2022 Nobel Prize in Physiology or Medicine: Svante Pääbo, Resurrecting the Genomes of Extinct Humans

What You'll Learn in This Article

The 2022 Nobel Prize in Physiology or Medicine was awarded to Svante Pääbo, a Swedish scientist, for his groundbreaking work in sequencing the genomes of extinct human species from ancient bone fragments, thereby redrawing the map of human evolution. For over 30 years, he led the Max Planck Institute for Evolutionary Anthropology in Leipzig, Germany, where he successfully obtained the complete genome sequence of Neanderthals (2010) and, using a single finger bone fragment discovered in a Siberian cave, demonstrated the existence of a completely new human species, the Denisovans, based solely on genomic data (2010). The impact of these two discoveries was the astonishing observation that genes from Neanderthals and Denisovans are actually present in the genomes of modern humans. In other words, our ancestors interbred with these extinct human cousins, and traces of this interaction remain within our genetic makeup. This discovery has reshaped the fields of anthropology, medicine, and history.

A Story That Challenges Conventional Wisdom: We Carry the Genes of Extinct Human Cousins Within Us

The conventional wisdom, prevalent in the late 20th century, was that "modern humans (Homo sapiens) are the only surviving human species after other human species went extinct." Neanderthals were believed to have gone extinct about 40,000 years ago, and Denisovans even earlier. However, this understanding was missing one crucial piece of information: that they actually interbred with our ancestors before their extinction, and that their genes are still present in us today.

Pääbo's discoveries fundamentally overturned this picture. The genomes of modern humans outside of Africa contain about 1-2% Neanderthal DNA. In Asia, particularly among Tibetan populations, there is DNA of Denisovan origin, one of which is crucial for adaptation to high-altitude, low-oxygen environments. Thus, we are a species that has inherited the genetic legacy of extinct human cousins, carrying their traces within us.

In computer science terms, this is like restoring an old log file to find traces of a deleted branch. Pääbo's methodology, which involves filtering out contaminants and reconstructing genomic sequences from fragmented DNA, is akin to resurrecting commits from a lost branch in the history of evolution. And this branch has been partially merged into our current branch—foreign branch merge actually happened in our evolutionary history—as evidenced by the genomic data.

The Landscape of the Times: War, the Death of a Queen, and ChatGPT

The world in 2022 began with the Russian invasion of Ukraine on February 24th. This marked the beginning of the largest European war of the 21st century, fundamentally reshaping the global security order and energy markets. This was followed by international sanctions, a refugee crisis, soaring energy prices, and the disruption of grain supply chains, leading many European countries to significantly increase their defense budgets.

On July 8th, former Japanese Prime Minister Shinzo Abe was assassinated in Nara, Japan. The unprecedented assassination during a campaign event shocked the world and had several repercussions on Japanese security and political landscape. On September 8th, Queen Elizabeth II passed away at the age of 96. Her 70-year reign marked the end of the Commonwealth era, and commemorative events were held around the world.

On November 30th, OpenAI released ChatGPT. This was the first time a large language model (LLM) was made available to the general public on a large scale, and it experienced explosive user growth in the following months. It marked the beginning of the age of AI and a major topic of discussion in the latter half of the 21st century.

South Korea experienced a tumultuous year. In the March 9th presidential election, Yoon Suk-yeol defeated Lee Jae-myung by a narrow margin and was elected, leading to a change in government. On October 29th, the Itaewon Halloween crush killed 159 people. The incident, caused by a large crowd crammed into a narrow alley, highlighted several issues with safety management and police response. This marked a moment where the fundamental issues of the national disaster response system were brought into question again, after the Sewol Ferry disaster.

In the world of culture and technology, Elon Musk acquired Twitter on October 27th and began rebranding it as X, leading to mass layoffs and policy changes. In October 30th, Lula was re-elected as president in Brazil, defeating Bolsonaro. The Qatar World Cup, held in November and December, was the first World Cup to be held in the Middle East, and Argentina won the tournament, with Messi lifting the trophy in what was likely his last World Cup.

In the scientific community, this award was strongly characterized by the combination of anthropology and genomics. It was one of the first cases in the history of the Nobel Prize in Physiology or Medicine where human evolution itself was the subject of the award, and it recognized Pääbo's 30 years of dedicated methodological development. His father, Sune Bergström (1982 Nobel Prize in Physiology or Medicine for prostaglandins), was also a Nobel laureate, which was also a topic of interest.

