Scientists reconstruct a 3.3 billion year old protein and discover an all new biochemical pathway critical to life and hiding in plain sight

We’re just starting to understand how evolution takes advantage of much more than mutations in our DNA.  Everything evolves, from the biochemical pathways to the cellular structures that support them.  Further, some of these structures are incredibly ancient, shared by all life, and still working today.

The human body is constructed from four basic building blocks, carbohydrates, lipids, nucleic acids, and proteins.  Proteins provide the substance of our muscles and other organs, carbohydrates store energy (and build body parts in some organisms), lipids also store energy and act as a structural component at a cellular level, and nucleic acids serve as the conductor, orchestrating the behavior of all the rest.  Nor are these basic molecules limited to humans, they are conserved throughout the animal kingdom, present in plants though sometimes with different usages, and even found in bacteria and other microscopic organisms.  In short, they are ancient, some versions of them arising over 3.5 billion years ago when life was limited to bacteria alone.

Of course, their modern forms come in many more varieties and tend to be much more complex and specialized in their use.  Further, the relationships between the different varieties isn’t nearly so clear cut.  Muscles are made of proteins, but also of course contain nucleic acids, lipids, and carbohydrates that interact in an astounding variety of ways, some of which we are just now beginning to understand, more on that in a moment.  Ultimately, even if our DNA could somehow be inserted into a cell from 3.5 billion years ago, the supporting systems would not yet be in place to build a human body.  This is partly because DNA alone doesn’t do the job.  There are chemical factories in our cells, known as organelles, that store their own genetic information and reproduce on their own.  These structures evolved along with our ancestors, first as part of larger, more complicated cells known as eukaryotes, and then as part of multicellular organisms, but what if you could look back in time and see these basic building blocks as they were in the ancient past, before the atmosphere even contained oxygen?

Amazingly, we can.  A research group at Uppsala University studied a portion of a cell’s protein synthesis machinery known as “translation factors” and ultimately recreated parts of the process as they existed almost 3.5 billion year ago, 3.3 billion to be precise.  Their focus was on an organelle known as a ribosome that is responsible for protein synthesis.  Ribosomes are found in a cell’s cytoplasm, they take RNA, the instruction set created by DNA in the nucleus, and use the instructions to link together the building blocks of a specific protein.  Given that there are somewhere between 80,000 to 400,000 proteins used by the human body at various times, some of which are actually coded by a single gene (up to 10 per gene actually), the modern process is incredibly complex and specialized, and must have arisen from a more simplified, generalized form.

The new study, led by Professor Suparna Sanyal of the Department of Cellular and Molecular Biology, took advantage of an earlier study that used a complex algorithm to predict the structure of primitive proteins based on their modern forms.  The prior study considered the ancestors of a specific translation factor, elongation factor thermo-unstable or EF-Tu.  The team at Uppsala University took the details of these ancestors and actually constructed the ancient translation factors, testing them to see whether they would work with modern ribosomes.

The study resulted in two important observations.

While the modern versions require specific ribosomes to build, the ancestral forms can work with a much wider variety, suggesting their usage was far more general.  The increased specificity that has developed over time makes the translation factors we use today more efficient, but at the expense of requiring more dedicated machinery throughout the process.  This should not be surprising:  Complexity tends to evolve over time, from a protein or other biochemical with a generalized function, subsequent mutations create more specialized versions for specific purposes.  Nature takes what is on hand and builds upon it, repurposing the present for the future.

The researchers also determined that there is a correlation between the average temperature and the proteins created.  Again, this should not be surprising.  Evolution is constrained by and must adjust to the environment.  As conditions change, proteins and the like must adapt to cope.  Suparna Sanyal explains, “It was amazing to see that the ancestral EF-Tu proteins matched the geological temperatures prevailing on Earth in their corresponding time periods. It was much warmer 3 billion years ago and those proteins functioned well at 70°C, while 300 million-year-old proteins were only able to withstand 50°C.”

It’s also an important window into how climate impacts evolution.  There are proteins today that simply couldn’t have existed in the distant past, the conditions being too warm or too cold for the molecule to take on a stable structure.  Many scientists believe that the Cambrian Explosion, a brief period of a couple of dozen million years when life began to take something resembling modern forms, was at least partly due to the warming of the planet following a period known as Snowball Earth.  Interestingly, once a protein evolves, however, organisms can adapt ways to cope with the changing climate.  For example, the crocodile fish or ice fish is native to the oceans around Antarctica.  It’s the only known vertebrate that doesn’t use hemoglobin in its blood, though they have the remnants of the genes to produce it. In other words, they have adapted another way to circulate oxygen given the frigid conditions close to the south pole.

