The Scientist Summer

more generations, several researchers who tively simple question: Can a young More generally, the data weren’t exhaus-
spoke to The Scientist expressed the view person’s diet shape the health of their tive. Although several of the studies collected
that more epidemiological and mechanistic grandchildren decades later? information on parental income, education,
data could yet swing the debate in favor of and other sociocultural factors, the research-
the phenomenon. The study—which reported more ers may still have missed the real reason for
deaths from diabetes among people the association they identified. This caveat
“I’m probably a bit skeptical we’re whose paternal grandfathers had lots applies broadly to any study drawing links
going to have a lot of inheritance of food available when they themselves between environmental factors and health
explained by epigenetics,” says Carrie were kids—decided that yes, it can.2 And outcomes in people, says Breton. “We try to
Breton, an environmental epidemiolo- because it’s unusual to see large-scale measure as many of the things that we think
gist at the University of Southern Cal- genetic changes in the course of just are the most important. . . . But undoubt-
ifornia (USC) who recently coauthored three generations, the authors specu- edly, we can’t measure everything that’s
a review of studies of epigenetic inheri- lated in their paper that the mechanism important,” she says. “And even the things
tance in humans and other animals.1 “But behind the observed link could be epigen- we measure, they may not be measured well,
when we talk about environmental expo- etic, perhaps via some sort of diet-driven so there’s still a lot of noise.”
sure causing an epigenetic change that change to the grandfather’s germline. The
might affect health risk, and whether findings were expanded on a few years Environmental epidemiologists are
that individual effect can persist, I do later, and in more-recent follow-ups by now trying to develop better datasets by
think there is mounting evidence in the same and other groups, all of which gathering more information—and in some
support of this.” Even if it happens only reported a relationship between a grand- cases, biological samples—from large,
rarely, she adds, “all it takes is an envi- parent’s nutrition and at least one health multigenerational groups of people. While
ronmental exposure to tweak a handful outcome in their grandchildren. The still observational, such studies could sup-
of loci in the system that might still be results seemed to jibe with animal studies port, or refute, particular connections
bad for you, and that effect might be car- published during the same period, show- between health outcomes and previous
ried forward.” ing, for example, that feeding mice high- generations’ exposures that have cropped
fat diets promoted metabolic or body-size up repeatedly, says Breton, and so help
Baccarelli, who studies how environ- effects one, two, or even sometimes three researchers decide which to pursue. (See
mental toxins could trigger changes in generations later. “What’s Passed On?” on page 48.)
DNA methylation and gene expression,
also takes an agnostic view. Many stud- I’m probably a bit skeptical we’re going to have a lot of inheritance
ies from the early 2000s, particularly explained by epigenetics.
those relating to transgenerational inher-
itance in animal models, haven’t been rep- —Carrie Breton, University of Southern California
licated, he says, and it’s often difficult to
interpret human studies. Taken together,
he says, while “we have enough evidence
to do more research, I’m not sure we have
enough research to say this is a thing.”

Finding connections
The Överkalix studies and their fol- One potential future source of data is
With a nearby Arctic moose farm and low-ups provide compelling evidence for the Environmental Influences on Child
prime views of the aurora borealis, the epigenetic inheritance in people—or an Health Outcomes (ECHO) program, a net-
municipality of Överkalix is in many illustration of the pitfalls associated with work funded by the National Institutes of
ways a typical little Swedish Lapland this type of research, depending on your Health (NIH) that comprises more than 70
township. But in scientific circles, this perspective. Critics of the original study cohorts of children plus their family mem-
forested area of northern Scandina- pointed out that the small cohort likely bers—and more than 50,000 children in
via is famous for a data set assembled contained multiple sibling and cousin total—across the US. Researchers started
from historical records, including birth pairs, for example, meaning that indi- following some of these cohorts decades
and death dates for several generations vidual grandparent-child observations ago and in a few cases are already collecting
bracketing the turn of the 20th century, weren’t really independent. And the study data from a third generation, which could
cause-of-death information, genealogy authors had analyzed multiple health out- be used to investigate whether a parent’s
records, grain prices, and harvest sta- comes simultaneously, increasing the like- early life affects their child or grandchild,
tistics. In the early 2000s, Swedish sci- lihood that at least one would appear to says Breton, who directs ECHO’s USC site.
entists used data from several hundred have a statistically significant relationship “Some of us who have older cohorts think
people in this cohort to tackle a decep- with grandparent diet. that that could be a really interesting path

SUMMER 2022 | THE SCIENTIST 47

WHAT’S PASSED ON?

Multiple studies have reported associations between child health and parental or grandparental
lifestyle, while a number of animal and human studies hint at connections between environmental
exposures and epigenetic changes in eggs or sperm. However, evidence to support causality in these
correlations is lacking in humans. Below are some of the factors frequently studied by researchers
interested in the idea of epigenetic inheritance.

1 ENVIRONMENTAL EXPOSURES

A multitude of environmental factors have been proposed to
influence a person’s health and potentially that of their children.
These include exposure to harmful chemicals from cigarettes or
pollution, lifestyle circumstances such as exercise and diet, and
other factors including age and experience of stress or trauma.

Non-coding RNA 2 EPIGENETIC MECHANISMS? © NANOCLUSTERING.COM
DNA methylation
Histone modification Reported epigenetic changes in
gametes, especially sperm cells, in
4 8 TSH EDISGCEI ESNT T| ItShTe-|stchieen-sticsite.cnotimst.com response to environmental factors
include changes in the level of
certain RNAs, in DNA methylation
patterns, and in modifications
to histones. The effects of these
changes on gene expression and
their persistence after fertilization
are largely unknown.

?

4 CONFOUNDING FACTORS forward,” she says. Currently, she and her
colleagues are analyzing cheek swab sam-
There are myriad ways that a parent’s exposure and experiences could ples to assess consistency in DNA methyla-
influence their child, and most have nothing to do with the epigenome of egg tion patterns—still the most-studied part of
and sperm. Often, a child will experience many of the same environmental the epigenome—across three generations
conditions as the parent, for example, while particular experiences might of people. “Overall, we’re seeing a very low
influence the way parents bring up their children. Some researchers percentage of loci correlated across these
argue that microbes passed from mother to child could also help explain generations,” she says. “It’s just one study . . .
associations between parental environments and offspring outcomes. All of but I think in the end, it’s not going to be a
these factors are difficult to rule out in studies of epigenetic inheritance. high number of loci that are sort of written
in stone and passed on in a concrete way
3 HEALTH OUTCOMES from one generation to the next.”

Epidemiological studies have Some cohort networks investigating
turned up numerous aspects inter- and transgenerational health effects
of child health that correlate have already begun publishing data. The
with parental or grandparental Pregnancy and Childhood Epigenetics
lifestyle. Studied measures of (PACE) consortium, set up in 2018 by
health in kids include birthweight, NIH researcher Stephanie London and
all-cause mortality, and risk of colleagues, aims to bring together nearly
developing asthma and metabolic 40 ongoing studies of children and par-
diseases, among other conditions. ents. Following mouse studies suggesting
that males fed high-fat diets had daugh-
ters with impaired insulin secretion and
particular DNA methylation signatures in
certain pancreatic cells, for example, the
PACE group combined a chunk of its own
data with information from other cohorts
to dig into a possible association between
a father’s body mass index (BMI) and a
child’s DNA methylation patterns. Analyz-
ing nearly 7,000 samples of newborn cord
blood and blood from older children, the
researchers found “little evidence” of any
associations with paternal BMI. Because
DNA methylation patterns vary among
cell types and tissues, the authors empha-
size in their paper that the results don’t
rule out a link altogether.3

Smaller observational efforts, such as
the Avon Longitudinal Study of Parents
and Children in the UK and the Norwe-
gian Mother and Child Cohort Study, con-
tinue to put out data too. While some semi-
consistent patterns have emerged from
these studies—an association between
grandparent smoking and grandchild
asthma, for example, and, more contro-
versially, a link between parental early-life
trauma and child mental health—most have
acknowledged that confounding factors
such as prenatal exposure, upbringing,
or other influences on child health have
not been ruled out. As such, researchers

SUMMER 2022 | THE SCIENTIST 49

who spoke to The Scientist agree that it vertently affect his future child through his Focusing on sperm has advantages
remains unresolved what might underlie own lifestyle. After joining the faculty at from the perspective of studying how
these associations in people. the University of Massachusetts Amherst, parental environments influence future
Pilsner decided to dig into this potential generations. For starters, because fathers
A working theory
link between parental exposure and child and their babies are physically separated,
Richard Pilsner started pondering sperm development. In 2014, he and colleagues it bypasses some of the confounding
epigenetics around the time he and his launched the Sperm Environmental Epi- effects of in utero exposure that lead to a
wife started planning a family a little over genetics and Development Study (SEEDS), common criticism of studies in the field—
a decade ago. Having trained in environ- a cohort that uses leftover samples from that they conflate prenatal with inter- and
mental health sciences, Pilsner recalls IVF clinics, with participants’ consent, to transgenerational effects. Additionally, it
warning his wife about the risks of smoking look at the relationship between a father’s could help researchers home in on what’s
and other behaviors that might affect con- environment and his sperm epigenome— physically transmitted across generations,
ception or fetal development. That made plus perhaps one day, his child’s epigenome rather than trying to infer it from parent-
them wonder whether he, too, might inad- and health outcomes. lifestyle and child-health associations. The

INHERITANCE OF ACQUIRED TRAITS: FROM LAMARCK TO NOW

Although theories of epigenetic inheritance have drawn new interest in the last 20 years or so,
the ideas they tap into have been around for centuries.

Jean-Baptiste Lamarck hypothesizes that traits an Embryologist Conrad Waddington coins The discovery of imprinted genes— CMROEDIDIFITELDI FNREOM © ISTOCK.COM, RUDZHAN NAGIEV, OLGAKORICA, SORBETTO, BRILLY, NVARD AKOPYAN
animal acquires during its lifetime—an extended the term “epigenetics” to describe the sequences that are methylated at an
neck after years of stretching up to reach high developmental processes that connect an organism’s birth and whose expression
leaves, for example—can be inherited by future organism’s genotype to its phenotype. The depends on which parent they were
generations. He proposes that this idea, versions term will later be coopted to describe work inherited from—launches the idea that
of which have been circulating since ancient in other disciplines, including research on DNA methylation carries information
Greek times, explains how species evolve. the regulation of gene expression. from parent to child.

Soviet agriculturalist Trofim Lysenko Research on chromatin structure takes The number of papers including the
rejects decades of genetics research while off, with DNA methylation and histone term epigenetics soars, and the idea
pushing his own theory of how traits that modifications becoming associated that the field offers an alternative to
organisms acquire in their environments with variation in the expression of genetic explanations for inheritance
can be inherited. He’ll use the idea to particular DNA sequences. It will gains traction in the public eye.
develop disastrous agricultural policies be many years before the research News stories claim that the field is
that contribute to crop failure and famine. becomes known as epigenetics. “rewriting the rules” of heredity.

5 0 TSH EDISGCEI ESNT T| ItShTe-|stchieen-sticsite.cnotimst.com

sperm-centric approach has taken off in Whether epigenetic changes seen in wish that people would avoid thinking
the animal literature, too—investigations sperm persist past fertilization or have that there is only one mechanism.”
of sperm epigenetics in rodent models biological effects in offspring is harder to
have found that both negative experiences gauge from these studies. Indeed, some Romain Barrès, an epigeneticist at
(exposure to harmful chemicals or trauma, of the rodent research that inspired the the University of Copenhagen and the
for example) and purportedly positive SEEDS phthalate study suggested the Université Côte d’Azur who heads up the
ones (exercise) are associated with differ- DNA methylation alterations in exposed Gametic Epigenetics Consortium against
ing levels of DNA methylation and of RNA males’ sperm were completely reverted in Obesity (GECKO), is of a similar opin-
modification in sperm, and with measur- the next generation. But a recent mouse ion. “We think that the epigenetic modi-
able changes in offspring phenotype. study by Pilsner and colleagues reported fications talk to each other,” he says. The
that while DNA methylation patterns did full picture “may be missed if you’re study-
Pilsner’s group, now at Wayne State differ between sperm and the embryonic ing DNA methylation only, in only a set
University in Michigan, has completed cells of newly conceived offspring, the lat- of tissues [such as] blood.” Failing to find
several studies with the SEEDS data set. ter varied consistently in relation to the a conserved signal across generations or
In a small-scale study a few years ago, former.6 “We see what we call an amplified within a single person during their lifetime
the team followed up on other groups’ effect—we see many more changes in the “doesn’t mean that the signal is totally
reports that exposure to chemicals found embryo than we see in the sperm,” says Pil- gone. Perhaps it is integrated into another
in many everyday plastics altered DNA sner, who holds provisional patents related epigenetic mark, like small RNA or chro-
methylation in rodent sperm. Using to age-associated epigenetic changes in matin conformation.”
urine samples to measure nearly 50 sperm. “There’s some sort of signal that’s
men’s exposure to phthalates, Pilsner being passed.” He adds that he’s now work- Conscious of the fact that the epig-
and colleagues identified more than 130 ing with Sarah Kimmins, an epigeneticist enome could change over time, Barrès’s
regions of the genome that were differen- at McGill University in Quebec whose group has been trying to study specific
tially methylated in the sperm of people life events rather than lifelong expo-
sures. A few years ago, his team tracked
I wish that people would avoid thinking that there changes in DNA methylation patterns
is only one mechanism. in the sperm of people undergoing bar-
iatric surgery for obesity. Using another
—Isabelle Mansuy, University of Zurich and ETH Zurich data set, the team found that slim and
obese men showed differences in sperm
MODIFIED FROM © ISTOCK.COM, FEDRELENA who were exposed to the chemicals Many team has shown that changes in the meth- DNA methylation patterns and non-
of these regions were found around genes ylation of histones, proteins that package coding RNA levels, even when controlling
involved in growth and development.4 DNA into chromosomes, can make it from for genetic sequence variation. Using the
sperm to embryo in certain mouse models. new cohort, the researchers found that
More recently, the researchers explored With their colleagues, the researchers are morbidly obese men showed remodel-
another proposed risk factor for certain now investigating these and other types of ing of sperm DNA methylation just a
health conditions in children: advanced epigenetic modifications. week after undergoing surgery to reduce
paternal age. While scientists have proposed
multiple mechanisms, including accumu- This more holistic approach to epi-
lated mutations and the decreased struc- genetics is one that’s gaining traction
tural integrity of DNA in sperm, to explain among researchers interested in this
reported connections between advanced type of inheritance, says Isabelle Man-
paternal age and risk of certain cancers and suy, a neuroepigeneticist at the University
neurodevelopmental disorders, Pilsner’s of Zurich and ETH Zurich. Mansuy, who
group published data suggesting that sperm recently summarized more than 100 stud-
methylation may also play a role. Specifically, ies on potential inter- and transgenera-
the researchers found that male age was tional effects of environmental exposure,
associated with particular epigenetic pat- says it’s likely that the pathways involved
terns at genes involved in embryogenesis will be complicated, and not, say, a strict
and neurodevelopment.5 one-to-one copy of DNA methylation.7 “I

