Murray’s Problem Chapter One ♦ Scientist and Son

Murray Blackmore stood at the lectern and tried to take in the dark conference room, the men and women in wheelchairs waiting for him to wrest a little hope from science. But in his preoccupied state, the room was a blur and hope a struggle.The 39-year-old researcher took a deep breath.

An assistant professor at Marquette University, Blackmore had looked forward to addressing the symposium on spinal cord research in Boston. Work filled his daylight hours; interrupted his dreams at night. Often he would wake at 2 or 3 in the morning, pitched from sleep into the scientific puzzles of a broken spinal cord. Ideas in the midnight hours seldom bore fruit, but his mind churned through them just the same.

He felt a responsibility. The National Institutes of Health had awarded him a $1.6 million grant. He ran a lab outfitted with cutting edge equipment. He pursued the newest ideas in the field.

But in the fall of 2013, the researcher with the short, black hair and slim cyclist's build was facing a year that would test the balance in his scientific life.

On one side of the scale weighed his deeply personal desire to cure spinal cord injuries; on the other, his profession's demand for detachment. He would need to balance the two if he wanted to produce strong results in the lab, an important paper, a groundbreaking technique, something promising.

As Blackmore addressed the audience in Boston, a shoulder drooped. His voice slowed.

"I've been thinking a lot about speed lately."

Family photo Bonnie Blackmore visits the White Cliffs along the Missouri River in Montana. She lived for 26 years as a quadriplegic.

A small sigh escaped and a slide appeared on a large screen up front showing several photos of an older woman. In one, the woman was laughing beneath an umbrella as her canoe cruised downriver past gray cliffs. Another showed her sitting in an office; only a close look revealed she was in a wheelchair.

"As some of you know, this is my mom. She was injured in 1987 and lived for 26 years as a C4 quadriplegic. She lived well. ... She never stopped going on adventures.

"She passed away recently, and to me it's really brought something into focus."

Blackmore scratched the back of his neck and blinked.

"Twenty-six years. That's a long time. And every day that she was living with spinal cord injury, there were scientists out there trying to solve spinal cord injury, and in the last several years that's included me and my lab.

"And when you get right down to it, we didn't get it done. Not yet."

He clenched his teeth.

"So I guess what I'm saying is, if there's anyone in this room that's feeling frustrated that we haven't finished this yet, believe me, I understand how you feel.

"And I'd like to have a conversation, a continuing conversation about how do I, as a researcher, move this faster."

For a moment, it was as if the scientist had stepped down from the stage and joined the 273,000 Americans living with spinal cord injuries and wondering if an answer will come in their lifetimes.

Watch Murray Blackmore's presentation at the Boston conference (30 minutes) See Murray Blackmore speak at the 2013 "Working 2 Walk" symposium in Boston. Video: Murray's Problem: Professor discusses paralysis research at Boston conference

The grief was still fresh. Blackmore's mother had died two weeks earlier. "Devastated," was how his wife, Dawn, described him.

The next slide appeared. He gathered himself and began: "I think everyone here is familiar with the basic problem of axon regeneration..."

•••

He might have chosen an easier path to contentment, this husband and father of three, a man who enjoys hiking and camping, fish fries and music in the park.

But in the pursuit that dominates his life, the quest to cure spinal cord injuries, experiments fail. Under the microscope, a treated mouse shows no improvement. In the cage, it cannot grip a food pellet.

And later, at dinner with his family, Blackmore is quiet and distant. He sleeps fitfully. Then he rises at daybreak and returns to the lab.

One winter morning, several months after the conference, Blackmore sat at his desk explaining how he came to work in an area of medical research that seems so high in desperation, so low in hope.

"What I'm passionate about is solving a problem," he said.

A spinal cord injury is a wiring problem.

The wiring works like this: When you decide to change channels on the TV, a neuron in the brain sends an electrical signal down a long, wire-like structure called an axon.

