A Remarkable Confluence of Genetic Changes Made Humans Exceptional

As a chemistry major in college and then a biochemistry student in graduate school, I had precious little time to watch TV. There were several shows that were an important part of pop culture in the 1980s that I wish I had the time to watch. One of them was The A-Team

One of the larger-than-life characters who was part of the A-Team was the cigar-chomping Colonel John “Hannibal” Smith, played by the legendary George Peppard. When things started to go as planned for the A-Team, he would smile, bite down on his cigar, and delightfully proclaim “I love it when a plan comes together.” 

This TV program’s influence on popular culture was pervasive in its time and it reverberates to this very day. I often hear people use Hannibal’s signature line when it’s evident that things are going to work out for them as planned. When I hear younger people say, “I love it when a plan comes together,” I wonder if they even know who the A-Team was. 

An Exceptional Genetic Plan That Came Together
The relevance of Hannibal’s signature line isn’t confined to pop culture. It has bearing on scientific questions surrounding our origins as modern humans. When the implications of several recently reported studies designed to explore the genetic differences between modern humans and Neanderthals are considered, it becomes increasingly evident that some type of plan came together to make human beings exceptional.

These genetic comparison studies (along with anatomical comparisons and surveys of the archaeological records of modern humans and Neanderthals) all affirm the growing scientific consensus that human beings are exceptional—different in kind, not just degree—when it comes to our advanced cognition and unique capacity for symbolism. This conclusion is affirmed by the latest work reported by a research team from the Max Planck Institute in Leipzig, Germany.1 Their work helps reveal features that make us unique and that can be understood as scientific descriptors of the image of God. 

Genetic Comparisons of Modern Human and Neanderthal Genomes
Understanding the origin of modern humans is a primary area of interest for physical anthropologists. Along this line, they ask these types of questions:

  • What makes modern humans the way we are? 
  • Are we different from the other hominins found in the fossil record?
  • If so, what accounts for the differences?
  • Do these differences explain why we’re the only hominin species alive today?

One of the most useful tools available to anthropologists to address these questions are the high-quality genome sequences of modern humans, the Neanderthals, the Denisovans, and the Great Apes. In fact, the 2022 Nobel Prize in Medicine and Physiology was awarded to geneticist Svante Pääbo for his pioneering work in ancient DNA studies. His accomplishments make these genomic comparisons possible. Comparisons of the protein-coding sequences in these genomes have identified just shy of 100 amino acid differences across about 20,000 genes. 

Anthropologists have cataloged these genes and noted that some of them play a role in brain development or have been implicated in neuropsychiatric disorders when they become mutated.2 Other studies have determined that some of these types of genes were regulated differently in the genomes of modern humans and the archaic humans (Neanderthals and Denisovans).3

These significant insights suggest differences in cognitive capacities between modern and archaic humans. But the evidence is circumstantial. Recently, however, researchers have developed experimental approaches to directly assess the impact of these genetic differences on brain development and brain function. 

Experimental Comparisons of Genetic Differences in Brain Development
Researchers’ experimental approaches rely primarily on the creation and analysis of brain organoids and the use of gene editing techniques to generate “Neanderthalized” brain organoids or to “humanize” developing brain cells in model laboratory organisms such as mice. In particular, the use of brain organoids to study the differences between modern human and Neanderthal brains looks to revolutionize physical anthropology and will likely become a technique with far-reaching utility. 

Brain or cerebral organoids are three-dimensional cell cultures. To grow brain organoids, researchers expose pluripotent stem cells to a variety of growth factors. Depending on the growth conditions lab workers can coax the cell cultures into developing into the different cell types of the nervous system. Lab workers can get the cell cultures to grow into three dimensions by cultivating them in a rotating bioreactor. These cultures take several months to grow and develop. The cultured cells lack a blood supply, so their growth becomes limited to about 3 to 5 mm. Depending on the growth conditions, brain organoids can develop into structures that roughly resemble different brain regions. The architecture, number of cell layers, and cellular diversity expand in brain organoids as they grow and develop in the lab. 

