A light shines from a house across the way and Dora Maendel takes it as a sign. In the middle of the night, she’s not alone.

Maendel [BEd/85, BA/88, PBDipEd/10] has always lived on Manitoba Hutterite colonies, first in New Rosedale, and now in Fairholme, a 90-minute drive west of Winnipeg. At 67, she still resides in her family home with her two sisters. When she can’t sleep, she finds comfort in the glow outside her window.

“You know this community is surrounding you. Even if you’re not related to all of them, it’s reassuring,” says Maendel, who is one of 12 siblings.

Her family tree, and that of her neighbours, is of interest to University of Manitoba genetics researchers who study rare, inherited diseases in unique communities like this.

Maendel offers a peek into life at Fairholme. She calls it “a blessing” that when a sensor breaks on her stove at 10:30 p.m., the colony’s electrician—her nephew, Jamie—fixes it within the hour. Everyone has a role. Maendel’s is high school teacher. She earned her education degree in part through distance learning from the University of Manitoba and now teaches English and German. It’s important, she says, that her students know community members needn’t feel self-conscious about their Carinthian German dialect in the world beyond their communal upbringing. Knowing a second language is a strength, she tells them.

It’s tradition that the men operate the grain farm and the hog barn, or load the turkeys (this affluent colony is one of the province’s largest turkey producers). But gender roles are changing, says Maendel. Her nieces drove the tractors a few years ago when there was a shortage of young men. Fairholme is also home to female hockey players, she notes.

The women tend gardens, sew and bring their creativity to knitting and crocheting. Each week, they rotate a lead role to plan and make all meals for the colony. If they require labour-intensive, homemade egg rolls or perogies, a request goes out over the PA system for help.

About 50 adults and 30 kids live here, notes Maendel, plus one (a baby born last fall) and minus one (a young woman, possibly in search of something different, who left the colony two weeks ago, but is always welcome back).

Their common way of dressing—dirndl-style dresses and head kerchiefs, and buttoned-down shirts and suspenders—speaks to a shared equality, she explains.

They eat together three times a day, and worship together several times a week.

“Even though there’s no cure, they know what causes it. And when you know what causes something, you also know what doesn’t cause it.”
Cheryl Rockman-Greenberg

“It’s peaceful but it’s not trouble-free,” Maendel says. “Being together this way requires kindness and forgiveness. And then accepting when you are not on your most perfect behaviour. That can be very difficult. Even though there is all of this support and security—that is the reality. But the other reality is that we’re not angels. People in our communities are very much human beings.”

The Hutterites of Fairholme are also navigating another very human hurdle—they are a population that faces an increased risk for some diseases because of inherited genetic mutations. U of M scientists and doctors are working alongside Manitoba’s Hutterite communities to find answers, and hopefully, treatments.

Geneticists believe the Hutterite population in North America is derived from a mere 89 “founders,” dating back to 16th-century Europe. Originally from Germany and Austria, the Hutterites have beliefs deeply rooted in non-violence, which ultimately led them to Canada as conscientious objectors to the Second World War. Their communal way of life came much earlier, in 1528, when a small group fled to a deserted island near what today is the Czech Republic. For survival, they shared the few belongings they carried on their backs—it’s now their most important religious tenet.

Because they marry within their faith—and have done so for nearly 500 years—their gene diversity is limited. Certain genetic mutations, like misprints in an alphabet, have passed from generation to generation. In the roughly 100 colonies in Manitoba, some disorders appear more frequently than in the general population, including cystic fibrosis and limb girdle muscular dystrophy. Many of these conditions can be fatal or result in physical or cognitive disabilities.

The carrier risk for any given genetic disorder overrepresented in the Hutterites can be as high as one in seven. The odds of having a child with one of these disorders is greatest if both parents have a misprint in the DNA sequence in the same gene.

“There is this dialogue always. It’s an ongoing discussion,” says Maendel, of the talk on her colony.

