NEWS | IN DEPTH failures,” says geneticist Michael Stebbins, a consultant and former White House sci- ence office official. The new agency would help promising ideas cross the so-called val- ley of death that prevents many discoveries from reaching patients. He thinks ARPA-H’s proposed $6.5 billion budget is warranted “because of the scale of the challenge.” Breaking the existing NIH mold is im- portant, agrees Robert Cook-Deegan, a research policy professor at Arizona State University, Tempe, and longtime propo- nent of a DARPA-like agency at NIH. “I’m totally in favor of giving senior NIH people a lot of money and the flexibility to push the boundaries and work outside the exist- ing system of peer review,” he says. But he wonders about the premise that new tech- nologies are the key to improving health Researchers excavating Estatuas cave in Spain found a long record of DNA in the sediments. outcomes in the United States. “I’m not sure that curing cancer is an engineering Downloaded from problem,” he says. As vice president, Biden became a cham- pion of cancer research after his son Beau DNA from cave dirt traces Biden died from brain cancer in 2015, and he led the Obama administration’s Cancer Moonshot that aimed to accelerate cures. Neanderthal upheaval http://science.sciencemag.org/ He floated the idea of ARPA-H during his presidential campaign and more re- First nuclear DNA from sediment shows turnover, cently during a visit to a plant making a migration among ancient cave dwellers in Spain COVID-19 vaccine. But Biden’s plan to place ARPA-H within the notoriously cautious NIH surprised By Ann Gibbons “This is a beautiful paper,” agrees popula- some of the idea’s staunchest advocates. “If tion geneticist Pontus Skoglund of the Fran- it’s just another fund within the NIH, we’re statuas cave in northern Spain was a cis Crick Institute. The sequences reveal not optimistic that it’s going to succeed,” hive of activity 105,000 years ago. Arti- the genetic identity and sex of ancient cave

says Liz Feld, president of the Suzanne facts show its Neanderthal inhabitants dwellers and show that one group of Nean- on April 18, 2021 Wright Foundation, a pancreatic cancer re- hafted stone tools, butchered red deer, derthals replaced another in the Spanish search advocacy group. Instead, Feld and and may have made fires. They also cave about 100,000 years ago, perhaps after allies want ARPA-H to stand alone within shed, bled, and excreted subtler clues a climate cooling. “They can see a shift in NIH’s parent agency, the Department of Eonto the cave floor: their own DNA. “You Neanderthal populations at the very same Health and Human Services. can imagine them sitting in the cave mak- site, which is quite nice,” Skoglund says. Other research advocates worry ARPA- ing tools, butchering animals. Maybe they To date, paleogeneticists have managed H would divert money from NIH’s existing cut themselves or their babies pooped,” says to extract ancient DNA from the bones or 27 institutes and centers and say it should population geneticist Benjamin Vernot, a teeth of just 23 archaic humans, including start smaller. “We do not believe it is in the postdoc at the Max Planck Institute for Evo- 18 from 14 sites across Eur- nation’s interest to channel funding away lutionary Anthropology (MPI-EVA), whose asia. In search of more, Vernot and Meyer’s from other research priorities,” says Mary perspective may have been colored by his team sampled sediment from well-dated Woolley, president of Research!America, own baby’s cries during a Zoom call. “All that layers in three caves where ancient humans which is seeking a 10% boost for NIH’s DNA accumulates in the dirt floors.” are known to have lived: the Denisova and core programs. He and MPI-EVA geneticist Matthias Chagyrskaya caves in Siberia and Estatuas The fate and final form of ARPA-H and the Meyer report this week in Science that dirt cave in Atapuerca, Spain. other proposed ARPA-like entities will not from Estatuas has yielded molecular trea- In what Skoglund calls “an amazing tech- be clear for months. Biden’s proposal is the sure: the first nuclear DNA from an ancient nical demonstration,” they developed new opening move in a budget process for the fis- human to be gleaned from sediments. Ear- genetic probes to fish out hominin DNA, cal year that begins on 1 October and will in- lier studies reported shorter, more abun- allowing them to ignore the abundant se- volve extensive negotiations with Congress. dant human mitochondrial DNA (mtDNA) quences from plants, animals, and bacteria. Separately, legislators have already started from cave floors, but nuclear DNA, previ- Then, they used statistical methods to home to debate Biden’s $2 trillion infrastructure ously available only from bones and teeth, in on DNA unique to Neanderthals and plan, which includes a one-time injection of can be far more informative. “Now, it compare it with reference genomes from $200 billion for a host of research initiatives, seems that it is possible to extract nuclear Neanderthals in a phylogenetic tree. including the new tech directorate at NSF. j DNA from dirt, and we have a lot of dirt in All three sites yielded Neanderthal nu- archaeological sites,” says archaeologist clear and mtDNA, with the biggest surprise

With reporting by Jocelyn Kaiser. Marie Soressi of Leiden University. coming from the small amount of nuclear FILMS SCIENTIFIC TRUEBA/MADRID JAVIER © PHOTO:

