Evolution of Multicellularity in the Laboratory

The development of multi-cellular organisms is considered to be one of the key milestones in the path from the origin of life to the emergence of a technological civilisation able to spread life throughout the universe. Robin Hanson cited it as item 6 in his description of the “Great Filter” which must be passed before life can spread from its place of origin outward to the stars.

Unlike many of the events in the development of life which appear to have happened only once, with all organisms having that property descended from a common ancestor, multicellularity has evolved numerous times among a wide variety of evolutionary paths. The mechanisms leading to its appearance and the evolutionary adaptation of single cells to become parts of a complex organism have remained largely mysterious.

A paper published in the 2023-05-10 issue of Nature, “De novo evolution of macroscopic multicellularity”, reports an ongoing experiment called “Multicellularity Long-Term Evolution Experiment (MuLTEE)”, running since 2018 at the Georgia Institute of Technology (Georgia Tech), in which 3000 generations of snowflake yeast (Saccharomyces cerevisiae) were bred in an anaerobic environment with 600 rounds of selection for organism size. Here is the abstract:

While early multicellular lineages necessarily started out as relatively simple groups of cells, little is known about how they became Darwinian entities capable of sustained multicellular evolution. Here we investigate this with a multicellularity long-term evolution experiment, selecting for larger group size in the snowflake yeast (Saccharomyces cerevisiae) model system. Given the historical importance of oxygen limitation, our ongoing experiment consists of three metabolic treatments—anaerobic, obligately aerobic and mixotrophic yeast. After 600 rounds of selection, snowflake yeast in the anaerobic treatment group evolved to be macroscopic, becoming around 2\times 10^4 times larger (approximately mm scale) and about 10^4-fold more biophysically tough, while retaining a clonal multicellular life cycle. This occurred through biophysical adaptation—evolution of increasingly elongate cells that initially reduced the strain of cellular packing and then facilitated branch entanglements that enabled groups of cells to stay together even after many cellular bonds fracture. By contrast, snowflake yeast competing for low oxygen remained microscopic, evolving to be only around sixfold larger, underscoring the critical role of oxygen levels in the evolution of multicellular size. Together, this research provides unique insights into an ongoing evolutionary transition in individuality, showing how simple groups of cells overcome fundamental biophysical limitations through gradual, yet sustained, multicellular evolution.

The full text of the paper is behind a Springer paywall, but you can read the original submission to Nature for free at bioRχiv. A popular description of the experiment was released by Georgia Tech the day of the Nature publication, “A Journey to the Origins of Multicellular Life: Long-Term Experimental Evolution in the Lab”.

This type of biophysical evolution is a pre-requisite for the kind of large multicellular life that can be seen with the naked eye. Their study is the first major report on the ongoing Multicellularity Long-Term Evolution Experiment (MuLTEE), which the team hopes to run for decades.

“Conceptually, what we want to understand is how simple groups of cells evolve into organisms, with specialization, coordinated growth, emergent multicellular behaviors, and life cycles – the stuff that differentiates a pile of pond scum from an organism that is capable of sustained evolution,” [co-author William C.] Ratcliff said. “Understanding that process is a major goal of our field.”

It is sometimes claimed that evolution only refines what is already present in an organism, but is incapable of invention and innovation. Yet here, in a laboratory experiment running only five years, a single-cell organism has modified itself to live in colonies, becoming 20,000 times larger and 10,000 times tougher than the organism in the wild, changing its form into an elongated shape with the ability to entangle to hold colonies together. Just image what you could do with a planet-sized laboratory and a few tens of millions of years.


This experiment* with yeast seems to me based on a bad methodology for one simple reason:

We used settling selection to select for larger cluster size. Once per day, after ~24 h of growth, we transferred 1.5 ml of culture into 1.5 mL Eppendorf tubes, let them settle on the bench for 3 minutes, discarded the top 1.45 mL of the culture, and only transferred the bottom 50 µl of the pellet into a new 10 mL of culture media for the next round of growth and settling selection. Once the anaerobic populations (PA1-PA5) had started to evolve visibly larger clusters with all biomass settling to the bottom of the tube in under a minute, we decreased the length of gravitational selection to 30 seconds, thus keeping them under directional selection for increased size.

IMHO, this begs the original question of what selects for multicellularity since, individual cell-size being equal, the phenotype of multicellularity is selecting for the same phenotype as “increased size”.

It seems a far more interesting experiment would be to come up with various hypotheses as to the conditions that select for specialization, and then subject long-term experimental conditions to those various conditions. Did I miss something in the Methods section that did this? Or did I miss something else in the paper that explained why specialization is a consequence of aggregation – hence aggregation must be a precondition for specialization and is therefore interesting in its own right?

*Experiments of this kind are incredibly important, and not just for understanding of the deep history of evolution. They are important for the social sciences – particularly as they pertain to specialization – because they permit us to bypass the evolution of virulence among humans. What I mean is that virulent humans such as Popper with his “Open Society” religion, prohibit mutually-consenting parents from imposing experimental controls to exclude confounders. Such exclusion terrifies pathogens like Popper. He claims they are “intolerant” and hence are justifiably the target of mob attacks if they don’t “engage in open debate”. But that’s not what Popper really fears. He fears that use of experimental controls, by permitting societies closed to men like him, would provide strong evidence not only that “Open Societies” are a bad idea, but that they are a bad idea specifically because of men like Popper!