SUMMER 2022 | THE SCIENTIST 51

weight, and to a greater extent after one ature. Many scientists still lament what ing them using epigenetics. That’s where MODIFIED FROM © ISTOCK.COM, FEDRELENA
year, particularly at genomic regions they view as hype, misreporting, and an I think it can be quite relevant.”
associated with appetite control. Some unhelpful blurring of definitions in the
of these regions were the same ones that field, particularly when it comes to dis- Perhaps, he speculates, the field is ready
differed between slim and obese men, the tinguishing between inter- and trans- for the sort of transition that many scientific
authors noted in their paper.8 generational effects. Some research- disciplines have to go through. “Sometimes,
ers in this field, meanwhile, say they the first question is not even answered by
Barrès is now working with research- feel their work’s been unduly maligned. the field, and then we all jump to the next
ers in Australia to launch a rare experi- Many people don’t appreciate how much question. It’s like when small children play
mental study in humans: pairs of adult effort it’s taken to get research on epi- football, you see them all where the ball is,
male identical twins will be split to receive genetic inheritance recognized, Mansuy not spread out across the field. . . . I think
either a processed or unprocessed diet, says over email, adding that “collecting in science it’s also a bit like that.” g
and then asked to give sperm samples data and publishing [in this discipline]
for researchers to analyze DNA meth- require more efforts and time than in References
ylation, small non-coding RNA levels, more classical fields.” She also points to 1. C.V. Breton et al., “Exploring the evidence for
and chromatin structure. “There’s a lot struggles that she and some of her col-
of things we cannot address looking just leagues have had obtaining funding for epigenetic regulation of environmental influences
at the sperm itself,” Barrès acknowledges. projects on epigenetic inheritance in on child health across generations,” Commun
“But if we find a common denominator mammals in recent years. Biol, 4:769, 2021.
of an epigenetic signature in gametes in 2. G. Kaati et al., “Cardiovascular and diabetes
response to nutritional stress, and we Other scientists say they’re still pre- mortality determined by nutrition during
identify that in these men we have more pared for concepts of epigenetic inheri- parents’ and grandparents’ slow growth period,”
of this signature, and these men have tance to fail, either because the relevant Eur J Hum Genet, 10:682–88, 2002.

children that themselves have specific mechanisms turn out to be vanishingly 3. G.C. Sharp et al., “Paternal body mass index and
traits, then we can build a model where rare in humans or because their effects offspring DNA methylation: findings from the PACE
we can appreciate whether this associa- end up being negligible compared to consortium,” Int J Epidemiol, 50:1297–315, 2021.

tion is likely to be causative or not.” everything else influencing development. 4. H. Wu et al., “Preconception urinary phthalate
“I don’t think we’ll ever point to a single concentrations and sperm DNA methylation profiles
Moving toward more experimental study across multiple generations [and among men undergoing IVF treatment: a cross-
approaches would be good for the field, say], ‘They finally showed it!’” Breton sectional study,” Hum Reprod, 32:2159–69, 2017.

agree researchers who spoke to The Sci- says. “I think it’s going to end up being 5. O.A. Oluwayiose et al., “Sperm DNA
entist. In animal models, researchers are the cumulative evidence. The more papers methylation mediates the association of male
increasingly trying to modulate the epig- that show the same set of relationships, age on reproductive outcomes among couples
enome rather than simply observe it. that’s where we’re going to end up saying, undergoing infertility treatment,” Sci Rep,
Mansuy and others have reported that ‘OK, I think we start to believe this’—or 11:3216, 2021.

injecting non-coding RNAs from mouse maybe we don’t. Maybe in the end it was 6. O.A. Oluwayiose et al., “Paternal preconception
sperm cells into eggs or embryos elicits all the other life stuff that was getting in phthalate exposure alters sperm methylome
physiological or behavioral changes in the the way that really made it look like an and embryonic programming,” Environ Int,
developing animals. Baccarelli notes that association, and really it isn’t.” 155:106693, 2021.

new technologies derived from DNA- 7. A. Jawaid et al., “Impact of parental exposure
editing enzymes could allow researchers For LUMC’s Heijmans, reduced inter- on offspring health in humans,” Trends Genet,
to edit DNA methylation patterns too. “I est in epigenetic inheritance now as com- 37:373–88, 2021.

think the big opportunity for epigenetics pared to several years ago offers a wel- 8. I. Donkin et al., “Obesity and bariatric surgery
now is to use epigenetic editing to actually come opportunity for epigeneticists to drive epigenetic variation of spermatozoa in
get to see what happens when you . . . edit focus efforts on more-fruitful research humans,” Cell Metab, 23:369–78, 2016.
a certain methylation site, to see whether directions, he says, noting that “there are
the gene turns on and off—that’s not some- more-relevant nuts to crack.” He has been
thing we can take for granted—and then studying how prenatal or early-life envi-
to see what is the phenotype that changes.” ronments might influence the epigenome,
and whether epigenetic alterations can be
Living with uncertainty
used as biomarkers to predict disease risk
As data trickle in, arguments about within a person’s lifetime. This could in
which, if any, aspects of epigenetic inher- theory “help us in identifying vulnerable
itance hypotheses are likely to apply to individuals, and also monitoring [their]
humans continue to simmer in the liter- health,” he says—in other words, “help-

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The First CREDIT LINE
Americans

New techniques have shown that people reached the
New World far earlier than the long-standing estimate
of 13,000 years ago, but scientists still debate exactly

when humans arrived on the continent—and how.
BY EMMA YASINSKI

5 4 TSH EDISGCEI ESNT T| ItShTe-|stchieen-sticsite.cnotimst.com

COMPOSITE FROM: © ISTOCK.COM, HOMUNKULUS28 ; © ALAMY.COM, MARK GARLICK, SCIENCE PHOTO LIBRARY W hen the National Park Service’s Daniel Odess was The footprints lent credence to various archaeological digs
invited in 2017 to work with an archaeological in both North and South America that had unearthed stone
team at White Sands National Park in New Mexico, tools and butchered animal bones predating Clovis tools. They
it was to help preserve fossilized mammoth track- also supported the claims of Indigenous scholars who have long
ways before they eroded. But upon his first visit to attested that their ancestors predated the Clovis, statements bol-
the site in person, he saw that along with the large mammoth stered by recent findings from geneticists who had started using
impressions, there were human footprints. a combination of ancient and modern DNA from humans and
They were “like a film clip,” he recalls. “You get to see what commensal microbes to trace multiple human migrations that
happened during that walk. And sometimes you get to see indi- date back as far as 24,000 years ago. Today, researchers agree that
vidual humans interacting. A woman carrying a child, setting the this growing trove of data has poked large holes in the Clovis-first
child down, picking the child up. And sometimes you get to see model, while simultaneously opening the field to many more mys-
how animals react to people and people react to animals. So, you teries about how and when the earliest groups of people arrived
know, it was kind of a light bulb moment where I went, ‘this is a in North America and spread across the landmass and beyond.
chance to see things that we never get to see.’”
It was also “pretty intriguing” to see the human footprints side A series of contradictions
by side with the tracks of now-extinct animals such as mammoths, From 1980 to the early 2000s, archaeologists uncovered habita-
Odess notes. Humans are often blamed for hastening mammoths’ tion sites in both North and South America that predated Clovis
extinction shortly after arriving on the North American land- times, but many of the sites were discounted by other scientists.
mass, which, according to what was once the prevailing hypoth- Bones that appeared to have been butchered by humans might
esis, occurred some 13,000 years ago via the Bering Land Bridge not have been, some argued; tools that looked deliberately carved
from modern-day Siberia to Alaska. But the footprints suggest could have been broken naturally.
the two species may have lived side by side for thousands of years,
Odess explains. Last year he and colleagues published radiocar- The first convincing chink in the Clovis-first model’s armor
bon dating of the layers of sediment where the human footprints came back in 1988, when archaeologist Tom Dillehay, then at Aus-
were found that determined their age to be between 21,000 and tral University of Chile, discovered artifacts at a site called Monte
23,000 years old.1 Verde in southern Chile that he and his team estimated to be as
The findings weren’t the first to challenge the so-called Clovis-first old as 33,000 years.3 In addition to their potential age, the arti-
model, named after the Clovis people, who were thought to have been facts were distinct from the well-known Clovis spear points found
the first to pass through Beringia. The White Sands findings were, elsewhere in the Americas, suggesting that at least one, if not sev-
however, the most conclusive, agree researchers who spoke with The eral, separate human groups infiltrated the continents before the
Scientist. “For a long time, there’s been a consensus view that [human- Clovis people. The Clovis-first model “was refuted effectively in the
occupied] sites that were 13,000 years old or so were legitimate,” but ’90s with this archaeological site of Monte Verde in Chile that was
that archaeological finds dating back further in time were potentially accepted as a ‘true’ pre-Clovis site,” says Lorena Becerra-Valdivia,
erroneous, says Odess. The idea that humans had arrived in the Amer- a radiocarbon dating scientist at the University of Oxford. More-
icas before that time “was controversial,” he explains, “because it was recent excavations of tools, remnants of campfires, a possible shel-
putting people here before the glaciers opened up the path”—an event ter, and food scraps preserved in peat at the site support Dillehay’s
estimated to have occurred around 13,000 years ago, several thousand initial finding that people lived there more than 12,500 years ago,
years after the peak of the most recent ice age, the so-called Last Gla- but narrowed the window to a maximum of about 19,500 years ago
cial Maximum.2 “But White Sands changes everything.” (the 33,000-year dating from the deepest levels of the site could
neither be verified nor falsified).4

