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The western world has written plenty about its high-profile COVID
vaccines: the mRNA products of Pfizer and Moderna, viral-vectored jabs
from AstraZeneca and Johnson & Johnson, and those that are just
emerging, such as Novavax’s protein-based vaccine. Many countries are relying on them for protection.
But not Cuba. It’s been quietly working on its own vaccines, immunising its population and selling doses abroad.
Cuba’s vaccine efforts have maintained a relatively low profile in
the west to date. Politics may well be a reason. The US embargo against
Cuba that began in the cold war is still in effect, and tensions between the countries remain high.
But for those familiar with Cuba, its COVID vaccine development should come as no surprise – the country has a long history
of manufacturing its own vaccines and medicines. Nor should it be
surprising that two of its COVID vaccines – Abdala and Soberana 02 –
appear to have performed very well in trials. Here’s how they work.
Abdala is a protein subunit vaccine, which is a well-established design. The hepatitis B vaccine and Novavax COVID vaccine
use this approach. These vaccines work by delivering just a portion of
the virus that they’re targeted against – in the case of Abdala, bits of
the coronavirus’s spike proteins, which cover its exterior.
The proteins used in the vaccine aren’t taken from the coronavirus directly. Instead, they’re grown in cells of a yeast (Pichia pastoris) that have been specially engineered.
Cuba has long punched above its weight when it comes to healthcare and biotechnology.Ernesto Mastrascusa/EPA-EFE
On their own, the portions of spike protein are harmless. But when
the immune system encounters them, it still trains itself to recognise
and destroy them. If the full coronavirus is then encountered in the
future, the body will attack these outer parts of the virus and quickly
destroy it. Abdala is given in three doses.
The other Cuban COVID vaccine, Soberana 02, uses a “conjugate”
design, along the lines of meningitis or typhoid vaccines. It contains a
different part of the spike protein to Abdala and generates an immune
response by attaching (conjugating) this to a harmless extract from the
tetanus toxin. When the body encounters these linked together, it
launches a stronger immune response than it would to either alone.
Soberana 02 is produced in hamster ovary cells, a process that can be slow, and this may restrict large-scale manufacturing.
Originally, it was given as two doses, but researchers later
identified that a third dose would be beneficial. This booster dose
contains just the spike protein parts, without the tetanus toxin, and is
known as “Soberana Plus”.
How effective are they?
Both vaccines have been approved by the Cuban regulator, though they started being rolled out in May – before authorisation had been granted – in response to a rise in cases. There have been concerns about a lack of information on their safety and efficacy.
On November 1 2021, a preprint
(research still awaiting review) was finally published of a Soberana
phase 3 trial that included 44,031 participants. The results suggest
that two doses of Soberana 02 with a booster of Soberana Plus are
together 92% protective against symptomatic COVID. The preprint notes
that during the trial, the vaccine was most likely being tested against beta or delta – two variants of the coronavirus that other vaccines have found harder to control.
Before this, a phase 1 study
of giving Soberana Plus to people who had already had COVID was
published in September. This was testing the effects of Soberana Plus as
a booster to natural rather than vaccine-induced immunity. It showed no
safety issues and stimulated a good immune response when used in this
way – though the study was small, involving just 30 participants.
For Abdala, the only phase 3 trial data available was issued by Cuban press releases in June and July
2021. The three-dose schedule is also reportedly 92% protective against
symptomatic COVID as well as allegedly fully protective against severe
disease and death.
This generated huge enthusiasm within Cuba. However, since then little further information has been made publicly available.
Cuba’s vaccine COVID coverage is among the best in the world.Yander Zamora/EPA-EFE
Around 90% of Cuba’s 11 million people have received at least one dose of a COVID vaccine, with 82% considered fully vaccinated, and it appears
Cuba is vaccinating children as young as two. Both Abdala and Soberana
have been used, with around 8 million people receiving three doses of
Abdala.
Following a big spike in cases
in August 2021 – when the country’s vaccine coverage was still
relatively low – new infections in Cuba have since declined greatly and
remain low. Without proper studies, it’s difficult to gauge how much of
this is down to the vaccines, but the virus’s suppression coinciding
with the country reaching high vaccine coverage is a positive sign.
Who could use a Cuban vaccine?
Given the difficult relationship between Cuba and the US, the market
for Cuba’s vaccines will probably be its political allies. Vietnam and
Venezuela are reported
to have received Abdala doses, Nicaragua has given emergency
authorisation to both vaccines, and doses have previously been sent to Iran for use in clinical trials. Mexico and Argentina are also interested in using these vaccines.
Cuba has submitted both to the World Health Organization (WHO) for
approval, which would improve the likelihood of them being used abroad.