The Human Story: 30 Years of Fighting Contamination, in the Shadow of His Father

Svante Pääbo (1955–) was born in Stockholm, Sweden. He received his bachelor's and doctoral degrees from Uppsala University. His life had an unusual background. His father, Sune Bergström, was a 1982 Nobel laureate in Physiology or Medicine, but Pääbo was born out of wedlock and raised outside of a formal relationship with his father. Pääbo addressed this personal story in his autobiography, "Neanderthal Man," reflecting on how his academic trajectory became independent of his father's shadow.

Pääbo's research question was ambitious from his early years as a graduate student: "Could we extract DNA from ancient Egyptian mummies?" This idea began as part of his doctoral research in molecular paleontology in the early 1980s, and in 1985, he published a paper in Nature demonstrating that he had extracted short DNA fragments from a mummy. It was the world's first study of ancient DNA. He then moved to the University of Munich and the Max Planck Institute for Evolutionary Anthropology in Leipzig, where he has led the institute for over 30 years.

The crucial obstacle in ancient DNA research was contamination. Most of the DNA extracted from ancient bones was damaged and in very small amounts, and even a small amount of DNA from modern human researchers could completely distort the results. The decisive technological achievement in this story was the extreme development of contamination removal methodologies in Pääbo's laboratory. He established sophisticated methods such as clean room design, sample handling protocols, and algorithms for filtering out DNA from researchers.

The first major success was the 1997 sequencing of Neanderthal mitochondrial DNA. Pääbo's team extracted short fragments of mitochondrial DNA from a 40,000-year-old Neanderthal bone and determined its sequence, confirming that it was distinctly different from modern human mitochondrial DNA. This was the first genomic data demonstrating that Neanderthals were a distinct genetic lineage from modern humans.

In 2010, a draft of the complete Neanderthal genome sequence was published. By combining DNA from several bone fragments, this genome sequence was compared in detail with the modern human genome, leading to a crucial discovery. Modern humans outside of Africa are more similar to Neanderthals than to Africans, and this similarity is about 1-4%. This means that our ancestors, who originated in Africa, interbred with Neanderthals in Eurasia, and the result is still present in us today. The map of anthropology was redrawn at this moment.

In the same year, the discovery of the Denisovans followed. Pääbo's team extracted a genome from a finger bone fragment excavated from a cave in Siberia, and confirmed that this genome belonged to a completely new human species, distinct from both Neanderthals and modern humans. It was the first case in which a completely new species was defined based solely on genomic data, and it fundamentally expanded the methodology of paleontology. Subsequently, it was confirmed that Denisovan genes are found in populations in Oceania and Tibet, and in particular, a variant of the EPAS1 gene, which is involved in high-altitude adaptation, was found to be of Denisovan origin.

Pääbo's 30 years of methodological accumulation and two crucial discoveries combined to completely reshape how humans understand their own evolutionary lineage.

Key Achievements: The Ancient Human Genomics Pipeline in a CS Framework

The pipeline for ancient DNA sequencing can be summarized as follows:

• Sample Acquisition: Collection of bone, teeth, or hair fragments. Mitochondrial DNA, with hundreds of copies per cell, is relatively well preserved, while nuclear DNA, which is much less abundant, is more difficult to sequence.
• Contamination Removal: Processing in a clean room to minimize physical contamination from researchers and the environment, and computationally filtering out modern human DNA patterns from the resulting data. This step is crucial for the success of ancient DNA research.
• DNA Extraction and Library Construction: Special methods are used to extract small amounts of damaged DNA. The patterns of damage themselves serve as fingerprints of authentic ancient DNA (cytosine deamination marker).
• Next-Generation Sequencing (NGS): The extracted DNA is fragmented and amplified, and then sequenced in parallel using high-throughput sequencing platforms such as Illumina.
• Read Alignment and Assembly: The short fragments are aligned with a reference genome (modern human or chimpanzee) to reconstruct the original sequence. Statistical methods are used to correct errors in damaged regions.
• Population Genomic Analysis: The obtained ancient genomes are compared with genomes of modern humans from around the world. Patterns of similarity are used to infer population movements, admixture, and divergence times.