The signal reaches the spinal cord and passes to a messenger called a motor neuron. The motor neuron dispatches its own axon carrying the message to the finger. Then the finger presses the remote.

Almost every movement — from bending a knee to moving the diaphragm in order to breathe — depends upon messages traveling along axons.

"It's the interruption of that signal that's the heart of the problem," Blackmore said. "No axon, no signal. No signal, no movement. That's paralysis.

"It's such a simple principle. It's the exact same problem the phone company has when a tree falls on one of their cables."

In theory, repair ought to be simple, too.

Before we're born, in the developing embryo, broken axons can repair themselves. When the axons mature, however, they lose that power. (Scientists know about this change from animal tests, but they believe it holds true in humans.)

This leaves one overriding mystery: What makes embryonic and mature axons behave so differently?

Figure that out and maybe you can reverse the process. Maybe old wires can be made new again.

•••

That's the essence of the problem facing Blackmore's team — but nowhere near its full dimensions. More than 1,000 genes differ between an embryonic and a mature axon. Some become more active as the axon develops, others are dimmed down.

Each axon is composed of thousands and thousands of proteins interacting in complex ways.

"Imagine a jet engine that's not working," Blackmore said. "And it comes from outer space. We don't understand all the components. We're trying to figure out which are working and which are not working."

Blackmore takes apart the human engine, testing components. He looks for genes that make axons grow, then inserts those genes into mice with spinal cord injuries. He searches for one gene, or maybe a combination, that will help the mouse function better.

But growing axons isn't enough. Injuries to the spinal cord cause scars and those scars block new axons, preventing them from establishing a connection. So Blackmore also tests enzymes, hoping to find one that breaks down scar tissue.

Scientists have grown axons in a dish and even in animals, but despite sporadic success, the injured animals are seldom much better. And success in humans has been rarer still.

Murray Blackmore talks about how nature has already solved a key problem in paralysis research: How to repair broken axons, the wiring essential for the brain to communicate with limbs.

"If before the injury, the human spinal cord could score 1,000 touchdowns," Blackmore said, "so far in animals we can move one football only 1 yard."

As he turns the problem over in his mind, Blackmore constructs a visual image: the communication between brain and spinal cord as a train carrying cargo over tracks. The cargo is signals to and from the brain. There is a break in the track, the injury. Maybe the signals are requests for repair supplies. Maybe the axon's failure to regrow is a communication problem, a muddled message between brain and spinal cord.

He freezes the picture. What signals are in the cargo?

This is how he thinks.

These are his tools.

A $90,000, state-of-the-art microscope allows Blackmore and his team to test 20 individual genes in a single hour and measure how much axon growth each one triggers. Previously it took weeks just to test a single gene.

Recently, he began applying a new technique called optogenetics, activating groups of brain cells by shining light on them. This lets the lab compare the behavior of cells that have received a gene treatment with cells that have not.

"Dr. Blackmore is doing exciting, cutting edge research, " said Lyn Jakeman, who oversees grants on spinal cord injuries for the National Institutes of Health.

Across the United States, 250 scientists work on spinal cord research. The NIH spent about $95 million last year on research studying spinal cord injuries, a little less than it spent on cervical cancer, a little more than it spent on traumatic brain injury.

Competition for the grants is fierce. Labs burn 80-hour weeks preparing applications only to get rejected; only about 15% receive NIH money. Success requires focusing research around the right question, a skill for which Blackmore has shown a knack.

"He's really, really logical and very reductionist. He can break things down into small problems," explained Vance Lemmon, who worked with Blackmore at the Miami Project to Cure Paralysis. "He's one of the most talented people at doing this that I've ever met."

•••

The lab's research tracks Growth genes Astrocytes Optogenetics Cancer genes

When Blackmore turned his mind to the big problem — the injury that changed his mother's life — he saw a group of smaller problems, each one now the focus of a project in his lab.

One involves hunting genes that make axons grow, narrowing long lists of candidates and testing the best on mouse brain cells in a lab dish.

