thescientist--2020-09-01--How Groups of Cells Cooperate to Build Organs and Organisms

Efforts to use regenerative medicine—which seeks to address ailments as diverse as birth defects , traumatic injury , aging , degenerative disease , and the disorganized growth of cancer—would be greatly aided by solving one fundamental puzzle : How do cellular collectives orchestrate the building of complex , three-dimensional structures ?
While genomes predictably encode the proteins present in cells , a simple molecular parts list does not tell us enough about the anatomical layout or regenerative potential of the body that the cells will work to construct .
Genomes are not a blueprint for anatomy , and genome editing @ @ @ @ @ @ @ it ’ s very hard to infer which genes to tweak , and how , to achieve desired complex anatomical outcomes .
Similarly , stem cells generate the building blocks of organs , but the ability to organize specific cell types into a working human hand or eye has been and will be beyond the grasp of direct manipulation for a very long time .
But researchers working in the fields of synthetic morphology and regenerative biophysics are beginning to understand the rules governing the plasticity of organ growth and repair .
Rather @ @ @ @ @ @ @ to implement directly at the cellular or molecular level , what if we solved the mystery of how groups of cells cooperate to construct specific multicellular bodies during embryogenesis and regeneration ?
Perhaps then we could figure out how to motivate cell collectives to build whatever anatomical features we want .
New approaches now allow us to target the processes that implement anatomical decision-making without genetic engineering .
In January , using such tools , crafted in my lab at Tufts University ’ s Allen Discovery Center and by computer scientists in Josh @ @ @ @ @ @ @ of Vermont , we were able to create novel living machines , artificial bodies with morphologies and behaviors completely different from the default anatomy of the frog species ( Xenopus laevis ) whose cells we used .
These cells rebooted their multicellularity into a new form , without genomic changes .
This represents an extremely exciting sandbox in which bioengineers can play , with the aim of decoding the logic of anatomical and behavioral control , as well as understanding the plasticity of cells and the relationship of genomes to anatomies .
Deciphering @ @ @ @ @ @ @ truly an interdisciplinary undertaking .
Resolving the whole picture will involve understanding not only the mechanisms by which cells operate , but also elucidating the computations that cells and groups of cells carry out to orchestrate tissue and organ construction on a whole-body scale .
The next generation of advances in this area of research will emerge from the flow of ideas between computer scientists and biologists .
Unlocking the full potential of regenerative medicine will require biology to take the journey computer science has already taken , from focusing on the hardware—the @ @ @ @ @ @ @ cellular operations—to the physiological software that enables networks of cells to acquire , store , and act on information about organ and indeed whole-body geometry .
In the computer world , this transition from rewiring hardware to reprogramming the information flow by changing the inputs gave rise to the information technology revolution .
This shift of perspective could transform biology , allowing scientists to achieve the still-futuristic visions of regenerative medicine .
An understanding of how independent , competent agents such as cells cooperate and compete toward robust outcomes , despite noise and @ @ @ @ @ @ @ engineering .
Swarm robotics , Internet of Things , and even the development of general artificial intelligence will all be enriched by the ability to read out and set the anatomical states toward which cell collectives build , because they share a fundamental underlying problem : how to control the emergent outcomes of systems composed of many interacting units or individuals .
Many types of embryos can regenerate entirely if cut in half , and some species are proficient regenerators as adults .
Axolotls ( Ambystoma mexicanum ) regenerate their limbs , eyes @ @ @ @ @ @ @ portions of the brain throughout life .
Planarian flatworms ( class Turbellaria ) , meanwhile , can regrow absolutely any part of their body ; when the animal is cut into pieces , each piece knows exactly what ’ s missing and regenerates to be a perfect , tiny worm .
The remarkable thing is not simply that growth begins after wounding and that various cell types are generated , but that these bodies will grow and remodel until a correct anatomy is complete , and then they stop .
How does the @ @ @ @ @ @ @ orchestrate individual cell behaviors to get there , and determine when the job is done ?
How does it communicate this information to control underlying cell activities ?
Several years ago , my lab found that Xenopus tadpoles with their facial organs experimentally mixed up into incorrect positions still have largely normal faces once they ’ ve matured , as the organs move and remodel through unnatural paths .
Last year , a colleague at Tufts came to a similar conclusion : the Xenopus genome does not encode a hardwired set of instructions @ @ @ @ @ @ @ metamorphosis from tadpole to frog , but rather encodes molecular hardware that executes a kind of “ error minimization loop , ” comparing the current anatomy to the target frog morphology and working to progressively reduce the difference between them .
Once a rough spatial specification of the layout is achieved , that triggers the cessation of further remodeling .
The deep puzzle of how competent agents such as cells work together to pursue goals such as building , remodeling , or repairing a complex organ to a predetermined spec is well illustrated @ @ @ @ @ @ @ understanding of stem cell specification pathways and axial chemical gradients , scientists really don ’ t know what determines the intricate shape and structure of the flatworm ’ s head .
It is also unknown how planaria perfectly regenerate the same anatomy , even as their genomes have accrued mutations over eons of somatic inheritance .
Because some species of planaria reproduce by fission and regeneration , any mutation that doesn ’ t kill the neoblast—the adult stem cell that gives rise to cells that regenerate new tissue—is propagated to the next generation @ @ @ @ @ @ @ genome shows evidence of this process , and cells in an individual planarian can have different numbers of chromosomes .
Still , fragmented planaria regenerate their body shape with nearly 100 percent anatomical fidelity .
So how do cell groups encode the patterns they build , and how do they know to stop once a target anatomy is achieved ?
What would happen , for example , if neoblasts from a planarian species with a flat head were transplanted into a worm of a species with a round or triangular head that had @ @ @ @ @ @ @ result from this heterogeneous mixture ?
To date , none of the high-resolution molecular genetic studies of planaria give any prediction for the results of this experiment , because so far they have all focused on the cellular hardware , not on the logic of the software—implemented by chemical , mechanical , and electrical signaling among cells—that controls large-scale outcomes and enables remodeling to stop when a specific morphology has been achieved .
Understanding how cells and tissues make real-time anatomical decisions is central not only to achieving regenerative outcomes too complex for @ @ @ @ @ @ @ to solving problems such as cancer .
While the view of cancer as a genetic disorder still largely drives clinical approaches , recent literature supports a view of cancer as cells simply not being able to receive the physiological signals that maintain the normally tight controls of anatomical homeostasis .
Cut off from these patterning cues , individual cells revert to their ancient unicellular lifestyle and treat the rest of the body as external environment , often to ruinous effect .
If we understand the mechanisms that scale single-cell homeostatic setpoints into tissue- @ @ @ @ @ @ @ conditions under which the anatomical error reduction control loop breaks down , we may be able to provide stimuli to gain control of rogue cancer cells without either gene therapy or chemotherapy .
The software of life , which exploits the laws of physics and computation , is enabled by chemical , mechanical , and electrical signaling across cellular networks .
While the chemical and mechanical mechanisms of morphogenesis have long been appreciated by molecular and cell biologists , the role of electrical signaling has largely been overlooked .
But the same reprogrammability @ @ @ @ @ @ @ supports learning , memory , and behavioral plasticity applies to all cells , not just neurons .
Indeed , bacterial colonies can communicate via ionic currents , with recent research revealing brain-like dynamics in which information is propagated across and stored in a kind of proto-body formed by bacterial biofilms .
So it should really come as no surprise that bioelectric signaling is a highly tractable component of morphological outcomes in multicellular organisms .
A few years ago , we studied the electrical dynamics that normally set the size and borders of the @ @ @ @ @ @ @ computer model of this process to shed light on how a range of various brain defects arise from disruptions to this bioelectric signaling .
Our model suggested that specific modifications with mRNA or small molecules could restore the endogenous bioelectric patterns back to their correct layout .
By using our computational platform to select drugs to open existing ion channels in nascent neural tissue or even a remote body tissue , we were able to prevent and even reverse brain defects caused not only by chemical teratogens—compounds that disrupt embryonic development—but by mutations @ @ @ @ @ @ @ we used optogenetics to stimulate electrical activity in various somatic cell types to trigger regeneration of an entire tadpole tail—an appendage with spinal cord , muscle , and peripheral innervation—and to normalize the behavior of cancer cells in tadpoles strongly expressing human oncogenes such as KRAS mutations .
We used a similar approach to trigger posterior regions , such as the gut , to build an entire frog eye .
In both the eye and tail cases , the information on how exactly to build these complex structures , and where all the @ @ @ @ @ @ @ to be specified by the experimenter ; rather , they arose from the cells themselves .
Such findings reveal how ion channel mutations result in numerous human developmental channelopathies , and provide a roadmap for how they may be treated by altering the bioelectric map that tells cells what to build .
We also recently found a striking example of such reprogrammable bioelectrical software in control of regeneration in planaria .
In 2011 , we discovered that an endogenous electric circuit establishes a pattern of depolarization and hyperpolarization in planarian fragments that regulate @ @ @ @ @ @ @ be rebuilt .
Last year , we discovered that this circuit controls the gene expression needed to build a head or tail within six hours of amputation , and by using molecules that make cell membranes permeable to certain ions to depolarize or hyperpolarize cells , we induced fragments of such worms to give rise to a symmetrical two-headed form , despite their wildtype genomes .
Even more shockingly , the worms continued to generate two-headed progeny in additional rounds of cutting with no further manipulation .
In further experiments , we demonstrated @ @ @ @ @ @ @ adjacent cells in the bioelectric network that guides regeneration led worms to regenerate head and brain shapes appropriate to other worm species whose lineages split more than 100 million years ago .
My group has developed the use of voltage-sensitive dyes to visualize the bioelectric pattern memory that guides gene expression and cell behavior toward morphogenetic outcomes .
Meanwhile , my Allen Center colleagues are using synthetic artificial electric tissues made of human cells and computer models of ion channel activity to understand how electrical dynamics across groups of non-neural cells can set @ @ @ @ @ @ @ gene expression , distribution of morphogen molecules , and cell behaviors to orchestrate morphogenesis .
The emerging picture in this field is that anatomical software is highly modular—a key property that computer scientists exploit as subroutines and that most likely contributes in large part to biological evolvability and evolutionary plasticity .
A simple bioelectric state , whether produced endogenously during development or induced by an experimenter , triggers very complex redistributions of morphogens and gene expression cascades that are needed to build various anatomies .
The information stored in the body ’ s @ @ @ @ @ @ @ we understand the dynamics of the biophysical circuits that make the critical morphological decisions .
This permanent editing of the encoded target morphology without genomic editing reveals a new kind of epigenetics , information that is stored in a medium other than DNA sequences and chromatin .
Cells can clearly build structures that are different from their genomic-default anatomical outcomes .
But are cells universal constructors ?
Could they make anything if only we knew how to motivate them to do it ?
The most recent advances in the new field at the @ @ @ @ @ @ @ are driven by synthetic living machines known as biobots .
Built from multiple interacting cell populations , these engineered machines have applications in disease modeling and drug development , and as sensors that detect and respond to biological signals .
We recently tested the plasticity of cells by evolving in silico designs with specific movement and behavior capabilities and used this information to sculpt self-organized growth of aggregated Xenopus skin and muscle cells .
In a novel environment—in vitro , as opposed to inside a frog embryo—swarms of genetically normal cells were able @ @ @ @ @ @ @ minimal sculpting post self-assembly , these cells form “ Xenobots ” with structures , movements , and other behaviors quite different from what might be expected if one simply sequenced their genome and identified them as wildtype X. laevis .
These living creations are a powerful platform to assess and model the computations that these cell swarms use to determine what to build .
Such insights will help us to understand evolvability of body forms , robustness , and the true relationship between genomes and anatomy , greatly potentiating the impact of genome @ @ @ @ @ @ @ for large-scale phenotypes .
Moreover , testing regimes of biochemical , biomechanical , and bioelectrical stimuli in these biobots will enable the discovery of optimal stimuli for use in regenerative therapies and bioengineered organ construction .
Finally , learning to program highly competent individual builders ( cells ) toward group-level , goal-driven behaviors ( complex anatomies ) will significantly advance swarm robotics and help avoid catastrophes of unintended consequences during the inevitable deployment of large numbers of artificial agents with complex behaviors .
The emerging field of synthetic morphology emphasizes a conceptual point @ @ @ @ @ @ @ but thus far resisted by biologists : the hardware-software distinction .
In the 1940s , to change a computer ’ s behavior , the operator had to literally move wires around—in other words , she had to directly alter the hardware .
The information technology revolution resulted from the realization that certain kinds of hardware are reprogrammable : drastic changes in function could be made at the software level , by changing inputs , not the hardware itself .
In molecular biomedicine , we are still focused largely on manipulating the cellular hardware—the @ @ @ @ @ @ @ But evolution has ensured that cellular collectives use this versatile machinery to process information flexibly and implement a wide range of large-scale body shape outcomes .
This is biology ’ s software : the memory , plasticity , and reprogrammability of morphogenetic control networks .
The coming decades will be an extremely exciting time for multidisciplinary efforts in developmental physiology , robotics , and basal cognition to understand how individual cells merge together into a collective with global goals not belonging to any individual cell .
This will drive the creation of new @ @ @ @ @ @ @ brain architectures , but on the multiscale problem-solving capacities of cells and tissues .
Conversely , the insights of cognitive neurobiology and computer science will give us a completely new window on the information processing and decision-making dynamics in cellular collectives that can very effectively be targeted for transformative regenerative therapies of complex organs .
Michael Levin is the director of the Allen Discovery Center at Tufts University and Associate Faculty at Harvard University ’ s Wyss Institute .
Email him at michael.levin @ tufts.edu .
M.L .
thanks Allen Center Deputy Director @ @ @ @ @ @ @ of this story .

