Hundreds of families share a lethal inheritance. This kidney researcher hopes to break the chain

Autumn Steen roiled in the pew of the chapel, Bowditch Union Free Will Baptist Church — the one she could see from home, the house of God she knew so well she could get in with a spare key.

If I just pray hard enough, none of this will happen, she thought. At just 17, she was unable to grasp that this had already happened. Her dad, Tommy Bruce Carroll, was dead.

Minutes earlier, she had arrived home from summer Bible school to find an ambulance in the gravel driveway, her mother sobbing uncontrollably on the back porch. Steen had known her father was sick with the same kidney disease he shared with more than half of his 13 siblings, and he’d slowed down a bit since starting dialysis. But he had been OK when they spoke that morning. He was only 50 years old. How could his heart just stop?

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So she ran to church.

“It never dawned on me that, oh, ‘This will happen to you one day,’” she said in an interview. “It still hasn’t.”

Steen inherited a lot from her dad. Mainly, she got hours of his undivided attention while fishing and hiking in the North Carolina mountains, which bred her outdoor skills and an interest in the wildflowers her father loved to photograph. She was named after his favorite time of year and time of day up in the wilderness — Autumn Dawn. And she got his jokes. Her family always told the story of how one day, Tommy snuck up behind his sister to scare her while he was eating a banana, and she turned around at the last second and screamed, somehow shoving the fruit up his nose. He deserved it, his family thought, because he was always pulling pranks. But in that Carroll bloodline, stretching back an unknown number of generations, there is another inheritance: a rare genetic mutation that has caused life-threatening kidney disease in half of the family.

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Many of the surviving Carrolls lived near one another, about a 40-minute drive northeast of Asheville, N.C., where Mount Mitchell reigns — the highest peak this side of the Mississippi River, so tall he wears a snowy cap even in the heat of May. Mitchell’s ribs are covered in the lush greenery of Pisgah National Forest, and then waterways and rural country roads and tiny towns where everybody knows everybody. In one such town, Burnsville, is Carroll Holler — as in, “hollow,” but real Southern — a tract of land subdivided among a bunch of Carrolls, including Steen’s family.

Steen with her dad at their favorite overlook on the parkway on the way to Mount Mitchell. Courtesy Autumn Steen

The Carrolls, like so many other families around the world, grapple with a rare genetic disease that has no cure. On the island of Cyprus, there are clusters of families in certain villages. In Salt Lake City, a large family shares the same illness. Each generation has a 50% chance of passing the problematic mutations on to the next. For those on the losing end of this harsh lottery, their kidneys often stop working in their 30s or 40s. Dialysis, or a transplant, if they’re lucky enough to get one, may bring another 10 years of life. But the clock keeps ticking, loudly.

Until recently, geneticists couldn’t crack the disease, no matter how hard they tried, no matter how many times they sequenced the DNA. The mysterious mutation was silently tucked away in a dark corner of the human genome — a single letter, C, added by mistake in the DNA code. It took until 2013 for Mark J. Daly and Andrew Kirby, researchers at the Broad Institute of MIT and Harvard, to find the culpable mutation. Still, they didn’t know how that genetic variant led to kidney failure, or how to stop that disastrous cascade.

Enter Anna Greka, a physician-scientist wunderkind whose first project in her own lab resulted in the discovery of a potential therapy that could stop cells in the kidney from falling apart. She joined the Broad after that initial breakthrough, and has made herself into a champion for patients with rare diseases, blurring the sharp lines that often lie between the lab and the real world, where people who need these therapies live.

Greka’s fascination with the kidneys began in the brain. Her Ph.D. research focused on a newly discovered type of ion channel, a gate in cell membranes that was quite mysterious and thought to play a vital role in how neurons communicate. As a resident at Massachusetts General Hospital in Boston, terribly sleep-deprived and shuttling among patients, she would often spend breaks at the hospital lounge computer, checking PubMed for new research on ion channels. It was during one of those groggy surfs on the web in 2005 that she came across a paper in the journal Science, about the first identified channelopathy, a genetic disease specifically related to those channels — and it was a kidney disease.

