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Stem cells + 10: Lessons limits and laments

ALS: The paralyzing killer

One good place to view the promise, progress and frustration of stem cell research is in Lou Gehrig's disease. Also called ALS, this untreatable, uniformly fatal disease is caused by a die-off of neurons that control voluntary muscles. The damage usually starts in the arms and legs, and eventually spreads to the muscles that control breathing and swallowing.

Although roughly one or two in every 100,000 Americans gets ALS every year, the lifetime risk is about one in 1,000, according to a 2006 study (see #1 in the bibliography).

Blue-stained circle of cells with green-stained cell corona
Image by C. Svendsen and A. Ebert, University of Wisconsin-Madison
These neural cells, from human embryonic stem cells, are used to understand how motor neurons develop and die in ALS, or Lou Gehrig's disease.

Theoretically, neurons grown from stem cells could help ALS patients by replacing the dying motor neurons, but Lawrence Goldstein, a professor of molecular and cellular medicine at the University of California at San Diego (UCSD), said, "it's devilishly difficult to imagine how to do that; some motor neurons are a yard long." A second approach may be more fruitful: use stem cells to improve the quality of the neighborhood.

Goldstein says Don Cleveland, working on mice in his UCSD lab, has found that "cells surrounding the motor neuron can either poison it, or if they are more normal, rescue it from dying… the quality of the neighorhood has a big impact on the health and viability of motor neurons. The important idea is that the cells that are dying are not necessarily the ones you want to focus on," says Goldstein, adding that Cleveland has begun placing cells derived from embryonic stem cells into a rat with a genetic version of ALS.

Studio photo of Svedson smiling in a red shirt
Photo: Michael Forster Rothbart UW-Madison
Professor of anatomy Clive Svendsen investigates the use of stem cells to treat ALS at the University of Wisconsin-Madison.

Act your age: Adult stem cells and ALS

Working along similar lines, last month researchers at the University of Wisconsin-Madison reported that they had injected adult stem cells into rats with genetic ALS and reduced the death rate. The rats had the same mutation that causes a small percentage of human ALS cases, says Clive Svendsen, a professor of anatomy. “They live 100 days and become paralyzed. It’s much like the patients, who on average are diagnosed with ALS at around age 55, although this disease has been recorded in patients aged between 12 and 98.”

The gene in question produces superoxide dismutase, an enzyme that normally protects cells from oxidative damage. Ironically, the mutated gene produces damage that eventually kills the cell.

Although the rats are considered a good “model” for ALS, most cases of ALS have an unknown cause. When patients are examined after death, says Svendsen, “It’s like the end of a car accident: The car is upside down in the ditch, and you want to know why the car ended up in the ditch. We don’t know why the patients are losing their motor neurons, because we don’t have a good enough way of looking at them early on in the disease, before the patient dies."

Fixing the neighborhood

One possibility is that the problem lies not in the neurons, but in the glial cells, which nourish neurons, detoxify wastes and produce glial-cell derived neural growth factor (GDNF), which helps keep neurons healthy. Previously, Svendsen, and Masatoshi Suzuki, a scientist in his laboratory at the university's Waisman Center, had injected neural stem cells, taken from the human brain and grown in a lab dish, into the spinal cords of ALS rats. Although many motor neurons survived when surrounded by healthy glial cells, they still lost their connection to the muscles, and the muscles withered away.

In the new study, the researchers worked at the other end of the nerve cell, injecting the muscles with stem cells that were engineered to release a large dose of GDNF and were able to survive transplantation into the muscle. The "mesenchymal" stem cells that were injected came from adult rat's bone marrow.

The treatment seems to offer multiple benefits. Bone marrow stem cells alone created a slight improvement in the spinal cord, explains Suzuki. "But only when we engineered the cells to release GDNF did we see a significant improvement. It's this combination of cells and drug delivery that seems to be so effective."

Network of red and green stained cells against black field.
Image: Leslie Meltzer, Stanford University, NIH
Birth of new neurons from adult neural stem cells (red = neurons; green = stem cell-derived cells, yellow = newborn neurons).

One healthy slurp

Motor nerves generally reach from the spinal cord to the muscles they activate, but why would changing the environment of the muscle affect the nerve cell's body, located a yard away in the spinal cord? Because the GDNF can travel along the axon into the nerve body, Svendsen says. "Neurons are like a straw, with the cup in the muscle. The neuron's body in the spinal cord sucks this GDNF back along the axon into the spinal cord. So we hope that by putting cells that release GDNF into the muscle, we can prolong survival of the neurons."

