Remembering Peter Nowell

By Lisa J. Bain

When Peter Nowell, MD’52, and David Hungerford, PhD, peered through a microscope and saw the stub of genetic material that would come to be known as the Philadelphia chromosome, they could not have foreseen that this observation would spark a chain reaction that would eventually enable the development of targeted and personalized cancer treatments. Yet friends and colleagues point to myriad factors that allowed Nowell to make some of the most important biomedical discoveries of the 20th century: He was smart, a true genius by some accounts; he loved basic science and was devoted to defining the principles that would lead to better therapies; he was humble and nurtured the careers of students and other scientists; and his thinking was not limited by existing dogma.

 “He always said that we made the boxes, biology did not,” said his long-time collaborator Jonni Moore, PhD, a professor of Pathology and Laboratory Medicine in the Perelman School of Medicine at the University of Pennsylvania. “And that was totally the way he approached science—always thinking outside the box, always open to new ideas and new approaches.”

Nowell died Dec. 26, 2016 at age 88. With the exception of two years at the U.S. Naval Radiological Defense Laboratory after his training in Pathology at Presbyterian Hospital (GME’56), he spent his entire career at the Perelman School of Medicine. A recipient of numerous international honors including the Lasker Award in 1998 and the Benjamin Franklin Medal in Life Science in 2010, he served at Penn as chair of Pathology and Laboratory Medicine from 1967 to 1973 and was the first director of what is now the Abramson Cancer Center. His far-reaching scientific legacy lives on through the fond memories of his professional peers and the lasting impact of his ideas that suffuse the medical landscape today.

Fundamental Discoveries Transform Cancer Therapy

The 1960 discovery of the Philadelphia chromosome—an abnormality initially seen only in the cancerous white blood cells of patients with chronic myelogenous leukemia (CML)—provided the first evidence that cancer was a genetic disease, and set off a chain of research that defined a new era for cancer care. Ten years later, Janet Rowley, MD, at the University of Chicago showed that the Philadelphia chromosome came about when part of chromosome 9 broke off and reattached itself to chromosome 22. Subsequently, Nora Heisterkamp, PhD, at the National Cancer Institute showed that the translocation resulted in the fusion of two genes known as BCR and ABL; and Owen Witte, MD, at UCLA showed that the BCR-ABL fusion gene produced a type of enzyme called a kinase that caused cancer cells to proliferate. Brian Druker, MD, of Oregon Health and Science University used this knowledge to study an inhibitor of the kinase, later called Gleevec, which became the first small molecule targeted therapy for cancer. The drug has made CML a manageable chronic disease for the approximately 5,000 U.S. patients newly diagnosed each year, saving these lives and others with related forms of leukemia, and transforming cancer treatment.

Following the discovery of the Philadelphia chromosome, scientists worldwide went on to document different kinds of mutations driving virtually every human cancer that has been studied.

Meanwhile, Nowell made other important discoveries. He showed that a plant substance called phytohemagglutinin stimulated lymphocytes to divide, a tool that launched a new era in the field of immunology.

He also made an observation that transformed a generation’s thinking about cancer genetics: By looking at the cells of patients multiple times over the course of their disease, he realized that additional changes in the genes accrued over time. In 1976 he published a “thought paper” in the journal Science describing his hypothesis that defined the concepts known as clonal evolution and tumor heterogeneity. He proposed that most tumors arise from a single genetically mutated cell, that cancer cells are prone to additional mutations over time, and that those additional mutations will persist and evolve if they enable continued tumor survival and growth. He went on to suggest the need for cancer therapies targeted to the genetic cause of an individual’s disease. The paper presented no data.

“It was incredibly prescient for him to come up with that hypothesis based on limited data,” said David Roth, MD, PhD, the Simon Flexner Professor and chair of Pathology and Laboratory Medicine. “It was almost like magic.”