If there are any plans to include them in the Covax vaccine-sharing
initiative, then WHO approval is a must.
Meanwhile, we’re still waiting to see what impact omicron will have. So long as there’s unequal access to vaccines, the pandemic will continue – and so too the risk of new variants arising.
Given most richer countries aren’t in the queue for Abdala or
Soberana 02, it’s entirely possible that in future, parts of South
America, Asia and Africa – where vaccine coverage is particularly low – may see Cuban vaccines in many arms.
From
his home in Portola Valley, California, Sanjiv Gambhir logged on to an
important meeting for his startup one afternoon in April 2020. He kept
the video camera off.
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This
was unusual, not least because he cherished face-to-face connections
and was obsessed with visibility. A pioneer of molecular imaging and the
director of Stanford’s Canary Center for Early Cancer Detection,
Gambhir, known as Sam, had spent decades trying to make small, hidden
tumors inside the body easier to see. Nearly 600,000 people in the U.S.
die from cancer every year, mostly because we tend to catch tumors when
they’re too late to effectively treat.
“Cancer doesn’t need to be a
death sentence,” Gambhir would tell the researchers in his lab, as he
reminded them of the actual patients they were trying to save. By the
time he was 50, his breakthroughs in early detection—including
developing the reporter genes used in positron emission tomography, or
PET scans—had led to three startups, millions in seed funding, and 40
patents.
His latest startup, Earli,
was the culmination of a decade’s-worth of research into whether you
could force tumors to show themselves, by having them send out a signal
that could be detected in blood tests or PET scans. If that worked, you
could open up a new frontier in cancer detection. Gambhir had pioneered
the technology, but cofounder Cyriac Roeding, an energetic e-commerce
entrepreneur had convinced him to turn it into a company. By the start
of 2020, they had already raised $19.5 million in venture funding to
fuel the commercialization of their technology.
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But
in 2019, doctors had detected something inside Gambhir. A tumor of
unknown origin was quietly spreading in his bones. The irony of cancer
sneaking up on him was as brutal as the prognosis: After finding such
metastasis, the median survival time is three to four months. But
Gambhir turned his cancer and his experimental treatments—every few
weeks in Munich—into a learning opportunity for himself and his
colleagues. Now, a year after his diagnosis, he was bedridden and weak
from the treatments. But he was determined to be on this call.
For
three hours, Gambhir and the rest of the five-person board—including
Jorge Conde, a biotech veteran and partner at the prominent venture
capital firm Andreessen Horowitz—discussed manufacturing challenges, the
search for more cash, and the results of a recent study the company had
done in mice. “He was sharp as a tack. I mean, for God’s sake, the guy
was still pulling apart the science,” says Earli cofounder and chief
scientific officer David Suhy. “But you could hear in his voice, he was
physically weak.”
Sanjiv Gambhir [Photo: courtesy of Earli]Gambhir
was often reminding his cofounders how bedeviling biology could be, how
resistant it was to commercialization. “The world of biology will
always find a way to screw you over,” he’d warned Roeding as they were
founding the company in 2018. After establishing Stanford’s
Multimodality Molecular Imaging Lab in 2003, Gambhir had helped develop
an armory of futuristic advances for spotting tumors, including a smart
bra to continuously monitor for breast cancer and a smart toilet for
detecting colon cancers. But much of the tech was still experimental.
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As
Gambhir pursued this research, his wife, Aruna, battled back breast
cancer—twice. Then, in 2013, biology reared its head in another,
horrible way: Their 15-year-old son, Milan, was diagnosed with a rare
form of the most aggressive kind of brain cancer, the very type of tumor
Gambhir’s lab had been studying. Gambhir’s need to translate his work
from lab to practice had never been more urgent. But Milan’s cancer
proved quicker than the pace of medicine. He died in 2015, at the age of
16.
Five years later, as a tumor spread in his own body, Gambhir
felt a different kind of urgency. “The problem is, he knew too much,
even with Milan,” says Aruna. Now Gambhir’s ideas and multi-disciplinary
insights into molecular imaging—his one-of-a-kind knowledge of the
field—would need to go to the scientists and doctors who could make the
most of it, even in his absence.
When President Nixon launched the
war on cancer 50 years ago, Sidney Farber, the president of the
American Cancer Society, declared that with enough resources, scientists
could conquer cancer in seven years. Instead it has been a protracted
war with a roving target. Despite hundreds of billions of dollars spent
on research, cancer is now vying with heart disease to be the number one
cause of death in the U.S. “Since 1970, there’s maybe 50% improvement
in cancer survivors,” says Leland Hartwell, an advisor to Earli whose
work on cell growth earned him a Nobel Prize in Biology. “Given all the
effort, it’s not great.”