222 16 APRIL 2021 • VOL 372 ISSUE 6539 sciencemag.org SCIENCE

Published by AAAS DNA from multiple Neanderthals in Estat- BIOMEDICINE uas cave. Nuclear DNA from a Neanderthal male in the deepest layer, dating to about 113,000 years ago, linked him to early Nean- Lab-grown embryos mix human derthals who lived about 120,000 years ago in and in caves in Belgium and Germany. and monkey cells But two female Neanderthals who lived in Estatuas cave later, about 100,000 years Insights from these chimeras could boost efforts to grow ago, had nuclear DNA more closely match- replacement human organs in livestock ing that of later, “classic” Neanderthals, including those who lived less than 70,000 years ago at in Croatia and By Mitch Leslie the human cells showed staying power: Af- 60,000 to 80,000 years ago at Chagyrskaya ter 13 days, they were still present in about cave, says co-author and paleoanthropo- y slipping human stem cells into the one-third of the chimeras. The human cells logist Juan Luis Arsuaga of the Complutense embryos of other animals, we might seemed to integrate with the monkey cells University of Madrid. someday grow new organs for people and had begun to specialize into cell types At the same time, the more plentiful with faltering hearts or kidneys. In that would develop into different organs. mtDNA from Estatuas cave shows declining a step toward that goal, researchers By analyzing gene activity, the research- diversity. Neanderthals in the cave 113,000 have created the first embryos with a ers identified molecular pathways that years ago had at least three types of mtDNA. Bmixture of human and monkey cells. These were switched on or turned up in the chi- Downloaded from But the cave’s Neanderthals 80,000 and chimeras could help scientists hone tech- meras, possibly promoting integration be- 107,000 years ago had only one type. Exist- niques for growing human tissue in species tween human and monkey cells. Izpisúa ing ancient DNA from Neanderthal bones better suited for transplants, such as pigs. Belmonte says manipulating some of those and teeth had also pointed to a falloff in ge- “The paper is a landmark in the stem cell pathways may help human cells survive in netic diversity over the same period. and interspecies chimera fields,” says stem embryos of species “more appropriate for

Arsuaga suggests Neanderthals thrived cell biologist Alejandro De Los Angeles of regenerative medicine.” http://science.sciencemag.org/ and diversified during the warm, moist inter- Yale University. The findings hint at mech- Still, the human and monkey cells didn’t glacial period that started 130,000 years ago. anisms by which cells of one species can quite mesh, notes UM stem cell biologist But about 110,000 years ago, temperatures in adjust to survive in the embryo of another, Andrew Crane. The human cells often stuck Europe dipped suddenly as a new glacial pe- adds Daniel Garry, a stem cell biologist at the together, making him wonder whether riod set in. Soon after, all but one lineage of University of Minnesota (UM), Twin Cities. there’s “another barrier that we aren’t see- Neanderthals disappeared. Members of the In 2017, researchers reported ing” that could prevent human surviving lineage repopulated Europe during growing pancreases from cells from thriving if the em- later, relatively warm spells, with some tak- mouse stem cells inserted into The chimeras bryos were to develop further. ing shelter in Estatuas cave. rat embryos. Transplanting the “can’t experience In the United States , federal

Those survivors and their descen- organs into mice with diabe- funding cannot be used to cre- on April 18, 2021 dants include what Arsuaga calls the “fa- tes eliminated the disease. But pain and aren’t ate certain types of chimeras, mous” classic Neanderthals, such as skulls cells from more distantly re- including early nonhuman from Vindija and La Ferrassie in France. lated species, such as pigs and conscious.” primate embryos containing He notes they had bigger brains—up to humans, haven’t gotten along Katrien Devolder, human stem cells. The new 1750 cubic centimeters (cm3)—than earlier as well. That same year, devel- University of Oxford study was performed in China Neanderthals, whose cranial capacities opmental biologist Juan Carlos and funded by Chinese govern- were no larger than 1400 cm3. Arsuaga says Izpisúa Belmonte of the Salk Institute for ment sources, a Spanish university, and a this mirrors a similar pattern in modern Biological Studies and colleagues reported U.S. foundation. Bioethicist Karen Maschke humans in Africa, who also underwent a injecting human stem cells into pig embryos. of the Hastings Center in New York says she surge in brain size and multiple population After the embryos had developed in surro- is satisfied that the work, which passed lay- replacements with the onset of the ice age. gate mother pigs for 3 to 4 weeks, only about ers of institutional review and drew on ad- “This pattern—dispersal over perhaps one in 100,000 of their cells were human. vice from two independent bioethicists, was long distances and population replacement The pig study used human skin cells that performed responsibly. or admixture—is one that we find almost had been reprogrammed into stem cells. Human-monkey chimeras do raise a everywhere we look,” in humans or other But so-called extended pluripotent stem worry, addressed in a report released last mammals, says Beth Shapiro, a molecular (EPS) cells, made by exposing stem cells week by the National Academies of Sci- biologist at the University of California, to a certain molecular cocktail, can spawn ences, Engineering, and Medicine (p. 218): Santa Cruz. a greater variety of tissues. In the new that human nerve cells might enter ani- Cave dirt DNA is likely to yield more clues. study, Izpisúa Belmonte, reproductive bio- mals’ brains and alter their mental capa- Paleogeneticist Viviane Slon, a co-author of logist Weizhi Ji of Kunming University of bilities. But that concern is moot for the the Science paper now at Tel Aviv Univer- Science and Technology, and colleagues chimeras in this study because they don’t sity, says she and the MPI-EVA team are tested those more capable cells in a closer have a nervous system. They “can’t experi- analyzing ancient DNA from sediments at human relative—cynomolgus monkeys. ence pain and aren’t conscious,” says bio- dozens of sites worldwide. “Hopefully soon, They inserted 25 human EPS cells into each ethicist Katrien Devolder of the University we’ll start to get a very high-resolution, of 132 monkey embryos and reared the chi- of Oxford. “If the human-monkey chimeras fine-scale view of ancient humans and who meras in culture dishes for up to 20 days. were allowed to develop further,” she says, was where at what time,” she says. j The team reports this week in Cell that “that would be a very different story.” j

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