The Uppsala research team sees two potential applications for their research beyond the implications for the study of evolution.  First they can model what might happen in the future if we were to alter proteins.  “The fact that we now know how protein synthesis evolved up to this point makes it possible for us to model the future. If the translation machinery components have already evolved to such a level of specialization, what will happen in future, for example, in the case of new mutations?” explains Suparna Sanyal.  Second, more generalized proteins likely have promise for the pharmaceutical industry, offering the ability to make more broadly usable treatments.

Nor was the Uppsala team the only group of researchers to announce a breakthrough study in the world of biomolecules.  A team led by Ryan Flynn, now at Boston Children’s Hospital, discovered an entirely new biochemical pathway that has literally been hiding in plain sight for decades.  It has long been known that the fundamental chemicals of life combine in different ways at different times.  For example, carbohydrates combine with lipids to produce blood types.  Combinations like this use a special kind of lipid, called a glycan.  Glycans are chains of sugar molecules that have evolved to latch onto lipids and also proteins.  The process is called glycosylation and it is generally used either to help transport the lipid or protein through the cell, or even fold them into the correct shapes.  Perhaps needless to say, glycosylation has broad usages in our bodies, everything from our development from an embryo to our immune response to disease.

Now, we know it has another, unexpected use:  Glycans can also bond with RNA molecules.  This was thought to be impossible because they “live” in different parts of the cell and never the two should meet.  RNA was believed to function only inside the cell proper, either in the nucleus or traveling through the cytoplasm.  Glycans, on the other hand, were inside membranes or actually on the cell surface.  The latest research has shown these two biomolecules meet and work together, quite frequently in fact.

The team determined this by tagging glycol molecules with sialic acid and then extracting the RNA from the cell.  Much to their surprise, some of the RNA was coated in glycol.  Further, this was true of every cell they checked including humans, mice, hamsters, and fish, animals separated by hundreds of millions of years of evolution, making this an ancient process.  “We found that glycoRNAs are on the cell surface, just like proteins and lipids,” Flynn informed his colleague Nancy Fliesler at Boston Children’s Hospital.  “This is exciting because it means that glycoRNAs can participate directly in cell-to-cell communication. That was previously thought to be off-limits for RNAs, which had not been thought to play a role on the cell surface.”

Stanford biochemist Carolyn Bertozzi described the discovery as nothing short of stunning.  “This is a stunning discovery of an entirely new class of biomolecules.  It’s really a bombshell because the discovery suggests that there are biomolecular pathways in the cell that are completely unknown to us.”  There is more work to be done of course:  The team believes that glycol cannot bind to RNA on its own and another molecule must be involved.  Also, not all glycans contain sialic acid, meaning there might be other instances of this unique bonding that we are still unaware of.  To be sure, there was a not-so-positive aspect as well:  Some of the glycoRNA matched RNA linked to autoimmune diseases, but even then research like this could help provide treatments in the future.

Either way, the impact for our understanding of evolution shouldn’t be underestimated.  We have achieved experimental evidence about the function of proteins billions of years old.  This evidence demonstrated what has long been surmised:  As organisms evolved in complexity, so did the underlying proteins and the mechanisms to build those proteins.  Evolution isn’t simply about DNA; it’s about all of the building blocks of a body.  While some might find it surprising that ancient proteins work on modern ribosomes, it shouldn’t be:  The modern ribosome is built on top of the ancient one.  Evolution isn’t like the difference between a new Cadillac and a ‘57 Chevy where no parts are shared.  Everything is shared and conserved.

Likewise, we shouldn’t be surprised that the basic building blocks interact in countless ways all the time.  Proteins, lipids, carbohydrates, and nucleic acids predate the modern, highly organized structure of the cell.  It’s logical to assume that in the formation of the first protobacteria they were all jumbled together and any valuable interactions were preserved.  The additional complexity and efficiency that developed over time is layered on top of the older systems, not created anew each time.  A beneficial mutation doesn’t replace what came before, it modifies it, reuses it, amplifies it, or specializes it, building on the prior structures.  In this manner, evolution is able to simultaneously take advantage of the history of the cell itself, while spinning off new varieties.  We are just starting to understand how embedded these processes are in every aspect of life and how evolution takes advantage of far more than simple changes in DNA.  Everything evolves, from the chemical pathways to the genes, to the structures that support them.

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