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The
hope now isn’t a cure, but finding the right combination of diagnostics
and treatments to manage it. And after years of relatively miniscule
government funding, detection is getting more attention. The race to
catch cancer earlier has given rise to a $168 billion industry
touting a new class of tests that promise to detect tiny signs of
cancers in your blood or stool. Most are pursuing an approach known as
“liquid biopsy,” using a blood test to look for abnormal pieces of DNA
shed by cancer cells.
Finding bits of cancer cell sheddings,
however, is notoriously hard. Earli’s approach compels tiny tumors to
produce new signals, sending out flares—naturally-occurring
proteins—that can be more easily detected in a blood test or illuminated
for an imaging scan. A reliable diagnostic that could be administered
once a year by a doctor to find and pinpoint very early, aggressive
tumors in apparently healthy people could have a profound impact on
healthcare and its costs.
“Once you find [a tumor] and you can
localize it, you can act on it, and then it becomes protection, not just
detection,” Roeding says. Someday, Earli’s “synthetic biopsy” platform
could even be useful for targeting cancer cells with personalized
medicine, immunotherapies, or mRNA vaccines. Already the company has
shown an ability to detect certain cancers in mice and dogs; in June, it
began dosing its first human patients as part of a clinical trial. But
it still has a long way to go.
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Back
at the board meeting, Roeding reviewed the results of their first trial
in mice. The synthetic biomarker they were using to tag tumor cells had
shown up in PET scans of cancerous mice—a little glowing lighthouse in a
sea of uncertainty. Suhy and Roeding were ecstatic. Gambhir was
circumspect. “He asked us four questions,” Roeding recalls. Did the test
actually detect cancer? Did it have a low false negative rate? Was it
differentiating between malignant and benign? Could it determine the
stage of cancer?
The trial was promising, but Gambhir needed more
than promises. In June 2020, three months after the board meeting—and
the day after receiving Stanford’s Dean’s Medal, its highest honor—he
died at home at the age of 57.
For
the field of early cancer detection, the loss was devastating. Tributes
poured in from researchers around the world, and colleagues held a
string of academic symposia dedicated to his legacy. Last September, the
Journal of Nuclear Medicine bucked a 55-year tradition for the cover, trading its typical medical imagery for a full-page portrait of Gambhir.
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His
company, meanwhile, is forging ahead and confronting another big
question: Can they manifest a technology without the visionary who
dreamt it up? “We are working on a very low probability, but potentially
high impact thing,” says Roeding. “It’s a moonshot. There’s no doubt
about it.”
Light-haired and boyish, Roeding was born in
Germany, and yet is the archetypical energetic Silicon Valley
entrepreneur-investor. A veteran of business consulting, smartphone-era
startups, and venture capital, he can repeat a well-rehearsed pitch
verbatim and never sound scripted—skills that helped him build up the
in-store discount app Shopkick and sell it for $250 million to the
biggest telecom company in South Korea.
In 2016, a couple years
after that deal, Roeding was in the Bay Area looking for his next
startup idea. An interest in brain-computer interfaces brought him to
Stanford’s campus, which in turn led him down the rabbit hole of
precision medicine. But the deeper he got, the more confused he became.
Here were all these scientists saying they each had the solution to the
world’s various biggest problems. “I’m not a biologist,” says Roeding.
“I didn’t know who was wrong.”
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By
Thanksgiving, three months into his search, Roeding was feeling
deflated. That morning, his wife handed him a copy of Stanford’s alumni
magazine and suggested he read the cover story, about a prominent
radiologist’s struggle to save his son from metastatic brain cancer. The
piece shook him, and early that afternoon he sent an email to its
subject, Gambhir. “I can only imagine how hard especially holidays like
today’s are for you and your wife,” Roeding wrote. “But perhaps just on a
day like this, it is worth remembering that Milan, your journey to try
to save him, and the powerful ideas that have come from this journey,
have inspired others like me.” Roeding introduced himself, and said he,
too, was interested in health monitoring. “Perhaps there are ways we
could work together.”
Two months later, they met on a sun-drenched
Saturday at a small restaurant in Portola Valley, a town near Palo
Alto. They talked about innovation and science and the yawning chasm
between academia and commercial medicine. After years of navigating the
bureaucracies of biomedical research, Gambhir was drawn to Roeding’s
left-field thinking. The lunch became the first of many Saturday
meetings. Gambhir agreed to teach Roeding biology (“largely in vain,”
says Roeding) and introduced him to even more scientists. But Roeding
was more eager to hear what Gambhir was working on. When Gambhir told
him about his lab’s work around using biomarkers to catch tumors earlier
than other diagnostics, Roeding was hooked.
They used $400,000 of
their own money to get started, incorporating the company in June 2018.
