Battling Alzheimer’s disease has become William Klein’s life work – even if he never saw it coming.
A progressive disease impacting memory, thinking, behavior, and other mental functions, Alzheimer’s affects an estimated 6.7 million Americans, according to the Alzheimer’s Association, and that number is expected to soar to 13 million by 2050. The disease stifles quality of life for the afflicted, places a heart-wrenching, time-consuming burden on caregivers, and strains the nation’s healthcare system to the annual tune of $345 billion.
Over the last two decades, Klein, a professor in the Department of Neurobiology at Northwestern University’s Weinberg College of Arts and Sciences, has taken aim at Alzheimer’s disease with unrelenting purpose and an enterprising spirit. Blending his own scientific energy with earnest collaborators from Northwestern, the U.S., and abroad, Klein has fundamentally altered the course of Alzheimer’s research, diagnosis, and treatment, including the development of a novel antibody for treating the disease based on research initiated in his Hogan Hall laboratory.
After working under a pair of Nobel Prize-winning scientists – Paul Boyer at UCLA and Marshall Nirenberg at the National Institutes of Health – Klein arrived at Northwestern in 1976. Klein’s research focused on synapses – the places where neurons connect and communicate with each other. “I was enthralled by synapses and their role in all the amazing things our brains do, including learning and memory. I wanted to know how they were put together, how they adjusted, and how they ended up looking the way they do.” Yet for as fascinating as that research was, Klein wanted to apply his research to real-world problems. “It seemed to me it was feasible to take what I’d learned as a basic scientist and extend that to things that could make a difference in people’s lives.”
Klein remembers learning about the first Alzheimer’s patient, a German woman named Auguste Deter. When neuropathologist Dr. Alois Alzheimer asked Deter to pick up a pen and write her name, she couldn’t and famously said, “I have lost myself.” The story stuck with Klein, who believed he could tie his research to Alzheimer’s. “You know who you are thanks to the memories you have. When those start to dissolve, you’re no longer yourself. I thought I could do something to help.”
Klein’s first move into work with Alzheimer’s disease began in the early 1990s thanks to – of all things – a coffee maker. After Northwestern received a large grant from the state of Illinois to facilitate collaboration with local pharmaceutical companies, the University hired Catherine Propst, formerly of Abbott Laboratories, to lead the effort. To welcome Propst to Northwestern, Klein delivered a new coffee maker to her office, where the two discussed his research. A month later, Propst connected Klein, who was in the early stages of drawing a correlation between synapses and Alzheimer’s disease, to an Abbott Labs’ medicinal chemist named Grant Krafft. Klein and Krafft would become long-time collaborators on Alzheimer’s research, particularly after Krafft joined the pharmacology faculty at Northwestern’s Feinberg School of Medicine. “Who knew a ubiquitous biochemical instrument would help kick this off?”
Klein’s two decade-long run studying synapses and neurotransmitter receptors translated remarkably well to Alzheimer’s disease. “It turns out that the best pathological correlate of dementia and Alzheimer’s disease is loss of synapses.”
Alongside Krafft, Klein also teamed up with Caleb “Tuck” Finch, an eminent molecular biologist based at the University of Southern California. Through various experiments, the scientific trio posited that amyloid beta oligomers, not amyloid plaques as commonly thought, were the actual toxins responsible for Alzheimer’s disease. Those findings launched a company, Acumen, in 1996 and the group published its first paper in the Proceedings of the National Academy of Sciences (PNAS) in 1998. To date, that single paper has been cited more than 4,500 times.
Initially, however, the group’s boundary-breaking work struggled to gain a foothold in the scientific community. Klein recalls standing at a conference and overhearing a group of “very productive fellows” from a prestigious American university questioning the validity of his team’s results. Even after the researchers published a second PNAS paper in 2003 demonstrating amyloid beta oligomers existed in the Alzheimer’s brain, but not the control brain, skepticism remained. “For a long time, we had to be the salmon swimming upstream, and it was very, very difficult to get people to buy into the notion that the actual culprit [of Alzheimer’s disease] was amyloid beta oligomers.”
As Klein and his team shopped the potential for a receptor target to pharmaceutical companies, they encountered multiple dead ends. Promising deals collapsed and questions persisted about drug discovery’s ability to tackle Alzheimer’s. Disappointment began mounting and progress seemed slow, if not wholly elusive. “That leads to the question from my wife: ‘What’s taking so long?’”
Still, Klein and his collaborators continued pushing. They earned funding to power additional experiments; presented their findings at conferences; nurtured collaborations with investigators near and far; and entered an exclusive license and research collaboration with Merck & Co. They also created the first antibodies to amyloid beta oligomers and willingly shared those with other scientists to fuel additional experiments. Klein, in particular, stayed committed to the mission. “You just can’t roll over. The data was on my side, and I wasn’t going to give up.”
By the early 2010s, the group’s science gained wider approval – and the momentum has only accelerated over subsequent years. Today, laboratories and pharmaceutical companies around the world are studying amyloid beta oligomers and developing therapeutics to target the toxic proteins. Klein’s Northwestern-based lab, meanwhile, has collected a combined 170 papers and patents on the topic. “The dominoes are falling as people acknowledge amyloid beta oligomers look to be an authentic target for Alzheimer’s therapeutics.” In fact, over 5,000 papers have been published on amyloid beta oligomers and publications from Klein’s lab have been cited more than 35,000 times.
Acumen is among the foremost drug discovery companies attacking amyloid beta oligomers and its most promising therapeutic, ACU193, derives from an antibody program initiated in Klein’s research lab decades ago. In 2021, ACU193 entered a Phase 1 clinical trial and earned favorable results. Last November, BioTech Breakthrough, an independent organization recognizing standout life sciences and biotech companies, awarded Acumen and ACU193 its prestigious “Monoclonal Antibody Solution of the Year” as part of its BioTech Breakthrough Awards program. ACU193 is now preparing for a phase 2/3 trial with the U.S. Food and Drug Administration. “We’re finally on the fast track.”
Klein, who also has an appointment in the Department of Neurology at Feinberg, praises Northwestern’s intellectual horsepower, collaborative energy, and entrepreneurial ecosystem. He credits collaborations with some of Northwestern’s top scientists for propelling his team’s progress and spurring a deeper understanding of Alzheimer’s and how to combat the disease. Over the years, he’s partnered with renowned colleagues from Weinberg’s Department of Chemistry, such as Chad Mirkin, Neil Kelleher, Rick Silverman, Thomas Meade, and Milan Mrksich as well as researchers from Feinberg and the McCormick School of Engineering like Vinayak Dravid. Klein has also leveraged emerging resources at Northwestern, from imaging technologies to the Keck Biophysics Facility, to drive investigations and leaned on a capable team led by lab manager Kirsten Viola, who has worked on the Alzheimer’s project since its inception. “We have the intellectual camaraderie and the resources in terms of instrumentation at Northwestern to really help scientists like me make a difference.”
Five decades into his scientific career and nearly 30 years into probing the mysteries of Alzheimer’s to generate a molecular basis for the cause, diagnosis, and treatment of the disease, Klein remains as passionate and determined as ever. “It’s the chasing after it that inspires and the idea that I can really make a difference that continues to motivate me.”
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