Great ResignationClimate ChangeLeadershipInflationUkraine Invasion

Sam Shepard Died of ALS. Here’s Why It’s so Difficult to Treat.

August 2, 2017, 4:36 PM UTC

We lost an American icon Thursday with the death of actor and playwright Sam Shepard. He had ALS (amyotrophic lateral sclerosis), more commonly known in the U.S. as Lou Gehrig’s disease. It’s an invariably fatal neurological disease that robs individuals of their ability to move muscles, their ability to swallow, and eventually, their ability to breathe.

ALS often starts in a fairly nonspecific way, with weakness in a person’s hand or foot. Although I never examined the late Mr. Shepard, even in public photos from 2016, the atrophy of his hand muscle was evident—a hallmark of the loss of muscle that occurs in ALS.

In about 90% of cases diagnosed by neurologists, ALS happens out of the blue—it’s “sporadic,” and the cause isn’t known. About 10% of the time, ALS is inherited through a defective gene; that is, a patient has a family member who also had the disease. We can readily diagnose inherited ALS with a relatively simple blood test.

Five years ago, we learned that even in some patients who have no family history of ALS, a defect in a gene known as C9orf72 underlies the disease. In some patients, the disease may be initially diagnosed incorrectly as a nerve problem in the hands or wrist (carpel tunnel syndrome), or a pinched nerve in the neck or back. But those conditions are commonly associated with pain—ALS is not generally a painful disease.

The weakness typically progresses—slowly over many years in some patients, or rapidly over a few months in others—progressing from one hand to the other, from hand to foot, or foot to hand. Eventually it affects one’s ability to chew, swallow, and breathe. The weakness of the breathing muscles is what makes ALS fatal. Unlike cancer, with its rare but real remissions, ALS is always fatal. Patients might choose to have a ventilator artificially breathe for them; that intervention delays death, but not the progressive weakening and paralysis of all muscles.

As treating physicians, we have a paucity of options to slow down the disease and have no real effective drug to halt its relentless progression or to recover function—no cure. ALS is not really one disease, but a combination of different genetic, even environmental, insults, that culminate in this horribly disabling and life-ending malady. Not unlike what we have learned about cancers, there may be many different causes—genetic, molecular, biochemical—that underlie the disease. In cancers, sampling the actual diseased tissue, commonly through tissue biopsies, has provided a trove of clues about what underlies the basis of the different cancers and how to approach the different forms, sometimes quite successfully. But with ALS, we cannot readily take a “chunk “ of someone’s brain or spinal cord, so we are often left guessing as to what may underlie the cause of the disease and how to best treat it. That antiquated approach may soon end.

Advances in the generation of stems cells from individual patients provide the most powerful way to generate their own brain cells. We are now able to take a small tube of blood or skin and turn those cells into stem cells (by a procedure that won the Nobel prize several years ago), and then, by adding a few more chemicals and special genes, turn those cells into motor neurons—brain and spinal cord cells that die in ALS.


This procedure, which in essence creates a biopsy of the brain/spinal cord of ALS patients, will allow us to achieve what has been so successful in cancer—to truly understand the different kinds of ALS, to use our patients’ “brain” cells to discover their individual disease causes, and to develop a more individualized pathway for drug therapy. We aim to personalize ALS therapy—what we call Answer ALS. That is the hope on the horizon for ALS, along with drugs now already under development or in clinical trials that are specifically targeted to patients with known genetic mutations. How far that horizon is in the distance, we don’t know, but we can see it. We only wish Mr. Shepard and all our past patients could have reached that hopeful horizon.

Jeffrey D. Rothstein MD, PhD, a neurologist and professor at Johns Hopkins University, is the director of the university’s Brain Science Institute, ALS clinic and Robert Packard Center for ALS Research.