07-02-2021

SUnDAy, FeBrUAry 7, 2021
5
The coronavirus is a master of mixing its genome
roxAnne KhAmSi
In recent weeks, scientists have
sounded the alarm about new
variants of the coronavirus that carry
a handful of tiny mutations, some of
which seem to make vaccines less
effective. But it is not just these small
genetic changes that are raising
concerns. The novel coronavirus has
a propensity to mix large chunks of its
genome when it makes copies of
itself. Unlike small mutations, which
are like typos in the sequence, a
phenomenon called recombination
resembles a major copy-and-paste
error in which the second half of a
sentence is completely overwritten
with a slightly different version.
A flurry of new studies suggests that
recombination may allow the virus to
shapeshift in dangerous ways. But in
the long term, this biological
machinery may offer a silver lining,
helping researchers find drugs to stop
the virus in its tracks.
"There's no question that
recombination is happening," said
Nels Elde, an evolutionary geneticist
at the University of Utah. "And in
fact, it's probably a bit
underappreciated and could be at
play even in the emergence of some of
the new variants of concern."
The coronavirus mutations that
most people have heard about, such
as those in the B.1.351 variant first
detected in South Africa, are changes
in a single "letter" of the virus's long
genetic sequence, or RNA. Because
the virus has a robust system for
proofreading its RNA code, these
small mutations are relatively rare.
Recombination, in contrast, is rife
in coronaviruses. Researchers at
Vanderbilt University Medical Center
led by virologist Mark Denison
recently studied how things go awry
during replication in three
coronaviruses, including SARS-CoV-
2, which causes Covid. The team
found that all three viruses showed
"extensive" recombination when
replicating separately in the
laboratory.
Scientists worry that recombination
might allow for different variants of
the coronavirus to combine into more
dangerous versions inside of a
person's body. The B.1.1.7 variant first
detected in Britain, for example, had
more than a dozen mutations that
seemed to appear suddenly.
Dr. Elde said that recombination
may have merged mutations from
different variants that arose
spontaneously within the same
person over time or that co-infected
someone simultaneously. For now,
he said, that idea is speculative: "It's
really hard to see these invisible scars
from a recombination event." And
although getting infected with two
variants at once is possible, it's
thought to be rare.
Katrina Lythgoe, an evolutionary
epidemiologist at the Oxford Big Data
Institute in Britain, is skeptical that
co-infection happens often. "But the
new variants of concern have taught
us that rare events can still have a big
impact," she added.
Recombination might also allow
two different coronaviruses from the
same taxonomic group to swap some
of their genes. To examine that risk
more closely, Dr. Elde and his
colleagues compared the genetic
sequences of many different
coronaviruses, including SARS-CoV-
2 and some of its distant relatives
known to infect pigs and cattle.
Using specially developed software,
the scientists highlighted the places
where those viruses' sequences
aligned and matched - and where
Coronavirus test samples being unpacked in the Bonsignori Lab of Duke University this week.
Photo: Pete Kiehart
they didn't. The software suggested
that over the past couple of centuries
of the viruses' evolution, many of the
recombination events involved
segments that made the spike
protein, which helps the virus enter
human cells. That's troubling, the
scientists said, because it could be a
route through which one virus
essentially equips another to infect
people.
"Through this recombination, a
virus that can't infect people could
recombine with a virus like SARS-
CoV-2 and take the sequence for
spike, and could become able to infect
people," said Stephen Goldstein, an
evolutionary virologist who worked
on the study.
The findings, which were posted
online on Thursday but have not yet
been published in a scientific journal,
offered fresh evidence that related
coronaviruses are quite promiscuous
in terms of recombining with each
other. There were also many
sequences that cropped up in the
coronaviruses that seemed to come
out of nowhere.
"In some cases, it almost looks like
there's sequence dropping in from
outer space, from coronaviruses we
don't even know about yet," Dr. Elde
said. The recombination of
coronaviruses across totally different
groups has not been closely studied,
in part because such experiments
would potentially have to undergo
government review in the United
States because of safety risks.
Feng Gao, a virologist at Jinan
University in Guangzhou, China, said
that although the new software from
the Utah researchers found unusual
sequences in coronaviruses, that
doesn't provide ironclad evidence for
recombination. It could simply be
that they evolved that way on their
own.
"Diversity, no matter how much,
does not mean recombination," Dr.
Gao said. "It can well be caused by
huge diversification during viral
evolution." Scientists have limited
knowledge about whether
recombination could give rise to new
pandemic coronaviruses, said
Vincent Munster, a viral ecologist
with the National Institute of Allergy
and Infectious Diseases who has
studied coronaviruses for years.
Still, that evidence is growing. In a
study released in July and formally
published today, Dr. Munster and his
collaborators suggested that
recombination is likely how both
SARS-CoV-2 and the virus behind the
original SARS outbreak in 2003 both
ended up with a version of the spike
protein that allows them to deftly
enter human cells. That spike protein
binds to a particular entry point in
human cells called ACE2. That paper
calls for greater surveillance of
coronaviruses to see if there are
others that use ACE2 and may thus
pose similar threats to people.