SUMMER 2022 | THE SCIENTIST 55

Not everyone was as convinced as Becerra-Valdivia, however, in But the genetic data raise more questions than answers. One
large part because artifacts can be moved by wind and water. It was notable quandary comes from the genomes of a small modern pop-
possible, critics said, that the artifacts that Dillehay’s team had iden- ulation in Brazil, which contain a signal that José Víctor Moreno-
tified were actually younger than 13,000 years, but that they’d been Mayar, a geogeneticist at the University of Copenhagen, says he
moved into older sediment layers by weather events or other physi- cannot explain. About 2 percent of the DNA in some South Ameri-
cal factors. But footprints can’t be moved, Odess explains, and they can natives appears to be closely related to that of ancient Austral-
can’t be made by other natural phenomena, meaning that the find- asian remains from Southeast Asia, and a similar sequence hasn’t
ings at White Sands were nearly impossible to refute. “A four-year- been found in any other living Indigenous American population.
old can look at that and say, ‘Yep, that’s a person. Yep, I make tracks In the 2018 study that showed two waves of migration to South
like that when I play in the mud.’ Those are human—unquestionably America, Moreno-Mayar and his team sequenced 10,000-year-old
human. And there are lots of them.” He adds that the team hasn’t genomes from Brazil and were shocked to find this same genetic
yet excavated and tested the oldest layers of footprints, which might signature.9 “That’s really, really puzzling,” he says; it’s as if there was
push the date back even further than 21,000 to 23,000 years ago. a population that magically appeared in Brazil sometime before
10,000 years ago, without having traveled through North America
Still, Ben Potter, an archaeologist at the University of Alaska to get there. At that time, “there was absolutely no way in which it
Fairbanks, isn’t completely sold. When Odess’s study was pub- was possible to make it through the Pacific,” he says. And even if
lished in 2021, Potter told The New York Times that, because the ancient people did cross the ocean, they’d have had to then traverse
carbon dating could still be influenced by water, he thought that the Andes and the Amazon, a similarly challenging journey,
more evidence was required to build a conclusive case for such an without leaving any trace behind. “Every new explanation we come
early occupation of the Americas. In a recent email to The Scien- up with is worse than the previous one.”
tist, he suggests that the White Sands discovery was compelling,
but not definitive. “The recent White Sands paper provides some When you have data that doesn’t fit
evidence for a possible earlier expansion of humans.” a model, you don’t change the data.
You have to adjust the model.
Other findings have emerged that continue to support a pre-Clovis —Daniel Odess, National Park Service
habitation of the Americas. One study published in 2017 by a mostly
US-based group of archaeologists even suggests that date may be as The story gets even more complex as scientists look further back in
old as 130,000 years ago, as evidenced by mastodon bones found in time. Another 2018 study in which Moreno-Mayar and his colleagues
San Diego that appeared to have been processed by humans.5,6 How- sequenced the DNA of a child who lived in Alaska 11,500 years ago
ever, the bones were the only evidence found, and some scientists revealed that she’d been part of an isolated group of ancient Berin-
wrote a rebuttal7 saying that they may have been damaged in recent gians that separated from modern Native Americans about 20,000
years by heavy construction equipment, rather than by the stone tools years ago.11 “DNA shows isolation, but where were they isolated?” asks
of ancient humans. Other recent studies have gotten similar push- Jennifer Raff, an anthropological geneticist at the University of Kansas
back. But perhaps even more convincing than the accumulation of who was not involved in that study. Southern Siberia and East Asia
archaeological evidence are recent DNA analyses of ancient and mod- were home to populations other than those ancient Beringians 20,000
ern genomes that further confirm an early occupation of the Americas. years ago, she notes. “South Central Beringia would have been a really
good place for that isolation event to have taken place, but we don’t
DNA in America have any archaeological evidence that’s really secure putting people in
DNA sequences acquired from a handful of ancient human remains that spot at that time. It’s all underwater [now],” as melting glaciers
found at archaeological sites in the Americas suggest that the peo- raised water levels and sank the land bridge.
pling of the Americas is far more complex than a single population of
Clovis people crossing Beringia some 13,000 years ago. In 2018, one Because sequenceable ancient human DNA is hard to isolate
group of researchers found evidence of four separate migrations from and extract, some researchers have turned to the genetic sequences
North America to South America, with more-recent groups displacing of gut bacteria. About 20 years ago, Mark Achtman, a now-retired
older ones.8 That same year, another study pointed to a split of Native microbiologist then at the Max Planck Institute for Infection Biology
American ancestors between 18,000 and 14,000 years ago into two in Berlin, realized that the Helicobacter pylori (the bacterial species
separate branches, which then split and mixed again and again as they that can cause ulcers) in a person’s gut differed based on where they
radiated into the Americas.9 A couple of years ago, Becerra-Valdivia were from. This gave Achtman a “crazy idea,” recalls Yoshan Moodley,
and colleagues developed a model that integrated data from 42 differ- a zoologist at the University of Venda in South Africa and a former
ent archeological sites in North America and Beringia with emerging postdoc in Achtman’s lab. “It could be that this bacteria has been in
evidence from ancient DNA, and found support for the idea that peo- our stomach since before we even left Africa,” and could thus pro-
ple were indeed in the Americas 26,500–19,000 years ago.10“I would vide insights into early human migrations. Gut bacteria aren’t only
say the biggest development is in nuclear genomic analyses, which add transferred from parent to child but are also shared among people
an independent line of inquiry into movements of people, migrations,
and admixture among populations,” says Potter.

56 THE SCIENTIST | the-scientist.com

A HODGEPODGE OF EVIDENCE

For decades, scientists subscribed to the Clovis-first model of the peopling of the Americas, the idea that the earliest humans
on the landmass had crossed the Bering Land Bridge after the Last Glacial Maximum when glaciers began to recede, about
13,000 years ago. These people spread widely throughout North and South America, as evidenced by the leaf-shaped
spearheads they left behind. Some discoveries have begun to poke holes in the model, however. The Clovis people were
in the Americas 13,000 years ago and did spread widely, but it’s becoming more and more clear that they weren’t the first
humans to inhabit the New World.

SIBERIA ALASKA

18,000–20,000 years ago 11,500 years ago
Genetic sequencing of H. pylori Comparing DNA from the bones of a girl with sequences
bacteria from the stomachs of of DNA from other ancient populations and with
modern humans suggested that genomes of modern Native Americans showed that
an ancient population of people she was part of a previously unknown group that
survived in the area during the separated from modern Native Americans about
Last Glacial Maximum, when 20,000 years ago, suggesting that multiple groups
the land was covered in ice. migrated into and through North America.

ALASKA TO PATAGONIA WHITE SANDS, NEW MEXICO
21,000–23,000 years ago
8,700–21,000 years ago Footprints found in White Sands
Fifteen ancient genomes spread National Park revealed human activity
across the Americas revealed two in the area for thousands of years
distinct migrations from North to during the Last Glacial Maximum.
South America, highlighting the
complexity of early human MONTE VERDE, CHILE
migrations and suggesting that 14,500–19,000 years ago
early people had wide access to Stone artifacts, animal remains, and
the continents that allowed them burn sites uncovered in 1988, with
to rapidly spread throughout, new samples revealed and analyzed
despite obstacles such as glaciers. in 2015, were the first conclusive
evidence that humans were in the
Americas before 13,000 years ago.

© ISTOCK.COM, DARIA_ANDRIANOVA, who interact, and bacterial genomes evolve more quickly than do The results suggest that some people survived in Siberia,
SURFUPVECTOR; THE SCIENTIST STAFF human ones. These factors mean that bacterial sequences could pro- despite the extremely harsh environment during the Last Glacial
vide hints about how different groups may have traded or otherwise Maximum, with subsequent generations harboring their ancestral
associated with one another, Achtman and his colleagues reasoned. strain of H. pylori, a finding supported by fossils in the region. “The
bacteria that these people would have had in their stomachs 24,000
In a 2021 study, Moodley and an international team of scien- years ago, it’s still alive and well [in people] in Siberia,” says Mood-
tists took samples of H. pylori from the stomachs of more than 500 ley. While the ancient people may no longer exist as a distinct popu-
humans currently living in different regions of Siberia and Mongolia.12 lation, he adds, “the bacteria that originally populated the stomachs
The researchers then compared the genetic sequences of these bacteria of these ancestral northern Eurasians [is still there].”
to those of representative strains of the bacteria sampled throughout
the world, and found that the genetic lineages of the bacteria split dur- Challenges ahead
ing the Last Glacial Maximum: one group seemed to have remained These current genetic analyses offer many clues to how peo-
isolated in northeast Asia, while another showed new mutations that ple moved through the continents, but considered in isolation
researchers believe were introduced when people left Siberia during they can only tell us so much. Unfortunately, melting ice has left
the Last Glacial Maximum, then returned thousands of years later.

SUMMER 2022 | THE SCIENTIST 57

A NEW ROUTE INTO THE AMERICAS differently, and they don’t always work together. Scientists “from
archaeology, from chemistry, and from genetics are kind of all com-
For much of the last ice age, massive glaciers covered the ing together and approaching this really interesting piece of history
northern part of the Americas. After the last glacial maximum, from these multiple angles. And naturally, you get different data sets
that ice started to melt, and by 13,000 years ago, an ice-free from these different fields,” says Raff. “I would almost critique us
pathway opened through modern-day Canada that scientists geneticists for not steeping our work in the archaeological data as
know the Clovis people to have traveled. However, recent well as we should. I think that that’s been a real problem.”
archeological and genetic evidence suggests that some groups
of people migrated to the Americas before the last glacial Doing this work in the right way means
maximum, when there was no ice-free corridor, suggesting that developing long-term relationships with
they may have traveled along the western coastline. If so, many tribes and developing trust.
of the artifacts and remains they left behind may be under water.
—Jennifer Raff, University of Kansas

Clovis migration Another obstacle to an accurate telling of the peopling of the
~13,000 years ago Americas is a tenuous relationship between the scientific establish-
ment and the very populations central to the story. Researchers have
Coastal migration historically failed to collaborate with Indigenous populations that
~20,000 years ago could be affected by their work, breeding deep mistrust, experts agree.
“Scientists have tended to kind of disregard their perspective on these
things because they don’t see the ‘scientific proof,’” says Odess.

Many investigators who spoke with The Scientist agreed that con-
ducting genetic analyses in an ethical way is both crucial and one of the
biggest challenges they face. When human remains are found, tribes
often want to leave them undisturbed or give them a traditional burial
rather than allow DNA to be extracted for research. “Doing this work
in the right way means developing long-term relationships with tribes
and developing trust,” says Raff. “And that is difficult when so many
times, again and again, their trust has been violated.”

many ancient sites underwater, drowning the artifacts and other References THE SCIENTIST STAFF
evidence that might have shed light on ancient peoples’ paths 1. M.R. Bennett et al., “Evidence of humans in North America during the Last
through Beringia and possibly down the West Coast of North
America, where they would have had to travel if they entered the Glacial Maximum,” Science, 373:1528–31, 2021.
continent while glaciers still covered the more easterly routes 2. J. Clark et al., “The age of the opening of the Ice-Free Corridor and
thought to have been followed by the Clovis people.
implications for the peopling of the Americas,” PNAS, 119:e2118558119, 2022.
Aside from the limited amount of physical evidence, one of 3. T.D. Dillehay, M.B. Collins, “Early cultural evidence from Monte Verde in
the biggest challenges facing researchers seeking to revise the
story of the peopling of the Americas, they say, is intellectual Chile,” Nature, 332:150–52, 1988.
inertia. Eric Boëda, an archaeologist at University Paris Nan- 4. T.D. Dillehay et al., “New archaeological evidence for an early human presence
terre, told The Scientist in 2020 that there is “denialism” in the
field, and that the long-standing belief that humans didn’t live at Monte Verde, Chile,” PLOS ONE, 10:e0141923, 2015.
in the Americas until 13,000 years ago causes people to dis- 5. S.R. Holen et al., “A 130,000-year-old archaeological site in southern
count older artifacts found there. Odess says that when the
White Sands paper was published, some scientists rejected it California, USA,” Nature, 544:479–83, 2017.
because it didn’t fit their models. While it’s important to con- 6. L. Bordes et al., “Raman and optical microscopy of bone micro-residues on
firm the validity of new data, he says, “when you have data that
doesn’t fit a model, you don’t change the data. You have to adjust cobbles from the Cerutti Mastodon site,” J Archaeol Sci Rep, 34:102656, 2020.
the model.” Since the findings first came out, Odess adds, most 7. J.V. Ferraro et al., “Contesting early archaeology in California,” Nature,
experts he knows of have come to accept them as valid.
554:E1–E2, 2018.
Another aspect of the challenge is that many different types of 8. C. Posth et al., “Reconstructing the deep population history of Central and
scientists approach the question of migration into the Americas
South America,” Cell, 175:1185–97.e22, 2018.
9. J.V. Moreno-Mayar et al., “Early human dispersals within the Americas,”

Science, 362:eaav2621, 2018.
10. L. Becerra-Valdivia, T. Higham, “The timing and effect of the earliest human

arrivals in North America,” Nature, 584:93–97, 2020.
11. J.V. Moreno-Mayar et al., “Terminal Pleistocene Alaskan genome reveals first

founding population of Native Americans,” Nature, 553:203–7, 2018.
12. Y. Moodley et al., “Helicobacter pylori’s historical journey through Siberia and

the Americas,” PNAS, 118:e2015523118, 2021.

58 THE SCIENTIST | the-scientist.com

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and inflammatory progression of Long COVID. The 185(5):881-95, 2022.
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SUMMER 2022 | THE SCIENTIST 61

PHAGOCIDAL MACROPHAGES:
A NEW BATTLE TACTIC AGAINST
RESISTANT CANCERS

In this episode, Niki Spahich from The Scientist’s
Creative Services Team spoke with Stephanie Dougan,
an associate professor of immunology at Harvard
Medical School and a principal investigator at Dana
Farber Cancer Institute, about her research developing
new immunotherapies for resistant tumors.