Another: the study of astrocytes, star-shaped cells that show promise in helping axons to pierce the scar tissue barrier.

Yet another: a groundbreaking attempt to determine whether optogenetics can be used to assess spinal cord treatments.

For months, Blackmore and the half-dozen students and two postdoctoral researchers in his lab have chipped away at these problems, conducting experiments, then discussing the results at weekly lab meetings. They've tested, learned and retested, questioning what they saw, advancing cautiously, a little like a baseball team stringing together singles.

Then, at a meeting in early April, Blackmore decided to swing away.

"This is a crazy, unfunded project," he told his students and researchers.

Their eyes followed him as he explained where his recent thinking about how to grow axons had led.

Cancer. A disease of uncontrolled growth.

The idea of trying to use genes that make cancer grow to do the same for axons had been proposed before. But scientists lacked the technology for a systematic examination. Now, armed with the powerful screening microscope, Blackmore wanted to revisit the idea, to make it the lab's new line of inquiry.

Through online searches, he identified 1,400 genes that either trigger cancer or block it by suppressing tumors. Too many. He narrowed the list, focusing on genes that turn other genes on or off, master regulators. That dropped the number to 219. Then he looked at genes linked to axon growth.

So far, scientists have identified a dozen axon-growing genes — all but one either activate or suppress cancer.

"The axon growth field is already studying cancer genes, they just don't know it." Blackmore told his team. "So I wrote a grant to do that and it got laughed out of the room. And I said, 'Screw it. We're going to do it anyway.'"

The inquiry into cancer genes had begun as a side project. Now, he said, it is going to be one of the lab's focal points.

As the students returned to their experiments, Blackmore could tell he'd sparked their interest. He was both excited and worried. The lab had several promising lines of research and a pressing need to publish a paper soon.

The situation made Blackmore think of a professor he'd studied with in Hawaii, a man who had an odd way of staying fit. He chased wild goats.

Chasing goats was not an easy business. Run at the pack and they scatter. The only way to succeed, the professor had learned, was to lock in on a single goat and follow it without getting distracted by the others.

Blackmore wondered if he ought to be applying the same principle to the different projects his lab had been pursuing.

•••

He remembers the precise moment he decided what to do with his life.

It was in the fall of 1997, while bicycling on the Pan-American Highway through the Andes. He was 23 years old. He and a friend were in the midst of a 6,000-mile ride from St. Paul, Minn., to Santiago, Chile.

They'd slept under the stars. They'd been robbed at machete-point. They'd made it across flooded-out stretches of road. Now, they were riding in the mountains of Ecuador.

Blackmore had an undergraduate degree in environmental science from Stanford. But he no longer believed he could offer the field what it needed most. When it came to the environmental challenge of our time, climate change, Blackmore felt scientists had firmly established the predicament and the solutions. Missing was the will to respond.

The bike trip would be one last adventure before he settled into a career, marriage and parenthood. And maybe, somewhere in those miles, he would figure out what to do.

"I knew that I wanted to do something good in the world, something worthwhile," he said. "But I didn't know what that looked like."

So, there he was, pedaling at 10,000 feet above sea level, beneath a brilliant blue sky. To his left rose a steep cliff. To his right, the landscape fell away through a field of boulders.

The Pan-American Highway is one of the main truck routes through South America. The shoulders are narrow. White crosses dot the landscape, marking death on the highway.

Here, he found clarity.

The right problem had been in front of him all along, the legacy of another day, a decade earlier, on a distant highway.

•••

Thanksgiving weekend, 1987.

They'd been driving all night in the family station wagon, heading home to St. Paul, Minn., from Montana after visiting grandparents.

It was cold. In the early morning, black ice painted patches of Interstate 94, as the Blackmores approached the small western Minnesota town of Fergus Falls.

There were five in the car: Blackmore's older sister, Jenny, the driver; their mother, Bonnie, in the passenger seat; Blackmore behind them, and next to him, his other sister, Leah; and in the very back, sleeping on top of the luggage, their brother, Cameron.