ABOVE: MODIFIED FROM © istock.com, LUCKYSTEP48
Efforts to use regenerative medicine—which seeks to address ailments as diverse as birth defects, traumatic injury, aging, degenerative disease, and the disorganized growth of cancer—would be greatly aided by solving one fundamental puzzle: How do cellular collectives orchestrate the building of complex, three-dimensional structures?
While genomes predictably encode the proteins present in cells, a simple molecular parts list does not tell us enough about the anatomical layout or regenerative potential of the body that the cells will work to construct. Genomes are not a blueprint for anatomy, and genome editing is fundamentally limited by the fact that it’s very hard to infer which genes to tweak, and how, to achieve desired complex anatomical outcomes. Similarly, stem cells generate the building blocks of organs, but the ability to organize specific cell types into a working human hand or eye has been and will be beyond the grasp of direct manipulation for a very long time.
But researchers working in the fields of synthetic morphology and regenerative biophysics are beginning to understand the rules governing the plasticity of organ growth and repair. Rather than micromanaging tasks that are too complex to implement directly at the cellular or molecular level, what if we solved the mystery of how groups of cells cooperate to construct specific multicellular bodies during embryogenesis and regeneration? Perhaps then we could figure out how to motivate cell collectives to build whatever anatomical features we want.
New approaches now allow us to target the processes that implement anatomical decision-making without genetic engineering. In January, using such tools, crafted in my lab at Tufts University’s Allen Discovery Center and by computer scientists in Josh Bongard’s lab at the University of Vermont, we were able to create novel living machines, artificial bodies with morphologies and behaviors completely different from the default anatomy of the frog species (Xenopus laevis) whose cells we used. These cells rebooted their multicellularity into a new form, without genomic changes. This represents an extremely exciting sandbox in which bioengineers can play, with the aim of decoding the logic of anatomical and behavioral control, as well as understanding the plasticity of cells and the relationship of genomes to anatomies.
Deciphering how an organism puts itself together is truly an interdisciplinary undertaking.
Deciphering how an organism puts itself together is truly an interdisciplinary undertaking. Resolving the whole picture will involve understanding not only the mechanisms by which cells operate, but also elucidating the computations that cells and groups of cells carry out to orchestrate tissue and organ construction on a whole-body scale. The next generation of advances in this area of research will emerge from the flow of ideas between computer scientists and biologists. Unlocking the full potential of regenerative medicine will require biology to take the journey computer science has already taken, from focusing on the hardware—the proteins and biochemical pathways that carry out cellular operations—to the physiological software that enables networks of cells to acquire, store, and act on information about organ and indeed whole-body geometry.
In the computer world, this transition from rewiring hardware to reprogramming the information flow by changing the inputs gave rise to the information technology revolution. This shift of perspective could transform biology, allowing scientists to achieve the still-futuristic visions of regenerative medicine. An understanding of how independent, competent agents such as cells cooperate and compete toward robust outcomes, despite noise and changing environmental conditions, would also inform engineering. Swarm robotics, Internet of Things, and even the development of general artificial intelligence will all be enriched by the ability to read out and set the anatomical states toward which cell collectives build, because they share a fundamental underlying problem: how to control the emergent outcomes of systems composed of many interacting units or individuals.
(Re)Building a body
Many types of embryos can regenerate entirely if cut in half, and some species are proficient regenerators as adults. Axolotls (Ambystoma mexicanum) regenerate their limbs, eyes, spinal cords, jaws, and portions of the brain throughout life. Planarian flatworms (class Turbellaria), meanwhile, can regrow absolutely any part of their body; when the animal is cut into pieces, each piece knows exactly what’s missing and regenerates to be a perfect, tiny worm.
The remarkable thing is not simply that growth begins after wounding and that various cell types are generated, but that these bodies will grow and remodel until a correct anatomy is complete, and then they stop. How does the system identify the correct target morphology, orchestrate individual cell behaviors to get there, and determine when the job is done? How does it communicate this information to control underlying cell activities?
Several years ago, my lab found that Xenopus tadpoles with their facial organs experimentally mixed up into incorrect positions still have largely normal faces once they’ve matured, as the organs move and remodel through unnatural paths. Last year, a colleague at Tufts came to a similar conclusion: the Xenopus genome does not encode a hardwired set of instructions for the movements of different organs during metamorphosis from tadpole to frog, but rather encodes molecular hardware that executes a kind of “error minimization loop,” comparing the current anatomy to the target frog morphology and working to progressively reduce the difference between them. Once a rough spatial specification of the layout is achieved, that triggers the cessation of further remodeling.
The deep puzzle of how competent agents such as cells work together to pursue goals such as building, remodeling, or repairing a complex organ to a predetermined spec is well illustrated by planaria. Despite having a mechanistic understanding of stem cell specification pathways and axial chemical gradients, scientists really don’t know what determines the intricate shape and structure of the flatworm’s head. It is also unknown how planaria perfectly regenerate the same anatomy, even as their genomes have accrued mutations over eons of somatic inheritance. Because some species of planaria reproduce by fission and regeneration, any mutation that doesn’t kill the neoblast—the adult stem cell that gives rise to cells that regenerate new tissue—is propagated to the next generation. The worm’s incredibly messy genome shows evidence of this process, and cells in an individual planarian can have different numbers of chromosomes. Still, fragmented planaria regenerate their body shape with nearly 100 percent anatomical fidelity.
Permanent editing
of the encoded target morphology without genomic editing reveals a new kind of epigenetics.
So how do cell groups encode the patterns they build, and how do they know to stop once a target anatomy is achieved? What would happen, for example, if neoblasts from a planarian species with a flat head were transplanted into a worm of a species with a round or triangular head that had the head amputated? Which shape would result from this heterogeneous mixture? To date, none of the high-resolution molecular genetic studies of planaria give any prediction for the results of this experiment, because so far they have all focused on the cellular hardware, not on the logic of the software—implemented by chemical, mechanical, and electrical signaling among cells—that controls large-scale outcomes and enables remodeling to stop when a specific morphology has been achieved.
Understanding how cells and tissues make real-time anatomical decisions is central not only to achieving regenerative outcomes too complex for us to manage directly, but also to solving problems such as cancer. While the view of cancer as a genetic disorder still largely drives clinical approaches, recent literature supports a view of cancer as cells simply not being able to receive the physiological signals that maintain the normally tight controls of anatomical homeostasis. Cut off from these patterning cues, individual cells revert to their ancient unicellular lifestyle and treat the rest of the body as external environment, often to ruinous effect. If we understand the mechanisms that scale single-cell homeostatic setpoints into tissue- and organ-level anatomical goal states and the conditions under which the anatomical error reduction control loop breaks down, we may be able to provide stimuli to gain control of rogue cancer cells without either gene therapy or chemotherapy.
Organismal construction During morphogenesis, cells cooperate to reliably build anatomical structures. Many living systems remodel and regenerate tissues or organs despite considerable damage—that is, they progressively reduce deviations from specific target morphologies, and halt growth and remodeling when those morphologies are achieved. Evolution exploits three modalities to achieve such anatomical homeostasis: biochemical gradients, bioelectric circuits, and biophysical forces. These interact to enable the same large-scale form to arise despite significant perturbations. © N.R. FULLER, SAYO-ART, LLC BIOCHEMICAL GRADIENTS The best-known modality concerns diffusible intracellular and extracellular signaling molecules. Gene-regulatory circuits and gradients of biochemicals control cell proliferation, differentiation, and migration. BIOELECTRIC CIRCUITS The movement of ions across cell membranes, especially via voltage-gated ion channels and gap junctions, can establish bioelectric circuits that control large-scale resting potential patterns within and among groups of cells. These bioelectric patterns implement long-range coordination, feedback, and memory dynamics across cell fields. They underlie modular morphogenetic decision-making about organ shape and spatial layout by regulating the dynamic redistribution of morphogens and the expression of genes. BIOMECHANICAL FORCES Cytoskeletal, adhesion, and motor proteins inside and between cells generate physical forces that in turn control cell behavior. These forces result in large-scale strain fields, which enable cell sheets to move and deform as a coherent unit, and thus execute the folds and bends that shape complex organs.
PDF See full infographic: WEB
Bioelectrical software: Beyond the brain