“That was the moment that I thought, ‘Oh, my gosh, this is so interesting. Maybe it’s a sign. Maybe this is what I’m meant to do,’” Greka recalled as she sat in her tidy office at the Broad in Cambridge, Mass.

That paper set her on a course to specialize in nephrology, “with the explicit purpose of getting as quickly as possible back to the lab” so she could figure out what ion channels were malfunctioning and leading to kidney failure. “It was really that moment that changed the course of where I wanted to go.”

Physician-scientist Anna Greka in her lab at the Broad Institute of MIT and Harvard in Cambridge, Mass. Kayana Szymczak for STAT

Although she had studied neuroscience as an eager undergraduate at Harvard, kidneys were familiar to Greka. She was raised by two physicians, a pathologist mother and nephrologist father, in the seaside metropolis of Thessaloniki, Greece. Both instilled in her a love of science, letting her peer into microscopes and learn the parts of a cell as a young girl. At 14, she excitedly planned her summer — would she go to camp? Or maybe participate in Girl Scouts? — while one of her dad’s patients, a boy her age named George, was tethered to a dialysis machine. George had nephrotic syndrome, and his kidneys had given out by the time he met Anna through her dad. “There was no question of him having any summer plans. I remember that sort of struck me — the injustice of it all,” she said.

By the time Greka was a teenager, at the top of her class in a high school that taught college-level courses, she decided she would become a physician-scientist. She grew up in the 1980s, and watched as the HIV/AIDS epidemic crested. Greka remembers the panic, but she also recalls the admiration she felt for the researchers making lifesaving discoveries, and rather quickly (on a scientific time scale).

Despite getting into Harvard and immediately starting lab work as a freshman, Greka knew she had a slim chance of getting into a U.S. medical school as an international student. Advisers had told her so from the time she was 17. But she did get in, to the joint M.D.-Ph.D. program of the Massachusetts Institute of Technology and Harvard Medical School. She was doubted once again when she decided to make the switch to nephrology. Why waste her talents on a subspecialty with not a lot of research activity going on, her mentors pushed?

As they challenged her choice in Cambridge, back in Greece, George was dying. Despite having a transplant, his new kidney failed and he died at 24. Greka felt conviction.

Kidney disease was and is “severely neglected, hugely underserved. There is a tremendous unmet need,” said Greka, now 46. She saw that as an opportunity: “There’s a huge mismatch between the enormity of the clinical problem and the availability of scientific answers and, ultimately, therapeutic answers to the problem.”

There are an estimated 850 million people on the planet with kidney disease, including approximately 37 million in the U.S. (15% of the adult population) with chronic kidney disease. It’s an illness that disproportionately affects low-income people and Black people, and among the 15 leading causes of death in the U.S., kidney disease has the largest disparity between Black and white mortality rates. There are some treatments that slow its progression, but there is nothing that stops the disease completely. At the same time, Medicare spends more than $120 billion every year on kidney disease care, including dialysis for end-stage renal disease, totaling nearly 34% of total Medicare fee-for-service spending in 2017. That investment in care for a single disease at its end stage is also three times more than the entire budget for the National Institutes of Health, which funds scientific research.

“All of us, citizens and taxpayers, we contribute to that,” Greka said.

“There’s a huge mismatch between the enormity of the clinical problem and the availability of scientific answers and, ultimately, therapeutic answers to the problem.”

Anna Greka, Broad Institute

Her father, Demetrios, grew up in extreme poverty. He was raised by Anna, a “fierce, strong” single mother he later named his daughter after, in Pori Pierias, a small village on Mount Olympus during the civil war in Greece. His father was killed when he was just 6 months old. Against those severe odds, Greka’s dad became a devoted physician, just like her mother. So Greka was not deterred by the naysayers or slim chances of success — jumping obstacles was in her blood.

