The Ice Bucket Challenge Raised $220 Million, Yet ALS Still Has No Cure
The 2014 ice bucket challenge drew donations from nearly 30 million people, raising $220 million. Yet more than a decade later, riluzole, the only widely approved drug, extends median survival by just three months.
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Before opening the envelope, he both has the disease and doesn't
Mark Hopkins's great-uncle, uncle, and father all died of ALS, but the only known genetic test at the time—SOD1—came back negative for his uncle and father, leaving the family uncertain for 16 years whether they carried familial ALS. By 2023, ice bucket challenge research funding had enabled discovery of more causative genes, and his father's DNA was retested, revealing a C9ORF72 mutation. This qualified Mark for predictive genetic testing. Under international protocol, results stay on paper, not in electronic medical records, to prevent genetic discrimination. At his final consultation, even the medical geneticist doesn't know the result; the answer is sealed in an envelope, and he can change his mind before opening it.
— Mark HopkinsDiagnosis by elimination: no single test is definitive
ALS has no specific biomarker and is diagnosed entirely clinically, based on symptoms. Electromyography (EMG) and nerve conduction testing don't confirm ALS—they rule out other diseases, like brain tumors or demyelinating disorders, the ALS mimics. This raises an open question the episode keeps returning to: Is ALS one disease, or several different diseases lumped under one name? No one can say for certain.
— Erin Allman UpdykeWeakness and twitching: two neural systems sending different alarms
ALS damages both motor neuron systems. Upper motor neuron injury (brain to spinal cord) causes weakness, hyperactive reflexes, increased muscle tone, and spasticity—the brain's inhibitory signal to the spinal cord is lost. Lower motor neuron injury (spinal cord to muscle) causes atrophy and fasciculations—the muscle loses all nerve supply. About 60% of patients have spinal onset first (limb weakness); 30% have bulbar onset (speech and swallowing difficulty, tongue atrophy), which typically signals more severe disease and faster progression. Nearly all patients eventually develop both types of symptoms.
— Erin Allman Updyke90% of patients have no family history
Only 5–15% of ALS cases are familial, but no single gene is responsible—at least 20 known related genes exist, with new papers suggesting up to 40. Most follow autosomal dominant inheritance, like Huntington's disease or frontotemporal dementia; theoretically, a single mutation copy carries risk, but penetrance is not 100%, complicating genetic counseling—having the gene doesn't guarantee disease. Conversely, 85–90% of patients have no family history (sporadic cases); some test positive for the same genes found in familial cases, but not all do.
— Erin Allman Updyke95% of patients have the same protein piling up in their brains—no one knows why
In 95% of ALS patients, TDP-43 protein accumulates abnormally in neurons—normally confined to the cell nucleus, it migrates to the cytoplasm and forms clumps. The known related genes involve RNA/DNA metabolism, membrane transport, oxidative stress, mitochondrial dysfunction, inflammation, and other pathways, but no one can explain the mechanism. Erin Welsh posed the key question: Is this protein aggregation and genetic abnormality the cause of ALS, or a consequence of disease progression? The answer remains unknown.
— Erin Allman UpdykeTwo approved drugs, and even doctors can't explain why they work
Only two drugs have been approved specifically for ALS: Riluzole extends median survival by approximately three months and is the most widely approved globally. Edaravone helps only a subset of patients (typically those with faster progression) and is FDA-approved but not approved in most of Europe. Tofersen, a gene therapy approved in 2023, targets a specific gene and went through accelerated review; trials are still ongoing, and there is no clear evidence yet that it improves survival or slows progression. What has consistently proven to improve quality of life and survival is coordinated multidisciplinary care—physical therapy, occupational therapy, speech therapy, nutrition, respiratory care, social work, and palliative care—though not all patients can access these resources.
— Erin Allman UpdykeAfter 2,130 consecutive games, he missed for the first time
Lou Gehrig played consecutive games from June 2, 1925 until April 30, 1939—2,130 games—a record that stood until Cal Ripken Jr. broke it in the 1990s, earning Gehrig the nickname Iron Horse. During the 1939 season, his hitting and fielding visibly declined; the team physician initially suspected a gallbladder problem, but the Mayo Clinic diagnosed ALS. The diagnosing doctor could recognize it instantly because his own mother had died of the disease years before. After the diagnosis became public, the team held Lou Gehrig Appreciation Day. He delivered a farewell speech at Yankee Stadium that became known as baseball's Gettysburg Address. Gehrig died on June 2, 1941, at age 37, less than two years after his diagnosis.
