The 2022 Nobel Prize in Physiology or Medicine

Introduction

Humanity has always been curious about its origins: Where do we come from? How are we, Homo sapiens, related to the other humans who came before us? What makes Homo sapiens different from other humans?

Through his pioneering research, Professor Svante Pääbo accomplished something seemingly impossible: sequencing the genome of an extinct human relative, the Neanderthal. He also made the sensational discovery of a previously unknown human group, the Denisovans. Crucially, Pääbo found that genes from these now-extinct groups were transferred to Homo sapiens after our ancestors left Africa about 70,000 years ago. This ancient genetic legacy remains physiologically significant in people today, affecting, for example, how our immune systems respond to infection.

Pääbo’s groundbreaking work gave rise to an entirely new discipline: paleogenomics. By revealing the genetic differences that distinguish all living humans from extinct human groups, his discoveries laid the foundation for exploring what makes Homo sapiens uniquely human.

Where Do We Come From?

Questions about where we come from and why we are unique have occupied humanity since ancient times. Paleontology and archaeology are essential to the study of human evolution. Evidence from these fields indicates that anatomically modern humans, Homo sapiens, first appeared in Africa about 300,000 years ago. Our closest known relatives, the Neanderthals, developed outside Africa and inhabited Europe and western Asia from about 400,000 to 30,000 years ago, after which they became extinct. Around 70,000 years ago, groups of Homo sapiens migrated from Africa to the Middle East and then spread across the rest of the world. Homo sapiens and Neanderthals therefore coexisted across much of Eurasia for tens of thousands of years. But how much do we know about the relationship between Homo sapiens and the extinct Neanderthals? Genomic information might provide clues. By the late 1990s, almost the entire human genome had been sequenced. This major achievement later enabled scientists to investigate the genetic relationships among different human populations. Studying the relationship between people alive today and extinct Neanderthals, however, required the sequencing of genomic DNA extracted from ancient human specimens.

A Seemingly Impossible Task

Early in his scientific career, Svante Pääbo became fascinated by the possibility of using modern genetic methods to study Neanderthal DNA. He soon recognized the daunting technical challenges. Over time, chemical reactions break DNA down into short fragments. After thousands of years, only trace amounts remain, and those remnants are heavily contaminated by DNA from bacteria and present-day humans (Figure 1). As a postdoctoral student of Allan Wilson, a pioneer in evolutionary biology, Pääbo began developing methods for studying Neanderthal DNA—an effort that would continue for decades.

Figure 1. DNA is located in two different compartments within the cell. Nuclear DNA contains most of the genetic information, while the much smaller mitochondrial genome is present in thousands of copies. After death, DNA degrades over time until only small amounts remain. It also becomes contaminated by DNA from sources such as bacteria and present-day humans.

In 1990, Pääbo joined the University of Munich. As a newly appointed professor, he continued his work on ancient human DNA and decided to analyze Neanderthal mitochondrial DNA. Mitochondria are organelles that contain their own DNA. Although their genome is small and accounts for only a tiny fraction of the cell’s genetic information, thousands of mitochondria can be found in a sample, greatly improving the chances of success. Using his methods, Pääbo succeeded in sequencing a region of mitochondrial DNA from a 40,000-year-old bone. For the first time, a sequence from an extinct human relative was available. Comparisons with present-day humans and chimpanzees showed that Neanderthals were genetically distinct.

Sequencing the Neanderthal Genome

Because analysis of the small mitochondrial genome provided only limited information, Pääbo took on the formidable challenge of sequencing the Neanderthal nuclear genome. At this point, he was offered the opportunity to establish a Max Planck Institute in Leipzig, Germany. At the new institute, Pääbo and his team steadily refined their methods for isolating and analyzing DNA from ancient human remains. They took advantage of new technological advances that made DNA sequencing highly efficient. Pääbo also recruited key collaborators with expertise in population genetics and advanced sequence analysis. His efforts succeeded: Pääbo completed the seemingly impossible task and published the first Neanderthal genome sequence in 2010. Comparative analyses indicated that the most recent common ancestor of Neanderthals and Homo sapiens lived around 800,000 years ago.