It’s common for young people to ponder having large families, she says.

Her aunt and uncle lost three boys in infancy to hemophilia, an inherited disorder that prevents blood from clotting. And she has known several people, including a cousin’s son, who have lost a child to Bowen-Conradi syndrome, a severe disorder that to date has only been identified in Hutterite babies. Bowen-Conradi has no cure, is characterized by several abnormalities affecting facial features, the fingers and feet, and causes developmental delay.

Young couples recognize the risks.

“There are some who want to have carrier testing done and some who say, ‘I don’t want to know.’ But I think the advice from mothers and other women is: It’s better to know— then you will decide. And they say, ‘Well, if it means I have to separate from my boyfriend, I don’t want to do that.’ I know young women who have done exactly that because they felt they were too closely related,” says Maendel.

There’s an understanding you shouldn’t marry closer than a second cousin, yet “there are always cases where it happens anyway,” she adds.

For decades, Barbara Triggs- Raine [BSc(Hons)/83, PhD/87], a University of Manitoba researcher in biochemistry and medical genetics, and Dr. Cheryl Rockman- Greenberg, a pediatrics and child health professor, have worked with Manitoba’s unique populations. And what they’ve learned from these communities helps us better understand rare disease on a larger scale.

Triggs-Raine worked with collaborators to identify the mutation responsible for Bowen-Conradi and, together with Rockman-Greenberg, and Beth Spriggs [BSc(Hons)/88], a geneticist with Shared Health Manitoba, developed a diagnostic chip—basically a slide with DNA—to test for 30 gene-causing mutations in Hutterites.

If both parents are carriers, the risk of having a child with Bowen-Conradi is one in four. The odds of one family having three babies with the disease is less likely: about one in 64.

“But that has happened,” says Rockman-Greenberg, noting that families draw strength from their faith. “They have a faith I marvel at—how comforting it is for them. They are good people, good parents, and they have been wonderful partners in research.”

Over the years, she has held town-hall meetings on colonies to share research discoveries, answer questions and put minds at ease.

“Knowledge is very empowering for them. Even though there’s no cure, they know what causes it. And when you know what causes something, you also know what doesn’t cause it.”

IN THE BUBBLE

Manitoba has more babies born with Severe Combined Immune Deficiency Syndrome, or SCID, than anywhere else in Canada. The number of cases of this rare genetic condition is three times the national average. The overrepresentation is in two groups: Mennonites and select Indigenous communities.

These babies are born without an immune system—no protection from a killer as common as the common cold. The most well-known sufferer might be David Vetter, who became known as The Bubble Boy. He made headlines when doctors in Texas cocooned him within a clear, plastic chamber within seconds of his birth in 1971, given his SCID diagnosis. Vetter rarely left his enclosure, and only while wearing a NASA-engineered suit. Before treatment became available, most kids with the disease, including Vetter’s older brother, lived less than a year; Vetter survived 12.

“They obviously thought they were doing the right thing, and they could prove that you could keep these kids alive, but the quality of life was awful,” says pediatric hematologist and U of M Professor Emeritus Dr. Marlis Schroeder [MD/66]. “Can you imagine growing up without touch from another human being?”

Schroeder knows well the reality of what you can and can’t do to protect children diagnosed with SCID. Having dedicated a lifetime to their care, she still remembers the first child she observed more than 50 years ago, when she was a U of M medical student. He was this fragile boy who struggled with recurrent infections, which ultimately led to his death.

At that time, the team would isolate the babies in their own room, limit visitors and cover street clothes with scrubs, she says. “There was no definitive treatment so all you could do was provide supportive care with antibiotics. They all failed to thrive, they don’t gain weight and they ended up dying with malnutrition and usually an infection, frequently viral. We knew clinically it was SCID, but we didn’t know the molecular or genetic defect. None of that technology was available.”

Schroeder decided to specialize in bone marrow transplants in the 1970s after doctors in Minneapolis successfully treated SCID using stem cells from bone marrow to rebuild the body’s defenses.

