Trusting Her Gut
PublishedDecember 7, 2021
Inside one microbiologist’s quest to sequence and strengthen the microbiome.
Fourteen years ago, Colleen Cutcliffe woke up in the middle of the night feeling stressed and vastly unprepared. Her water had just broken, but the anxiety coursing through her went far beyond the normal fears provoked by impending labor. The problem: Cutcliffe’s due date was still a little over two months away. Her husband reached for the phone to contact the maternal nurse on call, only to discover that the line was dead. A power outage had left half of San Francisco in the dark. Their only option was to drive to the hospital.
The couple had no overnight bag packed yet, no crib or nursery set up. Cutcliffe hadn’t even set foot in the hospital where she was to give birth, let alone completed any delivery classes. Her vision of a safe and orderly birth was crumbling around her. Within an hour of arriving at the hospital, Cutcliffe was in active labor. She pushed for 15minutes until her daughter Annabella was born.
Annabella weighed four and a half pounds and spent the first month of her life hooked up to machines and monitors in the NICU, where she also received high doses of antibiotics for a prolonged period of time. “It was terrible,” Cutcliffe recounts. “When you’re in times of trauma you just put one foot in front of the other and you’re like, this is just what I have to do. I just lived in that NICU until I could bring her home.”
Although Cutcliffe didn’t know it at the time, those first few turbulent weeks of Annabella’s life would provide a guiding principle that Cutcliffe would revisit again and again as her career progressed. During her rocky introduction to motherhood, Cutcliffe realized that in order to move toward success, one must often embrace chaos, unforeseen problems, and the occasional blackout. Cutcliffe has brought the same ethos to her scientific and business pursuits, first as a prominent biochemist working in the pharmaceutical sector, and now as the CEO of Pendulum Therapeutics, a biotech startup working to improve microbiome health.
“Having a baby teaches you that you are not in control of anything,” she says, ascribing a similar philosophy to her approach to running Pendulum: “I think when you’re starting a company, feeling like failure is okay helps you to have that courage. Everybody will fall, it’s not that big of a deal. What matters is how you pick yourself up.”
Roelof Botha, a partner at Sequoia Capital who works closely with Cutcliffe, recalls with admiration how Cutcliffe’s openness to failure was foundational to her business. “When we started to run our initial clinical trial, she said, ‘If the data isn’t good we shut down the company. I want to make sure that the product actually works, otherwise we don’t have a company.’ That’s her attitude.”
For Botha this came as a relief—he also didn’t want a product that he couldn’t back wholeheartedly. But he especially valued her dedication to transparency and facts, no matter how ugly they may be. Cutcliffe is, in Botha’s words, “unflappable” in the face of obstacles: “We’ve had several setbacks along the way: there was a concern about whether the IP we have is protectable; the initial go-to-market plan didn’t quite work. Instead of going into a dark spot and getting depressed about it, Colleen draws new energy to tackle the problem at hand. She just doesn’t give up.”
“Having a baby teaches you that you are not in control of anything. I think when you’re starting a company, feeling like failure is okay helps you to have that courage. Everybody will fall, it’s not that big of a deal. What matters is how you pick yourself up.”COLLEEN CUTCLIFFE
There was another way that her daughter’s month in the NICU indirectly paved the way for Cutcliffe to found Pendulum Therapeutics. When Annabella began attending elementary school, she started to display some food sensitivities, as well as differences in metabolism compared to the rest of her family, which by then included a younger sister. At the same time, Cutcliffe, who was then working at a DNA sequencing company, read a paper about the microbiome that gave credence to her suspicions that her daughter’s food allergies and metabolic differences could be connected to her first month of life, when she was given extremely high doses of antibiotics.
“It struck me that, oh my gosh, that start to life she had, it wasn’t just traumatic to me, it was traumatic for her microbiome,” Cutcliffe says. “All these sensitivities she’s having around her gut and her metabolism are probably because of that.”
Ever since Louis Pastuer popularized the germ theory of diseases, modern medicine has declared war on germs—a binary approach that’s led to our current predicament, a society lacking the beneficial bacteria needed to maintain optimal health. Without a bacterial balance in the body, we’re susceptible to a host of autoimmune problems, such as thyroid issues, rheumatoid arthritis or diabetes, and digestive issues, like irritable bowel syndrome, constipation, diarrhea, heartburn or bloating. “The truth is we are an ecosystem unto ourselves,” says Botha, “[and] you need these microbes to flourish as a human.”