This pipeline can be seen as reverse engineering to restore the original commit history from a fragmented log file. Each bone fragment is a log file that has been neglected for tens of thousands of years, and a significant portion of the log has been degraded, contaminated, and partially lost. By collecting multiple fragments and combining them statistically, a plausible reconstruction of the original genome can be obtained.

The three key discoveries in a CS analogy:

• Reconstructing the Neanderthal Genome: Restoring the commit history of a lost branch.
• Neanderthal to Modern Human Gene Flow: Git merge from a foreign branch. Our genome is not a pure Homo sapiens lineage but a result of merges from multiple branches.
• Discovery of Denisovans: A completely new branch is discovered in the log. It was the first case in which a new species was defined based solely on genomic data, rather than morphological fossils.

However, we must also acknowledge the limitations of this analogy. Ancient genome data is still incomplete and biased. The preservation of DNA is poorer in warmer regions, so the ancient genome data we have is heavily skewed towards colder regions such as Siberia and Europe. Data on ancient populations from Africa, Southeast Asia, and Oceania are relatively scarce, which still creates an imbalance in the overall picture of human evolution. This bias is gradually being improved over time.

Why It Matters: Evolution, Medicine, and Self-Understanding

First, the map of human evolution has been redrawn. As modern humans migrated out of Africa and spread across the world, they interbred with several other human species, leaving traces in our genomes. The 20th-century "replacement model"—the idea that modern humans completely replaced other human species—has been revised into a mixed model of replacement and partial merging.

Second, a new understanding of modern human genetic diversity. Some of the genetic diversity within different regional populations can be explained by genes introduced from ancient human species. The adaptation of Tibetans to high altitudes (EPAS1, derived from Denisovans), and certain immune system variations in Eurasians (derived from Neanderthals) are prime examples. This means that the genetic diversity of human populations is not simply a product of time, but also a product of interbreeding between different human species.

Third, medical implications. Some of the genetic variations inherited from Neanderthals influence the susceptibility to various diseases in modern humans. A specific genetic locus (a specific region on chromosome 3) that affects the risk of severe COVID-19 was found to be derived from Neanderthals, in research conducted in Pääbo's lab. This was a remarkable observation: a gene inherited by our ancestors 60,000 years ago influenced the clinical outcome of a 21st-century pandemic.

Fourth, the expansion of methodologies. The methods for removing, restoring, and reconstructing ancient DNA developed by Pääbo's lab were later adopted by other laboratories, establishing a new field called paleogenomics. In the first two decades of the 21st century, thousands of ancient human genomes were sequenced from around the world, and many long-standing debates about human migration, cultural diffusion, and language change have been re-examined using genomic data.

Fifth, the combination of paleoanthropology and archaeology. Population movements in Bronze Age Europe, the spread of Neolithic agriculture, and the genetic background of the Bell Beaker culture have been re-examined through ancient DNA research. The first human migration to the Americas, the spread of the Lapita culture in Oceania, and the Bantu expansion in Africa are all being newly understood from a genomic perspective.

Sixth, reflection on self-identity. Pääbo's discoveries give us the powerful message that "humans were not one." While we are now the only surviving human species, tens of thousands of years ago, several human species coexisted on Earth, and our ancestors interacted with them and had children. The Neanderthal and Denisovan genes within us are living remnants of this diversity. This insight has added a new layer to our understanding of human identity.

Seventh, overcoming the limitations of fossil morphology. Until the 20th century, the definition of new human species relied mainly on comparing bone shapes. However, the discovery of Denisovans was the first case in which a new species was defined based on the genomic data from a single finger bone. This has established a new standard of methodology in which fossil morphology and genomic data are used complementarily.

Eighth, humility in evolutionary insights. The fact that the story of our species is not a story of pure lineage, but a complex web of lineages meeting and separating, presents a new perspective beyond the simple tree model of the late 20th century. Evolution is not a tree, but a web, and we are just one node within that web.

The genes of our extinct cousins remain within us. This fact has fundamentally reshaped our understanding of human evolution, and the 22nd Nobel Prize in Physiology or Medicine in this century has recognized this reshaping. Pääbo's 30-year journey from bone to genome has been a major achievement in humanity's long journey toward understanding itself.

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