STEPHANIE DOUGAN, PHD

Associate Professor,
Immunology Harvard Medical
School Principle Investigator Dana
Farber Cancer Institute

LISTEN HERE

viewonline.the-scientist.com/phagocidal-macrophages-
a-new-battle-tactic-against-resistant-cancers

SCIENTIST TO WATCH

Ana Marija Jakšić: Shaping Fly Brains

Research Group Leader, School of Life Sciences, Swiss Federal Institute of Technology Lausanne

BY CHLOE TENN

Ana Marija Jakšić was born and strong example of a motivated student, push- among other lines of research. Jakšić says that
raised in Zagreb, Croatia, the sec- ing research beyond what was expected. fruit flies continue to be a great model system
ond oldest of four siblings. When because their genetic background is very eas-
she was young, her father took her on hunt- Specifically, Jakšić investigated how ily manipulated, including the ability to silence
ing trips that inspired an interest in ani- Drosophila populations evolved when exposed “very specific types of neurons, which is quite
mals. Jakšić initially attended a vocational to high or low temperature regimes, finding important for the work that we’re doing in
high school for economics with the intent that “what was actually most impacted by my lab.”
of continuing her family’s business of mak- temperature were their brains,” she says. For
ing sliding doors, but her attraction to the example, there was a noticeable difference Starting her research group during the
life sciences sparked again when she studied in the way that certain neuronal genes were pandemic has been “challenging,” she notes,
agriculture as an undergraduate at the Uni- being expressed in warmer temperatures, and but adds that the lab has already welcomed
versity of Zagreb. Thereafter, her ambitions Jakšić found that the strongest and most con- multiple graduate students. Riddha Manna,
shifted towards establishing a dairy farm, sistent response was in dopamine-producing a current PhD student who works on devel-
and she graduated with a bachelor’s in ani- neurons, which dampened the expression of oping automated systems to perform behav-
mal science in 2012 before moving on to a several genes involved in neural signaling. As ioral assays on flies, tells The Scientist that one
master’s in animal genetics and breeding at a result, the flies developed higher levels of of his favorite parts of working in Jakšić’s lab
the same institution. spontaneous locomotor activity, as measured is the interdisciplinary nature of the research
by how fast they scaled the walls of a vial when and how his mentor makes everyone feel
During her master’s research, Jakšić learned startled (Mol Biol Evol, 9:2630-40, 2020). at home. Of her new lab group, Jakšić says
that “the most basic thing you need for agricul- that “it feels really exciting to work with all of
ture is a very good basis in quantitative genetics, In 2018, Jakšić began a postdoc at Cornell them. The whole journey of the discovery . . .
because everything is about breeding,” she tells University with population geneticist Andrew is something I very much enjoy.” g
The Scientist, adding that she “fell in love with Clark, who describes her as having a natural
IVAN DABAC genetics instantly.” In 2014, she began a PhD competence with “every aspect of fly genet-
in population genetics at the University of Vet- ics.” In his lab, Jakšić expanded on her previ-
erinary Medicine in Vienna, where she inves- ous research by artificially altering levels of
tigated experimental evolution in Drosophila dopamine in Drosophila. She says her goal was
under the mentorship of population geneticist to investigate whether different genotypes
Christian Schlötterer. are better able to “ameliorate” the locomo-
tor changes, adding that she hopes the work
Jakšić describes experimental evolution will lead to insights into human conditions
as the process of exposing organisms to dif- such as Parkinson’s disease, in which dopa-
ferent environments while tracking modifi- mine imbalances induce uncontrolled move-
cations to their genomes in real time. In her ment. The research was abruptly put on hold,
work, she might present flies with color cues however, after Jakšić was awarded a scholar-
that guide them to food, for example. The best- ship to launch her own research group at the
performing flies are then bred, and after mul- Swiss Federal Institute of Technology Laus-
tiple generations, “the shifts in frequencies of anne in 2019.
different gene variants in the population can
actually give you a clue” about the genes driv- Today, she is delving further into
ing changes in their performance over time, she Drosophila evolution, investigating
tells The Scientist. sex-specific differences in how
dopamine homeostasis is main-
Schlötterer recalls Jakšić’s energetic tained and how dopamine sig-
approach to tackling her research questions, naling and behavioral pheno-
noting that she “has great skill in pulling inter- types in males and females
esting signals out of these massive amounts respond to a hotter environ-
of data.” Schlötterer adds that she was a ment(eLife,9:e53237,2020),

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SCIENTIST TO WATCH

Giannina Descalzi: Chronic Pain Detective

Assistant Professor, Department of Biomedical Sciences, University of Guelph

BY NATALIA MESA

Growing up, Giannina Descalzi figured 5:6, 2012; Mol Pain, 8:90, 2012). Sheena Jos- turns into chronic pain for only some mice, as
she would teach—after all, the profes- selyn, a neuropsychologist at the University of well as how chronic pain forms after stressful
sion ran in the family. In the 1950s in Toronto who has mentored Descalzi for almost or traumatic situations.
Lima, Peru, her grandparents started a preK–12 two decades, says that Descalzi was always
school, where her father and aunt both worked “super positive” while working on her PhD Neuropsychopharmacologist and Univer-
as educators. Descalzi’s family eventually relo- and succeeded in producing a large volume of sity of Guelph colleague Jibran Khokhar tells
cated to Ontario, Canada, but the educational papers. “She was just in the groove.” The Scientist that Descalzi has been a staunch
bent remained: when she enrolled as an under- ally as the two start their labs. “She’s willing to
graduate at the University of Guelph in 2000, The work made her familiar with “the gar- support me and advocate with me . . . to make
she initially pursued a literature degree, intent gantuan amount of humans that suffer from science a more accepting place,” Khokhar
on following in their footsteps. chronic pain,” Descalzi says, as well as the fact says. Descalzi adds that as an immigrant, a
that “our treatment options are woefully inad- Latina, and a queer woman in science, she has
Descalzi stuck to that plan into her early equate.” She wanted to dig further into the a desire to advocate for underrepresented
college days, but her horizons broadened in molecular mechanisms of chronic pain and groups. “Chronic pain is an intersectional con-
2002, when she spent a year in London teach- elucidate how networks of neurons interact. dition where different people have a very . . .
ing at a learning center for children with autism “There are millions of cells and billions of syn- different experience of the medical world.
spectrum disorder. Working alongside speech apses in the brain. . . . I was looking for a bigger I’m very cognizant of this intersectionality in
pathologists and clinical psychologists, Des- picture of the networks involved.” the people I’m trying to help, both in academia
calzi says she developed an interest in the and out.” g
human brain and ended up changing her major During two different postdocs, Descalzi
UNIVERSITY OF GUELPH to psychology when she returned to Guelph. surveyed the brains of mice to identify the
In one class, she learned the concept of syn- genes and brain regions that drive persis-
aptic plasticity, or the idea that the strength of tent pain. At the Icahn School of Medicine at
connections in the brain can change based on Mount Sinai, she and her colleagues found
experience. “I walked out of that lecture seeing that chronic pain led to changes in the
the world in a completely different way,” she expression levels of more than 17,000
tells The Scientist. genes in multiple brain regions—includ-
ing some associated with stress and
Descalzi went on to complete a master’s depression—and in different cell types,
and a PhD in neuroscience at the University including astrocytes, which are thought
of Toronto, first working with neurologist Rob- to play a substantial role in chronic pain
ert Chen and later with neuroscientist Min (Sci Signal, 10:eaaj1549, 2017).  Descalzi
Zhuo. For her dissertation, Descalzi studied the spent her second postdoc at New York
long-term changes that occur in the brain fol- University studying these cells more
lowing chronic pain—ongoing pain that per- broadly, including their production of lactate
sists past normal healing time, typically three and its importance in the formation of long-
to six months. She detailed aversive learning term memories (Comm Biol, 2:247, 2019).
in mice that experience painful stimuli, includ- Josselyn says that Descalzi’s work “with astro-
ing changes in the expression levels and pro- cytes and at the intersection between emo-
tein composition of two receptors involved in tion and chronic pain” are among her biggest
modulating the strength of synaptic connec- scientific contributions.
tions in the anterior cingulate cortex, a brain
region involved in emotional regulation. She In 2019, Descalzi returned to the Univer-
also described how chronic pain changes the sity of Guelph as an assistant professor in
expression of CREB, a transcription factor the school’s Ontario Veterinary College.
thought to be involved in long-term memory She continues to study chronic pain in
formation, in the animals’ forebrains (Mol Brain, mice using large-scale sequencing tech-
niques to understand why acute pain

SUMMER 2022 | THE SCIENTIST 65



MODUS OPERANDI

CRACKing the Neural Code

A new technique reveals cells’ precise locations and functions in the brain. Its
developers have already used it to identify a previously unknown neuron type.

BY DAN ROBITZSKI

Neuroscientists examining a brain Step 1: Calcium Imaging Step 2: HCR-FISH
cell typically have to choose
© IKUMI KAYAMA, STUDIO KAYAMA between studying its internal mouse brain. According to Chen’s findings, ONE-STOP SHOP: First, calcium imaging provides
molecular activity or detailing its connec- Baz1a cells help coordinate neural activ- precise neural microscopy data on the arrange-
tions and electrical activation in the brain. ity related to learning in response to tac- ment and activity of individual cells within the
But in his lab at Boston University, biolo- tile sensations on mouse whiskers. Chen brain of a live mouse. Then, hybridization chain
gist and biomedical engineer Jerry Chen says that even though they created CRACK reaction–fluorescence in situ hybridization (HCR-
has developed a technique that allows for this specific experiment, they’ve just FISH) on tissue samples yields information on the
researchers to do both, mapping neurons scratched the surface of how the method- expression of specific genes of interest. Combining
within a living mouse’s brain and then ology could be used. these imaging methodologies into a technique
assessing their gene expression (Science, called comprehensive readout of activity and cell
375:eabl5981, 2022). “Now, if you have a tissue of a thou- type markers (CRACK), allows researchers to
The new technique, called compre- sand neurons, you can actually start to elucidate a cell’s type, connections within neural
hensive readout of activity and cell type label all eleven, twelve, thirteen, fourteen, circuitry, and function.
markers (CRACK), combines calcium fifteen different types of neurons that we
imaging microscopy with a variation on a know exist,” Chen says. “Then you can ask: of dozens of genes in a given neuron.” With
DNA labeling approach called hybridiza- How does cell type A communicate with CRACK, “you can record hundreds of neu-
tion chain reaction–fluorescence in situ cell type B?” Chen envisions several possi- rons’ activity and pretty precisely identify
hybridization (HCR-FISH) to label and ble uses for CRACK, including studying the the cell type of each of those hundreds of
track mRNA. CRACK allows research- neural function of species beyond mice and neurons,” adds Komiyama, who didn’t work
ers to first observe the electrical firing of humans for which tailored neuroscience on the paper but helped pioneer the use of
neurons in the brain of a live mouse dur- tools may not be available, or answering calcium imaging over the past two decades.
ing a behavioral task, and then track the “any question that involves trying to marry
expression of specific genes in slices of the molecular information with dynamics— Komiyama notes that “it’s a very spe-
animal’s brain, ultimately linking specific functional information” on the behavior cialized approach” and “takes a lot of man-
cells and their molecular activities to par- of neurons. ual practice,” but speculates that CRACK
ticular behaviors. could spread as members of Chen’s lab
“There was a technology gap that University of California, San Diego, train visiting scholars and other research-
required marrying molecular information neuroscientist Takaki Komiyama tells The ers, not unlike the way calcium imaging
[from existing databases] with the func- Scientist that the main benefit of the tech- has “become so common” after labs such as
tional information” from behavioral stud- nique is being able to “define the expression Komiyama’s introduced it in 1997. g
ies that his lab focuses on, Chen tells The
Scientist. Prior to CRACK, researchers
could only monitor the neural activity of
one cell type at a time, Chen explains, and
there was no feasible way to connect that
activity to the molecular workings going
on inside those cells because obtaining
each type of information required sepa-
rate experiments.
The paper describes how the team
used CRACK to identify a previously
overlooked neuron type, the Baz1a cell, in
the primary somatosensory cortex of the

SUMMER 2022 | THE SCIENTIST 67

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SUMMER 2022 | THE SCIENTIST 69

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EDITOR’S CHOICE

The Literature

CANCER Salmonella

Salmonella Takes Dendritic cell
On Cancer activated by

THE PAPER antigens

W. Wang et al., “Systemic immune responses
to irradiated tumours via the transport of
antigens to the tumour periphery by injected
flagellate bacteria,” Nat Biomed Eng, 6:44–
53, 2022.

© KELLY FINAN Getting the body to attack cancer can be a compared with just 25 percent in mice Antigens shed
challenge, as many tumors are able to sup- treated with radiotherapy and injected by tumor
press immune activity. One possible solu- with saline.
tion, published earlier this year in Nature IMMUNE ASSISTANTS: Following radiation therapy,
Biomedical Engineering, involves injecting The results suggest that the engi- which triggers the release of cancer-specific anti-
a weakened bacterial strain to help alert neered Salmonella helped ensure that gens, researchers injected Salmonella typhimurium
the immune system to a tumor’s presence. antigen-detecting dendritic cells, which bacteria covered in positively charged nano-
immunosuppressive tumors can disable particles near tumors in mice. The bacteria cap-
Lead study author Jinhui Wu, a bio- or keep at bay, came into contact with tured the negatively charged antigens and ferried
technology researcher from Nanjing Uni- the tumor antigens and activated an them to dendritic cells in the tumors’ periphery,
versity in China, tells The Scientist via immune response. Polina Weitzenfeld, where a tumor-targeting immune response was
email that the idea for the experiment came a tumor immunologist at the Rocke- initiated, improving the animals’ odds of survival.
from the 1966 science fiction film Fantas- feller University who did not work on the
tic Voyage, which “focuses on the process study, tells The Scientist that Wu and his cell line in their mouse model. Such tumors
of micron-sized robots entering the body to colleagues conducted a “well-designed tend to be more homogeneous than human
remove blood clots,” he explains. He and his study” with an “interesting approach” cancers, she notes, and do “not always
team wondered if they could do something that she says “includes all necessary con- completely simulate the tumor microenvi-
similar, but for cancer, and chose to use trols.” Weitzenfeld and Fred Hutchinson ronment of human cancers.”
Salmonella typhimurium as the therapeu- Cancer Research Center’s Kristin Ander-
tic vehicle because it’s already been demon- son, who also didn’t participate in the Growing tumor models like those used
strated to be safe for use in humans as part work, say they expect the treatment to in the study “can be great for asking proof-of-
of cancer therapy. Instead of using the bac- work better in tumors with a high muta- concept questions,” Anderson says, but they
terium as a weapon to attack tumor cells tion rate. As Anderson explains, “tumors sometimes make a poor proxy for human
directly, however, Wu and his colleagues that make a lot of proteins that look dif- cancers, in which immune cells may lose
saw its potential to empower immune cells ferent from healthy proteins will likely functionality over time. For these reasons,
to do so. result in more antigens for the bacteria Anderson says she suspects that this ther-
to transport.” apy may have subtler effects when applied
The team coated Salmonella with posi- to humans. Still, Wu says he plans to test the
tively charged nanoparticles before inject- One weakness of the study, Anderson treatment in humans, but that further safety
ing them into mice that had been treated tells The Scientist, is that the researchers testing is necessary before that happens.
with radiotherapy. The radiation triggered used transplanted tumors derived from a
the tumors to shed negatively charged “Unfortunately,” Weitzenfeld cautions, “it
antigens that clung to the bacteria. Mea- is much easier to cure mice than humans.”
suring dendritic cell activation as a proxy
for the anti-tumor immune response, —Dan Robitzski
they observed an 83 percent survival rate

SUMMER 2022 | THE SCIENTIST 71

THE LITERATURE

LANGUAGE TRICKS: Knocking out higher brain functions seems to help peo- GETTING AROUND: A micrograph from the first US case of COVID-19,
ple recognize where words start and end—at least on a subconscious level. with SARS-CoV-2 virus particles in blue

EDITOR’S CHOICE IN NEUROSCIENCE EDITOR’S CHOICE IN MICROBIOLOGY

Background Learning Cell Hopping

THE PAPER THE PAPER

E.H.M. Smalle et al., “Unlocking adults’ implicit statistical learning by C. Zeng et al., “SARS-CoV-2 spreads through cell-to-cell transmission,”
cognitive depletion,” PNAS, 119:e2026011119, 2022. PNAS, 119:e2111400119, 2022.