The software of life, which exploits the laws of physics and computation, is enabled by chemical, mechanical, and electrical signaling across cellular networks. While the chemical and mechanical mechanisms of morphogenesis have long been appreciated by molecular and cell biologists, the role of electrical signaling has largely been overlooked. But the same reprogrammability of neural circuits in the brain that supports learning, memory, and behavioral plasticity applies to all cells, not just neurons. Indeed, bacterial colonies can communicate via ionic currents, with recent research revealing brain-like dynamics in which information is propagated across and stored in a kind of proto-body formed by bacterial biofilms. So it should really come as no surprise that bioelectric signaling is a highly tractable component of morphological outcomes in multicellular organisms.
A few years ago, we studied the electrical dynamics that normally set the size and borders of the nascent Xenopus brain, and built a computer model of this process to shed light on how a range of various brain defects arise from disruptions to this bioelectric signaling. Our model suggested that specific modifications with mRNA or small molecules could restore the endogenous bioelectric patterns back to their correct layout. By using our computational platform to select drugs to open existing ion channels in nascent neural tissue or even a remote body tissue, we were able to prevent and even reverse brain defects caused not only by chemical teratogens—compounds that disrupt embryonic development—but by mutations in key neurogenesis genes.
Similarly, we used optogenetics to stimulate electrical activity in various somatic cell types to trigger regeneration of an entire tadpole tail—an appendage with spinal cord, muscle, and peripheral innervation—and to normalize the behavior of cancer cells in tadpoles strongly expressing human oncogenes such as KRAS mutations. We used a similar approach to trigger posterior regions, such as the gut, to build an entire frog eye. In both the eye and tail cases, the information on how exactly to build these complex structures, and where all the cells should go, did not have to be specified by the experimenter; rather, they arose from the cells themselves. Such findings reveal how ion channel mutations result in numerous human developmental channelopathies, and provide a roadmap for how they may be treated by altering the bioelectric map that tells cells what to build.
We also recently found a striking example of such reprogrammable bioelectrical software in control of regeneration in planaria. In 2011, we discovered that an endogenous electric circuit establishes a pattern of depolarization and hyperpolarization in planarian fragments that regulate the orientation of the anterior-posterior axis to be rebuilt. Last year, we discovered that this circuit controls the gene expression needed to build a head or tail within six hours of amputation, and by using molecules that make cell membranes permeable to certain ions to depolarize or hyperpolarize cells, we induced fragments of such worms to give rise to a symmetrical two-headed form, despite their wildtype genomes. Even more shockingly, the worms continued to generate two-headed progeny in additional rounds of cutting with no further manipulation. In further experiments, we demonstrated that briefly reducing gap junction-mediated connectivity between adjacent cells in the bioelectric network that guides regeneration led worms to regenerate head and brain shapes appropriate to other worm species whose lineages split more than 100 million years ago.
My group has developed the use of voltage-sensitive dyes to visualize the bioelectric pattern memory that guides gene expression and cell behavior toward morphogenetic outcomes. Meanwhile, my Allen Center colleagues are using synthetic artificial electric tissues made of human cells and computer models of ion channel activity to understand how electrical dynamics across groups of non-neural cells can set up the voltage patterns that control downstream gene expression, distribution of morphogen molecules, and cell behaviors to orchestrate morphogenesis.
The emerging picture in this field is that anatomical software is highly modular—a key property that computer scientists exploit as subroutines and that most likely contributes in large part to biological evolvability and evolutionary plasticity. A simple bioelectric state, whether produced endogenously during development or induced by an experimenter, triggers very complex redistributions of morphogens and gene expression cascades that are needed to build various anatomies. The information stored in the body’s bioelectric circuits can be permanently rewritten once we understand the dynamics of the biophysical circuits that make the critical morphological decisions. This permanent editing of the encoded target morphology without genomic editing reveals a new kind of epigenetics, information that is stored in a medium other than DNA sequences and chromatin.
Rewriting the planarian body plan Recent work from our group and others has demonstrated that anatomical pattern memories can be rewritten by physiological stimuli and maintained indefinitely without genomic editing. For example, the bioelectric circuit that normally determines head number and location in regenerating planaria can be triggered by brief alterations of ion channel or gap junction activity to alter the animal’s body plan. Due to the circuit’s pattern memory, the animals remain in this altered state indefinitely without further stimulation, despite their wildtype genomes. In other words, the pattern to which the cells build after damage can be changed, leading to a target morphology distinct from the genetic default. © N.R. FULLER, SAYO-ART, LLC First, we soaked a planarian in voltage-sensitive fluorescent dye to observe the bioelectrical pattern across the entire tissue. We then cut the animal to see how this pattern changes in each fragment as it begins to regenerate. We then applied drugs or used RNA interference to target ion channels or gap junctions in individual cells and thus change the pattern of depolarization/hyperpolarization and cellular connectivity across the whole fragment. As a result of the disruption of the body’s bioelectric circuits, the planarian regrows with two heads instead of one, or none at all. When we re-cut the two-headed planarian in plain water, long after the initial drug has left the tissue, the new anatomy persists in subsequent rounds of regeneration.
PDF See full infographic: WEB
Synthetic living machines and beyond
Cells can clearly build structures that are different from their genomic-default anatomical outcomes. But are cells universal constructors? Could they make anything if only we knew how to motivate them to do it?
The most recent advances in the new field at the intersection of developmental biology and computer science are driven by synthetic living machines known as biobots. Built from multiple interacting cell populations, these engineered machines have applications in disease modeling and drug development, and as sensors that detect and respond to biological signals. We recently tested the plasticity of cells by evolving in silico designs with specific movement and behavior capabilities and used this information to sculpt self-organized growth of aggregated Xenopus skin and muscle cells. In a novel environment—in vitro, as opposed to inside a frog embryo—swarms of genetically normal cells were able to reimagine their multicellular form. With minimal sculpting post self-assembly, these cells form “Xenobots” with structures, movements, and other behaviors quite different from what might be expected if one simply sequenced their genome and identified them as wildtype X. laevis.
These living creations are a powerful platform to assess and model the computations that these cell swarms use to determine what to build. Such insights will help us to understand evolvability of body forms, robustness, and the true relationship between genomes and anatomy, greatly potentiating the impact of genome editing tools and making genomics more predictive for large-scale phenotypes. Moreover, testing regimes of biochemical, biomechanical, and bioelectrical stimuli in these biobots will enable the discovery of optimal stimuli for use in regenerative therapies and bioengineered organ construction. Finally, learning to program highly competent individual builders (cells) toward group-level, goal-driven behaviors (complex anatomies) will significantly advance swarm robotics and help avoid catastrophes of unintended consequences during the inevitable deployment of large numbers of artificial agents with complex behaviors.
Understanding how cells and tissues make real-time anatomical decisions is central to achieving regenerative outcomes too complex for us to manage directly.
The emerging field of synthetic morphology emphasizes a conceptual point that has been embraced by computer scientists but thus far resisted by biologists: the hardware-software distinction. In the 1940s, to change a computer’s behavior, the operator had to literally move wires around—in other words, she had to directly alter the hardware. The information technology revolution resulted from the realization that certain kinds of hardware are reprogrammable: drastic changes in function could be made at the software level, by changing inputs, not the hardware itself.
In molecular biomedicine, we are still focused largely on manipulating the cellular hardware—the proteins that each cell can exploit. But evolution has ensured that cellular collectives use this versatile machinery to process information flexibly and implement a wide range of large-scale body shape outcomes. This is biology’s software: the memory, plasticity, and reprogrammability of morphogenetic control networks.
The coming decades will be an extremely exciting time for multidisciplinary efforts in developmental physiology, robotics, and basal cognition to understand how individual cells merge together into a collective with global goals not belonging to any individual cell. This will drive the creation of new artificial intelligence platforms based not on copying brain architectures, but on the multiscale problem-solving capacities of cells and tissues. Conversely, the insights of cognitive neurobiology and computer science will give us a completely new window on the information processing and decision-making dynamics in cellular collectives that can very effectively be targeted for transformative regenerative therapies of complex organs.
Michael Levin is the director of the Allen Discovery Center at Tufts University and Associate Faculty at Harvard University’s Wyss Institute. Email him at michael.levin@tufts.edu. M.L. thanks Allen Center Deputy Director Joshua Finkelstein for suggestions on the drafts of this story.