Diagram of healthy neuron adjacent to ragged ALS neuron
Image: FDA
ALS attacks the motor neurons in the brain and spinal cord that control the voluntary muscles. As the motor neurons begin to die, patients can speak, swallow and move only with great difficulty, but thinking, bladder and bowel function, sexual function, and the senses are unaffected.

The adult stem cells used in this work have some advantages over less specialized, more versatile embryonic stem cells. Because they are more fully developed, the adult stem cells are less likely to form teratomas, which are growths of body cells that can develop from human ES cells. The mesenchymal cells are also less likely to be rejected from the body, and if patients could provide these stem cells from their own bone marrow, that would reduce the risk of immune rejection that accompanies many types of cell therapy.

The next step in the ALS rats, Svendsen says, is to protect both ends of the neuron by treating the spinal cord and the muscles

The how-long blues

And how long until the first patients get treated? "It's all up to the money, and FDA [Food and Drug Administration] approval," Svendsen says. "We are working as fast as we can, but we need to do lots of toxicity work in animals, so it will be a few years at least."

Although Svendsen is a scientist, not a doctor, he knows that desperation reigns among ALS patients and their families. Still, he stresses, medicine is a step-wise process. "One has to be really careful about how we present the data. We have made some steps, some progress, but I avoid the word 'cure.'"

Patients are always impatient, but, Svendsen says, "No mountain was ever climbed by standing at the bottom and trying to jump to the top. We need to keep a steady ascent going, and that’s what this research is about. For patients, even a small step could be significant. If you are completely paralyzed, the ability to move one finger and control a mouse opens up communication with the world. This is what we are striving for right now and I think it may be possible, with an eye on an eventual cure always in mind."

Interview The face of ALS

Stephen and Barbara Byer are the parents of Ben Byer, a Chicago actor and filmmaker who produced the film “Indestructible,” about having ALS. The Why Files talked about the politics, the science, and the heartache of ALS with the Byers less than three months after Ben died at age 37.

Close up of Byers staring solemnly at the camera
Stephen Byer helped guide his son, Ben, through the labyrinth of international "treatments" for ALS; Ben died in 2008.

The Why Files: What is your role in ALS now?

Stephen: We are trying break the isolation. The doctor’s diagnosis comes with the classic ALS message, “I’m sorry, you have two to four years; there is nothing I can do to help. Enjoy your time, and make sure you have a will. We can loan you a wheelchair or a walker” -- "loan" because they assume you are going to die. They offer to loan you a respirator, but only 30 percent want that … . It’s so isolating, most people crawl into the family shell. They may go to a support group for a short period, but when they see what they will be like in two or four or eight months, they quit.

TWF: You took your son to a stem cell clinic in China that produced, at best, a few weeks’ improvement. Do you have much hope that stem cells can someday treat ALS?

Stephen: Yes. This is a progressive, degenerative, invariably fatal disease; as long as the potential harm is not as profound as the possible benefit, we should go forward. But a lot of clinics are worthless or their treatments are unproven. Still, the mindset among medical researchers is not always conducive. The message some experts give is, "We can't do anything with ALS unless and until we know the cause." I don’t believe that. I believe you have to try anything reasonable, appropriate, to help patients whose neurons are dying.

TWF: What’s your reaction to being at the Stem Cell Summit?

Barbara: Coming to this meeting is my way of staying close to Ben; doing his work that he could not finish. Is it hard to be here? Of course. He did not have time for his future. He was supposed to talk here, there is a deep regret that he is not here.

Stephen: Our promise was that we would continue his work. It’s like [the myth of] Sisyphus. We are pushing Ben’s boulder up the hill, and like Ben and Sysiphus, the boulder frequently falls down the hill during the night.

TWF: Are you frustrated with the pace of medical science in finding cures for grievous diseases like ALS?

Stephen: Yes, In the time since [President George W.] Bush was first elected, the pace of science has slowed significantly. It’s not just the extreme restrictions on funding embryonic stem cell research. In the past eight years, people have been trying to confirm that dinosaurs walked on the Earth 4,000 years ago! How could real science have advanced quickly in that time?

Real science rules in the bibliography.

Megan Anderson, project assistant; Terry Devitt, editor; S.V. Medaris, designer/illustrator; David Tenenbaum, feature writer; Amy Toburen, content development executive

©2018, University of Wisconsin, Board of Regents.