When she started her first lab in January 2012 at Mass. General, Greka had trouble convincing funders to give her money. For a while, it was just her and a couple of researchers. Then they discovered what was causing a precious, limited supply of kidney cells called podocytes to fall apart and die. Greka and her team found that the same family of ion channels she studied as a graduate student, called TRP channels, can become overactive. When that happens, a dangerous amount of calcium enters the cell, triggering a vicious cycle that breaks down the cell structure and causes the podocyte filters to fall off, which interferes with one of the essential functions of the kidney: filtering. The result is kidney failure.

But more than that, they figured out — and found evidence in rodent models — that by inhibiting a channel subtype called TRPC5, they could stop the disintegration of these crucial cells.

Fortuitously, Greka attended a scientific meeting in Boston in mid-2014 and sat next to Eric Lander, then the director of the Broad Institute. They got to talking, and Lander was immediately interested in her work, in part because Broad scientists had recently found that gene mutation hiding in a shadowy corner. He hired her in January 2015 to focus on those mutations.

At the Broad, the diverse, mostly female team in the Greka Lab specializes in “molecular sleuthing.” It’s the kind of microscopic research that landed her lab yet another breakthrough: demystifying the cause of this rare kidney disease. That single-letter insertion the Broad researchers had sniffed out jumbles the genetic script from that point on, resulting in a pile-up of mangled, misshapen, mucus-producing proteins that couldn’t be shredded by the cellular trash can, the lysosome.

The key discovery, published in the journal Cell in July 2019, was that a specific molecule, a so-called cargo receptor named TMED9, was to blame for the accumulation of crooked proteins. That meant this form of kidney disease — autosomal dominant tubulointerstitial kidney disease-MUC1, or ADTKD-MUC1 — was a toxic proteinopathy. A sister protein-pileup illness, ADTKD-UMOD, is caused by a mutation in the protein uromodulin, and is what runs in the Carroll family. Certain forms of dementia, ALS, Parkinson’s, and the degenerative eye disease retinitis pigmentosa, fall under the same umbrella, along with other diseases, all caused by some quirk in a protein.

“So that actually gave us a new handle on brand new biology,” Greka said. By identifying a specific molecule that was responsible for the accumulation of those wacky proteins, the lab now had a lead on a possible target for treatment.

Yet even as researchers snooped around for potential cures, a treatment isn’t much help if patients don’t know they need it. In many families, members don’t even know they carry these lethal mutations. And by the time they know, there isn’t enough time to reverse the disease course.

Roscoe Nelson, a World War II fighter pilot-turned-surgeon, with his wife and children. The Nelson family carries a rare genetic mutation that causes kidney disease. Roscoe died at 43, and his daughter Marcia Ann (bottom right) died in 2017. Richard, held by his mother, developed kidney failure caused by the disease. Courtesy Nelson family

Richard Nelson, 73, was a young boy when his dad, a World War II fighter pilot-turned-surgeon, died of kidney failure. For decades, nobody knew (or, if they knew, never revealed) why Roscoe died at just 43, leaving his wife to care for their six children. “In fact, the family story was that he got an infection in World War II and it eventually shut down his kidneys. Well, that’s not exactly the whole story,” Nelson said.

Roscoe was one of many in the bloodline to die young. His father, Andrew, died at 36. Andrew’s brother died at 39, and his younger sister at 25. Roscoe’s children — Richard Nelson and his siblings — were unsuspecting. “Until the late ’80s, when a couple of my uncles started getting sick,” said Drew Ludlow, one of Roscoe Nelson’s many grandchildren. “And they’re like, huh, this is kind of strange.”

Four of the six siblings had kidney failure caused by the disease, including Richard. Doctors pinned it on polycystic kidney disease, or PKD, a genetic illness that causes many cysts to develop inside the kidneys and disrupt normal functioning. Except the Nelsons’ kidneys weren’t studded with the many cysts associated with PKD. They also didn’t have blood or protein in their urine, the usual markers of kidney disease.