thescientist--2020-09-01--Infographic: Dialing Down the Glitz

Infographic: Dialing Down the Glitz

In some finch species , BCO2 , a gene that encodes a carotenoid-destroying enzyme , is expressed in many female @ @ @ @ @ many male feathers .
This generates dramatic sexual dichromatism that makes males dazzle while females @ @ @ @ @ common canaries , which are not sexually dichromatic , both males and females have little @ @ @ @ @ .

In some finch species, BCO2, a gene that encodes a carotenoid-destroying enzyme, is expressed in many female finch feathers but not in many male feathers. This generates dramatic sexual dichromatism that makes males dazzle while females look relatively drab. In common canaries, which are not sexually dichromatic, both males and females have little BCO2 expression in their feathers.
© Kelly Finan
Read the full story.


thescientist--2020-09-01--The Peopling of South America

The Peopling of South America

In 2007 , while searching for signs of ancient human inhabitants of the Andes mountain range , more than 4,300 meters above sea level , Kurt Rademaker came across a field littered with chunks of obsidian—some of them fashioned into tools .
“ There were hundreds and hundreds of them , ” recalls Rademaker , then a graduate student at the University of Maine .
“ Adjacent to this open-air workshop , just up above it on the hillside , was a beautiful rock shelter .
.
.
.
I just had a gut feeling that it was the kind @ @ @ @ @ @ @ looking for.
” A decade earlier , Rademaker ’ s advisor , archaeologist Daniel Sandweiss , had made the unexpected discovery of flakes and tools made of obsidian , a volcanic rock , in excavations at one of the oldest archaeological sites in South America .
Quebrada Jaguay , which dates to 13,000–11,000 years ago , sits along the Peruvian coast , where there are no natural deposits of obsidian .
Sandweiss and his colleagues had analyzed the elements in the artifacts and found that they were likely from a source in the @ @ @ @ @ @ @ ancient people at Quebrada Jaguay had probably split their time between the coast and the highlands .
Curious about the early inhabitants of the Andes , Rademaker used the obsidian finding as a clue and began searching for early highland sites in an area with deposits of the rock .
Rademaker struck pay dirt with his 2007 discovery : the site had clear evidence of human activity , including beads made of bone and hundreds of stone tools .
Carbon dating of food residue and collagen from animal bones on the floor of @ @ @ @ @ @ @ pinned that activity to as early as 12,500 years before present ( BP ) , more than 1,000 years before the oldest previously dated Andean archaeological sites .
The finding of such early occupation of the Andes upended some assumptions about the ancient people of the Americas , says Rademaker , now a professor at Michigan State University .
For example , scientists generally thought that before 11,000 or so years ago , the Andes would have been covered with glaciers or otherwise too cold for humans to inhabit .
But in addition @ @ @ @ @ @ @ , analyses of the geology at Cuncaicha revealed that “ ice was already well in retreat way before people arrived , ” Rademaker says , and the environment would have been about as warm as it is today , temperate enough for human habitation .
Researchers had also previously thought that the low-oxygen environment of the high Andes would have forced ancient people to stick to lower altitudes after their initial migration into the continent , says Rademaker .
Yet Quebrada Jaguay and other nearby sites along the coast have been dated to @ @ @ @ @ @ @ .
“ That suggested a more rapid colonization process of a very challenging environment , ” he says .
Research on Cuncaicha is just one of the many recent inquiries into the peopling of South America that are challenging previous assumptions about how migrations , cultures , and ancestries shaped that continent ’ s human landscape .
In addition to archaeological clues , genetic investigations of ancient and modern humans are yielding intriguing new details about when and how the continent was populated .
But many fundamental questions remain unresolved , such as @ @ @ @ @ @ @ and how they spread across the continent , and a coherent picture of its prehistory has yet to emerge .
When anthropologist Tom Dillehay , now at Vanderbilt University , began working at a site called Monte Verde near the southern tip of Chile in 1977 , most archaeologists thought the first humans moved into South America from North America about 11,000 years ago , he says .
But in 1988 , he and a colleague published an analysis of traces of human occupation at Monte Verde—including stone tools , mastodon bones with @ @ @ @ @ @ @ of burned plants—that were dated to 12,500 BP .
( They also unearthed charcoal and what might have been stone tools from a layer dated to 33,000 BP , but Dillehay now says he doesn ’ t think the evidence is strong enough to support occupation of the site that early . )
More recently , Dillehay ’ s group reported new excavations that unearthed human-linked materials dated to between 18,000 and 15,000 BP .
That timeline positioned Monte Verde as the oldest archaeological site in South America , says Lars Fehren-Schmitz , @ @ @ @ @ @ @ California , Santa Cruz , who was not involved in Dillehay ’ s work .
The site “ shows that people must have reached southern South America quite quickly after they even entered North America.
” While the timing is unclear of humans ’ first migrations out of a region known as Beringia—which spanned parts of present-day Siberia and Alaska—and into North America , most archaeologists put the date at no more than about 20,000 years ago .
The dating of Monte Verde suggests , then , that people made it from one @ @ @ @ @ @ @ other—about 10,000 miles—remarkably quickly .
Several other sites in South America similarly point to a quick dispersal , Fehren-Schmitz notes .
“ We actually have a bunch of archaeological sites that are securely dated that fall into the time range of 14,000 to 12,000 BP , that tell us that people were more or less all over South America quite early after the initial peopling of the Americas in general.
” There ’ s wide variation in the style of artifacts found at different early sites , such as projectile points and stone @ @ @ @ @ @ @ indicating that groups on the continent quickly developed diverse cultures and technologies , Dillehay says .
“ People adapted to a very wide range of different environmental zones and habitats , ” exploiting the various food sources they offered .
Some studies point to an even earlier occupation of South America than that indicated by Dillehay ’ s most recent work at Monte Verde .
For example , research on a site in Brazil yielded stone artifacts associated with charcoal remnants , suggesting the possibility of cooking fires , that researchers carbon dated @ @ @ @ @ @ @ And a site in Uruguay called Arroyo del Vizcaíno , dated to between 30,000 and 27,000 BP , yielded more than 1,000 bones of ancient animals , some with apparent cut marks .
It ’ s not widely accepted that such remnants truly represent evidence of ancient human activity .
In some cases , what are presented as artifacts likely aren ’ t really human-made , says Dillehay ; other times , genuine artifacts might have been carried by floodwaters into layers that don ’ t reflect their true ages .
Eric Boëda @ @ @ @ @ @ @ , says the lack of consensus that humans occupied the Americas before the period known as the Last Glacial Maximum , which extended from about 26,500 to 20,000 years ago , reflects “ denialism ” in the field .
Boëda , who has worked at archaeological digs all over the world , including some of the Brazilian sites with purported human activity dating to more than 20,000 years ago , says artifacts that would be quickly accepted as human-made tools if they turned up in Europe or Africa are discounted when they are @ @ @ @ @ @ @ belief that the Americas weren ’ t home to any people until more recently .
Boëda says there ’ s not enough evidence yet to understand how and when people first reached South America or what subsequent migrations might have taken place to or within the continent .
One possibility , he says , is that people came from East Asia through Alaska via an ice-free corridor more than 24,000 years ago , before complete glaciation made overland travel through North America impossible during the Last Glacial Maximum .
( See “ Where @ @ @ @ @ @ @ below . )
In the view of André Strauss , an archaeologist at the University of São Paulo in Brazil , such an early occupation is possible—but he says he thinks that such an extraordinary claim requires more evidence .
“ I don ’ t find any of the evidence available at this point [ convincing ] without a doubt , ” he writes in an email to The Scientist .
One gaping hole in the evidence is the lack of human remains in the Americas from before the Last Glacial Maximum , @ @ @ @ @ @ @ !
