Big breakthroughs in the evolution of the brain and its connection to the stomach

The human brain is the most complex object in the known universe, but key parts of its evolutionary history, from the earliest brains and nervous systems on the planet to more recent changes in our lineage, remain shrouded in mystery.  New studies shed light on both ends of the spectrum, answering an over one hundred year old question and illuminating a longstanding hypothesis about our digestive system.

The evolution of the human brain remains one of biology’s biggest mysteries.  Despite all we have learned about how the brain functions and the genes that regulate those functions, the precise manner in which the most complicated object in the known universe, the organ which makes us who we are and has enabled humanity to reach the moon, remains a matter of fierce debate in the scientific community.  The fossil record gives us a reasonably clear sense of what happened, allowing scientists to track changes in the size of the brain as humanity evolved over the past five million years or more.  New insights into the underlying genes are finally allowing us to understand what supported this rapid growth and what makes us different from our primate cousins, but this remains only part of the story.  The full picture will only emerge when we understand where brains and nervous systems came from in the first place, another sequence of events dating back some 600 million years ago that is still shrouded in mystery.  Consider that all animals have some form of nervous system composed of some number of neurons, but not all nervous systems are arranged the same.  Mammals, for example, feature a concentrated mass of neurons that control all motor functions known as a brain, but cephalopods, octopus, squid, and the like, use a far more distributed network.  The octopus has nine brains, one in the head and one in each tentacle.  The overall network comprises some 500 million neurons, enough that it appears these strange creatures can dream, about two third of which are distributed throughout the limbs, amounting to approximately 40 million neurons in each limb.  For comparison, a frog only has about 20 million total.  Scientists have conducted experiments using preserved, disconnected octopus tentacles and found that they respond much the same way as when they were attached.  Imagine your arms and legs having minds of their own.

Thus, the underlying mystery:  Which came first, the centralized mass, the distributed approach, or some combination of the two?  Mammals and cephalopods are both modern, highly advanced groups of animals, but what might the nervous system have looked like 600 million years ago when it was still in its infancy?  Unfortunately, the soft tissue of neurons, whether in the brain or part of the larger nervous system, does not leave much of a fossil record, forcing scientists to speculate, guesstimate, and debate.  Since the late 1800’s scientists believed the nervous system came first, but new discoveries and research are beginning to yield important insights that question conventional wisdom.  Nicholas Strausfield of the University of Arizona Department of Neuroscience and Frank Hirth of King’s College London lead a team that provided the first detailed look of a tiny, seemingly insignificant creature that lived 525 million years ago, Cardiodictyon catenulumC. catenulum is a wormlike organism measuring less than half an inch, found in China’s southern Yunnan province, first discovered in 1984.  The discovery, however, held a hidden secret for almost four decades:  The small creature’s brain was meticulously preserved and ripe for study.  Dr. Strausfield believes this the oldest preserved brain ever discovered.  Though wormlike, C. catenulum is actually a member of an extinct group of animals, the armored lobopodians which once were abundant in the seas of the Cambrian Explosion, when most of the major lifeforms began to evolve rapidly.  They moved about the ocean floor on pairs of stubby legs that lacked the joints that would later evolve in the euarthropods, literally “real jointed foot” in Greek.  It is believed that these armored worms were the earliest arthropods, setting the stage for the most diverse group of animals on the planet, including insects, crustaceans, spiders, millipedes, centipedes and more.  The modern arthropod is known for its segmented appearance and body plan.  The head is believed to have been the foremost body segment, and their nervous systems were believed to have evolved originally in each segment, the distributed network approach known as ganglia.  “From the 1880s, biologists noted the clearly segmented appearance of the trunk typical for arthropods, and basically extrapolated that to the head,” explained Dr. Hirth. “That is how the field arrived at supposing the head is an anterior extension of a segmented trunk.”

The team’s analysis upended this belief:  C. catenulum has both.  The segments contain ganglia, but the head has its own brain and does not appear to be segmented.  “This anatomy was completely unexpected because the heads and brains of modern arthropods, and some of their fossilized ancestors, have for over a hundred years been considered as segmented,” explained Dr. Strausfeld.  This “suggests the brain and the trunk nervous system likely evolved separately,” he added.  Nor did the team’s research stop there.  They also looked at the genetics underpinning these structures and compared them to other fossils and modern animals.  The findings were equally dramatic, though they should not have been surprising.  Much like the Hox genes that underpin development of the body plan, it appears there is a sequence of genes that underpins the layout of the brain and nervous system, and this sequence might be preserved in all animals.  “By comparing known gene expression patterns in living species,” Dr. Hirth said, “we identified a common signature of all brains and how they are formed.”  “We realized that each brain domain and its corresponding features are specified by the same combination genes, irrespective of the species we looked at,” Dr. Hirth continued. “This suggested a common genetic ground plan for making a brain.”  More research needs to be done, but it appears this plan is preserved and all animals, including humans, share an architecture where the brain is distinct from the spinal cord.  On the surface, it seems astounding that two sets of neural tissue evolved simultaneously, but it also explains how organisms were able to develop such a diversity of overall approaches to the nervous system, from the nine brains of an octopus to the more common configuration in mammals with a single brain and spinal chord.  The separation between the brain and nervous system allowed each to evolve independently based on the unique evolutionary pressures facing each individual species.

