This year’s Nobel discoveries in Medicine have provided us with answers about ourselves, for example our immune system and how to decipher genetic risks, but also about our origin and context.

On October 3rd 2022, the Nobel Prize in Physiology or Medicine was awarded to Swedish geneticist Svante Pääbo, a professor at the Max Planck Institute for Evolutionary Anthropology, “for his discoveries concerning the genomes of extinct hominins and human evolution”.

The Nobel Assembly went further in the recognition of Pääbo, stating his “seminal research gave rise to an entirely new scientific discipline; paleogenomics. By revealing genetic differences that distinguish all living humans from extinct hominins”.

“The Prize is another in a long list of awards for someone who has done so much to help us understand to what extent we are unique and how we fit in in the evolutionary history,” says Anders Götherström, Professor of Molecular Archaeology of the Centre for Palaeogenetics at Stockholm University.

 

Anders Götherström, Professor of Molecular Archeology, Stockholm University. Photo: Rickard Kilström

 

The Neanderthal genome

This story begins in 1856, in a cave near Dusseldorf, Germany when two quarry workers accidentally dug up the bones of an early hominid. Initially, the bones were identified as those of a bear, before ending up in front of Johann Carl Fuhlrott who recognized them as something altogether different. Fuhlrott would take the bones to Hermann Schaaffhausen, and together they would publish a paper outlining their belief that the bones belonged to an ancient race of humans, utterly distinct from modern humans.

Slightly more than 140 years later, in 1997, a paper titled “Neanderthal DNA Sequences and the Origin of Modern Humans” by Pääbo, showed that after successfully extracting DNA from the 1856 specimen and sequencing the mitochondrial DNA, “the Neanderthal sequence falls outside the variation of modern humans”, meaning humans and these ancient hominins were distinct branches of the same tree. In 2010, the entire Neanderthal genome of one individual would eventually be sequenced.

A near-impossible mountain

The work and commitment that it has taken to get from where our knowledge was just thirty years ago, to where we are today could be considered a near-impossible mountain to climb. To even begin the journey, the extraction, reconstruction and analysis of ancient DNA (aDNA) is an incredibly complex process.

Writing in 1994 of the methodological challenges in studying aDNA, Pääbo and colleagues noted in particular “These problems can be summarized in one word: reproducibility”. DNA degrades over time; a living organism’s DNA repairs itself continuously, and after an organism dies this process stops, and this is only the first hurdle. Contamination is also a major issue as even a few molecules of modern DNA which make their way into extracts prepared from ancient tissues will be amplified and cause incorrect results.

Two big game changers

The first time aDNA was extracted in small quantities was in 1984, from a species of zebra, that became extinct in the early 20th century. The data at the time was limited, but the door to understanding how the modern world came to be had been opened. In their paper Ancient DNA: Methodological challenges, Pääbo and colleagues suggested several key ways in which obtaining valid reproducible results could work that would lay the foundations for the uncovering of the neanderthal genome. While the methodology was being perfected, technological advances also contributed.

“The first big game changer in the last forty years was when silica purification came in 1993. We could get clean ancient DNA and all of a sudden we could start to do things.”

Götherström says, “The two big game changers in the last forty years are first, when silica purification came in 1993. We could get clean ancient DNA and all of a sudden we could start to do things.” Initially, polymerase chain reaction (PCR) based analyzes made it possible to at least begin molecular studies of aDNA, but a paper written by Pääbo and Matthias Höss in 1993 proposed a new method that had “high extraction efficiency, is simple and fast and therefore allows large numbers of bone samples to be screened in order to identify those that contain surviving DNA molecules”. This silica-based method successfully demonstrated the ability to remove impurities from the extraction of aDNA, allowing for a drastic improvement in the quality of results.

“The second game changer was next-generation sequencing (NGS). This revolution began when 13 million DNA base pairs of the woolly mammoth genome was published in 2006.”

The second game changer was next-generation sequencing (NGS). This revolution began when 13 million DNA base pairs of the woolly mammoth genome was published in 2006. The cascade of discoveries and refinements each decade lead to the truly groundbreaking moment in 2009 when A complete Neanderthal mitochondrial genome sequence determined by high-throughput sequencing was published. Using samples from several neanderthal individuals, Pääbo’s team was able to “unequivocally establish that the Neanderthal mtDNA falls outside the variation of extant human mtDNAs and allows an estimate of the divergence date between the two mtDNA lineages of 660,000±140,000 years”. The next step, the full neanderthal genome, was not a matter of if, but when.

The evolutionary history

While initially it was assumed that humans and neanderthals diverged long enough ago, roughly 500,00 years, we now know did humans and Neanderthals lived side by side until about 40,000 years ago. How much these ancient humans intermingled was somewhat of a debate until even ten years ago. It has been shown some modern humans can share between 1% and 4% of their DNA with these ancient hominins, showing us that the tree of life is not as simple as we first thought. This is equally true of Denisovans,  another hominin that migrated out of Africa between 300-400,000 years ago, which some modern humans also share 1-4% of their DNA.

What this means for us as modern humans can be seen in several ways. Götherström suggests that “You can argue that it is medically good to know what separates homo sapiens from close relatives. But in the end, a better understanding of our evolution is mostly beneficial for those who want to know more about our prehistory, and philosophically [how] that helps us understand to what extent we are unique and how we fit in in the evolutionary history”.

For example, the DNA of a Denisovan (from Denisova Cave, in Siberia) has been found in Baishiya Karst Cave in Tibet, showing Denisovans adapted well to high altitudes. Human bodies produce extra haemoglobin at high altitudes, which too much of, can make it harder to pump blood around the body. Analysis shows that modern Tibetans’ DNA contains a gene called EPAS1 which prevents this process, and it is shared with Denisovans.

 

Hugo Zeberg, Assistant professor, Karolinska Institutet. Photo: Andreas Andersson

 

Who are we?

A more recent curiosity in the relationship between Neanderthals and modern humans is that we now know know that people with a haplotype on chromosome 12 is associated with a approximately 22% reduction in relative risk of becoming severely ill with COVID-19 when infected by SARS-CoV-2.

These insights can go further. Hugo Zeberg, Assistant professor at the Department of Neuroscience at Karolinska Institutet, who worked with Pääbo, found Neanderthal genes can continue to influence us in the face of modern diseases and says that part of his work is to “come up with medically relevant questions on the Neanderthal genome, such as pain, fertility, infectious, diseases, inflammation.”

Being able to decipher genetic risks we may have not only comes from long-dead ancestors.

“With a lot of ancient genomes, not only from neanderthals, but also from modern humans, we can start to see how gene variants can go up and down over time, and that can give clues. What happened with the genome in Europe during the plague, for example, we can learn something about the immune system,” continues Zeberg, “You never know what can come from the findings.”

“Science must not always be about its application. We are interested in cosmic questions. That’s a part of being human.”

The appreciation of curiosity is something that permeates the subject. As Zeberg says, “Science must not always be about its application. We are interested in cosmic questions. That’s a part of being human. Who are we? Where do we come from? What’s our origin? What’s behind the stars?.”

 

Tree of life

Featured illustration: iStock