” Indeed , the oldest human remains found in South America thus far date to just 10,000 years ago or so .
But while these fossils don ’ t shed much light on how long the continent has been occupied , they can reveal a lot about its ancient inhabitants .
For example , skeletons at the Brazilian cave Lapa do Santo are among the earliest remains found in South America , and they paint an intriguing picture of the people who called it home , says Strauss , who ’ s @ @ @ @ @ @ @ he and his colleagues reported in 2016 , some skeletons at Lapa do Santo revealed signs of elaborate mortuary rituals involving cutting apart bodies , burning parts of them , and burying several individuals together .
And while archaeologists have long envisioned early South Americans as highly mobile hunter-gatherers , he says , isotopic analyses revealed that the people at Lapa do Santo consumed food and water from a circumscribed area that he estimates to be around 1,000 square kilometers , and were thus relatively settled .
As archaeologists continue to search for @ @ @ @ @ @ @ the continent ’ s prehistory , researchers are also mining modern genomes , together with ancient DNA from sites such as Lapa do Santo , for data that reveal more about ancient South Americans .
In late 2018 , two studies compared human genomes from across the Americas to infer that there were multiple waves of migration from North to South America .
One of the studies , led by geneticist David Reich of Harvard University , analyzed both ancient and modern genomes and surmised that before European settlers arrived , there were @ @ @ @ @ @ @ .
One wave was made up of people genetically related to the Clovis culture , distinguished by a style of tools found across much of North America , the researchers concluded .
Beginning around 9,000 years ago , that lineage was partly replaced by a separate wave of migrants to South America .
The second study , led by Eske Willerslev of the University of Copenhagen , included 15 ancient genomes unearthed in North and South America .
It found evidence for two waves of migration into the southern continent , one about @ @ @ @ @ @ @ by a dispersal of people who had diverged from North American groups and spent time in Central America .
While the results are somewhat similar to those of the paper from Reich and colleagues , Willerslev says his study didn ’ t find the widespread replacement of the first migrants that Reich ’ s did .
Rather , Willerslev ’ s data suggested the two groups intermixed with one another .
Willerslev ’ s team also turned up a puzzling signal in 10,000-year-old skeletons from Brazil : between 2 percent and 6 percent @ @ @ @ @ @ @ to modern-day inhabitants of the Andaman Islands in Southeast Asia than to any other population .
Willerslev points out that the ancestors of the Andaman Islanders once occupied a much broader swath of East Asia , making it plausible that some could have crossed the land bridge into North America—although that leaves open the question of why their genes haven ’ t appeared in any ancient or modern North American samples .
As for the possibility that they could have crossed the Pacific by boat , “ in many people ’ s minds @ @ @ @ @ @ @ a very unrealistic scenario .
.
.
to have done a journey like that ” so early in prehistory , Willerslev says .
How genetic traces of this population have shown up in Brazil and nowhere else in the Americas “ is still a mystery , ” he adds .
Other recent genetic studies have homed in on what occurred in particular regions during South America ’ s prehistory .
In a study published shortly before the Reich and Willerslev papers , for example , a team led by Anna Di Rienzo of @ @ @ @ @ @ @ sequences of ancient human remains found in the Andes with the sequences of modern people living in the Andes and nearby lowlands .
While that study didn ’ t indicate when people might first have begun settling the Andes , it did reveal that the highland and lowland populations began to diverge around 9,000 years ago , says coauthor John Lindo , an anthropologist now at Emory University .
“ That ’ s pretty early to start [ having established populations ] at 9,000 years , I think , ” he says .
@ @ @ @ @ @ @ Fehren-Schmitz agrees , noting that in contrast to Eurasia , which experienced multiple mass migrations of humans , South American prehistory overall shows a pattern of populations staying relatively stationary after the initial peopling .
In the case of the Andes and nearby coastal regions , he says , “ the [ west ] coast is actually only a very narrow stretch of land and [ then ] the Andes directly start , so we ’ re talking about distances between populations of a day or two days of travel—like fifty to one @ @ @ @ @ @ @ patterns of genetic distinctness between these groups , which is quite stunning.
” Based on current evidence , says Tábita Hünemeier , a population and evolutionary geneticist at the University of São Paulo in Brazil who conducts genetic studies of indigenous Brazilian groups , present-day Andeans seem to have descended from the wave of migrants that replaced the Clovis-related population , together with a more recent wave that occurred around 4,000 BP .
After the highland and lowland populations divided around 9,000 years ago , the highland population further split into northern and @ @ @ @ @ @ @ study led by Reich and Fehren-Schmitz recently suggested .
Less is known about the dynamics of ancient Amazonian groups , says Hünemeier , but genetic evidence points to an initial arrival of people in the first large migration event .
That population appears to have been replaced by a second wave of migration into the continent , and linguistic evidence indicates these people quickly differentiated into different groups beginning around 9,000 years ago , leading to a panoply of languages , more than 100 of which still exist today .
The current goal @ @ @ @ @ @ @ is “ to figure out how [ people in the second group ] settled Amazonia and how they split , ” as well as “ which was the original group that came to Amazonia.
” In a study published earlier this year , she and her colleagues found modern genetic traces of a population known as the Tupí that dominated the Brazilian coast during the 15th century but had supposedly been driven extinct by European conquerors .
Modern people known as the Tupiniquim , who live in cities and do not speak an @ @ @ @ @ @ @ as descendants of the Tupí , and the researchers found that they do indeed have signals of indigenous ancestry , along with European and African heritage , in their genomes .
Furthermore , their indigenous ancestry was distinct from that of any other modern groups who have been studied .
The team ’ s analysis points to a migration of Tupí people from central Amazonia northeast toward Brazil ’ s coast around 2,000–3,000 years ago , followed by a later migration of a separate Tupí group who traveled southeast but also ultimately expanded @ @ @ @ @ @ @ the first people to reach the Brazilian coast ; archaeological sites with distinctive shell mounds known as sambaquis indicate that others had settled the coast 10,000–8,000 years ago , but they appear to have been completely replaced by the Tupí .
“ We don ’ t know where [ the people who made the shell mounds ] came from .
.
.
and which language they used to speak , ” says Hünemeier , who is now working with ancient DNA to try to learn more about the prehistoric coastal group .
Researchers @ @ @ @ @ @ @ earliest inhabitants would benefit from the discovery of more human remains , researchers say , but such finds have been hard to come by—which itself raises questions , Dillehay says , of what happened to the bodies of ancient people .
“ One major thing is to understand the mortuary practices [ of ancient people in the Americas ] a little better , ” he says .
With or without remains , more archaeological sites in parts of Central America and the northwest coast of South America are needed to reveal how people @ @ @ @ @ @ @ and how many waves of migration there were , Boëda notes .
The oldest widely accepted archaeological sites in Central America date to around 11,500 BP , and the oldest human remains in the area to about 6,000 BP .
The region ’ s acidic soil inhibits preservation of human remains , and some archaeologists suspect that rising sea levels at the end of the Last Glacial Maximum may have swallowed some of the earliest signs of human activity .
Thanks to newer technologies and approaches , archaeologists can now extract more information @ @ @ @ @ @ @ .
These methods include genome analysis and stable isotope analysis , which allows researchers to determine whether an individual ’ s early diet was made up of plants and animals from the local area or from further afield .
This in turn can reveal whether a person was from the area where their remains were found or had migrated there .
With these new methods , says Rademaker , “ each [ new ] site is going to tell us something incredibly useful .
”