— Erin WelshIce bucket challenge raised $220 million and got no miracle drug
The 2014 ice bucket challenge was popularized by Pete Frates, a former Boston College baseball player. Over 17 million people uploaded videos, generating more than 10 billion views and reaching approximately 500 million people. By summer's end, over 28 million donors had contributed, raising roughly $220 million globally—far exceeding typical annual ALS research budgets. More than a decade later, no game-changing drug has emerged. What impressed Erin was ALS Untangled, founded in 2009 by the North American ALS Research Group. It systematically reviews alternative therapies and off-label medications circulating online and publishes peer-reviewed assessments, helping patients and families with limited standard options who might otherwise turn to unproven treatments find evidence-based information.
— Erin Allman UpdykeIn their own words · checked verbatim
Until it was opened, it was like a genetic version of Schrodinger's cat. I both did and did not have the mutation.
Mark Hopkins3:18
I will probably die of ALS, but for now, I'm alive, and I'm healthy, and that's pretty amazing.
Mark Hopkins5:19
95% of people have this one called TDP43, which is a protein that's normally only found in the nucleus of our cells. But in ALS, we see it in the cytoplasm forming these aggregates.
Erin Allman Updyke26:54
at present, the prognosis is grave. As far as I know, there is no case in which all the symptoms occurred and a cure followed. Is this an absolute block? Only the future will tell.
Erin Welsh42:31
He would chew exactly one stick of gum per game, no more.
Erin Welsh50:43
Today, I consider myself the luckiest man on the face of the earth. I have been in ballparks for 17 years and have never received anything but kindness and encouragement from you fans.
Erin Welsh59:55
So I close in saying that I might have had a bad break, but I have an awful lot to live for. Thank you.
Erin Welsh1:00:57
Over 17 million people posted videos of themselves dumping buckets of water, ice water over their heads. And these videos were watched more than 10 billion times by nearly half a billion people around the world.
Erin Welsh1:06:02
Figures
| C9ORF72 carrier symptom penetrance | 50% develop symptoms by age 58; over 90% by age 83 | 4:18 |
| Familial ALS prevalence | 5–15% | 25:53 |
| Known ALS-related genes | At least 20; recent papers suggest up to 40 | 25:53 |
| Sporadic ALS (no family history) prevalence | 85–90% | 25:53 |
| Proportion of patients with TDP-43 protein aggregation in neurons | 95% | 26:54 |
| Median ALS survival | Approximately 2–5 years after symptom onset | 28:59 |
| Riluzole efficacy | Average survival extension of approximately 3 months | 34:07 |
| Lou Gehrig's consecutive games record | 2,130 | 48:41 |
| Lou Gehrig's age at death | 37; less than 2 years after diagnosis | 1:04:00 |
| 2014 ice bucket challenge fundraising | Approximately $220 million; over 28 million donors | 1:06:02 |
Glossary
- TDP-43 protein
- Normally located in the cell nucleus; abnormally accumulates in the cytoplasm of 95% of ALS patients
- C9ORF72 gene
- One of the most common genetic mutations associated with familial and some sporadic ALS
- Penetrance
- The proportion of people carrying a disease gene who actually develop the disease; not always 100%
- Bulbar onset / spinal onset
- Whether symptoms first appear in the head and face (speech, swallowing) or in the limbs and torso
- Upper motor neuron / lower motor neuron
- Two motor neuron systems: one runs from brain to spinal cord; the other runs from spinal cord to muscles
- ALS Untangled
- A peer-review organization that systematically evaluates alternative therapies and off-label medications discussed online
How to listen
Doctors and family members tracking rare and neurodegenerative diseases; anyone curious about genetic testing procedures and patient resources like ALS Untangled.
Skip the cocktail segment at 6–9 minutes and Gehrig's early baseball trivia and nicknames at 45–52 minutes; neither affects the medical and historical core.