Psychologists define two types of memory: declarative, covering con- Viruses typically spread among host cells as virions, particles compris- © ISTOCK.COM, PROSTOCK-STUDIO; HANNAH A BULLOCK, AZAIBI TAMIN
tent that people can explicitly recall; and nondeclarative, encompass- ing a cargo of genetic material enveloped by a protein shell. In addition
ing skills, habits, and procedures that are implicitly known but hard to to this so-called cell-free transmission, some viruses can also spread
articulate. Nondeclarative memory develops earlier and is thought to their genetic material by hopping directly from one cell to another via
be critical for language acquisition in children—and some scientists tight junctions, virological synapses, or other mechanisms—a more effi-
have suggested that adults’ greater reliance on declarative memory cient route that evades host immune defenses.
could inhibit implicit learning.
Shan-Lu Liu of The Ohio State University and colleagues set out to
Ghent University experimental psychologist Eleonore Smalle and see if this cell-to-cell transmission occurs in SARS-CoV-2. Engineering
colleagues tested this idea by having adults listen to a made-up lan- pseudotyped virus genomes to include spike protein and fluorescent
guage, in which the only way for the brain to distinguish individual words protein genes, the team tracked viral movement in two cultures: one
was through how frequently particular syllables appeared together— where cells could touch, and another where cells were physically sepa-
a type of pattern extraction known as statistical learning. For some par- rated. Neither condition prevented cell-free transmission, but only the
ticipants, researchers disrupted parts of their brain involved in higher first allowed cell-to-cell transmission.
cognitive functions beforehand, either by having them complete men-
tally demanding tasks on a computer or by zapping them with transcra- The results indicated that around 90 percent of viral transmis-
nial magnetic stimulation. Afterward, participants had to say if they sion was cell-to-cell, possibly via fusion between neighboring infected
recalled individual words and indicate their confidence each time. and uninfected cells, Liu says. Further in vitro experiments that paired
authentic SARS-CoV-2 with either the antiviral medication remdesivir
Focusing on unconfident answers, which Smalle says represent or serum samples from people who received mRNA vaccines hinted that
implicitly learned information, the team found that cognitive disruption cell-to-cell transmission helped the virus avoid being neutralized by drugs
was associated with an improved ability to distinguish words. Penn State or antibodies. This ability to spread without exiting the intracellular envi-
University’s Elisabeth Karuza, who was not involved in the work, calls the ronment could help “lead to persistent or prolonged infection,” Liu notes.
study “a really compelling demonstration that if you soak up cognitive
control resources in young adults, you can induce a more child-like learn- Clare Jolly, a virologist at University College London who was not
ing state” that improved participants’ sensitivity to statistical patterns involved in the work, says Liu’s team presents good experimental evi-
in a spoken language. She adds that experimental psychologists could dence for cell-to-cell transmission. It’s less clear how much this happens
do more to pick apart differences between implicit and explicit learning. in vivo or whether it’s a result of cell-cell fusion, she says, noting that
other viruses typically use different tactics. “Whether that’s really what
Smalle says that while the study only addresses word segmenta- the authentic [SARS-CoV-2] virus does in primary epithelial cells is an
tion and not grammar or other parts of language acquisition, the findings open question.”
suggest ways to enhance learning abilities. “For instance, while doing
the dishes, listen to a podcast in another language—just to appeal to Liu says his lab is now digging into mechanisms and, as the current
your unconscious brain as much as possible.” study focused on the SARS-CoV-2 Alpha and Beta variants, expanding the
work to consider Omicron.
—Catherine Offord
—Catherine Offord

72 THE SCIENTIST | the-scientist.com

ROAMING REINDEER: A North American caribou (Rangifer tarandus) in Jasper TALKING HEADS: Not-to-scale renderings of the skulls of various primate
National Park in Canada species, including the crowned lemur (Eulemur coronatus, center), with the
analyzed teeth shown in blue

EDITOR’S CHOICE IN GENETICS EDITOR’S CHOICE IN PHYSIOLOGY

Wanderlust Genes Mega Bites

THE PAPER THE PAPER

M. Cavedon et al. “Genomic legacy of migration in endangered cari- A.R. Deutsch et al., “Primate body mass and dietary correlates of tooth
bou,” PLOS Genet, 18:e1009974, 2022. root surface area,” Am J Biol Anthropol, 177:4–26, 2022.

MARK BRADLEY; ASHLEY DEUTSCH AND ADAM HARTSTONE-ROSE Each spring and fall, groups of caribou (Rangifer tarandus) undertake Animals’ remains are often incomplete, but even a handful of teeth
marathon migrations of up to 400 kilometers, the longest of any land can reveal key traits, including an organism’s size and diet. Typically,
animal. “It’s a phenomenal behavior,” says University of Calgary wild- a tooth’s crown (the portion above the gum) is used to extrapolate
life ecologist Marco Musiani. Recently, he and other scientists started these details, but North Carolina State University biologist Adam
teasing apart the environmental and genetic contributions to these Hartstone-Rose and colleagues recently explored whether tooth
long-distance journeys, yielding findings that might explain why some roots, which are less likely to chip or crack than crowns, might pro-
subpopulations of caribou travel less far or frequently than others. vide useful information too.

Musiani and his colleagues tracked the movements of 139 female Hartstone-Rose’s group mapped the tooth root surface area
caribou wearing GPS collars and classified the animals either as more (TRSA) of 75 rear teeth—those behind the canines—from the lower
sedentary or more migratory. Sequencing parts of their genomes, the jaws of 73 extant primate species and compared their measurements
team identified 57 single-nucleotide polymorphisms (SNPs) associated to estimates of body size for each individual. The team also categorized
with migration, 27 of which were found in or linked to genes thought each specimen by its diet—whether it ate insects, fruits, leaves, or hard
to influence migratory behavior in other species as well. These genes foods such as bones or seeds—and plotted the variation in TRSA for
spur changes in energy metabolism, hormone production, body devel- each category. The team found a strong, positive correlation between
opment, and brain activity. Ancestry seemed to play a role in migratory root surface area and body size, but the relationship between TRSA and
behavior, too. Caribou of the barren-ground subspecies, which live in diet varied across lineages.
harsh, variable conditions, made significantly longer hauls than their
woodland counterparts, including caribou of the Northern mountain The researchers plan to look at other types of teeth, including
and boreal ecotypes, even when controlling for location. those in the upper jaw, to determine whether they have a closer
relationship to diet, says biologist Ashley Deutsch, a PhD student
Francisco Pulido Delgado, a zoologist at the Complutense University in Hartstone-Rose’s lab who completed the work for her disserta-
of Madrid who was not involved in the research, calls the use of GPS track- tion. Meanwhile, the team has added TRSA to its toolkit for analyz-
ing “the biggest strength of the study,” but adds that without knowing how ing tricky specimens. “Just knowing how big [an animal] is tells you
the SNPs affect surrounding genes, future research will be necessary to enormous amounts about how it interacts with the environment,”
determine the specific mechanisms driving migratory behavior. says Hartstone-Rose.

Tying migration to particular genes in caribou could have conser- Peter Ungar, an anthropologist at the University of Arkansas who
vation implications, Musiani says. “With the expansion of human pop- was not involved in the research, calls the study an example of “good
ulations and with the increase in human infrastructure, these animals science,” but adds that establishing a clearer link to diet would be even
that migrate are having additional difficulties” and declining in numbers. more useful, especially if the metric was used to study extinct species
Future selective breeding programs may want to matchmake caribou, about which far less is known. “There would have been a much big-
he explains, with the goal of maintaining variation in these migration- ger splash if you found an entirely new way of reconstructing diet in
associated genes. the past.”

—Maddie Bender —Maddie Bender

SUMMER 2022 | THE SCIENTIST 73

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CAREERS

Making Peace with the Press

There are many benefits to communicating science to the media,
but talking with journalists doesn’t always go smoothly.

BY KATARINA ZIMMER

MODIFIED FROM © ISTOCK.COM, PCH-VECTOR Not long after SARS-CoV-2 was But interactions with journalists thing, the pace of science is far slower than
first detected in the US in Janu- don’t always go as smoothly. On top the news cycle. And while researchers’
ary 2020, emergency medicine of the usual gripes that scientists main audience is the scientific community,
physician Esther Choo’s inbox began buzz- can have when media organizations cover sci- journalists typically convey information to
ing with interview requests. One TV sta- entific findings—that they can sensationalize the wider public. Such cultural differences
tion even wanted her to appear live several research or get it downright wrong—many are “where I think a lot of pain points pop
nights a week during the early stages of the have had disappointing experiences due to up between scientists and journalists,” says
pandemic to help viewers understand what confusion over journalistic practices and Tori Fosheim, a neuroscientist turned sci-
the virus’s arrival meant. challenges in getting scientific messages ence communicator, “and where having an
across. While some researchers emphasize understanding of each other’s cultures can
Choo hesitated at first. She had no for- that the responsibility for a story’s accuracy help alleviate some of that.”
mal training in media interviews, and lies with journalists, scientists can improve
although she had spoken with journalists the outcomes of interviews by gaining a bet- That’s why many communication
about basic health topics in the past, it was ter understanding of the journalism world training programs for researchers—such
a different matter to speak authoritatively and honing their own communication. as the ones offered by SciLine, a Wash-
about a pathogen that was brand-new to sci- When successful, researchers often find that ington, DC–based nonprofit affiliated
ence. “Getting contacted by the media is def- giving interviews both provides a public ser- with the American Association for the
initely this high-anxiety thing,” says Choo, a vice and can benefit their own research. Advancement of Science (AAAS) that
professor at Oregon Health & Science Uni- strives to improve the media-science rela-
versity. “At the beginning [it] was like, ‘Can I Managing expectations tionship, or the Oregon-based nonprofit
do this?’—especially at a time when we were For all their similarities—a focus on facts COMPASS—spend some time unpack-
scrambling to figure out what we were actu- and an outlet for curiosity—science and ing how journalists operate in addition to
ally doing in our clinical practice.” journalism are different worlds. For one sharing communication strategies scien-
tists can use. For example, some scientists
Persuaded by a sense of responsibil-
ity to share what the medical community
knew so far, she ended up agreeing, she
tells The Scientist. Choo has since given
more than 100 interviews to national
and local newspapers and TV and radio
stations about everything from COVID-
19 vaccines and shortages of protective
equipment to topics closer to her own
field of research: the health disparities
that were amplified by COVID-19. Today
she sees interviews as a key weapon in the
fight against misinformation.

Journalists have their own goals
when reporting and writing their sto-
ries. But especially during the pandemic,
most journalists and scientists strive to
get good, accurate information to the
public. Choo says, “It felt like we both
had a stake in sharing what was happen-
ing on the ground.” At its best, she adds,
“it felt like a partnership.”

