Early in the 1600s, a Spanish conquistador and a Colombian Indian woman conceived a child – maybe several children. The Spanish invader very likely carried a mutation that causes the onset of Alzheimer’s disease in the mid-forties.
Today, the offspring of this couple make up about 5,000 extended family members, many of whom harbor that early onset Alzheimer’s mutation.
Four hundred years later that coupling may offer clues toward treating Alzheimer’s, which has become one of the most dreaded diseases of modern civilization
UC Santa Barbara Harriman Professor Kenneth S. Kosik has worked for nearly 30 years with his close collaborator Francisco Lopera, a Colombian neurologist, to characterize this family of enormous medical interest.
Using blood samples from the Colombian population, Kosik and another colleague Alison Goate, from the University of Washington, identified the early onset Alzheimer’s gene as an E280A mutation in a gene called PSEN1 on chromosome 14.
The findings and the research into the unique population of the state of Antioquia, Colombia may succeed at a time when several pharmaceutical trials into Alzheimer’s treatments have repeatedly hit dead ends. In recent years, more than 190 drug trials involving Alzheimer’s cures have flopped.
Researchers now believe that drug treatments are being tested when it is already too late in the progression of the disease. Instead, treatments need to be introduced before the onset of extensive cell death caused by the plaques and tangles which are the hallmarks of Alzheimer’s disease.
That’s where the Colombian population and Kosik’s research becomes important. Once you can identify through DNA tests who is most likely to get Alzheimer’s disease, then you can start therapeutic drugs at an early age. The pharmaceutical company Genentech, in collaboration with Banner Health, has launched a clinical trial to prevent the onset of Alzheimer’s disease.
In the early 1900s, German psychiatrist Alois Alzheimer described the first case that bears his name. His patient Auguste Deter suffered from dementia. When she died, Alzheimer autopsied her brain and discovered the plaques and tangles that typify the disease.
Clinically, he performed autopsies on his patients who suffered a severe form of dementia – and again, he found plaques and tangles in the brain. The plaques form in the space between brain cells and interrupt brain impulses through which neurons talk to each other. Plaques are made up of amyloid proteins. The tangles form inside the brain cells and consist of a protein called Tau.
There is no question that under the microscope, at the cellular level, that Alzheimer’s disease is a vicious and ruthless condition.
Research at the big pharmaceutical companies is driven by the more than 5 million current Alzheimer’s patients in the United States (35 million people worldwide) and the prediction that number of U.S. patients will grow to almost 14 million by 2050. The cost to our medical system could “bankrupt it,” asserted Kosik. Companies have spent 30 years trying to unravel the Alzheimer’s mystery and eager investors have poured about $350 million into startups looking at Alzheimer’s cures.
After several expensive clinical trials flopped, interest in Alzheimer’s patients in Colombia grew. (On July 28, the Wall Street Journal reported that the very latest experimental drug to target Tau proteins related to Alzheimer’s had failed to improve patient conditions. The drug, by TauRx Pharmaceuticals was the first Tau-targeted therapy to reach late stage testing in humans, the Journal reported.)
Kosik and Lopera had worked in obscurity for decades, but with the realization that disease treatments had to begin earlier, the Colombian population became increasingly attractive as a study population because it was possible to predict who would get the disease – and when.
The genetic mutation offered a definitive predictive diagnosis and provided a rationale for the pharmaceutical industry to step up with a candidate drug that could help the local people.
This past June, Kosik was invited to be the commencement speaker for UCSB’s graduates from the Division of Humanities and Fine Arts. A very unusual choice, having a neuroscientist talk to philosophy and fine arts graduates. But Kosik very quickly illustrated why his personal story is one for all young students of the humanities and fine arts.
Kosik received both his bachelor’s and master’s degrees in English at Case Western University. As he told the UCSB graduates, “I was absorbed in a fictional multiverse—entire world’s created by the Brontes, Dickens, Eliot, Hardy, Conrad, Melville, Faulkner, Joyce…I learned that unlikely events -- the things we say could never happen to us—happen all the time because there are so many possible unlikely events that a few of them will happen.”
Kosik’s career is just such a series of unlikely events. Deciding that fiction was too finite—“it ends on the last page of a novel”—Kosik struck out for medical school. He was accepted at Medical College of Pennsylvania. There, he found himself “restless” and joined a theater group. The most dramatic and important day in the life of a medical student is the “match” they receive at graduation, an invitation to join a hospital or institute for their residency training. As his fellow medical students tore open their invitations, Kosik realized he was not going to receive one. The dean told him to come into his office the next morning and that they would find something.
In the dean’s office, going through a list of small community hospitals, Kosik spotted the name The Faulkner, a hospital in Boston. “That’s the one,” he told the UCSB students. “I don’t know anything about the place, but remembered William Faulkner…”
In his residency, Kosik learned a tough lesson about being a doctor. When one of his patients had a horrible setback from complications of the drug Kosik had administered, he became completely preoccupied by the patient’s slow descent to death. “In medicine we learn the importance of empathy, but we also learn that too much empathy is paralyzing. I was too emotionally involved…”
As his medical training came to a close, Kosik faced a new choice – to continue as a doctor or to become a researcher in a field that captured his imagination: brain cells. He ultimately joined the faculty of the Harvard Medical School and became a full professor there.