Figure 2. A. Pääbo extracted DNA from skeletal specimens of extinct humans. He first obtained a bone fragment from the Neander Valley in Germany, which gave Neanderthals their name. Later, he used a finger bone from Denisova Cave in southern Siberia, after which the Denisovans were named. B. The phylogenetic tree shows the evolution of and relationships between Homo sapiens and extinct human groups. It also illustrates the gene flow discovered by Pääbo.

Pääbo and his colleagues could now investigate the relationship between Neanderthals and modern humans from different parts of the world. Comparative analyses showed that Neanderthal DNA sequences were more similar to those of present-day people of European or Asian descent than to those of present-day people of African descent. This meant that Neanderthals and Homo sapiens had interbred during the thousands of years in which they coexisted. In modern people of European or Asian ancestry, approximately 1–4% of the genome comes from Neanderthals (Figure 2).

A Sensational Discovery: The Denisovans

In 2008, a fragment of a 40,000-year-old finger bone was discovered in Denisova Cave in southern Siberia. The bone contained exceptionally well-preserved DNA, which Pääbo’s team sequenced. The result caused a sensation: compared with all known sequences from Neanderthals and present-day humans, the DNA sequence from the finger bone was unique. Pääbo had discovered a previously unknown human group, which was named the Denisovans. Comparisons with sequences from present-day people in different parts of the world showed that gene flow had also occurred between Denisovans and Homo sapiens. This relationship was first identified in populations in Melanesia and elsewhere in Southeast Asia, whose genomes contain up to 6% Denisovan DNA.

Pääbo’s discoveries transformed our understanding of evolutionary history. When Homo sapiens left Africa, at least two now-extinct human populations inhabited Eurasia. Neanderthals lived in western Eurasia, while Denisovans occupied the continent’s eastern regions. As Homo sapiens expanded beyond Africa and migrated eastward, they encountered and interbred not only with Neanderthals but also with Denisovans (Figure 3).

Paleogenomics and Its Relevance

Professor Svante Pääbo’s pioneering research established an entirely new scientific discipline: paleogenomics. Following his initial discoveries, his group completed analyses of the genome sequences of several other extinct human groups. Pääbo’s discoveries created a unique resource that scientists have used extensively to gain a better understanding of human evolution and migration. Powerful new sequence-analysis methods indicate that ancient humans may also have interbred with Homo sapiens in Africa. However, because ancient human DNA degrades more rapidly in tropical climates, no genome from an extinct African human group has yet been sequenced.

Thanks to Pääbo’s discoveries, we now know that ancient genetic sequences inherited from our extinct relatives continue to influence people today. One example is the Denisovan gene EPAS1, which confers an advantage for survival at high altitudes and is common among present-day Tibetans. Other examples include Neanderthal genes that affect our immune responses to different kinds of infection.

Figure 3. Pääbo's discoveries provide important information about the world's human populations when Homo sapiens migrated out of Africa and spread across the globe. Neanderthals lived in western Eurasia and Denisovans in the east. As Homo sapiens spread across the continent, the groups interbred, leaving traces that remain in our DNA.

What Makes Us Uniquely Human?

Homo sapiens created diverse cultures and great art, and developed the ability to cross oceans and reach every part of the planet (Figure 4). Neanderthals also lived in groups and had large heads (Figure 4). They, too, used tools, but those tools developed very slowly over hundreds of thousands of years. The genetic differences between Homo sapiens and our closest extinct relatives remained unknown until Pääbo’s groundbreaking work identified them. Professor Pääbo’s ongoing research focuses on analyzing the functional effects of these differences, with the ultimate goal of explaining what makes us uniquely human.

Figure 4. Pääbo's pioneering work provides a foundation for explaining what makes us uniquely human.

Translation: DeepL
Proofreader: Shiguang
Original: https://www.nobelprize.org/prizes/medicine/2022/press-release/