SUMMER 2022 | THE SCIENTIST 75

CAREERS

express annoyance at being given short Scientists typically have little say over the shape a story takes,
notice for interviews, says Fosheim, Sci- which can be unnerving for those used to assisting their
Line’s scientific outreach manager. But institution’s media offi­cers in crafting press releases.
rather than the reporter being disorga-
nized or disrespectful of a scientist’s time, ant surprises can also occur when little or no But to Najmanovich, it appeared that
“it’s that the speed of journalism moves material from interviews makes it into the some of the journalists hadn’t completely
very quickly,” she explains to researchers. actual publication, due either to a reporter’s grasped the basic elements of the research,
Another point of confusion, adds Mat- decision or an editor’s. For instance, after as he found many of the published articles
thew Libassi, the lead media relations ecologist Anabelle Cardoso of the Univer- both oversimplified and unclear, he says.
specialist at the Feinstein Institutes for sity at Buffalo sent a journalist a page or so Although he argues that the onus is on
Medical Research in New York State, is of detailed answers about a citizen science journalists to make sure they understand
why journalists typically don’t send inter- project she was running, she was disap- the research, he has begun to simplify his
viewees a full list of prepared questions. pointed to see that the article only included a explanations. “I think from now on, I will
According to US journalists surveyed in single quote from her. “When I spoke to my actively ask the person to explain to me
2015 by Sense About Science USA, a non- supervisor about it, they were like, ‘Oh yeah, what I explained to them, almost as if I was
profit that aims to promote public inter- journalists do that all the time. You just have in a classroom.”
est and literacy in science, the practice is to know to not put two hours into answer-
deliberate: it helps to ensure spontane- ing the questions,’” Cardoso recalls. Echoing Miscommunication can also arise
ous, lively conversation and to avoid the Libassi’s point, she notes that “loads of peo- when scientists converse with report-
answers being influenced by third parties ple still read about the project, even if it was ers as they would with colleagues. That
such as university press offices. only one sentence.” happened to evolutionary biologist Lou-
ise Johnson of the University of Reading
Additional frustrations stem from Fosheim adds that while scientists in the UK, when a journalist asked her
the fact that scientists typically have may have little control over a news story, to send emailed comments about a new
little say over the shape a story takes, their hands are not totally tied. “You do study by a different research group. The
which can be unnerving for those used have control over the way you frame the research in question reported a correla-
to assisting their institution’s media offi- information that you give to a journalist.” tion between a molecular characteristic
cers in crafting press releases, Libassi The key, she says, is clear communication. and a population-level effect in a complex,
notes. He says that in his experience, noisy ecosystem, and the study authors
most reporters convey scientific research Mastering the interview had hypothesized there was likely a causal
accurately, but they cannot allow inter- Researchers are often asked to distill relationship between the two. Johnson
viewees to influence the framing or years’ worth of research in the space of a wrote back to the reporter, expressing cau-
choice of material published. That’s for brief interview. That’s become particularly tion around that interpretation of results
much the same reasons that journalists challenging in recent years, Fosheim says, similarly to the way she would write to a
wouldn’t give a politician editorial con- as industry-wide layoffs have forced many journal editor, “saying something along
trol over a story, according to The Open local newsrooms to let go of journalists who the lines of, it’s remarkable that they
Notebook, an online publication for jour- specialize in science writing, while the pan- found such a clear relationship, given all
nalists. Indeed, the vast majority of US demic has pushed reporters from all spe- the noise in the system.”
journalists who responded to the 2015 cialties to cover the latest research.
survey said they never send drafts of When the story was published, she
articles to sources to review, and most That is something that computational realized that her comments had been mis-
only infrequently send quotes. biologist Rafaël Najmanovich of the Uni- interpreted—“not unreasonably,” Johnson
versité de Montréal says he experienced says—as enthusiastically affirming that the
As a result, the final product might when a flurry of local news reporters inter- study had detected a causal relationship.
present information differently than viewed him about a coronavirus-related Even worse, she tells The Scientist, there
scientists would have, or omit aspects preprint he published with colleagues in were quotation marks around a statement
important to scientists. In such cases, December 2020. He explained to them to that effect that was attributed to John-
Libassi often tells his institute’s scientists, how his team, through a complex compu- son, suggesting she’d said this verbatim,
“‘This is still a great article,’ because nine tational approach that simulated molecu- even though she hadn’t—something
times out of ten, it is. They highlighted lar structures, was able to determine that a Libassi writes in an email is “morally, eth-
you; they highlighted your research.” novel mutation made a SARS-CoV-2 vari- ically and journalistically wrong.” Libassi
ant circulating at the time more transmis- adds that reporters should make sure they
Fosheim also cautions scientists that cer- sible than the virus first detected in Wuhan. understand and represent their source’s
tain parts of the writing process are out of a
reporter’s hands—like headlines, which she
notes are often written by editors. Unpleas-

76 THE SCIENTIST | the-scientist.com

views correctly. “I do remember feeling mental Sciences Area for interviews, a pandemic. “I definitely have had these
very aggrieved,” Johnson says of the expe- guiding them in distilling key messages moments where I felt I’m on this show to
rience, adding that it taught her to be more to levels that laypeople can understand. bash a certain political party,” Choo says.
direct. Faced with a similar situation now, “With repetition, [scientists] get better In such situations, she tries to stay asser-
she’d stress that “you probably need to do and better” at this, Procopiou says. tive and steer the conversation back to her
a bit more work to find out whether this is main scientific messages.
a situation where the X is causing Y.’” Unexpected benefits
Another common fear scientists have That’s advice cognitive psychologist
Johnson didn’t let the experience put about giving interviews is being put on the Michael Silverman says he wishes he’d fol-
her off speaking with other journalists. In spot with a “gotcha” question, according to lowed some years ago, when he was asked
fact, she attended a day-long media train- one 2021 survey of some 3,300 scientists to speak on live TV about a recent incident
ing offered by an association in the UK conducted by SciOPS (Scientist Opinion in which a woman had killed her newborn.
called Media Woman, and says that for Panel Survey), a science communication Silverman, who studies reproductive psychi-
her, the workshop “really helped build platform developed at Arizona State Uni- atry—including postpartum depression and
confidence.” Many scientific institutions versity. Even experienced science commu- psychosis—at Icahn School of Medicine at
also offer media training. For instance, nicators can be caught off guard if report- Mount Sinai, wanted to shed light on how
at the Lawrence Berkeley National Lab- ers unexpectedly ask them to weigh in on such rare, yet catastrophic, situations can
oratory, science communications spe- a political issue related to their research, occur. Unbeknownst to him, the moderators
cialist Christina Procopiou helps prepare such as an administration’s response to had also invited three prosecuting attorneys
researchers in the Earth and Environ- on air, who cut Silverman off, fiercely argu-

TIPS FOR WHEN A REPORTER REQUESTS AN INTERVIEW

Vet the journalist. Communications specialist Matthew Libassi of the Feinstein Institutes for Medical Research recommends researching
the journalist and publication to get a sense of their tone, purview, and specialty. If you feel the reporter would represent your message fairly,
arrange the interview, he says. Cognitive psychologist Michael Silverman of the Icahn School of Medicine says to “respond as soon as you can”
to a request, as “reporters are often working last-minute.”

Practice. Mock interviews with your institution’s press officers, mentors, or colleagues can help hone simple, concise messages that can serve
as answers during interviews; one 2015 survey compiled questions that journalists typically ask. Science communications specialist Christina
Procopiou of the Lawrence Berkeley National Lab recommends staying away from scientific jargon and detail that might be confusing, instead
focusing on key messages about the research and why it matters.

Consider other perspectives. “Most reporters want a balanced story,” Silverman says. “As such, expect that they will be speaking to col-
leagues whom you may differ with in the field. It’s helpful to take into consideration the position of those in the field who disagree with you.”

Keep it interesting. Mental imagery and metaphors that can help communicate complicated scientific processes, as well as personal reflec-
tions and anecdotes related to your research, can increase the chances of being quoted in the final publication, says science communicator
Tori Fosheim. “Those are going to be what adds color to a story, [which is] something that a journalist is going to want to include.”

Consider journalistic practices. Although most reporters don’t provide questions in advance, you can ask for general discussion points,
Libassi says. He adds that scientists should assume they’re “on the record” during interviews, meaning that what they say can be printed
and attributed to them. “If you don’t want something said, don’t say it.” If in doubt, Fosheim advises scientists to ask reporters about their
practices—whether they’ll circle back to fact-check material or quotes after the interview, for instance. “Before you even leave the room,
make sure everybody is on the same page.”

Prepare for the unexpected. If you don’t immediately have an answer to a question, “take a breath, and . . . if it’s really not coming through to
you, ask them to rephrase it,” says biologist Susan Wray of the University of Liverpool. For questions you don’t feel comfortable answering, stay
on message, adds emergency medicine physician Esther Choo, who helped compile some other media interview advice last year in Science.
“Usually there’s ways to be like, ‘Well, I’m not sure about that. But the main point here is this,’ and really focus on the key points that need to
get across to a broader audience.”

Manage expectations. If a published article contains an error or “really needs clarification,” Libassi recommends contacting the reporter to
ask for a correction. But he and Fosheim remind researchers that they don’t have control over the framing or wording of an article or over
whether their quotes or research make it into the publication. Understanding more about how journalists work, Fosheim adds, “makes it a
little easier not to take it personally.”

SUMMER 2022 | THE SCIENTIST 77

CAREERS

ing that the woman’s act was premeditated, Many scientific institutions benefits from giving media interviews.
he recalls. Stressed under the pressure, Sil- also offer media training. She experienced a media splash in 2018
verman fumbled, and shut down entirely. when speaking to BBC Radio 4’s Today
“At the time it was humiliating,” he writes group of people about something that program and several newspapers about
to The Scientist in an email. “Even worse, by is worthy of being informed of.” the results of a small trial that tested a
not standing my ground I ended up hurt- new treatment for a particular childbirth
ing those I’ve worked so hard to help.” (In Procopiou says she has seen increas- complication. Afterward, friends, col-
her experience, Fosheim notes, the reporter- ing interest from scientists in media leagues, and her university’s vice chan-
scientist relationship isn’t an adversarial one.) training and other forms of science com- cellor reached out to congratulate her. “If
munication, often as a public service. it goes well—and most the time it’s going
Silverman says he now avoids But scientists can reap personal benefits, to—it does give you a lift,” she says.
interviews with certain news out- too. In fact, the vast majority of research-
lets that he perceives as prioritiz- ers who responded to the SciOPS survey Giving media interviews has even
ing entertainment over facts, but con- said that “helping me advance profes- enriched her perspective on her own
tinues to give interviews to others sionally within my university” was the research, Wray says. “It’s a good mental
because he enjoys communicating. top benefit they saw from interacting exercise on the whole, to talk to journal-
He says he thinks that many report- with the media. ists, to see where they’re coming from. . . .
ers he’s worked with genuinely want It makes you hone your arguments.” g
to understand and represent scientific Molecular and cellular physiologist
information accurately and fairly. When Susan Wray of the University of Liver- Katarina Zimmer is a freelance science
interviews go smoothly, “that’s great, pool says she has reaped other kinds of and environment journalist based in New
because we’ve just informed a whole York City.

TSU TECHNIQUE TALKS

STRAIGHTENING OUT
MESSY WESTERN BLOTS

Western blot-based protein analysis remains the
go-to experiment to assess a protein’s expression
level or posttranslational modifications. Despite its
popularity, it is difficult to obtain a reproducible,
publication-ready western blot, and researchers
often face a long-winded optimization process
when starting a new experiment with a different
antibody or tissue type.

TUESDAY, 3:00–4:00 PM Aldrin V. Gomes, PhD
JULY 12, 2022 EASTERN TIME University of California, Davis

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https://www.biorxiv.org/content/10.1101/2021.12.14.472674v3

BIO BUSINESS

Skin Deep

Researchers are revealing the complexity of the microbial community living on the body—and paving
the way for new microbiome-targeting treatments for acne and other dermatological conditions.

BY BIANCA NOGRADY

Overnight, Chris Callewaert But while the microbiome that cov- odor, says “it’s also very complex. . . . © ISTOCK.COM, DR_MICROBE
acquired body odor. The bioen- ers each person’s roughly two square There’s thousands of species, and they
gineer, then a student, had led a meters of skin might be more acces- all have an influence.”
largely odorless life. But several years ago, sible than that of the gut, that doesn’t
in the space of just 12 hours, he suddenly mean it’s equally amenable to scientific What lives on the skin?
noticed that he had acquired a distinctly study or manipulation, say researchers Sara Saheb Kashaf has long been inter-
unpleasant smell. The question of what who spoke to The Scientist. There is also ested in atopic dermatitis and the possibil-
and why has since set him on a scientific a risk that adding or removing species ity that the condition has ties to the skin
mission to understand how the population could destabilize the delicate balance of microbiome. Antibiotics have been shown
of bacteria, viruses, and fungi that colonize organisms and potentially do more harm to work as a treatment for the condition,
human skin—known as the skin microbi- than good. Although he sees a bright which causes red and itchy skin, suggesting
ome—can influence the body’s fragrance. future in this area of research, Callewaert, a microbial influence. But when she started
who now holds patents on the use digging into the problem a few years ago, “it
“From birth on, our skin microbiome of prebiotic (substances that selec- was really interesting to me that we didn’t
then goes through an evolution through- tively nourish or inhibit specific bacte- really know the true composition of the
out life,” says Callewaert, now a post- ria) and probiotic treatments for body microbiome of our skin,” she says.
doctoral fellow at Ghent University in
Belgium who also goes by the name of
“Dr. Armpit” on account of his research
focus. These changes are influenced by
internal factors such as diet, immune
system function, and diseases, and also
by external factors like pollution and
microbial exposures, he says. Callewaert
suspected that his swift transformation
from odorless to smelly was related to
such a change in his skin microbes. “I
somehow knew that that had to do with
bacteria,” he says.

While research on the skin microbi-
ome lags years behind studies of the gut
microbiome, there is now emerging evi-
dence that microbial imbalances, or dys-
biosis, on the skin could play a role not just
in body odor but in conditions including
acne, eczema, and even autoimmune dis-
eases such as psoriasis. The pharmaceuti-
cal sector is showing keen interest in the
subject; already, deals worth hundreds of
millions of dollars are being made by com-
panies including GlaxoSmithKline, Sanofi,
and Bayer, as the industry looks for ways
to alter the skin microbiome to treat der-
matological conditions that until now have
been relatively underserved by medicine.