He remained at Harvard for more than two decades. Then, he came to UC Santa Barbara. He told the UCSB students that in 2004, “I left Harvard Medical School and never looked back.” From his corner office in UCSB’s BioSciences II building, Kosik has spectacular views of the Pacific Ocean. It’s not the view that brought him from one of the premier medical schools in the world to a University that is both casual and pioneering.
The decision to come to UCSB was both “a good decision and a simple decision,” he explained. At Harvard he found himself in a silo of biomedical researchers. While he “loved it” he also saw that it was far too homogenous for what he wanted to do in brain cell research. “I wanted to interact with people who came to science from different directions, engineers and physicists and computer scientists.” UCSB, he explained, “is the perfect environment for building these bridges.” He noted that his first graduate student at UCSB was from the computer science department. “That would have never happened at Harvard.”
Today, Kosik is the Thomas Harriman Professor of Neuroscience in the department of Molecular, Cellular and Developmental Biology. He is also co-director of the Neuroscience Research Institute. In his lab, he has 15 post-docs and graduate students who conduct an extraordinary breadth of research in neuroscience – from studies on the Tau protein, to working on computer models that predict stem cell differentiation and the firing patterns of neurons.
For Kosik, a typical day involves teleconferences with other researchers, writing grants for future research, and producing research papers that will push the edge of scientific knowledge. “Unlike the image that many of scientists have, in fact, science is a highly social activity,” he explained. “You don’t do it alone.” So there are frequent conversations with his own lab members, international conference calls, Skype meetings and research conferences.
His two biggest activities: “Scientific exchanges with people in my lab and around the world, then digesting it all.”
Kosik’s breakthrough research came about as another series of unlikely events. His colleague, Colombian neurologist Francesco Lopera first encountered the multi-generational family of early-onset Alzheimer’s patients in the mid-1980s. At first he did not know if what he was seeing was Alzheimer’s disease or another case of dementia. In that region of Colombia, the malady was known as boberia or the “foolishness.”
In the early 1990s, Kosik went to Colombia as he was starting his research career at Harvard. He had received a small grant to give lectures in Latin America and organize neuroscience research projects. Lopera attended one of his talks and approached him afterwards to share with him his findings in Antioquia.
That began a 30-year collaboration between Lopera and Kosik that has led to numerous findings about the cellular behavior of those with the genetic mutation. (Their work was recently featured in the 2016 Nova TV documentary “Can Alzheimer’s Be Stopped.”)
Kosik and his many collaborators in Colombia and elsewhere have published a number of papers that describe features of Alzheimer’s disease in the population. As the realization that the treatment of Alzheimer’s disease has to begin well before the symptoms become obvious, Kosik said, “That’s when my phone began to ring. I was no longer a guy on the margins who was going to Colombia.”
Clinical trials of a drug developed by Genentech have begun in Colombia. With the clinical trial now proceeding in the hands of specialists, Kosik has continued to focus on the genetics of the population. He and Dr. Lopera have identified six individuals who have inherited the gene mutation from both their mother and father – and therefore receive a double dose of the mutation.
What the effects of this double dose will be, as these young individuals age, remains to be seen. Kosik also discovered a genetic variant present in some members of the family that can mitigate the effects of their mutation and delay the onset of the disease by as much as a decade. Remarkably, he and Lopera recently found a second large family with a different mutation in PSEN1.
One of the most difficult issues Kosik faces is the agreement among all researchers involved that the Colombian individuals will not receive the results of their genetic testing. At least for now, they have to agree that they will not be informed on whether or not they have the mutation.
The main reason behind this difficult decision is the absence of genetic counselors and support services to help people handle such serious information. A positive test for this mutation means the affected individual will inevitably get Alzheimer’s disease by age 50—on average—and will survive for about ten years.
Kosik agonizes over this decision, even though most people would opt not to know they have the gene for an incurable disease. “People should have the right to their own information,” he said. “But it needs to be delivered in a setting where individuals are fully informed, not only with the grave consequences of this mutation, but also with the hope that as the age of onset approaches, we are moving closer to a cure. We simply cannot say when that will happen.”
In 1999, Kosik wrote this for The Scientist magazine: “Scientific revolutions derive from small, incremental discoveries. Lopera and I, and other neurologists, who contribute a jigsaw piece here or there, cannot envision the completed puzzle. My experiences in Colombia have helped me put the genetic enterprise in perspective….”
“No matter how much progress we scientists make toward understanding the present and controlling the future, destiny will always hold the trump card. We cannot know, in advance, the eventual impact of genetic knowledge. We can only strive to untangle its secrets with a sense of responsibility toward the communities that hold the precious genetic clues.”comments powered by Disqus