But, of course, it was more than magic. “He used to always say that one of the most important things was to observe and then to actually take the time to think about what you observed and try and apply it,” said Jennifer Morrissette, PhD, an assistant professor of Clinical Pathology and Laboratory Medicine at the Perelman School and clinical director of the Center for Personalized Diagnostics. “He said one of the best things about the department of Pathology was that the pathologists would do their work and then walk around campus, particularly around the Biopond, and talk about what they thought about patterns they were seeing, the importance of different findings; constantly saying things out loud and talking about them with colleagues who would challenge you.”

Moore agreed that Nowell was a man of his time.  “He was a true scientist in the sense that he always looked at the big picture and wanted to ask important, very big questions that led to very important discoveries,” she said. “A scientist can’t do that today. Our system is not set up to allow people to ask the big questions.” In 1986, Nowell received an outstanding investigator award from the NIH, a 10-year grant that required no specific aims. “The NIH, in its infinite wisdom, knew that he was a gifted scientist and that their investment in him would be rewarded,” Moore said.

The Ripple Effect

Like drops in a vast pool of water, the discovery of the Philadelphia chromosome and Nowell’s theory of clonal evolution rippled outwards and continue to do so to this day. Mark Greene, MD, PhD, now the John W. Eckman Professor of Medical Science in Pathology and Laboratory Medicine, was recruited to Penn by Nowell and then-Pathology Chair Leonard Jarrett, MD, in 1986. Although Nowell worked at the cellular level and Greene at the molecular level, the two scientists were close colleagues and talked almost every day. And both made central discoveries that have led to promising new cancer therapies. (See below: “Targeted Therapies for Breast Cancer.”)

Kojo Elenitoba-Johnson, MD, who holds the Peter C. Nowell MD endowed professorship and directs the Center for Personalized Diagnostics at Penn Medicine, said that many scientists have built their stellar careers on Nowell’s fundamental observation of the Philadelphia chromosome: “The entire universe of understanding that acquired genetic mutations drive sporadic cancer emanated from that work.” Elenitoba-Johnson also noted that virtually everything Nowell predicted in his seminal paper on clonal evolution has also turned out to be true, including the fact that cancer cells acquire secondary alterations, among them metabolic alterations, that allow them to adapt, grow, and proliferate under oxygen-poor conditions while sacrificing efficiency of energy generation for production of cell mass. Nowell also predicted interactions with the immune system and envisioned a critical role for immunotherapy as an strategy to combat cancer long before the field matured. (See below: “Exploiting the Immune System to Target Cancer.”, )

The emergence of precision medicine—targeting treatments to an individual patient’s mechanism of disease—owes a debt to Nowell’s insights. “The field of precision medicine is bigger than cancer, but it really started in cancer, so not only is the Center for Personalized Diagnostics a direct outgrowth of Peter’s work but so is precision medicine in general,” Roth said. “Peter’s work started that whole line of thinking.”  (For an in-depth look at the Center for Personalized Diagnostics and the Penn Center for Precision Medicine, which Roth directs, see “One Size Does Not Fit All,” Penn Medicine Summer 2016.)

Educator and Enabler

To Nowell, education was paramount. One of his many sayings Moore recalled was, “We have to remember we’re a medical school primarily.” He felt that the people he trained were his real legacy, she said, even beyond his scientific discoveries. In his lab, there was also no hierarchy. “Everyone was respected for their role in the project and he well understood the concept of team science, well before team science was talked about,” she said. Moreover, his commitment to education and training was not restricted to the Penn students, postdocs, and fellows who passed through his lab. He also led courses for elementary and high school students, aiming to cultivate their love for science, Moore recalled.

