“I think primarily this is a story of discovery,” said neurologist and multiple sclerosis (MS) researcher Stephen Hauser, MD, of the University of California San Francisco, about his book, The Face Laughs While the Brain Cries.
“It’s a story that’s optimistic, that imbues faith in science, and shows that science can improve people’s lives,” he observed. “I wanted people to understand the phenomenal progress that we’ve made against MS, a disease that affects millions of people worldwide.”
It’s also a story about how fragile medical research is, noted Hauser, who helped open the frontier to B-cell depletion therapies in MS and led the phase III trials of the anti-CD20 agents ocrelizumab (Ocrevus) and ofatumumab (Kesimpta). Ocrelizumab, developed by Genentech, was the first anti-CD20 monoclonal antibody approved to treat MS.
“It was a miracle that ocrelizumab made it to the finish line,” Hauser told MedPage Today. “There were numerous places along the way where this could have been — and for a number of reasons, maybe should have been — scuttled.”
The Face Laughs While the Brain Cries is partly about medical research and partly a memoir. It takes its name from the pseudobulbar palsy exhibited by Andrea, a patient with severe MS whose facial expressions were disconnected from her cognitive intentions.
Meeting Andrea in the 1970s was a pivotal point in Hauser’s decision to study MS; it came at a time when little was known about the disease. MedPage Today spoke with him about the lessons he learned throughout his neurology career. An edited version of that discussion follows.
What was MS care like when you were in training?
Hauser: This was a time when we didn’t have any real options for MS. Modern neuroimaging wasn’t even a rumor. We’d have bathtubs on neurology floors, and we’d put patients who might have MS — but we weren’t sure — into hot tubs to see if their symptoms worsened or new signs appeared. Either was evidence for MS.
There was an aphorism about neurologists in that era, that we knew everything but did nothing. And for those of us who were interested in MS, senior leaders would — amazingly, in retrospect — advise us not to even try to find a treatment for MS. It would destroy our careers, they said.
Looking back, we were also just at the beginning of a new era of discovery, a transformation fueled by advances in cell and molecular biology, medicinal chemistry, imaging, and clinical research methods.
As I think about my journey and its lessons, one that stands out is the importance of seeking out a new path, one not traveled by others. We tend to travel together, but it’s often the different idea that leads to illumination.
That’s frequently where the great discoveries are made. Had I been able to step back more often and question ideas that were, in retrospect, based on pretty weak data — or worse yet, were flat-out wrong — the story would have moved much faster.
What ideas had to be challenged?
Hauser: The conventional wisdom was that the mouse experimental allergic encephalitis [EAE] model, also known as the mouse laboratory model of MS, was a faithful mimic of the human condition. That model indicated that acute EAE was caused by T cells and T cells exclusively, and if B cells had any role, they protected against disease. If you removed B cells, the disease would get worse. So, the same must be true for MS, because that’s what happens in mice.
But here was the catch: the pathology of EAE in mice looked almost nothing like the pathology in human MS. So, we set out to develop an animal model that mimicked the pathology of real MS, and after many years of failure finally succeeded, spectacularly so, in marmoset monkeys.
But we were still wedded to the idea that T cells alone must cause MS. We spent years trying to dissect out the components of the immune system that were responsible. We tried to produce the disease in marmosets using T cells alone, but after years of trying, all that T cells could produce was something similar to mouse EAE, never the MS-like pathology.
It was only when we tested B cells and antibodies that an explosive demyelinating pathology identical to human MS was reproduced. This overturned, at least in our minds, the conventional wisdom that MS was a purely T cell-mediated disease.
We published this in top-tier journals — Annals of Neurology, Nature Medicine, and JCI [Journal of Clinical Investigation]. We had the story out, but still people said it’s biologically implausible. Everyone knows, they said, that T cells alone cause MS. This new model was an anomaly; it must have nothing to do with actual MS.
Two lessons: believe in your data, and question conventional wisdom. We need better opportunities for young people to pursue novel avenues and challenge entrenched ideas. They need adequate resources to let them spread their wings.
As for me, how did that happen? Foundations and philanthropists, and fantastic visionary leaders in industry.
But even in industry, some people insisted B-cell therapy wouldn’t work.
Hauser: The Genentech prognosticator model said that the chance of a B-cell therapy working in MS was less than 15%. There was also a flaw in my argument, and I’ll talk about that in a moment, because that would soon come to the fore as well.
Despite the widespread reservations in some corners, Genentech nonetheless approved an initial $60 million pilot experiment to see if this biology worked at the bedside. The bedside — that’s where the rubber meets the road.
But then the FDA said, we won’t let you do this. It’s too risky. We’ll let you treat half the number of patients you want and administer only one dose of the drug that you propose to give. And that’s when I realized how tenuous this project was.
We thought at the time it was antibodies that we were targeting. We’d shown that the oligoclonal bands were being made by these B cells and these antibodies were directed against multiple myelin targets.
B cells weren’t what we thought we were going after; it was the antibodies that B cells made. But B cells first need to differentiate into plasma cells to make sufficient quantities of antibodies, and plasma cells can live for 100 years. So, we would need to winnow down the plasma cell-producing factory for this therapy to work if antibodies were the culprit.
And now the FDA was saying we can only treat once and observe for 6 months; there was not enough time for the antibodies to be removed. The prognosticators at Genentech now estimated that the chance of success now was even lower — less than 10%.
It was a Friday afternoon in 2006, the last Friday of September, when we unblinded the study. We were hoping to see just a hint of a benefit so we could go back to the FDA for a longer trial.
What we saw was an immediate and almost complete — over 90% — elimination of MS disease activity.
That was the best scientific outcome imaginable. Not only did we have a therapeutic that could potentially have immense benefit potential for patients, but the immediate benefit told us that our underlying scientific idea was not entirely correct.
The B cells themselves, and not antibodies, were responsible for MS attacks. And that changed the future direction of research, sending us back to the lab trying to understand how B cells function as direct culprits in MS.
Please enable JavaScript to view the