of metabolic goods between cells, cells can also assume different roles in a multicellular structure. For example, cells good at swimming (by using their flagella, similar to a tail) would have propelled a multicellular structure, while others would have specialized in engulfing the food that comes their way. Such a division of labor would have provided the multicellular structure with an advantage by minimizing the responsibilities for individual cells.

Combining theory and experiments, scientists have now been able to evolve multicellularity in laboratories from unicellular microbes. One remarkable example of this is multicellular yeast, normally a unicellular organism, evolved in the lab. Yeast cells normally separate after cell division and form individual entities. Mutations in these separation pathways render them stuck to one another after division, enabling them to form multicellular structures. In some specific environmental conditions, these clusters have more fitness compared to their unicellular ancestors, illustrating the incentives of being multicellular. For example, forcing yeast cells to survive on less food gives rise to multicellular structures that can trap nutrients and reduce their leakage away from cells.  

Taking a closer look at how the body works, we can see numerous examples of these mechanisms. For example, in a metabolic process known as the Cori cycle, liver cells and muscle cells crossfeed lactate and glucose produced during muscular activity to ensure a steady energetic status of the muscles. Similarly, cardiomyocytes keep the heart beating so that it can supply nutrients and hormones to different parts of the body through the blood, while neurons process and transmit information across the body. Additionally, skin bears the brunt of the sun to make sure the cells underneath are able to function properly. The human body is a remarkable example of the division of labor among cells.

It is absolutely breathtaking to imagine the evolution of complex and conscious multicellular organisms from single cells across millennia. Multicellular evolution has occurred on at least 25 independent occasions and is a remarkable example of the superiority of cooperation. Getting deeper insights into these questions will not only help us understand the evolution of diseases that attack the multicellular nature of the human body, but also leave us with takeaways about design principles of nature. It is possible that, in the not so distant future, we may be able to use synthetic biology to design our own multicellular organisms that can capture carbon dioxide, produce fuels, clean up the ocean, or even make biological computers that could outcompete silicon based systems currently being used in medicine. 

Piyush Nanda is a 2nd year Ph.D. student in the Biological and Biomedical Sciences Program at Harvard Medical School. You can find him on Twitter as @NandaPiyush

Corena Loeb is a Ph.D. student in the Harvard-MIT program in Speech, Hearing, Bioscience and Technology. 

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For more information: 

  • To learn about the different model systems for understanding the evolution of multicellularity, check out this article.
  • For more information on experiments that have given insights into the multicellular transition, read this article.
  • To find out how multicellularity arises in algae so it can escape from a predator’s attack, read this article.

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