Svante Pääbo: searching for secrets in ancient DNA
Neanderthal woman. Image: PLOS Biology
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Where did we come from? And how are we related to the ancient species that came before us? Asking questions like these is part of what makes us human. But, genetically speaking, what really does make us human?
Well, Swedish geneticist Svante Pääbo is helping us find out - and, as has recently been announced, his work has led to him winning the 2022 Nobel prize in physiology or medicine “for his discoveries concerning the genomes of extinct hominins and human evolution”, as the committee put it.
Pääbo was the first to sequence DNA from our closest ancient human relatives, the Neanderthals who went extinct tens of thousands of years ago, revealing that we still have traces in our modern human genes that connect us to these ancient ancestors.
Sequencing DNA this old is no mean feat. Bodies decompose, with only traces left in bones after thousands of years. Over time the DNA molecule itself also breaks down, making it tricky to read and piece together to get sequences of whole genes, let alone whole genomes. Ancient DNA is also likely to be contaminated with other DNA, for example from bacteria or present-day DNA, whether from humans or other species, which further confuses things.
But this didn’t stop Pääbo. It was while he was studying for his doctorate at Uppsala University in Sweden during the 1980s that he first caused a stir by trying – and succeeding – to isolate DNA from a 2,400 year old Egyptian mummy.
However, this wasn’t what his PhD was meant to be about. Pääbo was supposed to be studying how a protein in adenoviruses affects the immune system, but he had always been fascinated by archaeology and ancient secrets. Fearing a reprimand from his doctoral supervisor he carried out his experiments in secret, liaising with a friendly Professor of Egyptology to get hold of small samples from 36 different mummies in museums in Uppsala and Berlin. Pääbo snuck around the lab at night analysing the samples, initially looking at them down the microscope to see if there were any traces of genetic material lurking in there. When he spotted signals suggesting that there was still DNA within the samples, he set about extracting it and cloning it - effectively putting small fragments of DNA into bacteria, so they could be amplified and sequenced. And, amazingly, it worked.
It wouldn’t be the first time that a grad student has gone somewhat off-piste in their project, but it paid off. Pääbo bagged himself a single-author paper in the journal Nature published in 1985 describing his initial extraction and analysis of mummy DNA. This is an impressive achievement for a young scientist, and certainly gathered a lot of attention. Although Pääbo himself has since raised questions about whether the mummy samples were contaminated with modern DNA, it was enough to set him firmly on the path towards the past and his ultimate goal of sequencing the Neanderthal genome.
He headed to the University of California Berkeley to work with Allan Wilson - a pioneering geneticist working in the brand new field of paleogenetics – the study of ancient DNA – and he soon set about trying to find new techniques to study this fragile and often fickle molecule.
Pääbo initially started extracting and analysing mitochondrial DNA - much smaller stretches of DNA found within the ‘power stations’ within cells - rather than the larger chromosomes found within the nucleus of the cell, known as nuclear DNA, which we usually think of as making up the human genome. This is because each cell has many thousands of copies of the mitochondrial genome, whereas there’s only one copy of the human genome per cell, increasing the chances of being able to get a handle on these ancient sequences.
In 1997 he and his colleagues managed to sequence a region of mitochondrial DNA from a 40,000-year-old Neanderthal bone found in Germany in 1856 - the first time that anyone in the world managed to see what a piece of this ancient human’s genome looked like. The team’s analysis suggested that the Neanderthal DNA was very different to modern humans, and they conclude that “Neanderthals went extinct without contributing mitochondrial DNA to modern humans,” supporting the idea that modern humans and Neanderthals were truly two separate species.
However, more recent analysis from Pääbo and others suggests that Neanderthal mitochondrial DNA actually came from early humans in the first place, and their work went on to show that there must have been multiple ‘gene flow events’ (that’s the scientific term for sexytimes) between Homo sapiens and our Neanderthal cousins along the way.