The need to identify the mutation responsible in Manitoba families felt all the more urgent, she says. If babies could be screened before they got sick, they could be saved before they became too ill to survive the long and bumpy road of a transplant. Schroeder established the Pediatric Manitoba Blood and Marrow Transplant Program at Health Sciences Centre in 1993. It now treats one or two kids with SCID each year.

“The babies don’t get sick for at least three months because they still have their mother’s immunity. If you identify them earlier, you can usually transplant them before they get sick,” she says.

For a child to be born with SCID, both parents must be carriers, and the genetic disorder is much more often seen in communities where people are having children within a small group. The Mennonites and select Indigenous communities are each considered by the researchers as “isolates.”

The Indigenous communities are isolated by their remote, northern location. The Mennonite communities are isolated by their cultural and religious beliefs. “You see SCID in the Mexican Mennonites too, which has to do with how they moved around,” Schroeder says.

A breakthrough came in the late 1980s when she worked with a group from Toronto’s Hospital for Sick Children who successfully identified the genetic mutation responsible in Manitoba Mennonites. They analyzed blood samples of selected families.

Then, in 2013, another leap forward: Schroeder, U of M colleague Teresa Zelinski [BSc/78, MSc/81, PhD/84] and a team of German scientists revealed the IKBKB gene was linked to a form of SCID in the Indigenous community. Their work was published in the New England Journal of Medicine.

“It was sort of, finally,” Schroeder says.

The team also discovered the need for a more complex screening methodology. Specific variances in the Mennonite and Indigenous communities were missed using standard methods since the tests look for the absence of T cells—these groups have these cells but they don’t activate, Zelinski explains.

Parents carrying the same SCID mutation face a one in four chance their child will have it and this risk holds steady for each pregnancy. Schroeder has seen as many as four SCID siblings in one family. “Sometimes they don’t believe it could happen a second time,” she says.

Despite the urgency to identify SCID babies as early as possible, it is not among the disorders examined in Manitoba’s newborn screening program.

“The screening is urgently required,’’ adds Schroeder. “Right now, you often don’t get the babies until they’re quite ill so, obviously, the success of a transplant is significantly less.”

PHOTO OF AMY TINSLEY SUPPLIED

A BREAKTHROUGH

U of M researchers working on rare diseases are part of a crowd of medical researchers often battling for attention, says Rockman-Greenberg, a physician and scientist in the Children’s Hospital Research Institute of Manitoba.

“Just because it’s a rare disease doesn’t mean it isn’t as important to understand as a common disease,’’ she says. “I’ll speak for rare diseases anytime.”

Also known as orphan diseases, these disorders can be neglected by the pharmaceutical industry because the market for a new drug is so limited. Prices are often sky high.

Still, Montreal-based Enobia Pharma developed an enzyme replacement therapy to treat a bone disease called hypophosphatasia, or HPP. It strikes one in roughly 100,000 worldwide but the odds of having the disease narrow to one in every 2,500 among Mennonites in Canada, and Rockman-Greenberg is one of the global experts.

The bones of babies with its most severe form appear translucent on X-rays. Without treatment, their lives are measured in hours, weeks at most, with chest cavities so narrow it stifles their breathing, and bones so delicate they can’t even be hugged.

Rockman-Greenberg and her colleagues began researching HPP in the 1980s. Through family studies and gene sequencing, she and her team uncovered the genetic cause of HPP in Manitoba’s Mennonite community: a misprint in the gene coding for the enzyme alkaline phosphatase, normally responsible for mineralizing the bones. Years later, in 2008, she became the principal investigator for Canada for the first clinical trials of Enobia Pharma’s drug asfotase alfa, now marketed by Alexion Pharmaceuticals as Strensiq.