They negotiated a licensing deal with Stanford for Gambhir’s related
patents and tapped Suhy, who previously led gene therapies at Australian
biopharma Benitec, to serve as chief scientific officer. Gambhir would
be a scientific advisor and Roeding became CEO.
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Earli cofounders Cyriac Roeding, Sanjiv Gambhir, and David Suhy [Photo: courtesy of Earli]Roeding
was an unusual choice to helm a breakthrough biotech company. He
recalls asking Gambhir: “Should someone with my background bother the
world of biology with my presence?” The field of biology has a surplus
of experts and no generalists, said Gambhir, and few people who knew how
to run a startup. On top of that, he said, biology is fickle:
biological exploration will always take longer and be harder than you
think. He argued that being able to move fast—and, yes, fail fast—could
help the company resist the inertia of experiments, trials, and
regulations.
At the start, Roeding’s aggressive targets raised
eyebrows among investors. “We said, we want to be in humans within three
years, and they kind of chuckled,” says Roeding. Most weren’t
convinced, but the pitch caught the attention of Andreessen Horowitz’s
Conde, who is a biotech industry veteran. Before the year was out,
Gambhir and Roeding had secured just shy of $19.5 million in seed
funding from a group led by Andreessen Horowitz that included Salesforce
founder Marc Benioff, Menlo Ventures, and Chinese venture firm
ZhenFund.
Even with buy-in from the likes of Andreessen and
Benioff, the founders knew their operation faced an uphill battle.
Diagnostics that require injecting patients face a phalanx of clinical
trials, a process that takes years even with the enormous resources of
giant pharmaceutical companies. While Earli had shown some promise in
the lab, there wasn’t a guarantee it would translate to animals. And
scientists had never tested synthetic biomarkers in humans: There were
likely to be unusual regulatory hurdles to getting a clinical trial
approved.
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For
the first year, Suhy and Roeding met with Gambhir every four to six
weeks to talk about the company’s progress. They managed day-to-day
operations, but Gambhir could find the holes in their thinking and minor
successes—an invaluable perspective in setting the direction until
their next meeting. As the hours wore on, their conversations would
inevitably give way to heady discussions on the state of science.
In
late spring of 2019, Roeding got a call from Gambhir. His voice sounded
funny. He told Roeding that he was sitting on the couch with his wife.
They had just found out that he had cancer, and it wasn’t clear where it
had started. By definition, it was metastatic and almost impossible to
treat. If they didn’t know where it originated, they couldn’t know what
they were fighting.
Roeding tried to stay optimistic. “It’s battle
time,” he told his cofounder. Gambhir said there were possible
treatments, but he was also clear-eyed. They agreed that they needed to
prepare the company for a world without Gambhir.
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“We
have to make sure that our science is advanced enough so that we can
move forward without having to rely on his input at a deep level
continuously,” Roeding recalls realizing. “For us, really the main
question became, does Earli have enough escape velocity so that we can
become what [Gambhir] wants us to be?”
The biggest victories
in the war on cancer have been scored via anti-smoking campaigns and
cigarette taxation. They’re largely responsible for the 27% drop in
deaths from cancer in the U.S. between 2009 and 2019, according to the
Center for Disease Control and Prevention (in lung cancer, advances in
targeted therapies also played a role). Still, little has progressed in
screening, which scientists see as the best opportunity to find cancer
before it gets out of control.
Chances are, you’ve been through
multiple cancer screenings: mammograms, pap smears, colonoscopies, when a
doctor takes a look at the weird mole on your back. Long-time smokers
over 50 years old might get a CT scan. For certain cancer types, these
screens, which mostly rely on seeing physical changes, can save lives.
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But
there are lots of forms of cancers that can’t be screened for: ones
that are too small to see or that haven’t necessarily caused any bodily
changes. Tumors mutate and evolve in unique ways, so each person’s
cancer is a little different. A tumor that’s benign in one body could be
deadly in another. “What we’re faced with is just enormous diversity,”
says Earli advisor Hartwell.
As a result, cancer treatment has
become more personalized, with scientists tailoring dosage and type of
therapeutic to the genetic makeup of a cancer’s cells. But some
scientists, including Hartwell, think that developing better earlier
detection methods will offer a far less invasive—and far more
affordable—path to lowering cancer deaths. So far, however, early
detection has proceeded in fits and starts. “The cost per advance is not
impressive,” he says.
[Photo: courtesy of Earli]The
latest and greatest tools in cancer diagnostics are genetic testing and
liquid biopsy tests. Genetic testing alerts doctors to potential genes
that are associated with an increased risk of cancer, like BRCA-1 and
BRCA-2 for breast cancer. Liquid biopsies capitalize on advances in
machine learning to analyze blood samples for the tiniest clues of
cancer, by detecting and analyzing fleeting fragments of cells that
tumors shed. These can include DNA, RNA, proteins, and other pieces of
cancer cells that circulate in the body and sometimes contain clues
about their location.