Yes, yeast are far from humans in their characteristics, so we aren’t able to gather much of direct relevance. But that’s what we’re reduced to given that Popper’s attack on science succeeded not only in attacking experimental controls, but, with his “falsification” dogma, managed to deep-six Algorithmic Information Theory’s provision of a model selection criterion that would permit us to decide between causal models even in the absence of experimental controls!

Popper was the quintessential “evil genius”, whose deep understanding of how to destroy science enabled him, along with his other “gifts” to protect he and his kind from exposure for what they truly are – hence maintain inclusion with their food.


Depends on what the meaing of “multicellularity” is, as a previous US President might have said.

In this paper, it seems the definition of multicellularity is “single cell organism which likes hanging out with its fellow single cell organisms”. One cell in a cluster can die, and the rest don’t notice.

But surely the real definition of multicellularity is “single cell organism which creates differentiated but mutually dependent offspring, thus forming a unified single organism in which very different cells perform different functions essential to the continued existence of the unified single organism”.

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This is not the definition used in biology according to the references I’ve seen. By “multicellularity”, they mean just that—an organism which consists of two or more (usually a large number) of cells—period. Such organisms may range from colonial organisms where multiple cells cluster or are connected to one another all the way to complex organisms such as animals where cells have differentiated into more than 100 types and reproduction involves special germ cells distinct from somatic cells.

Biology Dictionary defines “multicellular” as:

A tissue, organ or organism that is made up of many cells is said to be multicellular. Animals, plants, and fungi are multicellular organisms and often, there is specialization of different cells for various functions. In contrast, unicellular, or single-celled organisms are much smaller in size and less complex as they are composed of just one cell that senses its environment, gathers nutrients and reproduces asexually.

Specialisation of cells occurs “often”, but is not a requirement for multicellularity. Many algæ are multicellular, but not differentiated into multiple cell types. Some organisms, such as slime molds and social amoebæ are unicellular in part of their life cycle and multicellular in others.

Multicellularity is believed to have evolved independently from a number of different origins leading to lineages extant today.


A common theory for the origin of multicellularity, dating to 1874, is the colonial theory, which posits that unicellular organisms first aggregated to form colonies, the components of which differentiated, eventually separating germ cells from somatic cells. Evidence for this theory is that behavior all along the spectrum it predicts have been observed in species alive today.

Note that in the press release from Georgia Tech (quoted in the original post), one of the researchers described the goal of the project as:

Conceptually, what we want to understand is how simple groups of cells evolve into organisms, with specialization, coordinated growth, emergent multicellular behaviors, and life cycles — the stuff that differentiates a pile of pond scum from an organism that is capable of sustained evolution. Understanding that process is a major goal of our field.

Thus, they want to test the colonial hypothesis by seeing whether, as the experiment progresses and they continue to apply selective pressure, they will observe differentiation into distinct cell types and other characteristics of more complex multicellular organisms.

And don’t call me Shirley.


That would indeed be very interesting – but that is not what they are achieving so far. All it seems to be is undifferentiated cells clumping together. Understanding the mechanism by which a clump of identical cells decides to specialize – I’ll be a brain cell, you be a muscle cell, and that guy over there can be a liver cell – now that would be a real step forward. Redefining multicellularity downwards seems more like a step towards seeking more grants.


So they shouldn’t have published until they achieved your preferred definition of multicellularity, which is not the one used by working biologists? They have clearly caused an organism which does not grow in colonies in the wild to form colonies, adapting its morphology so that it entangles with other cells as do colonial organisms in nature and, in the process, elongating itself by a factor of 20,000 and increasing its strength by a factor of 10,000.

All it seems to be is undifferentiated cells clumping together.

That is the definition of colonial multicellular organisms.

Redefining multicellularity downwards seems more like a step towards seeking more grants.

The editors of Nature and their peer reviewers thought the work worthy of publication and had no objections to “macroscopic multicellularity” as a description of the results reported.


I think we are talking about another one of those areas where the English language lacks sufficient words to be precise. To a non-biologist like me, “multicellular” conjures up a vision of a multicellular organism – be it a fish, a bird, a human being. For in-group biologists, the term apparently includes a mat of single cell organisms. An ape and a pond scum are both organisms but very different. It seems like it would be useful to have two different words to describe them.


It’s more than a mere limitation of language since even with pond scum – with which I have some experience* – there are observed but poorly-understood advantages to “clumping” that results in “mats” of algae. Some of the advantages are well understood but not all.

Bottom line, since mitosis produces virtual “clone armies” it’s best to think of mitosis as the strata of life evinced by the phrase “clone wars”: eat or be eaten.

Out of such clone wars arise the advantages of specialization.

*I was the guy responsible for Algasol’s technical market research that established the proper pricing for their photobioreactors. I also was the guy who integrated the proposal to the DoE incorporating LLnL, UoMI and Algasol’s technologies – which was rejected based on a reason that evinced corruption in the DoE.