For organs to develop, grow and regenerate, cells must proliferate. But when that process goes awry, leading to uncontrolled cell growth, cancer can emerge. 

New CU Boulder research, published , offers unprecedented insight into how an enigmatic enzyme, known as CDK7, drives this complex process. The research shows that novel cancer drugs designed to inhibit CDK7 can, within minutes, shut down gene expression pathways that drive cell proliferation in dozens of different kinds of tissues.

“This work addresses a long-standing mystery surrounding an enzyme critical for regulating the cell cycle and cell proliferation,” said senior author Dylan Taatjes, a professor in the Department of Biochemistry. “Not only does it help us understand a fundamental biological process important for development, it also has broad therapeutic applications.”

Understanding an enigma

For decades, cancer researchers and pharmaceutical companies have eyed cyclin dependent kinase (CDK7) with interest due to its role as a “master regulator” of cell proliferation. CDK7 does this in two ways: It switches on other enzymes known as kinases, including CDKs 1, 2, 4 and 6, which kick-start cells to divide and multiply. It also regulates gene expression in ways that, until now, have remained unclear. The new study found that it controls the function of proteins called transcription factors, which influence when and how genes are expressed.

While CDK7 is critical for normal development, certain cancers, including aggressive and hard-to-treat “triple negative” breast cancers, hijack this process to drive runaway growth.

In recent years, several companies have developed CDK7 inhibitors that, in clinical trials, have worked to slow tumor growth. But it’s not entirely clear how they do this. The drugs have serious side effects, and in clinical trials they have fallen short of killing tumors entirely.

To better understand how this master regulator works, Taatjes teamed up with Robin Dowell, a professor of Molecular, Cellular and Developmental Biology; Taylor Jones, then a graduate student in biochemistry; and colleagues at CU Boulder’s BioFrontiers Institute.

The researchers applied a CDK7-inhibitor provided by Syros Pharmaceuticals and already used in clinical trials to cancerous human tissue cells. Then they used sophisticated computational techniques to watch, essentially in real time, what happened next.

They found that within 30 minutes, a core set of transcription factors that turn on genes that prompt cells to proliferate was uniformly shut down. In other experiments, this same set of transcription factors was found to be consistently on in all proliferating cell lines tested. This included 79 cell lines, mostly from human cancers, representing 27 different tissue types.

This points, for the first time, to a universal mechanism by which CDK7 controls human cell proliferation, said Taatjes.

“We found that the second that you inhibit CDK7, all of these core transcription factors shut off at once, stopping proliferation in its tracks,” said Taatjes.

Smothering cancer promoters

The research team points to one particular protein that, like a blanket thrown on a patch of growing flames, seems to smother all those transcription factors at once when CDK7 is inhibited. The protein, retinoblastoma protein 1 (RB1), is well known as a key tumor suppression gene whose normal function is often compromised by cancer. But efforts to target RB1 with medication have been largely unsuccessful.

“This study reveals that CDK7 controls RB1 function—a finding that could open doors to new ways of therapeutically targeting RB1,” said Taatjes.

Meanwhile, CDK7’s other role—of kick-starting enzymes that nudge cells to divide and multiply—is also blocked by the inhibitor they tested, but this occurs more slowly and is not dependent on the core set of transcription factors.

Taken together, these findings suggest that it may be possible to develop new therapies that disable some of the enzyme’s disease-causing functions rapidly, while leaving its beneficial roles intact.

“Instead of, essentially, using a sledgehammer to shut down all CDK7 activities, it could be that you could shut down just one branch of its activities that is more important for tumor proliferation while minimally disrupting normal cell function,” said Taatjes.

The result: a more precise cancer killer that inflicts less collateral damage. 

  Beyond the story

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On May 6, 1954, a lanky medical student named Roger Bannister pushed through the finishing tape at Iffley Road track in Oxford, England, and collapsed into the arms of friends after becoming the first human to run a mile in less than four minutes.

The milestone cracked open a world of possibility for male athletes.

“It was the running equivalent to summiting Mount Everest for the first time,” said CU Boulder Integrative Physiology Professor Rodger Kram. “Prior to Bannister, it was considered impossible—beyond the limits of human physiology.”

Seven decades later, a female runner has yet to follow in Bannister’s footsteps, and some have questioned, as they did with males in the 1950s, whether it’s possible. A published this week by Kram and his colleagues suggests that with the right strategically timed and placed pacers, the answer is yes— and Kenyan Olympian Faith Kipyegon is on the brink of doing it.

The study was published this week in the journal Royal Society Open Science.

“We found that if everything went right, under a couple of different drafting scenarios, she could break the 4-minute barrier,” said co-author Shalaya Kipp, an Olympic middle-distance runner who earned her master’s degree in Kram’s lab. “It’s extremely exciting that we are now talking about, and studying, the limits of female human performance, too.”

From ‘Breaking 2’ to ‘Breaking 4’

In 2016, Kram’s lab calculated what was required for a man to break the fabled two-hour marathon barrier.