Some scientists are studying
recombination machinery not only to
fend off the next pandemic, but to
help fight this one. For example, in
his recent study on the
recombination of three
coronaviruses, Dr. Denison of
Vanderbilt found that blocking an
enzyme known as nsp14-ExoN in a
mouse coronavirus caused
recombination events to plummet.
This suggested that the enzyme is
vital to coronaviruses' ability to mixand-match
their RNA as they
replicate.
Now, Dr. Denison and Sandra
Weller, a virologist at the University
of Connecticut School of Medicine,
are investigating whether this insight
could treat people with Covid. Certain
antiviral drugs such as remdesivir
fight infections by serving as RNA
decoys that gum up the viral
replication process. But these
medications don't work as well as
some had hoped for coronaviruses.
One theory is that the nsp14-ExoN
enzyme chucks out the errors caused
by these drugs, thereby rescuing the
virus.
How scientists shot down
cancer's 'death star'
GinA KoLAtA
After 40 years of effort,
researchers have finally
succeeded in switching off one
of the most common cancercausing
genetic mutations in
the human body. The finding
promises to improve treatment
for thousands of patients with
lung and colorectal cancer, and
may point the way to a new
generation of drugs for cancers
that resist treatment.
The finding has already led to
a new medication, sotorasib, by
the drugmaker Amgen. Other
companies are close behind
with their own versions.
Amgen tested its drug in
patients with the most
common type of lung cancer,
called non-small cell cancer.
The disease is diagnosed in
228,000 Americans a year,
and for most patients in the
advanced stages, there is no
cure.
The new drug attacks a
cancer-causing mutation,
known as KRAS G12C, that
occurs in 13 percent of these
patients, almost all of whom
are current or former smokers.
Sotorasib made the cancers
shrink significantly in patients
with the mutation, Amgen
reported last week at the World
Conference on Lung Cancer.
On average, tumors in the
patients stopped growing for
seven months. In three out of
126 patients, the drug seems to
have made the cancer
disappear entirely, at least so
far, although side effects
included diarrhea, nausea and
fatigue.
It already is routine to test
lung cancer patients for the
mutation, because they are
often resistant to other drugs,
said Dr. John Minna, a lung
cancer specialist at the
University of Texas
Southwestern Medical Center
in Dallas.
Amgen's drug is not as
drastically effective as some
new cancer medicines, said Dr.
Bruce Johnson, the chief
clinical research officer at the
Dana-Farber Cancer Institute
in Boston. But in combination
with other drugs, those
targeting specific mutations
can change the course of the
disease in many patients, he
added.
For example, drugs targeting
specific mutations in
melanoma patients at first
seemed unimpressive, but
when combined with other
medicines, they eventually
changed prospects for patients
with this deadly disease.
"The more I looked at it, the
more optimistic I became," Dr.
Johnson said of Amgen's new
data. While the KRAS G12C
mutation is most common in
lung cancer, it also occurs in
other cancers, especially in
colorectal cancer, where it is
found in up to 3 percent of
tumors, and particularly in
pancreatic cancer. KRAS
mutations of some type are
present in 90 percent of
pancreatic tumors.
How the off-switch was
discovered is a story of
serendipity and persistence by
an academic chemist who
managed the seemingly
impossible. In 2008, that
chemist, Kevan Shokat, a
professor at the University of
California, San Francisco,
decided to focus on the
mutated gene. It had been
discovered 30 years earlier in
rats with sarcomas, a type of
cancer that begins in bones and
soft tissues.
Researchers found the
mutation in human tumor
cells, and then discovered that
it was one of the most
frequently mutated genes in
cancers of many types.
Different cancers tend to
spring from different
mutations in the KRAS gene
and the protein it encodes. The
G12C mutation occurs mostly
in lung cancers.
A colored scanning electron micrograph of a cell of a common type of
lung cancer.
Photo: Steve Gschmeissner
The search for drugs to block
previously discovered cancercausing
mutations was always
straightforward: Researchers
had to find a molecule that
attached to the mutated
protein and could stop it from
functioning. That strategy
worked for so-called kinase
inhibitors, which also block a
protein created by gene
mutations. There are 50
approved kinase inhibitors on
the market now.
KRAS was different. The
gene directs production of a
protein that normally flexes
and relaxes thousands of times
a second, as if it is panting. In
one position, the protein
signals cells to grow; in the
other, it stops the growth. With
the KRAS mutation, the
protein remains mostly in an
"on" position, and cells are
constantly forced to grow.
The standard solution would
be a drug that would hold the
mutated protein in the "off"
position. But that seemed
impossible. The protein is large
and globular, and it doesn't
have deep pockets or clefts on
its surface where a drug could
slip in. It was like trying to drive
a wedge into a ball of solid ice.
"Our medicinal chemists
referred to it as the Death Star,"
said Dr. David Reese, executive
vice president for research and
development at Amgen. "It was
so smooth." So Dr. Shokat and
his colleagues began looking
for a molecule that could do the
trick. Five years later, after
screening 500 molecules, they
found one and discovered why
it worked.