80 THE SCIENTIST | the-scientist.com

To address this, the MD/PhD student, as the back of the head, the crease along- the question of how to treat skin condi-
based at the European Molecular Biol- side the nose, and the cheek, the makeup tions a challenging one to answer.
ogy Laboratory’s European Bioinformat- of the microbiome hardly changed over
ics Institute in the United Kingdom and the course of the study. “But then there Good or bad microbes
at the US National Institutes of Health, were other body sites, which may be very Segre says that there isn’t yet a good sense
recently conducted a comprehensive sur- intuitive, like our hands and feet, that are of what makes a skin microbe benefi-
vey of skin microbes. Each of a dozen or constantly in flux,” she says, adding that cial, but there are some obviously patho-
so volunteers had samples taken from much less is known about what microbial genic species that set off alarm bells.
multiple sites on the body—including the species live on these sites. One of these is methicillin-resistant
forehead, hands, feet, groin, armpits, and Staphylococcus aureus (MRSA), which
ears—and some of the volunteers were Despite these variations, other can cause infections of the skin as well as
sampled again on three or four different research has shown that the overall skin of the lungs and bloodstream. The mere
occasions over several years. microbiome changes throughout our life- presence of MRSA—in the nose, for exam-
time in such a predictable fashion that ple—poses such a threat that people going
Saheb Kashaf and colleagues used its composition can be an accurate pre- in for surgery who are found to carry the
metagenomic sequencing to detect the dictor of age. Belgian biotechnology bacterium are given prophylactic antibiot-
genes in each sample, and then employed company S-Biomedic has characterized ics to clear it, Segre says. Another patho-
computational methods to reconstruct indi- some of these changes in the microbiome gen Segre has worked on is the fungal spe-
vidual genomes and identify the organisms of the face, and the Cutibacterium species cies Candida auris, which is classified as
present. Two key challenges were the low that dominate there.
biomass of microbes on the skin and the
risk of environmental contamination, so There is already considerable intere­ st in altering the micro-
for every patient sample, the team also biome by eliminating pathogenic species, transp­ lanting
took a negative control by waving a swab beneficial species, or selectively engineering microbes so
in the air. “The microbial load is that low as to reduce harm or increase benefits.
that you need to do that, or else you end
up thinking that microbes that are really The abundance and composition a global health threat because of its asso-
contaminants of your reagents are parts of this part of the skin microbiome are ciation with bloodstream infections that
of your microbial community,” says study affected by major life events, says synthetic are resistant to common antifungal drugs.
coauthor Julie Segre, a microbial genomi- biologist Bernhard Päetzold, S-Biomed-
cist and senior investigator at the National ic’s cofounder and chief scientific officer. But that’s where the easy labelling of
Human Genome Research Institute. “Right when we are born, in the first days, “bad” microbes ends. For example, Cuti-
there’s a lot of Cutibacterium that then dis- bacterium has been unfairly demon-
Overall, the team’s study identified 622 appears,” says Päetzold. “It stays flat until ized, Päetzold argues, as one of several
species of microbes, including 174 new- the moment when puberty comes, and at bacteria thought to be a causal factor in
to-science species of bacteria, 12 fungal that moment, our sebaceous glands switch acne. “There was this conundrum: peo-
species, and 20 types of large bacteria- on.” When those glands become active, ple said it must be a bacterium causing
killing viruses known as jumbo phages they create the perfect environment for acne because when we put antibiotics or
(Nat Microbiol, 7:169–79, 2022). The Cutibacterium, he says, and the microbe disinfectants on, [acne] gets better,” he
exact composition of the skin microbi- becomes the dominant inhabitant of the says. But Cutibacterium is also commonly
ome varied by body part. For example, the follicles connected to those glands. found in people without acne.
area between the toes was teeming with
viruses, the back of the head was domi- The association between increased Päetzold says acne is likely the result of
nated by the well-known skin-dwelling Cutibacterium and puberty had suggested interactions between particular strains of
Cutibacterium, the bottom of the heel to some researchers that the bacterium’s Cutibacterium and the person they’re liv-
housed almost entirely Staphylococcus presence was a major contributor to ing on. “If you have a host that is partic-
species, and the cheek microbiome fea- adolescent acne, leading biotech companies ularly resilient to acne-inducing factors,
tured the greatest relative abundance of a such as S-Biomedic to investigate the spe- you could have a more aggressive strain on
newly identified bacterial type, which the cies as a therapeutic target. But it appears your skin and you wouldn’t see anything,”
team dubbed Candidatus Pellibacterium. the simplistic notion of “good” and “bad” he says. “But if you’re a person who is sus-
microbes—a healthy or unhealthy micro- ceptible to it, it’s very important which
The team also found that the microbi- biome—doesn’t capture the true nature of strains you have and which ones are there,
ome changed at different rates over time microbial diversity and how it influences because that can shift the balance [of the
depending on the body site. “In oily sites, health and disease, says Päetzold, making skin microbiome] over” to an acne-pro-
we had [low rates of change] in the micro- moting composition.
biome,” Saheb Kashaf says. In regions such

SUMMER 2022 | THE SCIENTIST 81

BIO BUSINESS

Similarly complicated is our skin’s rela- Eligo’s platform targets bacterial genes ciated with healthy skin. After participants
tionship with S. aureus. Even strains that specifically associated with diseases of the applied their formulation twice daily for
aren’t methicillin-resistant can be asso- skin and other organs—for example, the five weeks, the team saw the composition of
ciated with flare-ups of atopic dermati- company has worked on the Shiga toxin the facial skin microbiome shift toward the
tis. Moreover, Saheb Kashaf notes, while gene that is found in some E. coli bacte- transplanted species, and noted a decrease
the bacteria become more abundant dur- ria and is a cause of gastroenteritis. Using in the frequency of non-inflamed lesions—
ing disease flares and decline as symptoms CRISPR to introduce a double-stranded the precursor of inflamed lesions charac-
start to improve, it’s not clear whether break in the DNA of that gene selectively teristic of acne—but no significant decrease
these dynamics are a cause or a conse- kills any bacteria carrying it. CRISPR in inflamed lesions themselves at six weeks.
quence of the disease. “Is this Staphylo- methods can also selectively disable a However, the authors commented in their
coccus species just expanding on this der- gene, such as one for antibiotic resistance, paper that the treatment duration was
matitic skin because [this environment without killing the bacteria. “The ability to short, and the study lacked a control group,
provides them] the nutrients that they alter a gene but leave the bacteria in place meaning the role of the formulations in the
need to survive?” she says. “Or is it actually has tremendous applicability,” Hessel says. reported changes was unclear.
playing a part in the disease process? Is it Like Sanofi, the company is using its plat-
worsening the symptoms of these patients forms to develop treatments that target C. Segre is interested in whether it’s pos-
by having these species on their skin?” acnes, which, while associated with condi- sible to alter the skin microbiome using
tions such as acne vulgaris, is also impor- a prebiotic approach—that is, applying
Shifting the balance tant for skin health. “You don’t want to treatments containing particular nutrients
Despite unanswered questions such as completely eliminate the C. acnes bacteria that shift microbial community composi-
these, there is already considerable interest because it actually does a lot of good for tion—in conditions such as atopic derma-
in altering the microbiome by eliminating health,” she says. “You want to very specifi- titis. There’s also the possibility of using
pathogenic species, transplanting ben- cally just eliminate those C. acnes [strains] the microbiome as a way to predict when
eficial species, or selectively engineering that carry disease-associated genes.” disease flares might occur, she says. “For
microbes so as to reduce harm or increase example, with the studies we do on atopic
benefits. In 2020, Bayer invested $8 mil- There isn’t yet a good sense dermatitis or eczema, we’re looking at:
lion in US medical dermatology biotech When do you see changes in the skin micro-
company Azitra, which has focused on of what makes a skin microbe biome, and when does the child or the par-
identifying potentially beneficial strains of ent start to perceive that the kid is having
Staphylococcus epidermidis for use in skin beneficial. a flare of eczema?” She envisages a future
care products and in therapies for condi- when treatments for conditions such as
tions such as atopic dermatitis. Sanofi spent Others have more hope for the direct- eczema could be tailored to an individual’s
an undisclosed sum in 2021 to acquire Aus- transplant route. After his own experience skin microbiome profile, and analyses of
trian company Origimm for its vaccine- acquiring body odor, Callewaert conducted one’s skin microbiome could enable early
based immunotherapy, which targets Cuti- a trial involving 18 volunteers with body intervention with preventive treatments to
bacterium—specifically C. acnes. odor who received a course of spray-on stop flares before they develop.
transplants of skin microbiome samples
A targeted, species-specific approach to cultivated from a non-malodorous donor, Getting to that point will require a
microbiome tinkering is favored by Paris- usually a family member. He says that early much better understanding of the many
based biotech company Eligo Bioscience, results, still unpublished, hint at improve- and varied species of microbes that inhabit
which late last year signed a research agree- ments in recipients’ body odor, as assessed the skin. On this front, Segre says she’s
ment with GlaxoSmithKline worth up to by a panel of eight trained odor assessors, excited by the possibilities offered by
$224 million to develop a CRISPR-based for at least a month following treatment, technologies such as metagenomic analysis.
approach to treating acne. Edith Hessel, a although the lack of a control group pre- “With these genomic advances, we can
mucosal immunologist and chief scientific vents clear conclusions. Callewaert says more fully identify all of the components
officer at Eligo, says that when it comes to he managed to get rid of his own acquired of the skin microbiome: the bacteria, the
the skin microbiome, precision strategies body odor partly by using this method, fungi, and the viruses,” she says. “We can
are better than transplants like the ones although it took three years to do so. even see bacteria that we can’t yet culture,
that have shown promise in manipulat- but we know their genomes, and that
ing the gut microbiome to treat conditions Another team of researchers, includ- means that we can see things that we never
such as ulcerative colitis and Clostridium ing Päetzold, did an open-label pilot study could see before.” g
difficile infection. In her view, transplant- a couple of years ago in which eight volun-
ing new species or removing existing spe- teers with mild-to-moderate acne received Bianca Nogrady is a freelance science
cies carries “a big risk of causing dysbiosis.” one of two topical formulations contain- journalist and author based in Sydney,
ing a mix of C. acnes strains that are asso- Australia.

82 THE SCIENTIST | the-scientist.com

READING FRAMES

The Ape-Man of Flores

Do members of Homo floresiensis still inhabit the Indonesian island where
their fossils helped identify a new human species fewer than 20 years ago?

BY GREGORY FORTH

In 2004, the scientific world was shaken include reports of sightings by more than Pegasus Books, May 2022
by the discovery of fossils from a tiny 30 eyewitnesses, all of whom I spoke with
species of hominin on the Indonesian directly. And I conclude that the best way ing complex expressions of culture, language,
island of Flores. Labeled Homo floresien- to explain what they told me is that a non- and technology exclusively to humans.
sis and dating to the late Pleistocene, the sapiens hominin has survived on Flores to
species was apparently a contemporary the present or very recent times. Like other folk zoologists, the Lio put
of early modern humans in this part of humans first, most notably as the origin of
Southeast Asia. Yet in certain respects Between Ape and Human also considers nonhuman animals, a sort of Darwinism
the diminutive hominin resembled aus- general questions, including how natural in reverse. In contrast, evolutionary the-
tralopithecines and even chimpanzees. scientists construct knowledge about living ory puts humans (or hominins) last, just
Twenty years previously, when I began things. One issue is the relative value of vari- as does the biblical story of Genesis. Yet in
ethnographic fieldwork on Flores, I heard ous sources of information about creatures, all instances, the position confers on Homo
tales of humanlike creatures, some still including animals undocumented or yet to sapiens a unique status, thereby separating
reputedly alive although very rarely seen. be documented in the scientific literature, us from the rest of the animal kingdom.
In the words of the H. floresiensis discov- and especially information provided by tra-
ery team’s leader, the late Mike Morwood, ditionally non-literate and technologically For the Lio, the ape-man’s appear-
last at the University of Wollongong in simple communities such as the Lio—a peo- ance as something incompletely human
Australia, descriptions of these homi- ple who, 40 or 50 years ago, anthropologists makes the creature anomalous and hence
noids “fitted floresiensis to a T.” Not least would have called primitive. To be sure, the problematic and disturbing. For aca-
because the newly described fossil spe- Lio don’t have anything akin to modern evo- demic scientists, H. floresiensis is sim-
cies was assumed to be extinct, I began lutionary theory, with speciation driven by ilarly problematic, but not so much for
looking for ways this remarkable resem- mutation and natural selection. But if evo-
blance might be explained. The result is a lutionism is fundamentally concerned with
book, Between Ape and Human, available how different species arose and how differ-
in May 2022. ences are maintained, then Lio people and
Coming from a professional anthropol- other Flores islanders have for a long time
ogist and ethnobiologist, my conclusions been asking the same questions.
will probably surprise many. They might
even be more startling than the discovery Lio folk zoology and cosmology also
of H. floresiensis—once described by paleo- include stories of natural beings, specifically
anthropologist Peter Brown of the Univer- humans, transforming permanently into
sity of New England in New South Wales animals of other kinds. And they do this, in
as tantamount to the discovery of a space part, by moving into new environments and
alien. Unlike other books concerned with adopting new ways of life, thus suggesting
hominin evolution, the focus of my book is a qualified Lamarckism. As my fieldwork
not on fossils but on a local human popu- revealed, such posited changes reflect local
lation called the Lio and what these people observations of similarities and differences
say about an animal (as they describe it) between a supposed ancestral species and its
that is remarkably like a human but is not differentiated descendants. Like the major-
human—something I can only call an ape- ity of named categories in Lio animal classi-
man. My aim in writing the book was to fication, these derivatives coincide with the
find the best explanation—that is, the most species or genera of modern systematics. At
rational and empirically best supported— the same time, Lio distinguish humans from
of Lio accounts of the creatures. These nonhuman animals in much the same way
as do modern Westerners, that is, not just
on morphological grounds but by attribut-