Children came to Winnipeg from Lebanon, France and other corners of the globe seeking a treatment they couldn’t access in their home country. The first to arrive, on a Learjet, was Amy Tinsley, a baby from a dairy farm outside Belfast, Northern Ireland, whose bones had broken in her mother’s womb.

“That was certainly a very emotional day,” says Rockman-Greenberg. “She would not have survived had she not had been able to have access to this new drug.

“She was the first child to enroll in the clinical trial. It changed the natural history of the disease completely, from a mortality rate in our population of the most severe forms of HPP from 100 per cent to a mortality rate of four per cent.”

Amy didn’t bounce back right away. It’s not unusual for HPP babies to get sicker before they get better. On a particularly dim day, as the parents debated a palliative approach, Rockman-Greenberg instead encouraged perseverance. “I just had this feeling that things were going to turn around.

And I remember the day it did. Whenever I speak with the parents, they remind me of that day when I said, ‘Stay the course. Give it a little bit longer.’”

Rockman-Greenberg recently visited Amy in Dublin, bringing her a pink University of Manitoba hoodie—and lots of hugs. “I just got a picture from the family. She’s 10 years old now, a loving little girl. It’s not often that you actually get a treatment that really works. It was brilliant.”

HUNTING FOR ANSWERS

The mapping of blood-group genes in families began decades ago at the U of M. Thousands of samples now provide a major resource for tracking genes in Manitoba’s unique populations.

Over 32 years, scientist and professor Teresa Zelinski has expanded the database to include multiple generations and analyze DNA in increasingly complex ways. The techniques have evolved but the goal remains the same: She looks for gene patterns of family members carrying diseases that don’t repeat in genes of non-carrier family members.

Stacks of handwritten family trees stretch out like accordions in her office in the Pathology building, documenting up to five generations. For the rarest mutations, Zelinski might be the only hope for a family who wants to know: Why us? And will it happen again?

She says the refrain “Why the heck can’t I figure this out?” plays in her head during her daily commute to the U of M’s Bannatyne campus.

“There are some things that are so very rare, so very unusual, whose underlying genetic cause is equally as unusual. We have families where we have no answer for them and they might be the only family in Canada whose kids are suffering from that specific disease,” she says.

One puzzle has haunted her for 10 years. Two children in the same family died of a neurological disorder so mysterious it doesn’t yet have a name. Zelinski, now 61, feared retirement would come sooner than an answer. “It’s something that kind of eats at you,” she says.

But then, within weeks of this interview, a victory. She can’t share the findings yet (they’re pending publication) but it means two grown sisters, now at an age to ponder motherhood, finally can look ahead. Knowing the mutation means they can find out whether they are carriers.

“We’ve found a lot, we know a lot, but the next generation will do equally as much if not more.” Teresa Zelinski

“We’ve found a lot, we know a lot, but the next generation will do equally as much if not more,” she says.

But how much do we all want to know, really?

Since the completion of the Human Genome Project in 2003, scientists can tell us which mutations cause thousands of diseases. When you undergo gene sequencing, your DNA is compared with the norm, identifying what’s different and whether that might bring trouble. You can now sequence your “coding genome”—a less thorough glance, but still, one that looks at your risk for key diseases—for a couple thousand dollars, she says.

Zelinski predicts the future of genetic scanning will go something like this: “You can go vroop and they’ll know all the changes and what it could mean. It’s going to be a little freaky, a little scary. Do you want to know, at 16 or 17, that by 40 you are going to die within, say five or six years?”

A BIT FRANKENSTEIN

The genome-editing technology CRISPR, now being used by scientists across the globe, is the newest addition to the U of M research toolkit for the study of rare genetic diseases.

First described by researchers in Japan in 1987, CRISPR (pronounced crisper) uses a protein like a pair of scissors to cut problematic DNA. The protein takes its location cue from a molecular guide, which also tells cells what template to use while repairing themselves. The result: a corrected gene.

Scientists have tried tweaking the genetics of insects—like mosquitoes—to stop them from carrying communicable diseases, and of people to thwart symptoms from immobilizing disorders, like Huntington Disease. If done on embryos, could parents correct mutations before their child is born?