ABOVE: © SHUTTERSTOCK.COM, DICOGM
In 2007, while searching for signs of ancient human inhabitants of the Andes mountain range, more than 4,300 meters above sea level, Kurt Rademaker came across a field littered with chunks of obsidian—some of them fashioned into tools. “There were hundreds and hundreds of them,” recalls Rademaker, then a graduate student at the University of Maine. “Adjacent to this open-air workshop, just up above it on the hillside, was a beautiful rock shelter. . . . I just had a gut feeling that it was the kind [of site] I had been looking for.”
A decade earlier, Rademaker’s advisor, archaeologist Daniel Sandweiss, had made the unexpected discovery of flakes and tools made of obsidian, a volcanic rock, in excavations at one of the oldest archaeological sites in South America. Quebrada Jaguay, which dates to 13,000–11,000 years ago, sits along the Peruvian coast, where there are no natural deposits of obsidian. Sandweiss and his colleagues had analyzed the elements in the artifacts and found that they were likely from a source in the nearby Andes. The researchers suggested that ancient people at Quebrada Jaguay had probably split their time between the coast and the highlands. Curious about the early inhabitants of the Andes, Rademaker used the obsidian finding as a clue and began searching for early highland sites in an area with deposits of the rock.
Rademaker struck pay dirt with his 2007 discovery: the site had clear evidence of human activity, including beads made of bone and hundreds of stone tools. Carbon dating of food residue and collagen from animal bones on the floor of the rock shelter, dubbed Cuncaicha, pinned that activity to as early as 12,500 years before present (BP), more than 1,000 years before the oldest previously dated Andean archaeological sites.
In late 2018, two studies compared human genomes from across the Americas to infer that there were multiple waves of migration from North to South America.
The finding of such early occupation of the Andes upended some assumptions about the ancient people of the Americas, says Rademaker, now a professor at Michigan State University. For example, scientists generally thought that before 11,000 or so years ago, the Andes would have been covered with glaciers or otherwise too cold for humans to inhabit. But in addition to their archaeological work on the site, analyses of the geology at Cuncaicha revealed that “ice was already well in retreat way before people arrived,” Rademaker says, and the environment would have been about as warm as it is today, temperate enough for human habitation.
Researchers had also previously thought that the low-oxygen environment of the high Andes would have forced ancient people to stick to lower altitudes after their initial migration into the continent, says Rademaker. Yet Quebrada Jaguay and other nearby sites along the coast have been dated to about the same time period as Cuncaicha. “That suggested a more rapid colonization process of a very challenging environment,” he says.
Research on Cuncaicha is just one of the many recent inquiries into the peopling of South America that are challenging previous assumptions about how migrations, cultures, and ancestries shaped that continent’s human landscape. In addition to archaeological clues, genetic investigations of ancient and modern humans are yielding intriguing new details about when and how the continent was populated. But many fundamental questions remain unresolved, such as when people first arrived in South America and how they spread across the continent, and a coherent picture of its prehistory has yet to emerge.
A shifting archaeological picture
When anthropologist Tom Dillehay, now at Vanderbilt University, began working at a site called Monte Verde in southern Chile in 1977, most archaeologists thought the first humans moved into South America from North America about 11,000 years ago, he says. But in 1988, he and a colleague published an analysis of traces of human occupation at Monte Verde—including stone tools, mastodon bones with cut marks, and hearths with traces of burned plants—that were dated to 12,500 BP. (They also unearthed charcoal and what might have been stone tools from a layer dated to 33,000 BP, but Dillehay now says he doesn’t think the evidence is strong enough to support occupation of the site that early.) More recently, Dillehay’s group reported new excavations that unearthed human-linked materials dated to between 18,000 and 15,000 BP.
That timeline positioned Monte Verde as the oldest archaeological site in South America, says Lars Fehren-Schmitz, a biological anthropologist at the University of California, Santa Cruz, who was not involved in Dillehay’s work. The site “shows that people must have reached southern South America quite quickly after they even entered North America.” While the timing is unclear of humans’ first migrations out of a region known as Beringia—which spanned parts of present-day Siberia and Alaska—and into North America, most archaeologists put the date at no more than about 20,000 years ago. The dating of Monte Verde suggests, then, that people made it from one end of the New World to the other—about 10,000 miles—remarkably quickly. Several other sites in South America similarly point to a quick dispersal, Fehren-Schmitz notes. “We actually have a bunch of archaeological sites that are securely dated that fall into the time range of 14,000 to 12,000 BP, that tell us that people were more or less all over South America quite early after the initial peopling of the Americas in general.”
There’s wide variation in the style of artifacts found at different early sites, such as projectile points and stone tools used for cutting and scraping, indicating that groups on the continent quickly developed diverse cultures and technologies, Dillehay says. “People adapted to a very wide range of different environmental zones and habitats,” exploiting the various food sources they offered.
Some studies point to an even earlier occupation of South America than that indicated by Dillehay’s most recent work at Monte Verde. For example, research on a site in Brazil yielded stone artifacts associated with charcoal remnants, suggesting the possibility of cooking fires, that researchers carbon dated to between 35,000 and 28,000 BP. And a site in Uruguay called Arroyo del Vizcaíno, dated to between 30,000 and 27,000 BP, yielded more than 1,000 bones of ancient animals, some with apparent cut marks. It’s not widely accepted that such remnants truly represent evidence of ancient human activity. In some cases, what are presented as artifacts likely aren’t really human-made, says Dillehay; other times, genuine artifacts might have been carried by floodwaters into layers that don’t reflect their true ages.
Eric Boëda, an archaeologist at Paris University Nanterre, says the lack of consensus that humans occupied the Americas before the period known as the Last Glacial Maximum, which extended from about 26,500 to 20,000 years ago, reflects “denialism” in the field. Boëda, who has worked at archaeological digs all over the world, including some of the Brazilian sites with purported human activity dating to more than 20,000 years ago, says artifacts that would be quickly accepted as human-made tools if they turned up in Europe or Africa are discounted when they are discovered in Brazil because of a longstanding belief that the Americas weren’t home to any people until more recently.
DIGGING DEEP: Ancient sites such as the Cuncaicha rock shelter (left) in Peru and Lapa do Santo in Brazil, where archaeologists unearthed this skull (right, top) and projectile point (right, bottom), are adding new details to the picture of South America’s prehistory. KURT RADEMAKER; ALBERTO BARIONI; ANDRÉ STRAUSS
Boëda says there’s not enough evidence yet to understand how and when people first reached South America or what subsequent migrations might have taken place to or within the continent. One possibility, he says, is that people came from East Asia through Alaska via an ice-free corridor more than 24,000 years ago, before complete glaciation made overland travel through North America impossible during the Last Glacial Maximum. (See “Where Early South American Migrants Came From” below.)
In the view of André Strauss, an archaeologist at the University of São Paulo in Brazil, such an early occupation is possible—but he says he thinks that such an extraordinary claim requires more evidence. “I don’t find any of the evidence available at this point [convincing] without a doubt,” he writes in an email to The Scientist. One gaping hole in the evidence is the lack of human remains in the Americas from before the Last Glacial Maximum, he adds—“not a single tooth!”
Indeed, the oldest human remains found in South America thus far date to just 10,000 years ago or so. But while these fossils don’t shed much light on how long the continent has been occupied, they can reveal a lot about its ancient inhabitants. For example, skeletons at the Brazilian cave Lapa do Santo are among the earliest remains found in South America, and they paint an intriguing picture of the people who called it home, says Strauss, who’s worked extensively on the site. As he and his colleagues reported in 2016, some skeletons at Lapa do Santo revealed signs of elaborate mortuary rituals involving cutting apart bodies, burning parts of them, and burying several individuals together. And while archaeologists have long envisioned early South Americans as highly mobile hunter-gatherers, he says, isotopic analyses revealed that the people at Lapa do Santo consumed food and water from a circumscribed area that he estimates to be around 1,000 square kilometers, and were thus relatively settled.
As archaeologists continue to search for more human remains to help flesh out the continent’s prehistory, researchers are also mining modern genomes, together with ancient DNA from sites such as Lapa do Santo, for data that reveal more about ancient South Americans.
Evidence of Early Human Presence in South America Excavations of South American sites containing traces of ancient human activity have suggested that humans reached the southern region of the continent at least 14,500 years before present (BP)—remarkably quickly after first entering the Americas—and that they soon developed diverse technologies across different sites. But the picture yielded by these archaeological investigations is a patchwork, leaving open key questions, such as whether the first humans migrated south along the Pacific coast or by some other route. The history is further complicated by disputed claims (examples marked by red headers with asterisks) that certain sites reflect a much earlier occupation of the continent beginning more than 20,000 BP. © JULIA GALOTTA Cuncaicha Site: Rock shelter at 4,480 meters in elevation dated to ~12,400 BP Contains: Remains of plants and animals consumed as food and other human-made debris; human remains; stone tools Significance: Oldest known site in high Andes; shows humans had adapted to high altitudes Quebrada Jaguay Site: Remains of a seasonally occupied fishing village dated to ~13,000–11,000 BP Contains: Seafood remnants; hearths; tools made of obsidian and other types of stone Significance: Demonstrates that people were using marine food sources and, together with Cuncaicha, that coastal people had contact with the Andean highlands Monte Verde Site: Settlement dated to ~18,500–15,000 BP Contains: Remains of plants and animals consumed as food; charcoal; wooden artifacts; stone tools Significance: Pushed back the date of earliest known human occupation of the Americas by as much as 5,000 years Lapa do Santo Site: Cave with signs of human activity dated to as early as ~12,700–11,700 BP Contains: Remains of 50 people, dating as far back as 10,600–9,700 BP, who were buried at the site; stone tools; rock art; animal remnants Significance: Yielded ancient DNA for analysis and new insight into early cultures Arroyo del Vizcaíno* Site: Assembly of more than 1,000 animal bones dated to ~30,000–27,000 BP Contains: Bones of giant sloths and other large animals, some with apparent cut marks that may indicate they were butchered by humans; purported stone tools Criticisms include: The bones could have been carried to the site by flowing water rather than human activity; the scenario the authors propose (including human transport of large, killed animals) is not consistent with the way known hunter-gatherer groups operate. Toca do Sítio do Meio* Site: Rock shelter with signs of human occupation dated to ~35,000–28,000 BP Contains: Charcoal remnants; purported stone tools Criticisms include: Rocks resembling stone tools could have come about through natural geological processes or been made by monkeys.