Richard was able to get a kidney transplant from a 17-year-old girl in upstate New York who had died of a brain aneurysm in February 1991. Miraculously, the organ was a perfect match. A longtime president and CEO of the Utah Technology Council, he decided, at the urging of his siblings, to start intensively networking with people in the field of kidney diseases. He attended medical conferences, rubbed elbows with the top researchers in nephrology, and searched for answers to his family’s mysterious inheritance.

It was through that scientific community that the Nelsons met Greka, one of many researchers on the circuit, but one who stood out for her commitment to patients. With her wide grin and palpable enthusiasm, Greka is adept at both navigating the upper echelons of science (she was recently elected to serve as president of the American Society for Clinical Investigation in 2024) and explaining complicated concepts in laypeople terms.

The Nelsons — nearly two dozen of them — raised their hands to get diagnostic testing for genetic diseases at the Broad and contributed to a database of health information assembled by Wake Forest University’s Rare Inherited Kidney Disease Team, which has followed families with UMOD and MUC1 for years. It’s a pool of data that, for now, mostly helps researchers better understand the illness. Studying a rare disease first requires finding a group of sick patients, and then finding the even smaller cohort that’s willing to participate in research without the promise of a cure. Getting a large family like the Nelsons on board was huge. Greka, fundamentally curious and warm, even joined a Nelson family reunion via videoconference to answer questions and talk about her lab’s work.

But, of course, the clock doesn’t stop, even if research is underway. At any point, one of those younger Nelsons could call and find out if they have the gene. “It’s a daunting thing for some people to find out every bit of genetic information about themselves,” Ludlow said. “Especially when they’re young, and it doesn’t matter yet. … I actually don’t know how many of the cousins have called.” Ludlow has called, but didn’t wish to publicly disclose whether he has the mutation or not.

Others in the family likely have too little time to benefit from a future therapy. One of the Nelson siblings had two failed transplants and is back on dialysis. Another, Marcia Ann Ludlow, died in 2017. She thought she was in the clear once she entered her early 50s (her two brothers got sick in their 30s). But eventually, she found herself on the same route, getting a kidney transplant, which her body rejected and had to be removed immediately. Then dialysis until 2007, and another kidney, from her son-in-law. The organ seemed to take initially, but failed again six months later, forcing her back on dialysis. When she had that kidney removed, she said, “I’m not doing that again,” her son, Drew, recalled.

A person of deep faith, she led other women in the Church of Jesus Christ of Latter-day Saints. And as a mother to seven children, she was eternally hopeful, intensely invested in the personal lives of those she cared about and determined to watch her family grow. She lived on dialysis for a decade past that final attempt at a transplant. “She wasn’t afraid of dying. She was doing that to be around for us,” her son said.

A few months after Ludlow’s death in late 2017, her son and brother started the Rare Kidney Disease Foundation in her memory. Their advocacy and outreach paired perfectly with Greka’s passion. It was her who invited the Nelson family to visit the Broad, to talk to researchers and attend events related to kidney disease. It was Greka who encouraged them to organize an annual summit, rallying patients with the same mutation. When she flew to the island of Cyprus on her annual trip in February 2019 to meet families with the disease, Greka invited Ludlow to go with her. It’s science for the modern, hyper-connected age, a strategy that defies a long history of extractive relationships between patients and researchers, and instead puts patients at the center of the work.

“The lengths to which she goes to try to do the right thing and do it in the right way. Making sure that it’s truly collaborative,” Ludlow said of Greka. “She’s never putting her thumb on the scale. She’s really just that incredible. She’s really just doing the hard work, and she’s obviously a genius.”

Just decades ago, scientists only knew of 10 families in the U.S. with MUC1. Now they have a database of 924 families with rare kidney diseases, of which 218 have UMOD mutations and 127 have MUC-1, according to Anthony Bleyer, a rare kidney disease specialist at Wake Forest who frequently works with Greka. Many in the world of rare kidney diseases hypothesize these illnesses are probably not rare at all. There’s a real market for these therapies, they argue — and a pressing need.