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Menlo
Park-based Grail—one of dozens of companies that Gambhir advised—now
sells a liquid biopsy test called Galleri, which purports to find 50
types of cancers in apparently healthy people. The test, at $950, is not
covered by insurance, but that could change after full FDA approval,
which Grail intends to seek in 2023. Another California company,
Redwood-based Guardant Health, is currently running trials of its
early-stage colorectal cancer test, eyeing a market for early detection
that’s expected to reach $280 billion by 2027.
Not everyone is so
bullish on liquid biopsies, however. “I should be careful what I say. I
could make myself persona non grata,” says Judy Garber, Director of the
Center for Cancer Genetics and Prevention at Dana-Farber Cancer
Institute and board member to Earli. Several liquid biopsy companies,
she says, “want to find all cancer at once, which I agree would be
great. But I think that hasn’t been what the data supports, and yet they
seem to be in this huge rush to sell their test.”
The most compelling recent data
showed that Grail’s test could positively identify stage I to III
cancer more than 67% of the time in a set of twelve cancers including
head and neck, liver, and pancreatic cases. Overall, the test had a
false positive rate of 0.5%, and was able to identify the tumors’ organ
sites 88.7% of the time. But its ability to detect other cancers was
lower: It identified less than 20% of thyroid, kidney, and prostate
cancer cases, for instance.
[Photo: courtesy of Earli]One
major challenge with looking for natural biomarkers, like cell
sheddings, is that young tumors produce far fewer of these fragments.
Even when these cancer bits do make it into the bloodstream, they spend
less time in circulation, making it exceedingly difficult to pull them
out in a sample.
Earli’s diagnostic takes a more proactive
approach to the search for tumors. The platform consists of an
injectible compound that carries a reporter gene, engineered to activate
at the faintest hints of tumor cells, wherever they are. Once it’s
tapped into the cellular pathways driving the tumor’s uncontrolled
growth, the gene is designed to express a synthetic biomarker,
effectively “boosting” the cancer’s signal. For its biomarker, Earli
chose an enzyme that typically only appears during embryonic
development. (A Cambridge-based startup called Glympse is developing
synthetic biomarkers to identify liver disease, though cancer detection
is also on its roadmap.)
The approach has several apparent
advantages over current liquid biopsy technologies. Because it uses a
synthetic biomarker, Earli can more easily control the amplitude of the
signal. Where liquid biopsy companies use the genetic code of cancer
fragments to try to determine a tumor’s location in the body, Earli
pinpoints the tumor itself. This could also help physicians better track
the success of ongoing therapies, and lead to novel therapies: With an
additional molecule designed to trigger an immune response in cancer cells, Earli’s surveillance platform could eventually be harnessed to kill elusive tumors too.
Hartwell
remembers hearing Earli’s concept for the first time, and being struck
by it as “incredibly brilliant.” “You sort of wonder why it took us so
long to think of it,” he says. “But that’s not what makes a successful
company.” If Earli is going to be “a company rather than just a research
project,” he stresses, it needs to quickly identify—and market—an
application of its technology. “That’s a race that you can’t predict.”
When
Gambhir died, the company was still in semi-stealth. Earli barely had a
web presence, save for a recruiting website, and had interesting, but
nascent progress in mice. It needed more cash, to hire more scientists,
double down on pre-clinical research, and start building out a new lab.
Before
Gambhir’s last board meeting, the company began getting feedback from
his longtime colleagues and friends, a Who’s Who of cancer pioneers:
Hartwell and Garber, but also Nobel Prize-winning cancer researcher Jim
Allison, Moderna founder Bob Langer, Charlie Rudin, who heads up
thoracic oncology at Memorial Sloan Kettering, and Aruna, who now runs
another company related to her husband’s research called CellSight,
which is working on technology that recognizes if cancer treatment is
working.
In fall 2019, Langer dashed off an email to investor
Vinod Khosla, founder of Khosla Ventures, introducing him to Earli and
laying out how it differed from liquid biopsy firms. Khosla had for
years passed on high-flying biotech investments, but says he was drawn
to Earli’s “orthogonal approach” to early detection, versus the
“incremental” efforts of other ventures. Khosla likens Earli to
Cambridge-based Commonwealth Fusion Systems, one of his biggest
investments, which is aiming for the moonshot of nuclear fusion. “In our
fund, we sort of say, ‘large impact, large technology breakthroughs
that cause a large impact’—if you do that, the money will follow.”