Max Planck scientists have illustrated the power of this approach in their new research. Over the next few sections, I’ll explain the research in some technical detail. Feel free to skim and proceed to “Origin of Modern Humans Appears to Be Miraculous.”

A Single Amino Acid Difference Leads to a Greater Number of Nerve Cells in the Modern Human Neocortex
One of the genes that is different and unique to the modern human genome compared to the versions found in the genomes of Neanderthals and Denisovans (and other primates) is called TKTL1. The version of TKTL1 found in modern humans has an arginine instead of a lysine in one of the key locations in the enzyme. This difference occurs only in the modern human variant of this enzyme. Lysine occurs in the version shared by archaic humans and other primates. 

TKTL1 plays a role in mediating the carbon-shuffling reactions of the pentose phosphate pathway. Some of the metabolic intermediates of this pathway double as intermediates in fatty acid biosynthesis. The energy-currency compound NADPH is also produced by the pentose phosphate shunt. NADPH is used by the cell’s machinery to power fatty acid biosynthesis. Fatty acids serve as building blocks for many of the lipid components of cell membranes. 

As it turns out, TKTL1 is expressed at high levels in the human fetal neocortex, specifically in cells called basal progenitors. One type of basal progenitor cell is called the basal radial glia cell. This cell undergoes asymmetric cell division, resulting in one daughter cell that is a basal radial glia cell and one that turns into a neuron. This asymmetric cell division allows the basal radial glia cells to self-amplify. Through this process, the cells produce more neurons than any other progenitor cell in the developing brain. Life scientists believe that this self-amplification explains the greater expansion of the neocortex in humans compared to other primates. 

To assess the effect of this single amino acid difference, the team from the Max Planck Institute first genetically engineered mice so that they expressed both the modern and archaic human versions of TKTL1 in their developing neocortex in successive experiments. (Mice don’t express TKTL1 in fetal brain cells.) Researchers saw an increased abundance of basal radial glia cells in the fetal mouse brain when the modern human version of TKTL1 was expressed. When the Neanderthal and Denisovan version was expressed, the basal radial glia cell levels were the same as in wild-type mice. 

The team repeated this same experiment using ferrets. The developing neocortex of ferrets is folded. (Ferrets express TKTL1 in their developing neocortex. The version of this gene in ferrets is the same as the version found in archaic humans.) Not only did the number of basal radial glia cells increase when the modern human version of TKTL1 was expressed, but so too did the size of the folds. 

The research team also used CRISPR gene editing to convert the modern human version of TKTL1 into the archaic human version in human embryonic stem cells. These cells were used to grow brain organoids and the researchers found that the number of basal radial glia cells in the “Neanderthalized” brain organoids was fewer than in brain organoids grown from unedited embryonic stem cells. 

Differences in Number of Neurons in Human and Neanderthal Brains 
The Max Planck team argues that these results point to a fundamental difference between the brains of modern humans and archaic humans. Neanderthals had a brain size that was comparable (maybe even slightly larger) to that of modern humans. The results of this study suggest that the density of neurons in the neocortex of modern humans is greater than it would have been in the brains of archaic humans, thanks to a single amino acid difference in TKTL1. This difference ultimately increases the production of fatty acids, making key building blocks available for cell membrane growth and, hence, cellular reproduction. This increased production allows basal radial glia cells to proliferate more rapidly in the modern human brain than they would have in Neanderthal and Denisovan brains. And the enhanced proliferation results in a greater number of neurons per volume in the modern human brain than would have existed in archaic human brains. 

Other Genetic Differences with Consequences for Brain Development
This finding by the team from the Max Planck Institute follows on the heels of three other studies that have identified significant differences in proteins that play a critical role in brain growth and development. All of these proteins differ in only a single amino acid.

NOVA1. The first study looked at the NOVA-1 protein, a master regulator that influences the expression of other genes that impact brain development through a mechanism called alternate splicing. NOVA1 plays a role in synapse formation and mutations to this gene have been implicated in neurological disorders. A single amino acid difference distinguishes the modern human version of the protein encoded by this gene from the versions found in archaic humans’ genomes. 