He and his students determined that, along with intense training, state-of-the-art shoes and an ideal course and weather conditions, drafting—running behind or in front of another runner to reduce air resistance—was key.

Informed in part by their research, Nike hosted the Breaking2 Project in May 2017 to create those conditions for Kenyan marathoner Eliud Kipchoge. Kipchoge narrowly missed his goal that day but nailed it in a similarly staged race in Vienna in 2019.

Four years later, Kram watched with interest as Kenyan runner Faith Kipyegon crushed record after record—the women’s 1,500 meter; the 5,000 meter and the mile—in less than two months, all while raising her daughter.

After watching Kipyegon smash the mile world record for women with a time of four minutes, 7.64 seconds, Kram reached for his calculator.

“I realized she was just a hair over 3% off” from breaking the four-minute mile, he said.

Coincidentally, when his team first started doing their research, the marathon world record holder was about 3% shy of a two-hour marathon.

An idea was born. Kram and his former students, now spread out at research institutions around the world, reconvened—this time to explore the limits of female human performance.

The power of drafting

Run alone, even on a still day, and air molecules bump into you as you move through them, slowing you down. Run in the shadow of a pacer or, better yet, with runners in front and back, and you use less energy.

“The runner in front is literally pushing the air molecules out of the way,” said Kram.

At a breakneck four-minute-mile pace, a runner of Kipyegon’s size must overcome a surprisingly large air resistance force—about 2% of her body weight. The team previously determined that completely eliminating that force would reduce the energy required by about 12%, allowing her to run even faster.

“Anyone from top elite to lower-level runners can benefit from adopting the optimal drafting formation for as much of their race as they can,” said Edson Soares da Silva, first author on the new paper.

For instance, da Silva calculated that a 125-pound, 5-foot-7 female runner who typically runs about a 3:35-minute marathon could improve her time by as much as five minutes.

A magic number

For the new study, the team pored over video of in Monaco. The wind was dead calm. A slight humidity (which reduces air resistance) hung in the air, and she was wearing state-of-the-art shoes.

But her pacers ran too fast at first, said Kram, letting the gap between them and her widen. By the last lap, her pacers had dropped out and she was on her own.

   Beyond the Story

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Ideally, he said, one female pacer would be perfectly spaced in front, another in back, for the first half mile; then another fresh-legged pair would step in to take their place at the half-mile point. Collectively, previous research suggests, they could cut air resistance by 76%. Using that value, the team calculated her projected finish time: Remarkably, 3:59.37—the same time Bannister hit in 1954.

“We didn’t cook these numbers,” joked Kram. “We saw that and just smiled.”

Inspiring scientists and runners

Kipp, now a postdoctoral researcher at the Mayo Clinic, stresses that their study, like most in the field of exercise physiology, comes with a caveat: Their calculations were based on previous studies that exclusively involved men.

The authors hope their paper will help spark more interest in studying the physiology of female athletes. If Kipyegon is successful, they say, it could inspire lots of people, whether their goal is to lose a few pounds or finish their first 5K.

“It would show that things people have told you are impossible may actually be possible,” said Kram.

He recently sent a copy of the paper to Kipyegon, her coaches and her sponsors at Nike, floating the idea of another staged race, similar to Breaking2.

“Hopefully,” the last line of the paper reads, “Ms. Kipyegon can test our prediction on the track.”

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In CUriosity, experts across the CU Boulder campus answer pressing questions about humans, our planet and the universe beyond.

This week, Zoe Donaldson, a professor in the departments of Molecular, Cellular, and Developmental Biology and Psychology and Neuroscience, answers: "What is Love?"

For centuries, romantics have turned to musicians, artists, writers and philosophers in their quest to define one of humankind’s most complex, and arguably critical, emotions.

Neuroscientist Zoe Donaldson takes a different approach. She looks to fuzzy, palm-sized rodents called prairie voles.

“From a neuroscientific perspective, love is the biological drive that allows us to form relationships,” she explains, as a family of four hungry newborn voles chase their mom around a glass enclosure in her office, their dad looking on.

The scene unfolding behind her says a lot about the evolutionary utility of love, she explains: It enables babies to bond with mothers who provide them with food and siblings who protect them and keep them warm. For some, it ultimately leads them to a mate, with which they reproduce, perpetuating the species. 

“The vast majority of rodents out there mate and leave. But these guys are different,” she says.

Like humans, and only about 5% of all mammal species, prairie voles can form long-term bonds with a partner, staying together to build a home and raise offspring. They also experience something akin to longing when separated from their partner and grief when their partner dies. This makes them ideal for studying the neurochemical glue that bonds are made of, she says.

Three brain chemicals play a starring role in this love story: Dopamine, oxytocin and vasopressin.

Dopamine, the same brain chemical at the root of dependency to cocaine, heroin, alcohol and other drugs of addiction, appears to draw us in and keep us coming back. 

“There’s essentially more dopamine being released in the brain when an animal is engaging in an effort that will gain them access to their partner,” Donaldson says, noting that when a prairie vole presses a lever that opens a door leading to their partner, their tiny brain is awash with the endogenous love drug. “We think of this as a chemical signature of desire within the brain.”