Pendulum’s flagship product is a medical probiotic, the Pendulum Glucose Control capsule, used to lower glucose levels in people living with type 2 diabetes. For decades now, scientists and medical researchers have questioned whether the gut microbiome—the microscopic colony of bacteria, fungi, viruses and protozoa that live in our gastrointestinal tract—could determine the onset and progression of diabetes. Pendulum’s probiotic capsules attempt to do two things: the first is to help metabolize fiber into butyrate, a fatty acid that’s crucial in aiding the body’s ability to regulate sugar. Many people suffering from type 2 diabetes exhibit gut dysbiosis—an imbalance in the bacterial community of the gut (the microbiome)—which hinders them from metabolizing fiber that would keep glucose spikes in check.
The second aim of the capsules is to keep the gut lining intact so that once the microbiome starts to rebuild it can be kept within the gut itself. Cutcliffe describes it like a wooden fence surrounding a backyard: “When we first moved into our house, the fence was great, it was shiny, and new, and solid. Your gut lining is like that fence. Over time, through seasons, and snow, and rain, and sun, the fence starts to get worse. Sometimes you can lose a plank, and now all of a sudden, you’re really exposed. That’s what happens to your gut lining through things like stress, aging, menstrual cycles, menopause, pregnancy.” The Pendulum capsule’s ability to help the body metabolize fiber, as well as strengthen the gut lining, has been proven to help bodily regulation of sugar.
Catie Rosemurgy, a poet and professor of creative writing at the College of New Jersey, has been taking the Pendulum capsule since her diagnosis of diabetes 2 in March 2020. Even before her diagnosis, Rosemurgy had been considered pre-diabetic, but after taking Pendulum for the past 20 months, her A1C (the blood test commonly used for diabetes) displayed her glucose levels in a normal range—numbers she hasn’t seen in years. Rosemurgy discovered Pendulum on her own after initially being prescribed the medication Ozempic by her doctor, but she was wary of the side effects, which range from anxiety and depression to nausea, diarrhea and indigestion. When she started the probiotic she was hopeful, but skeptical: “It was something I found via a Facebook ad,” she says. Nevertheless, Pendulum piqued Rosemurgy’s curiosity, and, as she learned more about the microbiome, she became optimistic that a probiotic could help her. “I told my doctor about Pendulum and said, ‘Give me six months to see an improvement.’” She has since watched her A1C normalize and her weight plummet—she’s lost nearly 80 pounds.
It worries Rosemurgy, however, that she had to bring Pendulum to her doctor’s attention: “They had never heard of it before, and I felt like I was educating them.” She sees this as a crucial failing of the healthcare system and hopes that Pendulum, as an over-the-counter product, can disrupt the diabetes community’s reliance on injections. Pendulum hopes to create more awareness around their services by building out a continuing education credit so that doctors can learn more about the microbiome and how it affects diabetes. Then, Cutcliffe hopes, doctors will bring the probiotic to their patients’ attention: “Getting the healthcare professional community on board is really important,” she says.
Although she may seem unflappable now, Cutcliffe’s scientific career nearly ended before it started. When Cutcliffe embarked on her PhD in biochemistry at Johns Hopkins University, she got off to a rough start. During her first semester she went through a difficult breakup and then rebounded by partying excessively. The end result: she received a C in one of her courses, which Cutcliffe tells me was an automatic fail out of the entire PhD program. Cutcliffe called her parents and explained she might have to come home. “They said, ‘That’s fine. We were shocked you got in in the first place,’” she laughs.
Yet something had changed in Cutcliffe. She initially chose biochemistry as an undergrad at Wellesley because memorization and recitation of facts were easy for her—she knew she could get an A in the course. But at Johns Hopkins, she went beyond textbook learning and had a deeper experience of science, driven by creativity, problem solving and the joy of uncertainty. She found the work electrifying: “I mean, you’re with the smartest people, they’re doing amazing things. They’re literally [curing] cancer. Once I got a taste for that, I just didn’t want to lose it.”
So Cutcliffe went to her program’s dean, Dr. Sharon Krag, and made her case for why she should stay on in the program. She told the dean how a second chance would allow her to do something meaningful with the degree. Krag was ultimately persuaded. “That was a huge deal, because it really did shape the trajectory of everything I did afterward,” Cutcliffe says.