Researchers created and compared the anatomy and physiology of modern human brain organoids and “Neanderthalized” brain organoids created by introducing the Neanderthal version of NOVA1 into the genome of the stem cells used to grow the brain organoid.4 They discovered significant differences between the modern human and Neanderthalized brain organoids. For example, cell proliferation was slower in the Neanderthalized brain organoids than in their modern human counterparts. Also, the Neanderthalized brain organoids possessed a greater number of apoptotic cells. 

The gene expression profile of the two brain organoids was different when characterized at 1 month and 2 months. These variations involved genes that are under the control of NOVA1 and are known to play a role in neural development. 

Adenylosuccinate Lyase. This enzyme catalyzes two reactions that generate purines (compounds that are components of DNA). The modern human version of adenylosuccinate lyase differs from the versions found in archaic humans and other primates by 1 amino acid. The modern human version of this enzyme has a valine in place of an alanine at a key location in the enzyme.

In the second study, an international team of investigators sought to learn if this difference had biological consequences. To assess this possibility, the research team analyzed the concentration of metabolic intermediates in the kidney, muscles, and three brain regions taken from humans, chimpanzees, and macaques.5 They discovered that purine synthesis is less active in humans than in chimpanzees and macaques. 

Using CRISPR gene editing, they “humanized” the adenylosuccinate lyase gene in mice and discovered that purine synthesis became less active, particularly in brain tissue. When they performed the same experiment using the Neanderthal version of the gene, they effectively saw no change in purine synthesis. 

At this juncture, the consequences of this change are unknown, though it clearly has unique and specific effects on modern human brain biochemistry. Mutations in the gene that encodes this enzyme are associated with brain pathologies.  

KIF18A, KNL1, and SPAG5. These three proteins play a role in cell division, specifically during chromosome segregation. The genes that code for these proteins are expressed at high levels in the developing neocortex. The neocortex is significantly larger in modern humans than in the great apes and many of the hominins found in the fossil record. The size difference can be explained (at least, in part) by an increased number of neocortical stem cells and progenitor cells. (In the developing brain, these cells are precursors to neurons and macroglial cells.) These two cell types also proliferate more rapidly in the developing human brain. 

Neanderthals, Denisovans, and chimpanzees all share identical versions of the three proteins. But the modern human versions are unique.

In a third study, researchers have learned that the apical progenitor cells found in the modern human brain organoids spend more time in the metaphase than those in chimpanzee organoids.6 (Apical progenitor cells generate the types of neural cells found in the developing cortex.) This time difference has important consequences. During cell division, a longer metaphase gives the chromosomes more time to align at the metaphase plane, which ensures greater accuracy when the chromosomes are pulled apart during anaphase.

Researchers have also used CRISPR gene editing to “humanize” the gene sequences of the KIF18a, KNL1, and SPAG5 proteins in mice. They discovered that the apical progenitor cells of “humanized” mice spend more time in metaphase than the same cells found in the brains of wild-type mice.

In addition, researchers used CRISPR gene editing to “Neanderthalize” the gene sequences for the KIF18a, KNL1, and SPAG5 proteins in the stem cells used to grow modern human brain organoids. As expected, this change led to a shorter metaphase for the apical progenitor cells.

Taking these studies together, the cells in the developing neocortex of Neanderthals and Denisovans would have been prone to a greater number of chromosome segregation errors than the developing neocortex of modern humans. These errors would have made modern human brains healthier than archaic human brains and would have rendered modern human populations more robust than archaic human populations. 

The list of genetic differences with biological consequences is destined to grow. Researchers have discovered several genes that code for proteins involved in brain, face, and skull development that differs between humans and Neanderthals. It isn’t clear if these differences are biologically relevant, but future experiments will likely make such determinations.  

Origin of Modern Humans Appears to Be Miraculous 
A convergence of genetic evidence has identified significant cognitive differences between modern humans and Neanderthals. These findings add support to an emerging consensus among anthropologists that human beings are exceptional and likely cognitively superior to archaic humans. 

