706 18 FEBRUARY 2022 • VOL 375 ISSUE 6582 science.org SCIENCE
pable of synthesizing a vast array of or-
ganic compounds. Their chemical building
blocks had different shapes but all con-
tained two chemical linkers, one called a
MIDA that’s attached to one carbon atom,
the other called a boronate that’s attached
to a different carbon.
The machine piped in reactants sequen-
tially so that the MIDA on the first build-
ing block came together with the boronate
on the second, joining their carbon atoms.
Then the second building block’s MIDA
hooked up with boronate on the third,
and so on, until the desired molecule was
complete. The MIDA and boronate linkers
wash away in the process.
The setup allowed the creation of many
druglike organic compounds. By now, more
than 250 academic and industrial labs have
used MIDA-boronate chemistry to synthe-
size new molecules, Burke says.
But the process almost always creates an
“sp^2 -sp^2 ” bond, which links two carbon at-
oms and the atoms attached to them into
a single plane. “Nature is not flat,” Cernak
says. “It lives in 3D.” Innumerable organic
molecules, from antibiotics to perfumes, in-
clude sp^3 bonds, in which some of the two
carbons’ attachments jut out of the plane.
Burke and his colleagues tried to use
MIDA-boronate connectors to forge sp^3
bonds. But doing so required harsher re-
agents, which wound up ripping MIDA off
the building blocks, causing a cascade of un-
controlled chemical reactions that created a
broad mix of byproducts.
The team has now solved this problem by
discovering a MIDA relative, known as TIDA.
TIDA linkers are up to 1000 times more sta-
ble than MIDA linkers, which allows them
to withstand the harsher reagents needed to
construct sp^3 bonds. TIDA-boronate linkers
in hand, the team used its molecular synthe-
sizer to create two complex natural products,
an antibiotic called ieodomycin C and an
antifungal compound called sch725674. Both
contain what are known as chiral centers,
in which elements are arranged in just one
of two distinct mirror-image orientations.
Such chiral centers are key to the function of
many drugs and other organic compounds.
Burke is now working to commercialize
the new setup and come up with libraries
of building blocks that contain TIDA and
boronate linkers so that chemists can as-
semble molecules at will. He says he’s also
working with colleagues to create artificial
intelligence software to dream up novel or-
ganic compounds as potential new medi-
cines. “We want nonspecialists to be able
to make molecules at the push of the but-
ton,” he says. “If it becomes child’s play to
make new molecules, the bottleneck be-
comes imagination.” j
F
rom very early in the pandemic, it was
clear SARS-CoV-2 can damage the
heart and blood vessels while people
are acutely ill. Patients developed
clots, heart inflammation, arrhyth-
mias, and heart failure.
Now, the first large study to assess cardio-
vascular outcomes 1 year after SARS-CoV-
infection has demonstrated the virus’ im-
pact is often lasting. In an analysis of more
than 11 million U.S. veterans’ health records,
researchers found the risk of 20 different
heart and vessel maladies was substantially
increased in veterans who had COVID-
1 year earlier, compared with those who
didn’t. The risks rose significantly with
severity of initial disease and extended to
every outcome the team examined, includ-
ing heart attacks, arrhythmias, strokes,
cardiac arrest, and more. But even people
who never went to the hospital had more
cardiovascular disease than those who were
never infected.
The results are “stunning ... worse than I
expected, for sure,” says Eric Topol, a cardio-
logist at Scripps Research. “All of these are
very serious disorders. ... If anybody ever
thought that COVID was like the flu this
should be one of the most powerful data
sets to point out it’s not.” He adds that the
new study “may be the most impressive
Long Covid paper we have seen to date.”
Others agree the results of the study,
published in Nature Medicine on 7 Febru-
ary, are powerful. “In the post-COVID era,
COVID might become the highest risk fac-
tor for cardiovascular outcomes,” greater
than well-documented risks such as smok-
ing and obesity, says Larisa Tereshchenko, a
cardiologist and biostatistician at the Cleve-
land Clinic. She cautions that the new study
will need to be replicated and that it was
retrospective. “It looked back. We have to
do prospective studies to calculate accurate
[risk] estimates.”
Nor do researchers know how the virus
orchestrates this long-term damage. But
they think the cardiovascular risks and
the constellation of symptoms collectively
known as Long Covid (which in addition toheart symptoms includes brain fog, fatigue,
and loss of smell) could have common roots.
“This is clearly evidence of long-term heart
and vascular damage. Similar things could
be happening in the brain and other organs
resulting in symptoms characteristic of
Long Covid,” says senior author Ziyad Al-
Aly, a clinical epidemiologist at Washington
University in St. Louis and chief of research
at the VA St. Louis Health Care system. In a
parallel study, out this week, his team found
higher risks of neuropsychiatric effects, in-
cluding brain fog, 1 year after COVID-19 in-
fection (see sidebar, p. 707).
Myriad other studies have suggested
COVID-19 prompts lingering damage. For ex-
ample, a preprint on 320,000 health records
from Estonia, posted on 7 February by The
Lancet, found all-cause mortality over the 12
months after infection was more than three
times higher than in uninfected people. But
most published studies examining long-term
outcomes of COVID-19 have followed pa-
tients for just a few months and focused on
far fewer outcomes; many lacked controls.
In the new study, the team drew on the
largest set of electronic health records in the
United States, at the Department of Veterans
Affairs (VA). They analyzed data from nearly
154,000 people who contracted COVID-
between 1 March 2020 and 15 January 2021,
and who survived at least 30 days after be-
coming infected. They identified two con-
trol groups: 5.6 million people who sought
VA care during the pandemic but were not
diagnosed with COVID-19, and 5.9 million
people who went to the VA in 2017.
The authors analyzed data from a period
before vaccines were widely available: 99.7%
of infected veterans were unvaccinated
when they got COVID-19. (The paper
doesn’t address what might happen after
breakthrough infections in already vacci-
nated people, although the authors have a
paper in review on that question.) In addi-
tion, the study demographics were skewed:
About 90% of participants were men and
71% to 76% were white. Patients were in
their early 60s, on average.
The researchers controlled for the pos-
sibility that the people who contracted
COVID-19 were already more prone to de-COVID-19 boosts risk of heart
disease 1 year later
Giant study shows even mild cases can take
a long-term toll on heart and blood vessels
COVID-By Meredith WadmanNEWS | IN DEPTH