Dr. Michael Kent, pictured with his dog Danson, is helping Earli conduct trials at his canine lab at UC Davis [Photo by Don Preisler/UCDavis]In
January 2020, Khosla Ventures led Earli’s $40 million series A,
alongside Andreessen Horowitz. The board now includes Conde, Justin Kao,
who led Khosla’s investment, and Marc Andreessen, who serves as a board
observer.
“It’ll never be quite as good as if Sam was working
on it himself,” Khosla admits, “but they’re at a proof point that is
substantially lower risk today than it was two years ago.” He pointed to
“a cadre of world-class scientists” that Earli has recruited as
advisers. “If it can be done, I think this team can do it.”
With
the funds, Earli went on a hiring spree: 29 researchers now work at its
headquarters in South San Francisco. And Roeding and Suhy decided to
pursue a proof of concept in dogs. The company worked with the
Comparative Cancer Center at the University of California Davis School
of Veterinary Medicine, which connects sick dogs with clinical trials.
Together they studied the biomarker at four different doses in a total
of 23 dogs to see if it would show up in blood work.
Roeding and members of the Earli research team [Photo: courtesy of Earli]Michael
Kent, director of the center, says that Earli’s compound was well
tolerated, with only a few dogs developing a brief and low-grade fever.
Full trial results of the trial will be published later this year, but
the results were favorable. “This isn’t going to be in your doctor’s
office next year, but this could be game-changing,” Kent says. Unlike
the liquid biopsy tech Kent has tested, Earli doesn’t depend upon
serendipity to spot cancer. “You have something making a clear signal
and saying, ‘Hey, I’m here!” That’s unique.” Earli is now funding
subsequent trials with dozens of dogs.
Demonstrating that the
test was nontoxic for dogs was crucial in getting the Australian
government to agree to let Earli begin its first human trials in the
country, which began this past September. So far, two people have been
dosed, and another is on track. The aim is to detect advanced-stage lung
cancer in already diagnosed patients—and to amass the data Earli will
need to convince the U.S. Food and Drug Administration to let it proceed
with a U.S. trial of its novel technology.
Suhy says he’s
encouraged by the speed with which the FDA approved mRNA vaccines during
the pandemic. That suggests regulators are amenable to novel medical
technology like Earli’s diagnostic. Still, he notes, those approvals
were based on years of data. And even if Earli achieves FDA approval, it
will need to convince doctors to add a novel diagnostic to their
workflow.
Nora Pashayan, a professor of Applied Cancer Research at
University College London who is not affiliated with Earli, calls its
concept “amazing.” But says “it could take a long time” for Earli to
come to market. And its approach faces several pressing questions, she
says, related to the design of the biomarker, how often it’s deployed,
and in whom.
These elements—how and who—matter, because contrary
to conventional medical wisdom, early detection doesn’t always save
lives. The problem is that doctors can’t always tell the difference
between a benign or malignant tumor and therefore may treat a tumor out
of an abundance of caution. “Other than the psychological burden [of
diagnosis], there are side effects of treatment—going into chemotherapy,
endotherapy, or surgery,” says Pashayan. “So the harms are much more
than the benefits, [if] this cancer was not going to do anything.”
A failed public health effort in South Korea serves as a cautionary tale.
Between 2000 and 2011, thanks to a government recommendation, doctors
in the country started screening everyone for thyroid cancer.
Unsurprisingly there was a surge in thyroid cancer diagnoses and surgery
to remove these tumors. However, after ten years, deaths from thyroid
cancer remained stable. The screening campaign wasn’t preventing death.
If anything, it was creating problems for people who were experiencing
complications from unnecessary surgery. For companies like Earli, the
protocols around a diagnostic matter as much as whether it works.
The
greater scientific research community still believes that early
detection tools, like Earli’s, are critical. Cancer drugs treat, but do
not cure—and are immensely expensive. The hope is that finding cancer
early, identifying the tumor profile, and stopping it before it spreads
could one day make getting cancer a relatively anxiety-free experience.
“What we need to show are the success cases of what it means to find it,
get rid of it, and live on,” says Roeding. “And in order to do that, we
need to find more early stage cancers.”
More than 1,600
people logged into Gambhir’s memorial service, which was held at the
height of the pandemic, in July 2020. Colleagues described his
generosity and far-sightedness. “It would not be entirely accurate to
say that Sam presented a ‘vision’ for the field of molecular imaging,
because that sounds a little like the elements of the vision were out
there and others were also aware of it,” said Norbert Pelc, Stanford
University professor emeritus of radiology. “Sam created the vision and
then articulated it. He was able to do that: See a path ahead many years
ahead of his time and explain it to an audience at a wide range of
levels.”