“The lengths to which she goes to try to do the right thing and do it in the right way. Making sure that it’s truly collaborative.”

Drew Ludlow, one of Roscoe Nelson’s grandchildren, talking about Greka

To the families carrying this heavy inheritance, the scientific progress Greka and others have made is astonishing: three years from start to discovery of the mechanism and a possible solution. There could soon be a cure. A new company, still in stealth mode, is working on a compound to treat ADTKD-MUC1 and related toxic proteinopathies. That endeavor has attracted investors “with the experience and track record to bring this program to clinical trials soon,” Greka said.

And, at the same time, it is all moving too slowly. That is the tense nature of welcoming patients into the halls of one’s laboratory: It lends the work urgency, and lays bare what happens as people wait for a cure.

“That really makes it very real,” Greka said. “That’s part of this … privilege and anathema of being a physician-scientist. I completely understand, I see, I know what these patients are going through, but I can only go as fast as I can.”

The Nelson family, shown at the Roscoe Nelson Centennial — what would’ve been the patriarch’s 100th birthday — in 2016. Courtesy Nelson family

When Tommy Carroll died in 2004, and in the months and years after his daughter, Autumn, cried in that Baptist church, after she made the hard decision to go away to college in Chapel Hill, N.C., the first in her family to do so, as she studied to become a pharmacist and tried to smooth out the curved edges of her Southern accent, she felt, under it all, angry — at religion and life and God.

“It seemed like in the teachings, good things happen to good people, you get what you deserve. And I was like, he didn’t deserve this,” she said. Nor did his brothers and sisters. Nor did Autumn.

She doesn’t even remember the moment as a preteen that she found out she has the same UMOD mutation as her dad. At least eight of his 13 siblings carried the same gene, causing them to suffer from silent, creeping kidney disease: slightly smaller-than-average kidneys, high levels of uric acid in their urine, gout in some family members, and gradual kidney failure.

At college, she would receive emails updating her on the research into her family’s disease, but they became infrequent for some years when there was no new information. She attended annual family meetings with doctors, even as Carroll Holler dissipated, no longer the cluster of people that regularly hosted pig pickin’s and celebrations while she was a kid. The house where her dad grew up, built in the early 1900s, eventually collapsed in her backyard. Autumn became a pharmacist and moved to Asheville, where she lives now.

Through it all, one thought weighed on Autumn, especially once she met the man who would become her husband, and they planned their future: “I felt immense guilt thinking about putting something like this on an unsuspecting human life.” She told her husband early in their relationship that she didn’t know if she could have children.

Then, at an appointment with her nephrologist, she mentioned her concerns. He told her she could do IVF and screen for embryos that didn’t carry the gene. It took three years, a tubal pregnancy, a chemical pregnancy, and a harrowing birth that almost killed her, but the process gave her a beautiful daughter, Eva, who is now almost 2 years old. Autumn’s brother, Mitchell — named after the mountain in their backyard — has four children, and she doesn’t know whether they have been tested for the mutation.

She can’t blame them. Without a cure, it’s all just a series of arbitrary choices: whether to know, when to know, and what to do with that knowledge.

“If you grow up with it, it’s just part of your life. I have to go to the nephrologist every three months or whatever but honestly, there’s nothing I can do about it. … Pretty soon, probably not that far in the future, I will have to go to dialysis three days a week,” or undergo a transplant and take difficult drugs, she said. “I feel like I’m just trying to enjoy this sweet time period right now because it’s not always going to be this easy.”

She hopes to one day have a kidney transplant, and avoid the dialysis and the other symptoms that intensify as the disease takes its toll. But lately, there’s been a glimmer of another possibility. Zoom calls with doctors at Wake Forest have been happening more than once a year, ever since a promising compound was identified. And now the meetings include hundreds of people from all over the world — not just the Carrolls.

Source: STAT