After a postdoc at Northwestern University’s children’s hospital, Cutcliffe moved to San Francisco, chasing the same high of scientific mystery she felt at Johns Hopkins. There, Cutcliffe met fellow scientists John Eid and Jim Bullard at a startup called Pacific Bioscience, where they were all working on a faltering DNA sequencing tool. In a series of conversations, Cutcliffe and her colleagues realized the importance of sequencing the microbiome, and the dearth of companies interested in pursuing this project. So Cutcliffe marched into the CEO’s office and pitched the idea of applying the sequencing process to the microbiome. He passed, but in doing so, he offhandedly mentioned that perhaps she should start her own company. Thus Pendulum was born out of navigating yet another obstacle.
By the time Cutcliffe brought Pendulum to Sequoia for funding she had already received many rejections, and Sequoia, too, passed twice before investing. Botha had been looking for a company that was working with the microbiome ever since he’d listened to a 2009 TED Talk given by Bonnie Bassler, a professor of molecular biology at Princeton, about how gut bacteria communicate with one another through chemical signals. This discovery had huge implications for antibiotic-resistant bacteria. Botha was excited that Cutcliffe was turning a decade-old insight about the microbiome into something actionable, but he felt Pendulum was not yet launch-ready.
At that early stage, Cutcliffe was still only working with a theory. “When we first met it sounded like an interesting idea,” Botha says, “but they still had to figure out how to make the [capsules]. Then they had to figure out how to package them, then they had to test them on animals first to show that it works, and then they had to test them with humans and show that it actually worked in humans. The next step was going to be, how do you turn that into a business?” A year later, Cutcliffe met with Sequoia again, and the results were night and day. “She had done what she said they would do, and [it] worked,” Botha says.
Hugh Martin, a current Pendulum board member whom Cutcliffe met at her previous post at Pacific Bio, recalls two things about Cutcliffe in those early days: her tenacity as well as her inexperience. Martin describes an incredibly tense moment for Pendulum where Cutcliffe had to dismiss her entire marketing team. It was during their last round of fundraising this year, when Cutcliffe had mistakenly been led to believe that the 12-month rate of repeat customers for the capsule was close to 70%, a number almost unheard of for a first-time product. This created quite the buzz around Cutcliffe and Pendulum, and future commitments were staked on this number alone.
“Then she called me up one morning and said, ‘Holy shit. I think the number is closer to 25 or 26%,’” Martin says. “I’ve seen multiple boards where something like that happens, and they say ‘Okay, we need a new CEO.’ But because of Colleen and the way the board thinks about her, that didn’t even enter the situation.” Instead, Cutcliffe lived up to her reputation for transparency and came clean with her investors; she hired a new marketing team, fired her finance person, and set about fixing the problem. Instead of dismissing her, Martin remembers, the board said, “We’ll help you.”
Since Pendulum secured funding, it’s been able to turn its attention to some of its more pressing product-related challenges, namely the high cost of the Glucose Control capsule itself, which is currently priced between $165 and $195 per month, depending on the subscription service. It’s a price tag that neither Botha, Cutcliffe, nor Martin are comfortable with—mainly because a disproportionate number of diabetic sufferers live on or below the poverty line and simply can’t afford the product. “At the previous board meeting,” says Botha, “we listened to one health advisor describe how the product has completely changed her metabolic profile and a bunch of other health indicators. We asked her if she told her customers to use the product, and she said, ‘No, it’s just too expensive for most of them.’ That was really sad.”
How Pendulum deals with this conundrum will be a true test for Cutcliffe, and finding the solution will require her to master both the science and the supply chain. Now that Pendulum has conducted the clinical trials necessary to prove the capsule works, Botha believes it’s time for Cutcliffe to build out a team that can address urgent issues, foremost among them cost. “We need a finance person to help us understand the true cost of manufacturing: What is the customer acquisition cost? What’s this customer lifetime value? How do we turn this into a good business?” says Botha. “Colleen recognizes that those are not skills she has, but she’s trying to build a management team, and we have a good board that helps ask these questions.”
But beyond these immediate hurdles, Cutcliffe is also looking toward a future for Pendulum that is bigger than a single probiotic. She wants the company to bridge the divide between industries, combining the holistic efficacy of wellness products with the safety and rigor of pharmaceuticals. “I really envision a world where we can demand both of these things,” Cutcliffe says. “We can say that we’re not just a probiotics company, but really a partner for you in health, and we’re going to be around forever. That’s what we want to be.”
“That start to life she had, it wasn’t just traumatic to me, it was traumatic for her microbiome.”COLLEEN CUTCLIFFE