The George C. Cotzias Lecturer: Robert B. Darnell, D, PhD: Neurology Collides with the RNA World – From Intellectual Disability to Motor Neuron Disease
ARTICLE IN BRIEF
Dr. Robert B. Darnell discusses the people and ideas that helped shape his path from research on paraneoplastic neurologic disorders to the molecular biology of RNA regulation in the brain and nervous system.
Robert B. Darnell, MD, PhD, didn't plan on following in his father's footsteps — much less ending up on the faculty at the same academic institution.
His father, James E. Darnell Jr., MD, is Vincent Astor Professor Emeritus at Rockefeller University and the winner of the 2002 Lasker Prize in honor of his half-century of research on the intricate mysteries of RNA. In 2011, he published RNA: Life's Indispensable Molecule (Cold Spring Harbor Press).
“I grew up immersed in science as a kid, and at the same time it was the 1960s and my dad was a liberal idealist,” recalled Dr. Darnell, now the Robert and Harriet Heilbrunn Professor in the Laboratory of Molecular Neuro-oncology at Rockefeller. “He ended up on the FBI list for being involved in Scientists Against the Vietnam War, and we used to march with candles down the street. My rebellion against my father, such as it was, was that I didn't want to do ‘ivory tower’ basic science, but science related to humanity's problems.”
That focus directed Dr. Darnell toward the MD-PhD program at Washington University in St. Louis, where he trained with Viktor Hamburger, PhD, and Dale Purves, PhD, both noted neuroscientists. “They were leading figures in the field at the time and wonderful to train with, but I wanted to work more specifically on human disease.”
Initially, Dr. Darnell hoped to clone disease genes for congenital mental retardation as a way to both help understand how cognitive function works, and also to do science in service of humanity. `But at the time, most known genes for mental retardation were defects in housekeeping genes. “I worried that I could go clone a family kindred, spend ten years on it and come up with the Kreb cycle or something, which might be important for disease but wouldn't give any insight into the nervous system.”
For a time, he felt at sea. Then came the discovery of oncogenes, obviously an important signaling pathway for cancer cells, but also expressed in neurons, which don't divide at all. “That suggested an interesting tension of unexplained importance, so I began to look for diseases that had an overlap between brain disease and cancer.”
That also led Dr. Darnell to the mentorship of Fred Plum, MD, and Jerome Posner, MD, two eminent neurologists at Memorial Sloan-Kettering Cancer Center and Cornell. Dr. Plum chaired the department of neurology and neuroscience at Cornell from 1963 to 1998, and Dr. Posner, known as the founding father of neuro-oncology, served as chairman of the department of neurology at Sloan-Kettering from 1967-1997.
“I had read their stuff in medical school and was very excited by their work in neuro-oncology,” Dr. Darnell recalled. “I became interested in cloning genes for diseases like tuberous sclerosis (which hadn't been cloned at the time) — disorders where a single gene defect gives rise to neurologic problems and a predisposition for developing cancer.”
While working with Dr. Posner, Dr. Darnell encountered a very esoteric group of diseases that his mentor had been studying: paraneoplastic neurologic disorders (PNDs). These disorders are believed to arise when tumors begin to make proteins that are normally only made by the brain. Patients with PNDs carry antibodies that specifically target these proteins; while this situation produces an effective antitumor immune response, it can also lead to an autoimmune attack on brain tissue.
“Most neurologists didn't know about these disorders, much less doctors in general,” he says. “But they may be the Rosetta Stones both into understanding important clinical questions, and also into understanding what makes a neuron differ from a liver cell.”
Patients with PND, in the best cases, can spontaneously eradicate their cancer — in some cases perhaps not even realizing that they have cancer in the first place, until and unless a second event occurs. That second event is the crossing of an immune cell into the brain, where it identifies neurons as a foreign invader.
“Then, the patient very rapidly comes to the attention of a doctor, usually a neurologist,” said Dr. Darnell. “The symptoms will manifest in a whole range of disorders depending on which neuronal protein the tumor cell has turned against: some patients lose memory, some lose motor control, and some will develop peripheral neuropathy so severe that they lose all sensation. Even though these diseases are rare, they are important both to understanding the components of naturally occurring and effective tumor immunity, and to developing models for what could happen when immune proteins cross the blood-brain barrier.”
Dr. Darnell's lab has pursued PNDs to the point of developing clinical vaccines to mimic the things that they believe are “going right” in these patients, to test in people with cancer without triggering the brain attack. They are now in phase I trials.
“These disorders provide a really interesting opportunity to address the question of how brain cells differ,” Dr. Darnell added. “The tumor cell turning on this protein suggests it's doing something interesting for the tumor, but it only does it in the neuron.”
And that has led Dr. Darnell back to a field he tried to avoid, because he didn't want to work in precisely the same area as his famous father: RNA. “When we cloned these disease genes using the antibodies from paraneoplastic patients to identify the genes that were coding for these cancer and brain antigens, it opened up a whole world of molecular biology to do something we haven't been able to do with multiple sclerosis: identify the genes involved and understand the disease pathophysiology in the brain. These neuron-specific proteins that the cancer cells are turning on? Their function seems to be to regulate RNA. That's the great irony: as much as I tried to be independent doing molecular neuro-oncology, my father and I ended up in the same area.”
The implication of this work, said Dr. Darnell, is that the brain has its own system for regulating gene expression that no other cell in the body uses. And it's not about DNA — DNA regulation in the brain doesn't appear to differ much from other areas of the body. “But when DNA gets copied into RNA, many things can happen, and regulating that complexity is done differently in the brain than in any other cell in the body.”
A number of genetic and sporadic diseases, ranging from Fragile X and autism to amyotrophic lateral sclerosis and cerebellar ataxia, have recently been traced to defects in RNA regulation in the brain. “So we've been in a lucky place at the right time, developing all this methodology to look at RNA regulation in the brain and nervous system,” Dr. Darnell said.