“He gave you confidence in that future,” says Christina
Zavaleta, an assistant professor of biomedical engineering at USC and
one of Gambhir’s hundreds of former students. Sam may not get to see
where all of his ideas will travel, but “he was already there in his
mind,” she says. “We’re the ones that have to catch up.”
[Photo: courtesy of Earli]
Gambhir’s
technology is bound to introduce new conundrums, about if and how to
treat previously hidden tumors. Even if Roeding and Suhy can
successfully render Gambhir’s novel early detection technology into a
marketable diagnostic, it won’t end our battle with cancer. Still, if
they can pull it off, it could give patients and doctors the luxury of
choice, something that Sam and Milan Gambhir didn’t have.
“It’s
a cruel irony that Sam’s own cancer was only detected after it had
spread to his bones,” Aruna, Sam’s wife, said at his memorial, her voice
breaking. “Perhaps if some of the tools in precision health were in
place, he would have had a chance to live and contribute even more. He
told me towards the end days that he felt he had another decade of
productive work left in him. Imagine what that could have meant for
humanity.”
British vaccine developer Sarah Gilbert says next pandemic ‘could be worse’ than coronavirus
Sarah
Gilbert, professor of vaccinology at Oxford University and co-developer
of the Oxford-AstraZeneca coronavirus vaccine, is pictured at the
Cheltenham Literature Festival on Oct. 11 in England. (David
Levenson/Getty Images)
The
world should do more now to prepare for future pandemics, said Sarah
Gilbert, one of the inventors of the Oxford-AstraZeneca coronavirus vaccine.
“This will not be the last time a virus threatens our lives and our livelihoods,” Gilbert said as she delivered the 44th Richard Dimbleby Lecture,
an annual address by an influential figure that will be aired Monday on
the BBC. Gilbert is a professor of vaccinology at Oxford University.
“The truth is, the next one could be worse. It could be more contagious,
or more lethal, or both.”
“We
cannot allow a situation where we have gone through all we have gone
through, and then find that the enormous economic losses we have
sustained mean that there is still no funding for pandemic
preparedness,” Gilbert said, echoing earlier calls for more proactive
funding for scientific research.
Gilbert
touted industry and government speed in responding to the emergence of
SARS-CoV-2 by quickly developing and deploying coronavirus vaccines, and
she said it could be a model for other diseases. “Just as we invest in
armed forces and intelligence and diplomacy to defend against wars, we
must invest in people, research, manufacturing and institutions to
defend against pandemics,” she said.
Like other scientists from around the world, Gilbert said existing vaccines may be less effective against the omicron variant of the coronavirus; but while infections may become more common, that doesn’t mean hospitalizations and deaths will increase.
The
European Union drug regulator has given its backing to mixing different
types of vaccines in initial vaccination and booster campaigns to
battle the coronavirus
Photo by KATERYNA KON/SCIENCE PHOTO LIBRARY/Getty Images
President Nixon declared the "War on Cancer" with the National
Cancer Act of 1971, and in the decades since then cancer researchers
have delivered new targeted therapies and immunotherapies that radically
improved treatment. Even as more weapons are added to the medical
arsenal, however, cancer cells find new ways to resist them.
In a provocative book published in 2020, Athena Aktipis —
director of the interdisciplinary cooperation initiative at Arizona
State University who studies conflict and cooperation, in a whole range
of systems from human societies to cancer cells — argues that humanity
may need to rethink our war on cancer by focusing not on eliminating it,
but on transforming cancer from a set of deadly, acute diseases to
chronic, manageable ones. She writes: "Cancer evolves, but we have the
ability to anticipate that evolution and strategically plan our
response. We can trick it, send it down a blind alley, sucker it into
vulnerability, and shape it into something we can live with."
Aktipis’s book, The Cheating Cell: How Evolution Helps Us Understand and Treat Cancer, came out earlier in the spring and she tells Smithsonian
how taking an ecological and evolutionary approach to cancer has led to
novel treatment strategies—and why cancer is a lot like the mafia.
What was the impetus for writing this book?
There was a need for a book that would explain the origins of
cancer. Why is cancer something that we face as humans, and why do other
organisms get cancer? People think cancer is just a modern phenomenon,
but it has been around since the beginning of multicellularity. I wanted
to tell the story of how evolution operates within our bodies—among our
cells over the course of our lifetime—to give rise to cancer.
Cancer treatment traditionally uses high
doses of toxic drugs to wipe out cancer cells. But some oncologists have
started taking a different approach, inspired by integrated pest
management, that seeks to control rather than eliminate. Tell us more
about this approach to cancer treatment.
Imagine you have a field and you’re trying to grow crops, but
there are pests. If you use high doses of chemical pesticides, then you
end up selecting for the pests that can survive despite the pesticide.