PDF See full infographic: WEB
Clues in the genome
In late 2018, two studies compared human genomes from across the Americas to infer that there were multiple waves of migration from North to South America. One of the studies, led by geneticist David Reich of Harvard University, analyzed both ancient and modern genomes and surmised that before European settlers arrived, there were four waves of migration into South America. One wave was made up of people genetically related to the Clovis culture, distinguished by a style of tools found across much of North America, the researchers concluded. Beginning around 9,000 years ago, that lineage was partly replaced by a separate wave of migrants to South America.
The second study, led by Eske Willerslev of the University of Copenhagen, included 15 ancient genomes unearthed in North and South America. It found evidence for two waves of migration into the southern continent, one about 14,000 BP from North America, followed by a dispersal of people who had diverged from North American groups and spent time in Central America. While the results are somewhat similar to those of the paper from Reich and colleagues, Willerslev says his study didn’t find the widespread replacement of the first migrants that Reich’s did. Rather, Willerslev’s data suggested the two groups intermixed with one another.
Willerslev’s team also turned up a puzzling signal in 10,000-year-old skeletons from Brazil: between 2 percent and 6 percent of their genomes were more closely related to modern-day inhabitants of the Andaman Islands in Southeast Asia than to any other population. Willerslev points out that the ancestors of the Andaman Islanders once occupied a much broader swath of East Asia, making it plausible that some could have crossed the land bridge into North America—although that leaves open the question of why their genes haven’t appeared in any ancient or modern North American samples. As for the possibility that they could have crossed the Pacific by boat, “in many people’s minds, at least, it’s a very unrealistic scenario . . . to have done a journey like that” so early in prehistory, Willerslev says. How genetic traces of this population have shown up in Brazil and nowhere else in the Americas “is still a mystery,” he adds.
Thanks to newer technologies and approaches, archaeologists can now mine more information from sites once they’re identified.
Other recent genetic studies have homed in on what occurred in particular regions during South America’s prehistory. In a study published shortly before the Reich and Willerslev papers, for example, a team led by Anna Di Rienzo of the University of Chicago compared the whole-genome sequences of ancient human remains found in the Andes with the sequences of modern people living in the Andes and nearby lowlands. While that study didn’t indicate when people might first have begun settling the Andes, it did reveal that the highland and lowland populations began to diverge around 9,000 years ago, says coauthor John Lindo, an anthropologist now at Emory University. “That’s pretty early to start [having established populations] at 9,000 years, I think,” he says. “That’s pretty amazing.”
Fehren-Schmitz agrees, noting that in contrast to Eurasia, which experienced multiple mass migrations of humans, South American prehistory overall shows a pattern of populations staying relatively stationary after the initial peopling. In the case of the Andes and nearby coastal regions, he says, “the [west] coast is actually only a very narrow stretch of land and [then] the Andes directly start, so we’re talking about distances between populations of a day or two days of travel—like fifty to one hundred miles. And still we see patterns of genetic distinctness between these groups, which is quite stunning.”
Based on current evidence, says Tábita Hünemeier, a population and evolutionary geneticist at the University of São Paulo in Brazil who conducts genetic studies of indigenous Brazilian groups, present-day Andeans seem to have descended from the wave of migrants that replaced the Clovis-related population, together with a more recent wave that occurred around 4,000 BP. After the highland and lowland populations divided around 9,000 years ago, the highland population further split into northern and southern populations around 5,800 BP, a study led by Reich and Fehren-Schmitz recently suggested.
Less is known about the dynamics of ancient Amazonian groups, says Hünemeier, but genetic evidence points to an initial arrival of people in the first large migration event. That population appears to have been replaced by a second wave of migration into the continent, and linguistic evidence indicates these people quickly differentiated into different groups beginning around 9,000 years ago, leading to a panoply of languages, more than 100 of which still exist today. The current goal of her work, Hünemeier says, is “to figure out how [people in the second group] settled Amazonia and how they split,” as well as “which was the original group that came to Amazonia.”
In a study published earlier this year, she and her colleagues found modern genetic traces of a population known as the Tupí that dominated the Brazilian coast during the 15th century but had supposedly been driven extinct by European conquerors. Modern people known as the Tupiniquim, who live in cities and do not speak an indigenous language, have long identified themselves as descendants of the Tupí, and the researchers found that they do indeed have signals of indigenous ancestry, along with European and African heritage, in their genomes. Furthermore, their indigenous ancestry was distinct from that of any other modern groups who have been studied.
The team’s analysis points to a migration of Tupí people from central Amazonia northeast toward Brazil’s coast around 2,000–3,000 years ago, followed by a later migration of a separate Tupí group who traveled southeast but also ultimately expanded along the coast. They were not the first people to reach the Brazilian coast; archaeological sites with distinctive shell mounds known as sambaquis indicate that others had settled the coast 10,000–8,000 years ago, but they appear to have been completely replaced by the Tupí. “We don’t know where [the people who made the shell mounds] came from . . . and which language they used to speak,” says Hünemeier, who is now working with ancient DNA to try to learn more about the prehistoric coastal group.
Genetic Insights About the First South Americans Two studies published in late 2018, one led by David Reich of Harvard University (results depicted in cool colors) and the other by Eske Willerslev of the University of Copenhagen (results in warm colors), compared ancient and modern genomes from across the Americas to infer that there were multiple waves of migration from the northern continent to the southern one. ILLUSTRATION BY © JULIA GALOTTA; DATA TAKEN FROM CELL, 175:1185–97.E22, 2018; SCIENCE, 362:EAAV2621, 2018.
PDF See full infographic: WEB
Looking forward, looking back
Researchers’ understanding of South America’s earliest inhabitants would benefit from the discovery of more human remains, researchers say, but such finds have been hard to come by—which itself raises questions, Dillehay says, of what happened to the bodies of ancient people. “One major thing is to understand the mortuary practices [of ancient people in the Americas] a little better,” he says.
With or without remains, more archaeological sites in parts of Central America and the northwest coast of South America are needed to reveal how people migrated onto and within the continent, and how many waves of migration there were, Boëda notes. The oldest widely accepted archaeological sites in Central America date to around 11,500 BP, and the oldest human remains in the area to about 6,000 BP. The region’s acidic soil inhibits preservation of human remains, and some archaeologists suspect that rising sea levels at the end of the Last Glacial Maximum may have swallowed some of the earliest signs of human activity.
Thanks to newer technologies and approaches, archaeologists can now extract more information from sites once they’re identified. These methods include genome analysis and stable isotope analysis, which allows researchers to determine whether an individual’s early diet was made up of plants and animals from the local area or from further afield. This in turn can reveal whether a person was from the area where their remains were found or had migrated there. With these new methods, says Rademaker, “each [new] site is going to tell us something incredibly useful.”
Where Early South American Migrants Came From The widely, though not universally, held thinking among researchers in the field is that indigenous Americans came from East Asia at a time when sea levels would have been low enough to form an inhabitable region known as Beringia that spanned what’s now eastern Siberia and western Alaska. According to the Beringian standstill hypothesis, glaciers long prevented movement further into the Americas, so the founding population remained in the region for thousands of years. When the ice melted enough to permit passage, the Beringians moved fast. “I think we have pretty compelling evidence from the Y DNA studies and the mtDNA [mitochondrial DNA] studies that roughly between 15,400 or so years ago and maybe 14,300 . . . we have an expansion of lineages,” says Ben Potter, an archaeologist at Liaocheng University in China. “We have a star-like radiation” of groups that moved into different areas of North America. A caveat, he says, is that no human remains from this period have been found, and there is thus no fossil evidence to show where exactly the earlier initial expansion originated or where the genetic isolation took place. Some studies have challenged the majority view that that expansion represented humans’ first foray into the Americas. In a 2017 Nature paper, for example, paleontologist Kathleen Holen, then at the San Diego Natural History Museum, and colleagues reported finding 130,000-year-old mastodon bones at a site in California that appeared to have been smashed with human-made stone tools. The study was met with skepticism by researchers who said the bones could instead have been broken by other means, such as modern construction equipment. In July of this year, an international team led by Eske Willerslev of the University of Copenhagen garnered headlines with another report in Nature, this one of purportedly human-made tools dating to 33,000 BP in a cave in Mexico. But critics questioned whether the stones in question had truly been shaped by humans. Another disputed idea, known as the Solutrean hypothesis, is based on similarities between tools made by North America’s early Clovis culture and those made by Europe’s Solutrean people between 22,000 and 17,000 BP. Its main proponents, Bruce Bradley of the University of Exeter and the late Dennis Stanford of the Smithsonian National Museum of Natural History, suggested that some Solutreans could have migrated to North America via boats that hugged an ice bridge between the two continents (World Archaeol, 36:459–78, 2004). Other researchers have pointed out what they see as multiple problems with the hypothesis, including the 7,000-year gap between Solutreans’ use of the tools in Europe and the first Clovis site in North America, and a lack of genetic evidence that any early Americans had European ancestry. The Beringian standstill hypothesis continues to undergo revisions as new studies emerge. In 2018, for example, Potter and his colleagues reported a genetic analysis of 11,500-year-old remains of a baby girl found buried in Alaska at a site called Upward Sun. The infant belonged to a previously unknown lineage that split from the ancestors of today’s Native Americans between 22,000 and 18,100 years ago, the researchers suggested. Potter notes that the potential for interbreeding between known populations and extinct lineages such as this can complicate genetic models that estimate how long ago populations diverged, and he says he thinks future discoveries like that made at Upward Sun are likely. “There probably are more of those out there that we just haven’t detected yet,” he says.
Clarification (September 4): The language in the infographic has been updated to reflect the fact that Cuncaicha is the oldest known site in the high Andes, not the Andean region.
Correction (September 8, 2020): The language of the article has been changed to reflect the fact that Monte Verde is in southern Chile, but not near the country's southern tip. The first map has also been updated to correctly show Monte Verde's location. The Scientist regrets the errors.