Incredibly, there is another tantalizing parallel to the human evolution that occurred over 500 million years later.  In C. catenulum, there are three brain domains that are each associated with a pair of appendages on the head and one of the three parts of its digestive system, meaning there is a link between the origins of both the digestive tract and the brain.  This might seem surprising as well, but brains and guts are two of the most expensive tissues to produce in an animal’s body, and you cannot have one without the other.  In humans, this is known as the expensive tissue hypothesis, and it seems reasonable that the discovery of a linkage dating back so early in the evolution of multicellular life means the hypothesis applies far more broadly, perhaps to all animals.  As organisms make trade offs where to invest their energy, a balance needs to be struck between the costly enzymes and tissues required to digest different types of food and the usage of the energy extracted to develop a more complex nervous system.  Generally speaking, more complex nervous systems allow more complex behavior, increasing the adaptability of the organism and its chance of survival, while more complex digest systems allow for the extraction of energy from hard to digest food sources like grass and other fibrous plants.  Unfortunately, no organism can have it all, and trade offs have to be made.  Another new study establishes this link in modern humans as we separated from our primate cousins, illuminating the expensive tissue hypothesis like never before.

A team at Duke University identified a group of human DNA sequences that regulate brain development, digestion, and immunity.  The study itself sounds like the stuff of science fiction.  Craig Lowe, an assistant professor of genetics and microbiology at the Duke School of Medicine, and his team collaborated with Tim Reddy, an associate professor of biostatistics and bioinformatics, and Debra Silver, an associate professor of molecular genetics and microbiology.  Dr. Reddy’s lab had the technology to look at millions of genetic switches at the same time, while Dr. Silver could observe these switches in action in genetically modified mice brains.  They extrapolated this to infer what the ancestor of human-chimp DNA must’ve been like, as well as our Neanderthal cousins, enabling them to consider how the genes would act in even extinct lineages.  The set of genes they identified arose after we split from chimpanzees, but before we split from Neanderthals, a period dating back some 7.5 million years ago.  The result is brains that are bigger and guts that are smaller than our closest cousins.  The researchers refer to these DNA sequences as Human Ancestor Quickly Evolved Regions, HAQERs, pronounced “hackers,” which are responsible for regulating the behavior of other, much older genes.  “They seem especially specific in causing genes to turn on, we think just in certain cell types at certain times of development, or even genes that turn on when the environment changes in some way,” explained Dr. Lowe.  The regulatory innovations that separates us from other primates is found mostly in brain development and our gastrointestinal tract.  “We see lots of regulatory elements that are turning on in these tissues,” Dr. Lowe noted. “These are the tissues where humans are refining which genes are expressed and at what level.”  He continued, “People have hypothesized that those two are even linked, because they are two really expensive metabolic tissues to have around.  I think what we’re seeing is that there wasn’t really one mutation that gave you a large brain and one mutation that really struck the gut, it was probably many of these small changes over time.”  The study also suggests that these HAQER sequences are critical to a healthy human body.  There is very little divergence in these sequences across humans around the world, and what little variance there is appears to correlate with certain diseases including hypertension, neuroblastoma, unipolar depression, bipolar depression, and schizophrenia.  This suggests these diseases may be unique to humans and tied to our own evolutionary history.   “Maybe human-specific diseases or human-specific susceptibilities to these diseases are going to be preferentially mapped back to these new genetic switches that only exist in humans,” Dr. Lowe hypothesized.

Of course, these HAQER genes and their relationship to the brain and intestines are nowhere to be found in an organism as primitive as C. catenulum.  The HAQER genes are not like the sequences for laying out the overall design of the brain or the body, preserved in all animals.  They are unique to our species, but still they represent how all species have to balance the inevitable investments in expensive tissues.  What was true over 500 million years ago, remains true today.  The human brain is the most sophisticated object in the universe, but it is based on an ancient design and still confirms the same laws of evolution even our most distant and alien ancestors faced.  We are the far end of a continuum of multicellular life, stretching back close to a billion years.  Wherever we look in that continuum, we see something of ourselves and possibly solve another mystery of our origins.


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