SUMMER 2022 | THE SCIENTIST 83

READING FRAMES

its resemblance to H. sapiens; rather, animals that Lio people claim descended ously what Lio people say, I’ve found no
it’s because the species appears very late from humans. But this classification good reason to think so. What they say
in the geological record, surviving to a has nothing to do with geological dating about the creatures, supplemented by
time well after the appearance of modern or any paleoanthropological evidence. other sorts of evidence, is fully consistent
humans. Whether H. floresiensis would Instead, Lio people, who distinguish natu- with a surviving hominin species, or one
have been any harder (or easier) to accept ral from supernatural (or spiritual) beings that only went extinct within the last 100
had it been interpreted as a bipedal ape in essentially the same way religious years. Paleontologists and other life sci-
rather than a species of human is difficult Westerners do, interpret ape-men as non- entists would do well to incorporate such
to say. Nevertheless, it’s interesting that human animals with reference to observ- Indigenous knowledge into continuing
Morwood, taking an implicitly unilinear able features that clearly separate them investigations of hominin evolution in
view of hominin evolution and arguing for from invisible spirits; from other, more Indonesia and elsewhere. For reasons I
the species’ inclusion in Homo, spoke of familiar animals; and, of course, from discuss in the book, no field zoologist
the evidence that the diminutive hominin people. Some features of the ape-men is yet looking for living specimens of H.
walked the Earth relatively recently as one might suggest a scientifically undiscov- floresiensis or related hominin species.
“good reason” to classify H. floresiensis in ered species or population of modern apes. But this does not mean that they cannot
our genus. For this can only mean that, But Lio statements mostly count against be found. g
in the view of this author, what survives this hypothesis, as does all we know about
until recent times has to somehow belong the biogeography of eastern Indonesia. Gregory Forth, now retired, was a profes-
with us. sor of anthropology at the University of
Our initial instinct, I suspect, is to Alberta for more than three decades. Read
As for ape-men, the Lio identify them regard the extant ape-men of Flores as an excerpt of Between Ape and Human.
as animals. In fact, they are one of several completely imaginary. But, taking seri-

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READING FRAMES

The Dawn of Song

Listen to the sound of the land’s first known singer.

BY DAVID GEORGE HASKELL

We live on a planet thrumming municative sound evolved. Near the attach- Penguin Random House, March 2022
with the diverse voices of com- ment point of the wing, some veins were
municative animals. But it was thickened and raised. A prominent cen- covery of Permostridulus suggests how
not always this way. For more than 90 percent tral vein was buttressed by side veins, communicative sounds evolved after the
of Earth’s history, it seems, no animals sang creating a curved, corrugated ridge just a long silence of early land animals. In gen-
or cried. No creatures called when the seas couple of millimeters long on a wing half eral, wings likely unlocked communicative
first filled with complex animal life or when the length of my thumb. Such a structure sound in two ways. First, flight allowed rapid
reefs first rose. The land’s primeval forests had no function in supporting the wing escape from listening predators, reducing
contained no singing insects or vertebrates. membrane. Instead, it was very likely a the ecological risks of singing. After all,
These ancient times had sound—wind, stridulating device, analogous to the ridges predation is likely one reason that sound-
waves, thunder, geologic murmurs, and the used for sound production on the wings of making took so long to evolve. To this day, it
splash, scrabble, and crunch of moving, feed- modern crickets. When the insects rubbed is animals with wings or jumping legs that
ing animals—but hundreds of millions of their wings together, the raised central vein are most vocal. The slow and defenseless are
years of animal evolution unfolded in com- would have scraped over the base of the typically silent. The evolution of insect wings,
municative silence. other wing, making a chirping sound. therefore, probably lowered predation risk
and paved the way for the evolution of sonic
Who were the first singers? And what The bumps on the stridulating ridge of communication. Second, wings served as the
do their lives tell us about the evolution of Permostridulus were uneven compared to sound makers themselves.
sonic communication? Here I will focus, as the finely-wrought, regularly spaced ridges
in my recently published book, Sounds Wild of modern singing insects and even some Indeed, although wings allowed flight,
and Broken, on a cricket-like insect called Jurassic species. But despite their crude- they soon made sound production possible,
Permostridulus, the oldest known singing ness, when rubbed together the wings would too. Papery wing surfaces and pulsing wing
land animal for which we have physical evi- have rasped. By measuring the size and
dence of sound-making anatomy. The qual- spacing of the bumps and comparing them
ifier “known” is important because it is pos- to those of modern insects, I have created
sible that other singers were present even a speculative reconstruction of the sound
earlier, but either left no trace or have yet of a rasping individual and of a chorus.
to be unearthed by paleontologists. We do not know how fast the insect moved
its wings or whether the wings had resonant
As its name indicates, Permostridulus lived properties, and so this recreation may not
in the Permian, about 270 million years ago, be entirely accurate. We can say, though,
in what was then the hot, dry interior of the that the unevenness of the bumps would
ancient supercontinent Pangaea. The land- have yielded a rougher, less tonal sound
scape was bare and windblown, although than those of modern stridulating insects.
scrubby ferns and conifers grew alongside
streams and lakes, wet places that pro- The purpose of Permostridulus’s sound-
vided habitat for animals. The mud also making is unknown. The sound may have
caught and preserved the bodies of dead attracted mates or repelled rivals, just as
insects, especially their papery wings. the chirping of crickets does today. Alter-
It was from such fossilized remains that natively, the rasping sound may have served
paleontologists led by Olivier Béthoux at to startle predators, buying time for escape.
the Muséum National d’Histoire Naturelle Such vibratory startle responses are com-
in Paris described the only known speci- mon today among animals as diverse as
mens of Permostridulus. lobsters, crickets, and pillbugs.

The wings of this long-extinct insect In providing physical evidence of
not only revealed evidence of sound- when and in what form communica-
making, but suggested how and why com- tive sound-making appeared, the dis-

SUMMER 2022 | THE SCIENTIST 85

READING FRAMES

SINGING WING: The stridulatory apparatus of
Permostridulus is seen in this fossil impression of
the insect’s wing.

doubled as a sound-making organ; the EUR J ENTOMOL, 100:581–86, 2003
jumping hind legs of grasshoppers became
strumming devices; and the dextrous mam-
malian throat and mouth, originally used for
suckling milk, became a sophisticated tool
for shaping sound.

When we hear crickets chirping from
the bushes in a city park or katydids sing-
ing from trees in late summer, we hear
descendants and relatives of the first land
animals to escape the listening ears of
predators and use their wings to sing. g

muscles easily pump out sound waves, like in the subsequent evolution of sound mak- David George Haskell is a professor of biol-
loudspeakers driven by vibrating motors. ing in other animals: the vertebrate larynx ogy and environmental studies at Sewanee:
This innovative duality occurred repeatedly evolved as an anti-choking valve that later The University of the South and a Guggen-
heim Fellow. Read an excerpt of Sounds
Wild and Broken at the-scientist.com.

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FOUNDATIONS

Universe 25, 1968–1973

BY ANNIE MELCHOR UNIVERSE 25: John Calhoun crouches within his rodent utopia-turned-dystopia that, at its peak,
housed approximately 2,200 mice. Calhoun was studying the breakdown of social bonds that occurs
June 22, 1972. John Calhoun stood under extreme overcrowding, a phenomenon he termed a “behavioral sink.”
over the abandoned husk of what
YOICHI R. OKAMOTO, WHITE HOUSE PHOTOGRAPHER, PUBLIC DOMAIN had once been a thriving metropo- males compulsively groomed themselves; control efforts largely targeted at poor and
lis of thousands. Now, the population had females stopped getting pregnant. Effec- marginalized communities.
dwindled to just 122, and soon, even these tively, says Ramsden, they became “trapped
inhabitants would be dead. in an infantile state of early development,” But Ramsden notes that Calhoun didn’t
even when removed from Universe 25 and necessarily think humanity was doomed.
Calhoun wasn’t the survivor of a natu- introduced to “normal” mice. Ultimately, In some of Calhoun’s other crowding exper-
ral disaster or nuclear meltdown; rather, he the colony died out. “There’s no recovery, iments, rodents developed innovative tun-
was a researcher at the National Institute and that’s what was so shocking to [Cal- neling behaviors, while in others, adding
of Mental Health conducting an experi- houn],” says Ramsden. more rooms allowed the animals to live in
ment into the effects of overcrowding on the high-density environment without being
mouse behavior. The results, laid bare at Calhoun wasn’t shy about anthropo- forced into unwanted contact with others,
his feet, had taken years to play out. morphizing his findings, binning rodents largely minimizing the negative social con-
into categories such as “juvenile delin- sequences. According to Ramsden, Cal-
In 1968, Calhoun had started the quents” and “social dropouts,” and others houn wanted these findings to influence the
experiment by introducing four mouse seized on these human parallels. Popu- architectural design of prisons, mental hos-
couples into a specially designed pen—a lation growth in the 1970s was swelling, pitals, and other buildings prone to crowd-
veritable rodent Garden of Eden—with and films such as Soylent Green tapped ing. Writing in a report summary in 1979,
numerous “apartments,” abundant nesting into growing fears of overpopulation and Calhoun noted that “no single area of intel-
supplies, and unlimited food and water. urban violence. In a 2011 article, Rams- lectual effort can exert a greater influence
The only scarce resource in this micro- den writes that Calhoun’s studies were on human welfare than that contributing
cosm was physical space, and Calhoun brandished by others to justify population to better design of the built environment.” 
suspected that it was only a matter of time
before this caused trouble in paradise.

Calhoun had been running similar
experiments with rodents for decades but
had always had to end them prematurely,
ironically because of laboratory space con-
straints, says Edmund Ramsden, a science
historian at Queen Mary University of Lon-
don. This iteration, dubbed Universe 25,
was the first crowding experiment he ran
to completion.

As he had anticipated, the utopia be-
came hellish nearly a year in when the
population density began to peak, and
then population growth abruptly and
dramatically slowed. Animals became
increasingly violent, developed abnormal
sexual behaviors, and began neglecting or
even attacking their own pups. Calhoun
termed this breakdown of social order a
“behavioral sink.”

Eventually Universe 25 took another
disturbing turn. Mice born into the chaos
couldn’t form normal social bonds or
engage in complex social behaviors such
as courtship, mating, and pup-rearing.
Instead of interacting with their peers,

SUMMER 2022 | THE SCIENTIST 87

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FOUNDATIONS

The Spider Lady, Circa 1939

BY NATALIA MESA SILKING SPIDERS: Nan Songer crafted special magnifying glasses from YUCAIPA HISTORICAL SOCIETY
the flexible yucca plant, from which she also used fibers to carefully “silk”
In the 1940s, the small, wildflower-studded town of Yucaipa, black widow spiders, winding their thread around frames for transport.
California, was home to one of the most successful spider silk
refineries in the country. There, Nannie “Nan” Songer, a self- Songer continued to supply silk for weapons, telescopes,
taught naturalist, housed thousands of venomous spiders in jars microscopes, and medical instruments following the war,
in the front room of her small farmhouse, from which she har- until her product was supplanted by synthetic alternatives.
vested silk for her many clients—most notably the US govern- Even then, her passion remained, and Songer carried on col-
ment, which used Songer’s silk in military weapons. lecting and studying arachnids until her death in 1956. “She
Born in Cookeville, Tennessee, in 1892, Songer spent her was amazing,” says Quinn. “Quite a woman to never be afraid
youth hunting insects and arachnids in the garden of her child- of a spider.” 
hood home. After her family moved to California, Songer built a
life in Yucaipa, raising two children and taking biology classes
at the nearby University of California, Riverside. Eventually,
she began breeding arachnids.
Around the time that World War II broke out, Songer heard
from a friend that the US Bureau of Standards had put out a call
for spider silk that was 1/10,000th of an inch thick, roughly 10
times thinner than a human hair. Songer’s friend had been sup-
plying her own hair for use as crosshairs in aircraft bombsights
but, because human hairs freeze and break at high altitudes, the
military now wanted spider silk, which can be stronger than steel.
Songer began experimenting with black widows (genus
Latrodectus), which produce a silk dragline composed of six
strands to stabilize themselves in midair and control their
landings. By separating this thread into individual strands
with a needle, she achieved the width that the military needed.
“The strands were virtually invisible to the naked eye,” Sahara
Quinn, a historian and vice president of the Yucaipa Histori-
cal Society, tells The Scientist. Yet they carried illumination
better than silk from other species, helping the crosshairs
stand out against a background.
Through her experiments, Songer also devised a novel tech-
nique for extracting silk in greater quantities. She carefully
pinned living spiders belly up and then used a hairlike yucca strip
to stroke their abdomens until they produced strands, which
she collected with a small hook. Using this “silking” technique,
Songer was able to harvest reams of silk that she wrapped around
frames for transport. The US government quickly became her
biggest client; its couriers traveled to Yucaipa with empty brief-
cases handcuffed to their wrists to prevent theft.
Over the years, Songer tested more than 50 species of spiders,
further refining her skills. Writing in an article for Natural
History in 1955, Songer noted that her operation was “the only
business in the world where spiders are reared and silked for
webs of specific size, strength, and elasticity.” She was even-
tually able to produce silk that was 1/500,000th of an inch
thick by silking week-old spiders, she wrote, noting that even
at these widths, the silk was “possibly one of the strongest
materials made by a living creature.”

90 THE SCIENTIST | the-scientist.com

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