Blackmore was reading Agatha Christie's "Murder on the Orient Express." He had just taken off his seat belt to get more comfortable.

Suddenly, the car was spinning. Outside the window, a concrete overpass rushed in, then receded.

Now, the car was rolling backward. The car was crossing the median. The car was in oncoming traffic. A semi was bearing down. White headlights flooded the station wagon.

Then nothing.

Sprawled on the ground. Face down. His eyes opened. The first thing he saw in front of him: "Murder on the Orient Express." Shards of glass were embedded in the cover. He was 100 yards from the car with no idea how he'd gotten there.

Cameron was dead; Leah badly injured. The roof of the car had buckled on top of their mother. Her spine had been crushed at the C4-C5 level, a little below the chin. She could not move her legs or hands. She could only control her shoulder muscles enough to make the limp mass of her arms swing right or left, backward or forward. She was a quadriplegic.

Family photo Bonnie Blackmore on a canoe trip in 1968, years before her spinal cord injury. Blackmore was injured in a car crash in 1987. Her paralysis inspired her son Murray’s research.

"The goal posts changed radically," Blackmore would say of her life.

His mother was 45. She had just divorced his father. She was figuring out what she wanted to do. She loved the outdoors. She had a keen interest in psychology. She was taking lessons in tennis and guitar.

For the next two years, Bonnie Blackmore spent much of her time either in a hospital or a rehabilitation center. She came home in a motorized wheelchair. She had a splint that allowed her to hold a spoon and feed herself. For the other tasks of ordinary life, she had personal care attendants who lived in the house.

It took months before she could use a mouth stick to type and operate the phone.

•••

Try to envision what it must have been like to be Bonnie Blackmore.

Maybe once, for a "disability awareness" program, a teacher had you sit in a wheelchair and imagine how different your life would be. The wheelchair was supposed to represent the hardest-to-bear of all losses from a spinal cord injury: walking.

Only that isn't the case.

A 2004 paper in the Journal of Neurotrauma surveyed quadriplegics (those with partial or complete loss of movement in all four limbs and torso) and paraplegics (loss of movement in the legs and torso, but not the arms). They were asked to rank the abilities they would most want to regain.

Walking did not finish first with either group. Or second. Not even third.

Quadriplegics said they wished most of all to have arm and hand function restored, then sexual function, then trunk stability (the ability to keep oneself upright), then bladder and bowel function. Walking ranked fifth.

Among paraplegics, the order was different because they retained arm and hand function. They wanted most to have sexual function back; then bladder and bowel; then trunk stability; then walking.

If these priorities seem odd, imagine you cannot hold a pen, open a door, scratch an itch, stroke your daughter's hair. You cannot swipe a bee away from your face. You're helpless to stop a charging dog from jumping on you.

Now, imagine that you must depend on someone else in the most private moment — every time you go to the bathroom.

Murray Blackmore talks about his mother, Bonnie Blackmore, who spent much of her life as a quadriplegic after an accident severely damaged her spinal cord. That injury has inspired his research.

Blackmore didn't have to imagine. He had only to look in his mother's eyes.

An incident early on lodged in his memory. It was the summer after the accident, and his mother sat at the dining room table with the rest of the family. A splint clamped her hand around a spoon so that she could feed herself.

Unfortunately, she could not attach the splint herself, not even close. Someone had to put on the device and arrange her food perfectly, or it wouldn't work. After the meal, Blackmore watched as his mother tried to remove the splint. She was using her teeth. The intensity burned in her eyes. He'd never seen her so determined.

"In the end she couldn't do it," Blackmore recalled. "I don't think I have ever seen a person so defeated."

That's when he understood.

•••

On a chilly spring morning in late April, a few weeks after he'd announced the cancer gene investigation to his team, Blackmore arrived at his office feeling nervous. He'd slept poorly.