In cancer treatment, the approach has been to use the highest dose that
can be tolerated by the patient.
With integrated pest management, by contrast, you limit the use
of pesticides to try to avoid selecting for resistance. You may not get
rid of the pests completely, but you can keep their population under
control so they do limited harm to the crops. Adaptive cancer therapy is
based on the idea that resistance is going to evolve unless we manage
the evolution of the resistance itself.
Adaptive therapy is an approach pioneered by Bob Gatenby at
Moffitt Cancer Center in Tampa, Florida, who was inspired by integrated
pest management approaches. The idea of it is to try to keep the tumor a
manageable size and to maintain the ability to treat it with the
therapy that's being used. This is very different from hitting it with
the highest dose that the patient can tolerate to make it go away, which
is the traditional approach. With adaptive therapy, you're just trying
to keep the tumor at a stable size and not use so much chemotherapy that
you get the evolution of resistance. It is taking a long-term time
perspective and thinking about not just what's the immediate effect of
the treatment, but what's the long-term effect on the ability to keep
the tumor under control.
There are some cancers that we know are curable with high-dose
therapy, and so for those, we should continue doing what works. But when
it comes to advanced metastatic cancer, that is cancer that has spread
from the primary tumor to other organs in the body, it is often the case
that you can't eradicate the cancer. You can't achieve a full cure at
that point. So it makes sense to change the strategy in those cases to
thinking about how the patient can most effectively live with the tumor
and how we can keep it from becoming more aggressive. These are
important approaches as we truly integrate this evolutionary and
ecological cooperation theory for cancer biology.
You call cancer cells “cheaters” because
they take advantage of healthy cells without offering any benefit to the
body. Why do these harmful cellular cheaters exist across the tree of
life?
There's an epic struggle between the way that evolution works on
populations of organisms to help suppress cancer and then how evolution
works within our bodies. In a population of organisms, the individuals
that are the best at resisting cancer are favored. But within an
individual body, the cells that are best at replicating and monopolizing
resources—and therefore more prone to cancerous behavior—are the ones
that are selected. So you have two evolutionary processes in conflict.
A complicating factor is that there can be trade-offs between
suppressing cancer and other traits that might enhance your fitness,
like having more rapid reproduction and growth. Wound healing is a great
example. It is very clear how the same cellular characteristics can
both help you heal a wound quickly and lead to susceptibility to cancer.
When a wound occurs, the nearby cells need to replicate and migrate to
heal the wound. In that environment, the cells in the neighborhood are
temporarily more tolerant of cells that replicate and move.
That creates a vulnerability to cancer. You have this
possibility that cells will replicate more quickly and move, and that
they also create the signaling environment that calls off the immune
system. One of the oldest ways to refer to a cancer is actually “the
wound that will not heal.”
What tricks have other species evolved to resist cancer that we might be able to use to treat cancer in people?
Cancer is extremely widespread across the tree of life. Some
factors seem to predict having more cancer suppression mechanisms. For
example, we can think of the cancer suppression gene TP53 as the
“cheater detector” of the genome. It is part of this large network that
takes in information that could indicate a cell has gone rogue. If the
combination of signals is not right, then TP53 triggers a response such
as stopping the cell cycle to repair DNA. If that doesn’t work, it
triggers cell suicide.
This gene is really important for cancer suppression in a lot of
species. Elephants have 22 copies of this gene, while humans only have
two. It’s not clear if all the copies in elephants are functional, but
elephant cells do have more cell death in response to radiation. The
more copies of TP53 your cells have, the more likely they are to undergo
programmed cell suicide if they are exposed to a carcinogenic
situation. The fact that elephants have more copies of TP53 is an
interesting example of how large size can select for having more cancer
suppression mechanisms.
In addition to cheating healthy cells, cancer cells cooperate. How can cancer treatments take advantage of this?
Cooperation is not always good. The mafia is an amazing example
of cooperation to cheat. There are many parallels in cancer with the way
that organized crime uses cooperation within the organization to
exploit a broader system. For example, during the 1920s, members of the
mafia worked together to take advantage of prohibition and began
procuring and selling illegal alcohol. The fortunes that factions made
doing this allowed them to dominate organized crime in their cities.
There are several potential approaches involving cell
cooperation that we should be exploring more in cancer treatment. Rather
than trying to just kill the cancer cells, we can try to disrupt their
communication and their adhesion to one another. Those are good targets
for intervening in the processes that seem to require cell cooperation,
like invasion and metastasis, which are the processes by which cancer
cells leave the tumor of origin, circulate in the bloodstream, then
invade the tissue of a distant organ. Those invasion events are the
seeds of metastases: the spread of cancer throughout the body.
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