U of M researcher Barb Triggs-Raine imagines the possibilities.

“I don’t think it’s science fiction anymore. The ability to have an impact on genetic diseases is really real now,” she says. “It’s amazing how things have changed.”

Before she was a scientist, Triggs-Raine was an imaginative kid growing up on a farm near Treherne, Man., her nose always in a sci-fi book. One of her favourites, I Will Fear No Evil, described the swapping of a man’s head onto a woman’s body, and vice versa—and it fascinated her.

Today, her two millennial sons call CRISPR “a bit Frankenstein,” she says.

What she doesn’t condone: IVF gene manipulation for designer babies, customizing gender or upping athleticism. “I don’t think we should be using CRISPR to make changes in the genome that are not needed to cure a disease that has a significant impact on the well-being of that person.”

CRISPR is being used by Triggs-Raine to help humans fight disease. But instead of correcting genes, she does genetic edits to mouse models to mimic various human disorders.

The frequency of the disease she’s now targeting—Tay-Sachs—is highest among Ashkenazi Jews. They too are considered by geneticists to be a unique population. Their ancestry can be traced to 350 individuals, according to a 2014 Columbia University study by Shai Carmi. One in a mere 25 are carriers of Tay-Sachs, says Triggs-Raine.

Parents are fooled into thinking their baby is healthy until about six months, when missed milestones set in. These children never take a first step or learn to speak, and gradually fade to a vegetative state. They usually die before their fifth birthday.

It was a major advance when, in the late ’80s, as a sleuthing postdoctoral student at Toronto’s Hospital for Sick Children and then Montreal Children’s Hospital, Triggs-Raine was among the team to discover several mutations underlying this disease: some specific to Ashkenazi Jews, and some found in the general population. Given the disease’s progressive and cruel nature—and how that might impact a carrier couple’s decision on whether or not to have children—it was significant that she discovered the first pseudo-deficiency mutation that would gave parents inaccurate test results. A year later, in 1993, she led her own team at the University of Manitoba to identify a second pseudo-deficiency mutation, again improving the accuracy of screening for this disease.

Screening has reduced cases of Tay-Sachs tenfold, she notes. But still, no cure. CRISPR is not yet sophisticated enough to make the correction.

Now, Triggs-Raine is working with U of M professor Brian Mark [MSc/98], her former student, to replace the natural enzyme missing in people with Tay-Sachs with an engineered form, and then get it to where it needs to be: the brain. She tracks the mice in the university’s animal imaging facility, with its miniature CT, MRI and ultrasound machines.

A cure for Tay-Sachs could be within reach in the next five to 10 years, she says.

THE QUEST CONTINUES

With patience for progress, these Manitoba communities steeped in tradition await the next cutting- edge findings.

Alongside the Hutterite population, a new generation of U of M scientists are now working to develop projects aimed at identifying new genes and developing therapies for these commuities, says Triggs-Raine.

In the meantime, their everyday also means grappling with the risks and outcomes of genetic disease.

When a visitor, an American woman from outside the Hutterite community, came to Fairholme colony, she remarked to Dora Maendel how struck she was by the way everyone looked after one another.

“She said, ‘I don’t think you understand the wealth you have here,’” Maendel recalls.

If there’s any stigma attached to those diagnosed with genetic disorders or those who are carriers, Maendel says she hasn’t witnessed it. Rather, it’s people helping others, as they did recently for her cousin’s daughter, who has two children living with Joubert syndrome. It’s among the brain disorders U of M researchers want to better understand. Community members built the family a wheelchair-accessible home and ensured the children had extra resources in school.

“Just to know, they’re never going to walk or run like other children will, it’s very, very difficult.” Maendel says. “Of course, you have the whole community to help out. It’s teaching how we should love one another. Essentially, that’s what this whole way of life is about. It’s what we believe.”