Mental notes: A recording from Murray Blackmore as he wrestles with why results from some experiments don't seem to fit together.

Results were coming back on experiments involving some of these genes. As he saw it, genes that cause tumors to start growing or stop were like on-off switches that might be tailored to make axons grow.

Matt Simpson, a 20-year-old sophomore in the lab, had carried out the experiments. The data would appear on bar charts, and Blackmore knew the result he wanted. Heck, he could draw the chart he hoped to see. And this worried him.

"There are two things I think about," he said. "It's not the best idea for a scientist to be so invested in an outcome, even though we totally are. The other thing is about leadership. Even if it totally crashes, I can't show that. I have to find some way to keep Matt completely invested in the project."

The professor entered the lab and found Simpson sitting by his computer. The student called up the chart for the first of the two genes they'd tested. Blackmore stared at it hard.

"Interesting," he said. "We're so close to a slam dunk."

They were looking at a gene called HHEX, which shuts down growth. In the lab, they'd used a trick to alter the gene, hoping to turn the growth switch from "off" to "on." The bars on the chart showed they had succeeded — but the growth was modest.

"Not bad. Not bad," Blackmore said, pointing a little higher on the chart. "We would have opened the champagne if the bars were up here."

Results from the other gene ended any talk of champagne.

The gene called ETV5 appears in the brain and Blackmore hoped it would function like a close relative. The relative stops growth. Blackmore saw another off switch that might be turned on.

Only now that he looked at the charts, nothing made sense. ETV5 failed to stop growth. So did its relative, a baffling result. Either there was an error in the experiment, or the information they'd begun with was wrong.

"That's as bad as it gets," Blackmore said, staring at the chart. "Are you kidding me?"

The student and professor went over the experiment and tried to guess what had happened. They would have to run the experiment again. From Day 1, Blackmore had warned students in his lab about confusion; it is the way 90% of experiments end, he'd said.

After Simpson left the lab for class, Blackmore admitted he had gambled. Believing ETV5 would behave like its relative, he'd jumped the gun. He'd already modified the gene to make a version that turned on growth. The safest approach would have been to test a normal version of the gene on brain cells before going to the cost and trouble of modifying it.

But following that procedure felt too methodical, and worse, too slow. Now, he worried he had wasted lab resources.

"It's part of a bigger problem for the lab," Blackmore said. "It's my problem."

When a gene shows promise in growing axons, he wants so badly to bypass the confirmation tests and the tests to understand how the gene is triggering this growth.

His heart and mind leap to the bottom-line experiment: Will it help an injured animal?

"That's where I want to go, dammit," he said. "The problem is that the answer is almost always, 'Nope, it doesn't work.'

"And if the answer is 'no,' then you can't publish and you haven't learned very much."

This was the tension between his two selves.

The skeptical scientist who approached experiments with detachment.

The idealistic son who wanted to cure his mother.

Coming Monday

Chapter Two: A Cruel Mistress.

About the story

Marquette University professor Murray Blackmore allowed Milwaukee Journal Sentinel reporter Mark Johnson and photojournalist Richard Wood to sit in on virtually all weekly lab meetings, watch experiments and witness discussions of results. Johnson interviewed Blackmore and lab members extensively, as well as experts in the field and scientists who worked with Blackmore earlier in his career. He also read key scientific papers by Blackmore and others and, with Wood, traveled to the 2014 Working 2 Walk symposium on spinal cord research in Seattle, where Blackmore was a presenter.

Many of the scenes in the story were witnessed firsthand by the reporter or photographer. Scenes that took place before 2014 were described through interviews with those present, except for the opening scene, which was drawn from videotape of Blackmore's 2013 talk at a conference in Boston. The description of the 1987 accident was drawn from Blackmore's account and confirmed through news coverage from the time. The state of Minnesota no longer has the original accident report.

In a few instances a character's thoughts are described. In all such cases, people described their thoughts to the reporter.

twitter.com/majohnso markjohnson@journalsentinel.com