For centuries, scientists have thought of brain as single, unified organ. But new research led by Stanford Medicine reveals that what we call brain is two distinct organs that evolved independently over hundreds of millions of years.
The discovery overturns prevailing model of brain development. For decades researchers subscribed to theory that there is single progenitor cell early in development that gives rise to entire brain. Model suggested all parts of brain shared common developmental origin. New finding shows human brain consists of two ancient nervous systems cleverly packaged together — more primitive part that regulates hearts’ beating, breathing and other functions, and another that makes us distinctly human, capable of poetry, mathematics and wondering about own origins.
The discovery could help explain why scientists struggled for decades to grow certain types of brain cells in laboratory — and opens new avenues for studying devastating diseases that affect brain stem, such as spinal muscular atrophy also known as SMA and amyotrophic lateral sclerosis also known as ALS or Lou Gehrig’s disease.
“We’ve shown for first time that front of brain arises from totally different progenitor cell than back of brain,” said Kyle Loh, PhD, associate professor of developmental biology. “Our discovery means we can now grow neurons from back of brain, hindbrain, in petri dish and study their functions.”
Findings published in Nature Neuroscience. Loh is senior author. Graduate students Carolyn “C” Dundes and Rayyan Jokhai are co-first authors.
Two Brains In One Skull – Forebrain vs Hindbrain
Adult brain has three main regions: forebrain, midbrain and hindbrain. Forebrain handles higher-level thinking — language, consciousness and abstract reasoning. In contrast, hindbrain, located at back of skull and often called brain stem, controls essential, automatic functions that keep us alive: breathing, sleeping, and regulating heartbeat and hunger urges. Hindbrain neurons also control muscles of face, tongue and throat, which affect speech and swallowing.
Despite critical importance of hindbrain, scientists struggled for decades to generate human hindbrain neurons in laboratory. Gap has hampered research into devastating diseases affecting brain stem, including SMA and ALS. SMA is leading genetic cause of death in children under 1 year of age. ALS, often diagnosed between ages 40 and 70, affects both forebrain and hindbrain. In both disorders, certain hindbrain neurons gradually cease to function, and patient loses ability to swallow, which can cause pneumonia when food or liquid inhaled into lungs; eventually, patients lose ability to breathe.
Gastrulation Discovery – Otx2 vs Gbx2 Progenitors Never Overlap
Researchers’ breakthrough came from studying earliest moments of embryonic development, during stage called gastrulation when body first takes shape. Jokhai and Dundes discovered hindbrain follows separate developmental path, running in parallel to — rather than branching off from — pathway that creates forebrain and midbrain.
Researchers learned this from examining developing mouse embryos. They identified two different brain progenitor cells. One, which expresses gene called Otx2, is destined to become forebrain and midbrain. Other, which expresses gene called Gbx2, is committed to forming hindbrain. They showed these two cell populations never overlap; they are mutually exclusive from earliest stages.
Team then examined DNA packaging, or chromatin, in these cells. Chromatin is way cells determine which genes can be easily accessed and which bundled away out of reach. What they found striking: anterior neural ectoderm future forebrain and midbrain and posterior neural ectoderm future hindbrain have fundamentally different chromatin configurations. Differences essentially locked each progenitor cell into respective fate, like travelers on parallel tracks that never cross.
“Previous attempts to make hindbrain neurons likely tried to coax forebrain and midbrain progenitors into hindbrain cells, which our study shows is not possible,” Jokhai said.
This revelation explained decades of frustration — scientists had been trying to turn one type of progenitor into another that it is fundamentally incapable of becoming.
“In stem cell biology, people are always fixated with creating end cell type, like neuron,” Jokhai said. “But it’s important to begin at earliest stages of embryonic development. Our careful attention to that early time point allowed us to find fundamental split in brain development.”
Growing Hindbrain Neurons In Dish For First Time
Armed with this knowledge, researchers for first time successfully coaxed human pluripotent stem cells a kind of cell that can create any cell in human body to become functional hindbrain motor neurons in laboratory. Lab-grown neurons displayed all hallmarks of authentic hindbrain cells: They exhibited waves of electrical activity called action potentials and made proteins that identify segments of hindbrain that control facial and swallowing muscles.