According to John Reed, MD’86, PhD’86, GME’89, who worked in Nowell’s lab as an MD-PhD student, Nowell spent as much time training his students how to express themselves in writing as he did on scientific methods. Reed recalled how after completing research for his PhD thesis, he spent weeks writing what he thought was a brilliant manuscript that would impress Nowell. “Rather, he handed me a copy of Strunk & White’s book, The Elements of Style and instructed me to read it, then tell him whether I still wanted him to read my draft manuscript. The next day, after reading the book, I sheepishly returned to Peter's office and retrieved my manuscript, realizing that it was horribly flawed.” Reed and Nowell ultimately published more than 30 papers together. “Each time, we would spend hours debating how to construct particular sentences or phrase ideas succinctly,” Reed said. “That experience was more important in preparing me for a career as a scientist than any experimental technologies I mastered.”  

“I definitely won the training lottery,” Moore said. It was not easy to be a woman scientist with a family when she joined Nowell’s lab as a postdoc in the ’80s, but “if it was late in the day, he would say to me ‘please go home and be with your children,’” Moore said. “You would never have found anyone saying that back then, but that’s the way he lived because his family was really primary in his life.” That support extended to her growth as a scientist. She recalled a time when Nowell was invited to speak at a prestigious meeting of ten of the world’s leaders in the field of leukemia and lymphomas. As the parent of a special-needs child, Nowell rarely traveled, preferring to stay at home and help care for his eldest daughter, Sharon, who had severe disabilities from cerebral palsy. “He called them up and said, ‘I’m sending Jonni Moore, who is a postdoc in my lab, because I won’t come,’” Moore said. “I can promise you that they probably didn’t want me, but they weren’t going to tell him that.” She attended—and held her own as the only woman at the event and a postdoc at that. The meeting helped her make connections important for the rest of her career, she said.  

After her postdoc, Moore went on to collaborate with Nowell for 20 years in a specialty he had made possible (See below: “Cell-based Analyses Fuel Precision Medicine.”).  He encouraged her early on to find her own voice and establish independent scientific credentials, even advising her not to put his name on her papers. “You don’t want people to say ‘somebody in Peter Nowell’s lab,’” she recalled him saying. “And that was a very important piece of advice. Now, people know I trained with him but they never assume I accomplished what I did because of him.”

Elenitoba-Johnson, who joined the Penn faculty in 2015, never worked with Nowell himself but felt his influence after meeting him once in 2005. “He was very humble, inspiring, and insightful in his questions regarding my work, and also forward thinking in ways that I hadn’t even considered.” Then early in his faculty career, Elenitoba-Johnson was studying the signaling consequences of NPM-ALK, a fusion gene occurring in the most common form of pediatric T-cell lymphoma, and had started to investigate unanticipated consequences of expression of the fusion gene using mass spectrometry. Nowell suggested that in addition to signals that turned on growth promoting genes as a result of excessive activity of the protein, it was also likely that other pathways were switched off, and that it was the combination of these two signals that contributed to a tumor’s aggressive growth. “It was not his area, but he was able to see beyond a few technicalities and say, ‘here’s what’s going to be important,’” Elenitoba-Johnson said.

It is a testament to his impact that Elenitoba-Johnson and Roth, who knew Nowell only later in his life, as well as people who worked by Nowell’s side for many years like Reed, Moore, and Morrissette, can all trace much of their success back to Nowell. “He was an extraordinary man,” Greene said. “I’ve worked with Nobel laureates, but he was the most extraordinary of them all because of his total commitment to defining basic principles that would lead to better therapeutic opportunities. He was one of the believers that great science leads to great discoveries. He was a real hero.”

From Philadelphia (Chromosome) to the World (of Modern Precision Therapies)

Peter Nowell was renowned for his ability to see the big picture. His visionary 1976 Science paper predicting that cancer cells evolve and accumulate adaptive genetic changes over time was not only correct, but laid the groundwork for modern approaches to precision medicine. When Nowell peered into his microscope nearly 60 years ago and saw the Philadelphia chromosome for the first time, could he have envisioned how far that discovery and other discoveries built on his ideas would someday reach? 

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