The results of these four studies also point to something a bit “suspicious” about our origins as modern humans. The genetic comparison studies indicate that a confluence of just-right, single amino acid changes in several key proteins that play a role in brain development took place when modern humans appeared on the scene. The amino acid sequences of the modern human versions of these proteins are unique. And they appear to be precisely the changes needed to produce advanced cognition. The occurrence of these types of changes in one protein could be explained by chance. But the confluence of the just-right changes in several key proteins that all play a role in brain development points to something beyond chance. Either we got lucky, or someone intended that creatures like modern humans with exceptional and unique cognitive capacities would appear on Earth. 

I see only two options to explain this eerie set of coincidences: (1) either humans emerged through some type of God-guided evolutionary processes where several just-right mutational changes in the genome of an archaic human took place to create modern humans with advanced cognition, or (2) God intervened in a direct, personal way to create modern humans—us—with a unique set of capacities by modifying a design template we share with other hominins and nonhuman primates. In other words, we were planned. 

Don’t you just love it when a plan comes together. 


Who Was Adam? A Creation Model Approach to the Origin of Humanity by Fazale Rana with Hugh Ross (book)

Thinking about Evolution: 25 Questions Christians Want Answered by Anjeanette Roberts, Fazale Rana, Sue Dykes, and Mark Perez (book)

Brain Structure Differences between Modern Humans and Neanderthals

Neanderthal Brains Make Them Unlikely Social Networkers” by Fazale Rana (article)

Blood Flow to Brain Contributes to Human Exceptionalism” by Fazale Rana (article)

Differences in Human and Neanderthal Brains Explain Human Exceptionalism” by Fazale Rana (article)

Did Neanderthal Have the Brains to Make Art?” by Fazale Rana (article)

When Did Modern Human Brains—and the Image of God—Appear?” by Fazale Rana (article)

Brain Organoid Studies

Brain Organoids Cultivate the Case for Human Exceptionalism” by Fazale Rana (article)

Key Difference in Developing Human and Neanderthal Brains” by Fazale Rana (article) 

Genetic Differences between Modern Humans and Neanderthals

Ancient DNA Indicates Modern Humans Are One-of-a-Kind,” by Fazale Rana (article)

New Genetic Evidence Affirms Human Uniqueness,” by Fazale Rana (article)


  1. Laura L. Colbran et al., “Inferred Divergent Gene Regulation in Archaic Hominins Reveals Potential Phenotypic Differences,” Nature Ecology and Evolution 3 (November 2019): 1598–1606, doi:10.1038/s41559-019-0996-x.
  2. David Gokhman et al., “Reconstructing the DNA Methylation Maps of the Neandertal and the Denisovan,” Science 344, no. 6183 (May 2, 2014): 523–27, doi:10.1126/science.1250368; David Gokhman et al., “Extensive Regulatory Changes in Genes Affecting Vocal and Facial Anatomy Separate Modern from Archaic Humans,” bioRxiv, preprint (October 2017), doi:10.1101/106955.
  3. Anneline Pinson et al., “Human TKTL1 Implies Greater Neurogenesis in Frontal Neocortex of Modern Human Than Neanderthals,” Science 377, no. 6611 (September 9, 2022): doi:10.1126/science.abl6422.
  4. Cleber A. Trujillo et al., “Reintroduction of the Archaic Variant of NOVA1 in Cortical Organoids Alters Neurodevelopment,” Science 371, no. 6530 (February 12, 2021): eaax2537, doi:10.1126/science.aax2537.
  5. Vita Stepanova et al., “Reduced Purine Biosynthesis in Humans after Their Divergence from Neandertals,” eLife 10 (May 4, 2021): e58741, doi:10.7554/eLife.58741.
  6. Felipe Mora-Bermúdez et al., “Longer Metaphase and Fewer Chromosome Segregation Errors in Modern Human Than Neanderthal Brain Development,” Science Advances 8, no. 30 (July 29, 2022): eabn7702, doi:10.1126/sciadv.abn7702.