thescientist--2020-09-01--The Gene that Makes Female Birds Drab

The Gene that Makes Female Birds Drab

The paper M. Gazda et al.
, “ A genetic mechanism for sexual dichromatism in birds , ” Science , 368:1270–74 , 2020 .
Male red siskins ( Spinus cucullatus ) , a species of finch , flaunt orange-red bellies and backs , contrasting with their black heads and dark wing markings .
The females , on the other hand , are mostly muted shades of grey ( though pops of orange-red and black do appear on their bellies and wings ) .
Such differences in coloration between the sexes , called sexual dichromatism , occur in many bird species @ @ @ @ @ @ @ scientists for years .
Geneticist Miguel Carneiro of the Research Centre in Biodiversity and Genetic Resources ( CIBIO ) at the University of Porto in Portugal had previously discovered that a siskin gene called CYP2J19 encodes an enzyme that helps convert yellow carotenoid compounds from seeds in the birds ’ diet into the red carotenoids found in their feathers .
But he wanted to know why this happened only in males , so he and then–graduate student Malgorzata Gazda , together with Pedro Miguel Araújo of the nearby University of Coimbra , studied @ @ @ @ @ @ @ canary .
These birds were created by breeding red siskins with common domestic canaries ( Serinus canaria ) , which are not sexually dichromatic , and then backcrossing them with the common canaries and selecting for birds that are sexually dichromatic .
Apart from their color and sexual dichromatism , mosaic canaries are nearly genetically identical to common canaries .
Gazda sequenced the genomes of the mosaic canaries and compared them to the genomes of four non-dichromatic canary breeds and one slightly dichromatic wild canary .
They found one stretch of the mosaic @ @ @ @ @ @ @ .
They then looked for a region within that stretch that contained only siskin single nucleotide polymorphisms ( SNPs ) and found a sequence approximately 36 kilobases in length that contained three genes .
The researchers measured the expression of those genes in regenerating tail feather follicles of mosaic canaries and found that only one , beta-carotene oxygenase 2 ( BCO2 ) , was expressed differently in females and males .
When BCO2 is expressed , mosaic birds ’ feathers are white because BCO2 degrades carotenoids .
( In red siskins , color @ @ @ @ @ @ @ possess a gene for melanin , which adds a gray tint . )
Gazda next investigated whether other finch species also used BCO2 to generate sexual dichromatism , or if they ’ ve evolved different mechanisms .
She found that BCO2 expression varied with the amount of carotenoids in feathers in the sexually dichromatic European serin ( Serinus serinus ) and in wild canaries from the Canary Islands ( which show very slight sexual dichromatism ) , but not in the house finch ( Haemorhous mexicanus ) , which must use another molecular @ @ @ @ @ @ @ dichromatism are very exciting , and in this case it seems to be a common gene across finches ( and possibly other birds ! )
, ” Pennsylvania State University evolutionary biologist David Toews , who was not involved in this study , writes in an email .
Further experiments showed that it ’ s likely that an enhancer or promoter near the BCO2 gene turns it on , and Gazda suspects it is regulated by estrogen .
“ When the females get old [ and make less of the hormone ] , @ @ @ @ @ @ @ more like males—they have more color , ” she explains .
Females without ovaries also look like males .
Gazda says more experiments are needed to determine whether estrogen , or some other trigger , flips BCO2 ’ s switch .
“ Identifying and characterizing the role that carotenoid processing genes [ play ] , particularly this one , BCO2 , has been elusive , ” Toews writes , adding that the new study “ has important consequences for our understanding about the evolution and genetics of animal coloration and signaling .
”

ABOVE: A European serin
© ISTOCK.COM, SELIM KAYA
EDITOR’S CHOICE IN GENETICS & GENOMICS
The paper
M. Gazda et al., “A genetic mechanism for sexual dichromatism in birds,” Science, 368:1270–74, 2020.
Male red siskins (Spinus cucullatus), a species of finch, flaunt orange-red bellies and backs, contrasting with their black heads and dark wing markings. The females, on the other hand, are mostly muted shades of grey (though pops of orange-red and black do appear on their bellies and wings). Such differences in coloration between the sexes, called sexual dichromatism, occur in many bird species, but their root cause has confounded scientists for years.
Geneticist Miguel Carneiro of the Research Centre in Biodiversity and Genetic Resources (CIBIO) at the University of Porto in Portugal had previously discovered that a siskin gene called CYP2J19 encodes an enzyme that helps convert yellow carotenoid compounds from seeds in the birds’ diet into the red carotenoids found in their feathers. But he wanted to know why this happened only in males, so he and then–graduate student Malgorzata Gazda, together with Pedro Miguel Araújo of the nearby University of Coimbra, studied another, human-bred bird, the mosaic canary. These birds were created by breeding red siskins with common domestic canaries (Serinus canaria), which are not sexually dichromatic, and then backcrossing them with the common canaries and selecting for birds that are sexually dichromatic. Apart from their color and sexual dichromatism, mosaic canaries are nearly genetically identical to common canaries.
PDF DIALING DOWN THE GLITZ: In some finch species, BCO2, a gene that encodes a carotenoid-destroying enzyme, is expressed in many female finch feathers but not in many male feathers. This generates dramatic sexual dichromatism that makes males dazzle while females look relatively drab. In common canaries, which are not sexually dichromatic, both males and females have little BCO2 expression in their feathers. WEB © Kelly Finan
Gazda sequenced the genomes of the mosaic canaries and compared them to the genomes of four non-dichromatic canary breeds and one slightly dichromatic wild canary. They found one stretch of the mosaic genome that was associated with sexual dichromatism. They then looked for a region within that stretch that contained only siskin single nucleotide polymorphisms (SNPs) and found a sequence approximately 36 kilobases in length that contained three genes. The researchers measured the expression of those genes in regenerating tail feather follicles of mosaic canaries and found that only one, beta-carotene oxygenase 2 (BCO2), was expressed differently in females and males. When BCO2 is expressed, mosaic birds’ feathers are white because BCO2 degrades carotenoids. (In red siskins, color is bit more complex; they also possess a gene for melanin, which adds a gray tint.)
Gazda next investigated whether other finch species also used BCO2 to generate sexual dichromatism, or if they’ve evolved different mechanisms. She found that BCO2 expression varied with the amount of carotenoids in feathers in the sexually dichromatic European serin (Serinus serinus) and in wild canaries from the Canary Islands (which show very slight sexual dichromatism), but not in the house finch (Haemorhous mexicanus), which must use another molecular mechanism. “The genes responsible for dichromatism are very exciting, and in this case it seems to be a common gene across finches (and possibly other birds!),” Pennsylvania State University evolutionary biologist David Toews, who was not involved in this study, writes in an email.
Further experiments showed that it’s likely that an enhancer or promoter near the BCO2 gene turns it on, and Gazda suspects it is regulated by estrogen. “When the females get old [and make less of the hormone], they start to look a little bit more like males—they have more color,” she explains. Females without ovaries also look like males. Gazda says more experiments are needed to determine whether estrogen, or some other trigger, flips BCO2’s switch.
“Identifying and characterizing the role that carotenoid processing genes [play], particularly this one, BCO2, has been elusive,” Toews writes, adding that the new study “has important consequences for our understanding about the evolution and genetics of animal coloration and signaling.”


thescientist--2020-09-01--New RNA-Based Tool Could Assess Preeclampsia Risk

ABOVE : RNA transcripts circulating in a mother ’ s blood provide information about maternal , fetal , and placental health and might one day be used to diagnose preeclampsia .
© ISTOCK.COM , LOSTINBIDS S. Munchel et al.
, “ Circulating transcripts in maternal blood reflect a molecular signature of early-onset preeclampsia , ” Sci Transl Med , 12 : eaaz0131 , 2020 .
Preeclampsia , a potentially fatal complication that affects roughly 5 percent of pregnancies worldwide , can only be diagnosed after the onset of symptoms such as high blood pressure , so treatment is always reactive @ @ @ @ @ @ @ is better methods to diagnose or predict risk of pregnancy complications such as preeclampsia , ” says Fiona Kaper , a senior director of scientific research at the biotech company Illumina .
To identify possible biomarkers of the condition , Kaper and her colleagues drew blood from 40 pregnant women with early-onset severe preeclampsia and 73 unaffected expecting mothers .
Circulating in the blood of each mom-to-be is her own RNA , as well as transcripts from the placenta and the fetus .
Studying these circulating RNAs ( cRNAs ) , the team @ @ @ @ @ @ @ placental genes with altered expression patterns in women with preeclampsia compared with controls .
A machine algorithm also identified 49 genes with altered expression , including 12 that overlapped with the earlier list , suspected of being linked to preeclampsia .
To test the ability of the 49 suspect genes to predict preeclampsia , the researchers classified an independent cohort of two dozen women , half with early-onset preeclampsia and half without signs of the condition .
The model predicted which women had preeclampsia with 85 percent to 89 percent accuracy .
While @ @ @ @ @ @ @ , cRNA screening represents a step toward earlier preemptive diagnosis , says Kathryn Gray , an obstetrician at Brigham and Women ’ s Hospital who was not involved in the study .
She notes that researchers have been doing something similar in detecting circulating tumor DNA for cancer screening .
“ It ’ s really exciting that we ’ re applying some of these .
.
.
strategies that have been used in cancer to pregnancy .
We ’ re always a bit behind in women ’ s health and pregnancy in applying @ @ @ @ @ @

ABOVE: RNA transcripts circulating in a mother’s blood provide information about maternal, fetal, and placental health and might one day be used to diagnose preeclampsia.
© ISTOCK.COM, LOSTINBIDS
EDITOR’S CHOICE IN DISEASE & MEDICINE
The paper
S. Munchel et al., “Circulating transcripts in maternal blood reflect a molecular signature of early-onset preeclampsia,” Sci Transl Med, 12:eaaz0131, 2020.
Preeclampsia, a potentially fatal complication that affects roughly 5 percent of pregnancies worldwide, can only be diagnosed after the onset of symptoms such as high blood pressure, so treatment is always reactive. “The next really big need is better methods to diagnose or predict risk of pregnancy complications such as preeclampsia,” says Fiona Kaper, a senior director of scientific research at the biotech company Illumina.
To identify possible biomarkers of the condition, Kaper and her colleagues drew blood from 40 pregnant women with early-onset severe preeclampsia and 73 unaffected expecting mothers. Circulating in the blood of each mom-to-be is her own RNA, as well as transcripts from the placenta and the fetus. Studying these circulating RNAs (cRNAs), the team identified 30 maternal, fetal, or placental genes with altered expression patterns in women with preeclampsia compared with controls. A machine algorithm also identified 49 genes with altered expression, including 12 that overlapped with the earlier list, suspected of being linked to preeclampsia.
To test the ability of the 49 suspect genes to predict preeclampsia, the researchers classified an independent cohort of two dozen women, half with early-onset preeclampsia and half without signs of the condition. The model predicted which women had preeclampsia with 85 percent to 89 percent accuracy.
While large-scale, prospective studies are still needed, cRNA screening represents a step toward earlier preemptive diagnosis, says Kathryn Gray, an obstetrician at Brigham and Women’s Hospital who was not involved in the study. She notes that researchers have been doing something similar in detecting circulating tumor DNA for cancer screening. “It’s really exciting that we’re applying some of these . . . strategies that have been used in cancer to pregnancy. We’re always a bit behind in women’s health and pregnancy in applying the most cutting-edge technologies.”