Moving to the University of Munich in Germany in the 1990s, Pääbo continued to work on his methods for extracting, sequencing and analysing ancient DNA. He then headed to Leipzig in 1997 to become director of the newly founded Max Planck Institute for Evolutionary Anthropology.
It was here that he and his colleagues, including Michael Hofreiter, figured out a new technique called multiplexing, which enabled them to piece together fragmented sequences from extremely small ancient DNA samples. The team demonstrated their technique by sequencing the mitochondrial genome of a woolly mammoth in 2006.
This was a major step forward, as it offered the opportunity to start exploring the less abundant nuclear DNA, which is protected by proteins and better preserved than mitochondrial chromosomes, in theory allowing them to sequence whole genes or even a whole genome. And it was thanks to this advance and other new techniques that Pääbo and his team finally achieved his dream, revealing for the first time the draft sequence of the full Neanderthal genome, published in 2010.
The team were able to read nearly 3 billion ‘letters’ of the Neanderthal genome thanks to DNA from three females who lived in Croatia nearly 40,000 years ago. Comparisons with modern human DNA showed that Europeans and Asians share up to 4% of their DNA with Neanderthals, while Africans share very little, showing that the two species have met and interbred after some Homo sapiens left Africa, but before we made our way across Asia.
Over the years, Pääbo has become a leading expert in getting DNA out of old, dead stuff - whether that’s bones, skin, teeth, or even poop - and reading its secrets. He’s sequenced DNA from ancient sloths, cave bears, moas, woolly mammoths, extinct bees, and ancestral humans, shedding light on long-hidden evolutionary origins and relationships between species.
Pointing the way
This tiny fragment of a Denisovan finger bone was enough to identify an entirely new species of humans from 40,000 years ago.
Image: Thilo Parg
One of the most dramatic findings came in 2012, when he and his team sequenced DNA isolated from a tiny 40,000-year-old finger bone found in the Denisova Cave in the Altai Mountains in Siberia. From this single sample, they discovered an entirely new long-gone species of humans, known as Denisovans. Not only that, but like the Neanderthals, the Denisovans had not been able to resist the charms of Homo sapiens, with people in some regions of southeast Asia sharing up to 6% of their genes with these long-lost relatives.
Coming right up to the present day, Pääbo also found that a major genetic risk factor for severe COVID-19 is inherited from Neanderthals, thanks to a small segment of DNA carried by around half of people in south Asia and one in six Europeans.
There’s been plenty written over the years - and over the past few weeks - about the impact of Svante Pääbo’s discoveries and how they have helped shape our understanding of how we came to be here, including his own book, Neanderthal Man: In search of lost genomes. I’ve popped a few links in the page for this podcast at geneticsunzipped.com. And you can also check out our previous episodes exploring human origins. Pääbo has also made significant contributions in other areas of human evolution, such as his work on the FOXP2 gene, which is thought to contribute to the evolution of human speech and language.
Pääbo’s Nobel prize may seem like a bit of a left-field surprise, but in my opinion it’s no less richly deserved than a breakthrough in medicine or molecular biology. And, in a nice step forward for LGBT scientists, he’s the first openly bisexual Nobel laureate, as far as I can tell. Incidentally, Pääbo isn’t the first person in his family to win a Nobel prize - his father Sune Bergström, a biochemist, won the 1982 Nobel Prize for Physiology or Medicine for his work investigating a group of compounds known as prostaglandins, although I wouldn’t take that as evidence of a ‘Nobel gene’!
Pääbo’s work is showing us who we are as a species, and how we came to be here - our most fascinating story. Back in 2008, he was interviewed by Jane Gitschier for PLoS Genetics. He said, “What one dreams about is defining the genetic changes that we all share today but that made modern humans so special. That made us colonise the whole place, every little speck of land on the planet, which, after all, archaic humans had not done. They had been around for two million years, but they never crossed the water where they couldn't see land on the other side."
Gitschier wrote, “Svante Pääbo works on the edge of what's possible. He ignites our imagination, unlocking tightly held secrets in ancient remains.”
Who knows what other secrets we will find out?
Further reading