Finally, researchers looked back over 550 million years of evolutionary time. They found same two-origin brain pattern in chickens; zebrafish; and remarkably, in acorn worms, tiny creatures living on ocean floor that share distant common ancestor with humans. Jellyfish, which diverged from humans about 600 to 700 million years ago, have two nervous systems at different ends of body.
“Our research suggests evolution took two existing neural systems and pushed them together spatially,” Loh said. “Having brain as one organ would probably be more efficient, but we rely on this primordial way to make brain as two separate pieces.”
“I was surprised at our findings because word ‘brain’ implies contiguous organ that likely has singular origin,” Jokhai said. “But even 500 million years ago, there were these separate neural systems, which now almost operate as one, which is very cool.”
Implications For SMA, ALS And Obesity Drugs
Research also has implications for investigating treatments for SMA, ALS and other conditions affecting brain stem. Until now, studying these diseases has been nearly impossible because scientists cannot obtain brain stem tissue from living patients. Ability to grow neurons in dish opens new possibilities for understanding what goes wrong. There’s even unexpected connection to obesity treatment: Hindbrain contains circuits that regulate hunger — which is precisely how weight-loss drugs like semaglutide work.
Researchers would like to extend studies to determine developmental origins of spinal cord and to learn exactly how SMA and ALS compromise function of hindbrain neurons.
“Now we have model to better understand these devastating diseases, and work toward regenerative therapies for them,” Jokhai said. “This is very exciting new frontier in brain research.”
“I hope our study inspires future scientists to study developmental biology,” Dundes said. “I can’t think of anything more rewarding than unraveling little mystery of our brain’s origins, and there are so many more details of our central nervous system, both big and small, still waiting to be uncovered.”
Researchers from California Institute of Technology and University of California, San Francisco contributed to study.
Q&A
Q: Is human brain actually two organs?
A: Stanford Medicine study in Nature Neuroscience Sept 18 found human brain consists of two ancient nervous systems packaged together – forebrain midbrain from Otx2 progenitor and hindbrain from Gbx2 progenitor that never overlap from gastrulation.
Q: Why couldn’t scientists grow hindbrain neurons before?
A: Previous attempts tried to coax forebrain midbrain progenitors into hindbrain cells; study shows chromatin configurations lock fates on parallel tracks, not possible – now human pluripotent stem cells coaxed directly to functional hindbrain motor neurons with action potentials.
Q: How old is two-brain pattern evolutionarily?
A: Same two-origin pattern found in chickens, zebrafish, acorn worms on ocean floor, traced back 550 million years; jellyfish diverged 600-700 million years ago have two nervous systems at different ends.
FAQ
1. Who led Stanford two-brains study?
Senior author Kyle Loh PhD associate professor developmental biology, co-first authors graduate students Carolyn C Dundes and Rayyan Jokhai, published Nature Neuroscience Sept 18, with Caltech and UCSF contributors.
2. What does forebrain do vs hindbrain?
Forebrain handles language consciousness abstract reasoning poetry math; hindbrain brain stem controls breathing sleeping heartbeat hunger and face tongue throat muscles for speech swallowing.
3. How does discovery help SMA and ALS?
SMA leading genetic cause death under 1 year, ALS diagnosed 40-70, both lose hindbrain neurons for swallowing breathing causing pneumonia; lab-grown hindbrain neurons allow studying disease without brain stem tissue from living patients.
4. What is connection to weight-loss drugs?
Hindbrain contains circuits regulating hunger – precisely how semaglutide and similar drugs work – so growing hindbrain neurons may aid obesity treatment research.
5. What is Otx2 and Gbx2?
Otx2 gene marks progenitor destined for forebrain midbrain, Gbx2 gene marks progenitor for hindbrain; populations mutually exclusive from earliest gastrulation stage, with fundamentally different chromatin DNA packaging locking fate.