(Importantly, she adds, dopamine is designed to do this to help us execute our daily lives, unlike when it is hijacked by drugs of abuse.)

  Previously in CUriosity

What is the smallest thing in the universe?

Or read more CUriosity stories here

Oxytocin is probably best known for its not-particularly-romantic role as the drug given to laboring women to induce contractions. But it also nudges the maternal brain to want to take care of a newborn and stimulates milk production when an infant suckles. In prairie voles (and likely in people), the brain produces oxytocin when lovers couple up for the first time.

Vasopressin, the yang to Oxytocin’s yin, is a particularly important ingredient for helping males to form a bond, says Donaldson. It makes blood pressure rise and warms up the body, pleasant sensations worth coming back for. It can also make males a bit more aggressive, which comes in handy when (at least in the wild) males need to defend their territory.

"Each of these molecules is evolutionarily ancient,” says Donaldson. “We find them in worms and snails, where they are also important for motivation and social interaction.”

By studying these and other brain chemicals, Donaldson hopes to better understand not only what brings people together but also: What prevents some people from being able to form such bonds? Or renders others unable to bounce back, and reengage with life, when they lose a loved one (a disorder known as prolonged grief disorder)?

But is love just a collection of brain chemicals?

Donaldson gets that question a lot and doesn’t love the way it’s phrased.

“Adding ‘just’ into the question diminishes the fact that your brain chemistry is ultimately the seat of love,” she says. “We are beginning to learn that love is not something you have to learn, but something that is literally hard-wired into our brain from the moment we are born.”

You can’t get much more romantic than that.

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Women who go through menopause later in life have healthier blood vessels for years to come than those who go through it earlier, according to new CU Boulder research.

The study, published in the American Heart Association journal , offers new insight into why females who stop menstruating later are significantly less likely to have heart attacks and strokes in their postmenopausal years.

Arriving just in time for Women’s Heart Health month, the findings could help lead to new therapies, including dietary interventions, to reduce risk of heart disease which is the No. 1 killer of women.

“Our paper identifies that there’s actually a physiological benefit to later-onset menopause and is one of the first to identify the specific mechanisms driving these benefits,” said first author Sanna Darvish, a PhD candidate in the Department of Integrative Physiology.

Nearly half of women in the U.S. live with heart disease and it accounts for about female deaths each year. While females are less likely to die of a heart attack or stroke than males for most of their life, their risk spikes and overtakes male risk after menopause.

But there is one notable caveat to this trend.

Previous studies show that women who hit menopause—defined as going one year without a period—at age 55 or later are as much as 20% less likely to develop heart disease than those who cease menstruation at the usual 45 to 54 years old.

Darvish and her colleagues at CU’s Integrative Physiology of Aging Laboratory set out to determine why.

They assessed the vascular health of 92 women, looking specifically at a measure called brachial artery flow-mediated dilation (FMD), or how well their brachial artery—the main blood vessel in the upper arm—dilates with increased blood flow.

The team also measured the health of the women’s mitochondria, the energy powerhouses in the cells lining their blood vessels. And they took a close look at what molecules were coursing through their bloodstream.

Not surprisingly, all the postmenopausal women had significantly worse arterial function than their premenopausal counterparts. That’s in part because, as people age, they produce less nitric oxide, a compound that helps blood vessels dilate and keeps them from getting stiff and developing plaque. Mitochondria in cells lining the blood vessels also become dysfunctional with age and generate more damaging molecules called free radicals, explained Darvish.

A spike in risk

When menopause hits, the age-related decline in vascular health accelerates. But the 10% or so of women who experience late-onset menopause appear to be somewhat protected from this effect, said senior author Matthew Rossman.

For instance, the study found that vascular function was only 24% worse in the late-onset menopause group compared to the premenopausal group, while those in the normal-onset group had 51% worse vascular health.

Remarkably, such differences between the groups persisted five years or more after the women went through menopause, with the late-onset group still having 44% better vascular function than the normal onset group.

In the late-onset group mitochondria lso functioned better, producing fewer free radicals, the study found. The circulating blood of the two groups also looked different, with the late-onset group showing “more favorable” levels of 15 different lipid, or fat, -related metabolites in their blood.

“Our data suggest that women who complete menopause at a later age have a kind of natural inherent protection from vascular dysfunction that can come from oxidative stress over time,” said Rossman, an assistant research professor in the Department of Integrative Physiology.

More research is necessary to determine exactly what drives that protection, but the researchers suspect better mitochondrial function and certain lipids circulating in their blood may play a role.

Next, the team plans to explore how early-onset menopause might impact heart health, and whether nutritional supplements aimed at neutralizing free radicals inside blood vessels might reduce heart disease risk in women at greater risk.

In one previous study, Rossman found initial evidence that MitoQ—a chemically altered version of the antioxidant Coenzyme Q10 that targets mitochondria—reversed blood vessel aging significantly within weeks in male and female subjects. A larger clinical trial is now underway.

“We hope this work puts age at menopause on the map as a female-specific risk factor that women and their doctors discuss more,” said Darvish.

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