Science - USA (2022-02-25)

804 25 FEBRUARY 2022 • VOL 375 ISSUE 6583 science.org SCIENCE

But the third population, from Central Af-
rica and most closely related to people to-
day who live a foraging lifestyle there, came
as a surprise.
The distinct genetic signatures of those
ancestral populations indicate they were
mostly isolated from one another for vast
amounts of time before eventually coming
together, suggests David Reich, a popula-
tion geneticist at Harvard Medical School
who co-led the study. “If you look at Eu-
ropeans and East Asians, maybe they’re
separated by 40,000 or 50,000 years,” he
says. “These three groups were basically
separated 200,000 years ago, then come
together ... maybe 80,000 to 50,000 years
ago.” That range is only a rough estimate,
Reich notes, given none of the new genomes
dates beyond 20,000 years ago.
But that time frame for commingling
matches developments in material cul-
ture, says co-author Mary Prendergast, an
archaeologist at Rice University. In African
artifacts of that period, “we see a ton of
hints that people are connecting in differ-
ent ways,” she says, mixing and matching
artifacts from distant places.
Considered in that context, the new DNA
data suggest sometime after 20,000 years
ago, ancient Africans stayed closer to home.
Stone tools found in their rock shelters take
on a local flair. And their DNA suggests that
starting around this time, people traveled
shorter distances to find mates.
That date range marks the Last Glacial
Maximum, which affected climate worldwide,
points out Rick Potts, a paleoanthropologist
at the Smithsonian Institution’s National Mu-
seum of Natural History. Across tropical Af-
rica, forests contracted and grasslands grew
in between, forming fragmented savannalike
“islands” for many species—perhaps humans
among them. “It’s interesting to think about
whether sub-Saharan African foragers were
mapping onto a kind of refugium model.”
The six new genomes are a welcome ad-
dition to Africa’s sparse record of ancient
DNA, says Sarah Tishkoff, a geneticist at
the University of Pennsylvania. But she’s
not swayed by the team’s ideas about what
happened before 20,000 years ago. “There’s
a lot of assumptions in that analysis,” she
says, and it’s not clear to her that the au-
thors considered alternative explanations.
The analysis included some remains
from museums, highlighting the key role
of collections, says study co-author Maggie
Katongo, a curator at Zambia’s Livingstone
Museum and a doctoral student at Rice
University. “When you do this research, you
want to give back to the community,” she
adds. “We want to make sure that whatever
comes from this research is made public for
all people in Zambia.” j

Glowing tumor marker hampers

mouse cancer studies

Response to protein complicates immunotherapy research

BIOMEDICINE

C

ancer biologist Cyrus Ghajar was

gearing up to study how the immune

system can fight breast cancer when

he hit a snag: The supposedly fast-

spreading cancer cells he implanted in

mice stayed put and sometimes even

disappeared after about 11 days. Then, post-

doc Candice Grzelak identified the culprit:

the green fluorescent protein (GFP) the re-

searchers were using to track the cells. The

marker itself was stimulating the rodents’ im-

mune system to attack the tumor cells.

Ghajar’s lab at the Fred Hutchinson

Cancer Research Center got around this

unexpected problem, which

it described in a paper last

month. But he and oth-

ers say the experience re-

flects a broader issue in

mouse studies of immuno-

therapies, treatments that

harness the immune sys-

tem to vanquish tumors:

The glowing proteins bio-

logists use to track the can-

cer cells, often borrowed

from fireflies or jellyfish,

may provoke their own im-

mune attack on the cells.

Other foreign proteins

that are workhorses of lab

studies, such as components of the genome

editor CRISPR, could have the same effect.

And the phenomenon could explain why labs

sometimes can’t reproduce immunotherapy

findings from other groups, suggests Glenn

Merlino, a cancer biologist at the National

Cancer Institute.

As immunotherapy becomes more and

more important, he adds, scientists need to

be aware of confounding factors like this. “So

many preclinical experiments do not end up

telling you anything useful in the clinic,” says

Merlino, a co-author on commentary on the

issue last week in Cancer Cell.

Although it’s long been known that the

immune system can sense marker proteins

such as GFP as foreign, it didn’t much matter

for cancer studies. That’s because most labs

used mice lacking an immune system so they

would not reject the transplanted human

cancer cells often used to assess treatments.

But as immunotherapies have taken off

in the past decade, more labs are working

with mice that have intact immune sys-

tems. Ghajar and others shifted to mouse

cancer cells, which aren’t immediately re-

jected. Others use mice that have human-

ized immune systems and accept human

cancer cells.

Ghajar’s lab realized its mice were pro-

ducing immune sentinels called T cells

that attacked the GFP-labeled cells, block-

ing their growth. They lowered the levels of

GFP, but the cancer cells still didn’t metas-

tasize. The group found the best solution

was to trick the mouse immune system into

thinking the GFP was a natural protein, by

using mice engineered to

produce GFP in certain im-

mune cells known as den-

dritic cells, which induce

tolerance. In these rodents,

the breast cancer cells grew

as expected, they reported

in Cancer Cell.

“We wanted to draw at-

tention to the problem and

provide the field with re-

agents and metrics neces-

sary to solve it,” Ghajar says.

Merlino and his co-

authors warn in their com-

mentary that the same

problematic immune re-

sponse could arise in experiments using

other glowing proteins from various spe-

cies, viral proteins that cause cancer, and

even Cas9, CRISPR’s DNA-cutting enzyme,

which comes from a bacterium. Research-

ers may need to find workarounds, such

as mouse strains modified so they tolerate

the foreign proteins, like the mice turned

to by Ghajar’s lab. Merlino calls for other

researchers to share similar experiences,

perhaps in a database.

Peter Friedl, who studies metastasis at

Radboud University and the MD Anderson

Cancer Center, says he, too, has had experi-

ments fail because of an immune reaction

to a nonmouse marker protein. Research-

ers have fingered other causes for cancer

biology’s replication problem, such as vari-

ations in mouse colony microbiomes. But

the unexpected immune responses, Friedl

says, “absolutely” could contribute. j

By Jocelyn Kaiser

“We wanted to draw

attention to the

problem and provide

the field with

reagents and

metrics necessary

to solve it.”

Cyrus Ghajar,

Fred Hutchinson Cancer

Research Center

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