Their drug held the protein
steady, making a crevice visible
on its surface. "We never saw
that pocket before," Dr. Shokat
said. The protein normally
flexes and relaxes so quickly
that the narrow groove had
almost been impossible to see.
There was more good news.
The drug attached itself to
cysteine, an amino acid that
occurs in the groove only
because of the KRAS mutation.
The drug worked only against
the mutated protein, and
therefore only against cancer
cells.
"It is really specific," Dr.
Shokat said. "That's what's
amazing." He published his
findings in 2013, causing a
sensation in the field. Dr.
Reese, of Amgen, said that the
data "gave us the proof that we
could actually do this," and that
"it silenced many of the
doubters."
Dr. Shokat, too, began
working on a drug, which is
now being developed by
Johnson and Johnson. At least
eight companies have their
own KRAS inhibitors in clinical
trials. Lung cancer is only the
beginning, Dr. Shokat said. The
next challenge is pancreatic
cancer, one of the most lethal
types: "KRAS is the signature
mutation for pancreatic
cancer," he added.
Most patients have such a
mutation, and while it makes
the disease very difficult to
treat, now it may also make the
cancer particularly vulnerable.
Researchers have already
found drugs that seem
promising.
Climate change can endanger your health, both physical and mental, now and in the future.
Photo: Collected
How climate change may affect your health
JAne e. BroDy
Melting ice caps, warmer oceans,
intense storms, heat waves, droughts,
floods and wildfires - all these welldocumented
effects of climate change
may seem too remote to many people to
prompt them to adopt behaviors that
can slow the warming of the planet.
Unless your neighborhood was
destroyed by a severe hurricane or
raging wildfire, you might think such
disasters happen only to other people.
But what if I told you that no matter
where you live or how high your
socioeconomic status, climate change
can endanger your health, both physical
and mental, now and in the future? Not
only your health, but also the health of
your children and grandchildren?
Might you consider making changes to
help mitigate the threat?
Relatively few Americans associate
climate change with possible harms to
their health, and most have given little
thought to this possibility. Even though
I read widely about medical issues, like
most Americans, I too was unaware of
how many health hazards can
accompany climate change.
Studies in the United States and
Britain have shown that "people have a
strong tendency to see climate change
as less threatening to their health and to
their family's health than to other
people's health," according to Julia
Hathaway and Edward W. Maibach at
the Center for Climate Change
Communication at George Mason
University.
Two recently published reports set me
straight. One, by two public health
experts, called for the creation within
the National Institutes of Health of a
"National Institute of Climate Change
and Health" to better inform the
medical community, public officials and
ordinary citizens about ways to stanch
looming threats to human health from
further increases in global warming.
The experts, Dr. Howard Frumkin
and Dr. Richard J. Jackson, both
former directors of the National Center
for Environmental Health at the
Centers for Disease Control and
Prevention, warned that recent climaterelated
disasters, including devastating
wildfires and a record-breaking
hurricane season, demonstrate that our
failure to take climate change seriously
is resulting in needless suffering and
death. The second report appeared just
as I began investigating the evidence
supporting their proposal: a full-page
article in The New York Times on Nov.
29 with the headline "Wildfire Smoke in
California Is Poisoning Children." It
described lung damage along with
lifelong threats to the health of
youngsters forced to breathe smokeladen
air from wildfires that began
raging in August and fouled the air
throughout the fall.
Children are not the only ones
endangered. Anyone with asthma can
experience life-threatening attacks
when pollution levels soar. The risks of
heart disease and stroke rise. And a
recent study in JAMA Neurology of
more than 18,000 Americans with
cognitive impairment found a strong
link between high levels of air pollution
and an increased risk of developing
dementia.
"While anyone's health can be
harmed by climate change, some people
are at greatly increased risk, including
young children, pregnant women, older
adults, people with chronic illnesses
and disabilities, outdoor workers, and
people with fewer resources," Drs.
Hathaway and Maibach wrote in
Current Environmental Health
Reports.
Alas, said Dr. Jackson, emeritus
professor at the University of California,
Los Angeles, "Human beings respond
only to what is a threat to them at the
moment. Californians are now much
more aware - the fires got people's
attention." The wildfire season is now
starting much earlier and ending later
as a result of a warming climate, an
international research team reported in
The New England Journal of Medicine
in November.
Dr. Frumkin, emeritus professor at
the University of Washington, told me,
"Lots of people who don't consider
climate change a major problem
relative to themselves do take it
seriously when they realize it's a health
concern. Heat waves, for example, not
only kill people, they also diminish work
capacity, sleep quality and academic
performance in children."
"Our changing climate will have much
more of an impact on people's health
over time," Dr. Jackson said. People of
all ages will develop respiratory
allergies, and those who already have
allergies can expect them to get worse,
as plants and trees respond to a warmer
climate and release their allergens in
more places and for longer periods.
Infectious diseases carried by ticks,
mosquitoes and other vectors also rise
with a warming climate. Even small
increases in temperature in temperate
zones raise the potential for epidemics
of Lyme disease, Rocky Mountain
spotted fever, encephalitis and other
tick-borne infections, as well as
mosquito-borne West Nile disease,
dengue fever and even malaria.