By Lisa J. Bain
The Big-Thinking Penn Scientist Best Known for Discovering the Philadelphia Chromosome Pioneered Concepts Underlying Precision Medicine and Championed Education at All Levels
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.”
Photo by Candace Di Carlo
“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?
Targeted Therapies for Breast Cancer
“Peter Nowell was the major reason I came to Penn, because we worked on similar problems of the evolution of malignant cells,” said Mark Greene, MD, PhD. “However, my lab is much more atomic and molecular than his was; and we deal with principles of designing therapies.”
Greene’s work over the past 30 years has helped transform the treatment of breast cancer, achieving the translation of fundamental discoveries about the genetic basis of cancer into more effective therapies that was always Nowell’s ultimate goal. In 1985, Greene’s lab showed that antibodies directed against a protein called HER2 inhibited the growth of tumors driven by an oncogene called HER2/neu. This discovery led to development of Herceptin, the first targeted therapy for HER2-positive breast cancer, a particular aggressive form of breast cancer that is found in about 20-30 percent of cases. Approved by the FDA in 1998, Herceptin is thought to have saved many thousands of lives worldwide.
Greene’s lab has gone on to develop small molecule inhibitors of HER2, which have the advantage of oral delivery, in comparison to antibody-based treatments that are delivered by intravenous injection. Small molecules may also be able to penetrate more deeply into a tumor and are potentially easier and cheaper to manufacture. Since HER2 is also overexpressed in other types of cancer, these small molecule inhibitors may further expand the universe of targeted therapies.
New Class of Drugs for Blood Cancers
In 2016, the Food and Drug Administration granted accelerated approval to a drug called venetoclax for the treatment of chronic lymphocytic leukemia. Several more drugs in its class are in development and clinical trials for the treatment of hematologic cancers. These drugs target a protein called Bcl-2 and related molecules produced by genes that, like the Philadelphia chromosome, result from a translocation event. The 14:18 chromosome fusion that creates the Bcl-2 gene is now known to be the most common cytogenetic abnormality in cancers of the blood.
In the mid-1980s, Nowell’s lab, in collaboration with Carlo Croce, MD, then at Penn and now chair of Cancer Biology at Ohio State, were the first to discover the Bcl-2 gene in lymphoma cells from nearly all patients with Hodgkins lymphoma. Shortly thereafter, John Reed, MD, PhD, (now at Roche) joined Nowell’s lab as an MD-PhD student and set out to determine how Bcl-2 causes cancer. Over the next few years, Reed and his colleagues showed that Bcl-2 increased the formation of tumors in mouse cells, that blocking the Bcl-2 gene’s expression in cells could suppress tumor formation, and that the Bcl-2 protein is necessary for cell survival in both healthy cells and cancer cells. Reed’s team went on to show the Bcl-2 gene could switch leukemia cells from being chemosensitive to chemoresistant, and finally that synthetic DNA molecules that shut off Bcl-2 expression could convert chemoresistance to chemosensitivity in lymphoma—bringing the potential for today’s class of drug candidates within reach.
Exploiting the Immune System to Target Cancer
In Nowell’s seminal paper on clonal evolution, he predicted not only that cancer cells undergo stepwise, sequential mutations to adapt to their environment, but also that those changes could be exploited to develop immunotherapies for cancer. Since then, scientists at Penn’s Abramson Cancer Center (ACC) have pioneered a variety of approaches that marshal the body’s immune system to kill cancer. One of the most promising, and one that provides an ultra personalized approach, is CAR T-cell therapy.
Chimeric antigen receptor (CAR) T cells are engineered from a patient’s own immune cells to target the specific proteins expressed on their cancer cells. T cells isolated from the patient’s blood are modified in the laboratory to recognize the cell-surface proteins of interest and are then reinfused into the patient, where it is hoped they will go on attack against tumors.
Carl June, MD, the Richard W. Vague Professor of Immunotherapy at Penn, directs the ACC’s Center for Cellular Immunotherapies. In 2010, his team—including David Porter, MD, and Bruce Levine, PhD—used CAR T cells to treat three patients with advanced chronic lymphocytic leukemia; two experienced complete remissions of their disease and a third had a partial response. As of 2017, several hundred patients—both adults and children—have received investigational treatments using CAR T cells for other cancers, including acute lymphoblastic leukemia, non-Hodgkin lymphoma, multiple myeloma, glioblastoma, pancreatic cancer and ovarian cancer. The first two trial participants who went into remission remain well, six and a half years later. “In only a few years, we have generated significant achievements that have moved the field of personalized cellular therapies forward, opening clinical trials to test these treatments not only for patients with blood cancers, but also those with solid tumors,” June said.
“Fuller Spectrum of Clonal Evolution” Detected in Blood
Nowell’s early insights into tumors’ clonal evolution laid the groundwork for today’s targeted therapies, but determining which of the many new targeted therapies is most likely to work requires genotyping a tumor. This is usually done using tissue samples obtained from biopsy or surgical removal. But tissue is often unavailable, making genotyping and monitoring of clonal evolution challenging, said Erica Carpenter, PhD’09, MBA, director of the Circulating Tumor Material Center at Penn Medicine. Carpenter’s lab is using a relatively new method that requires only a simple blood draw to collect circulating tumor DNA or live circulating cells shed from tumors.
Carpenter calls it a “liquid biopsy,” noting that it is essentially non-invasive when incorporated into routine blood draws. Her lab recently demonstrated the power of the technique by studying a group of 102 patients with non-small-cell lung cancer. While tissue was only available for half of the patients, blood was obtained from all of them. Using ultra-deep sequencing techniques, Carpenter’s team identified one or more mutations in 86 of the 102 patients, including many mutations for which targeted therapies are available.
Testing the blood at multiple time points to monitor disease progression, response to therapy, and clonal evolution was also possible given the ease of drawing blood, Carpenter said. In addition, she said sampling from the blood may be more likely to show the full genetic spectrum of a patient’s disease from both primary and metastatic sites. “In other words, a fuller spectrum of clonal evolution.”
Epigenetics and Cancer
In Nowell’s landmark 1976 Science paper, he predicted that each malignancy might have to be considered as “an individual therapeutic problem.” Subsequent work has confirmed that tumors are highly heterogeneous, not just due to differences in genes themselves, but also due to chemical modifications to proteins that regulate the expression of genes—epigenetic changes. Recent insights from DNA sequencing of patient tumors across numerous cancers have led to a new view of cancer as arising from complex interplay between gene mutations and an altered epigenome.
For example, in the lab of Penn Epigenetics Institute Co-Director Shelley Berger, PhD, researchers have identified epigenetic changes due to a famous gene called TP53, which is the mutated in a remarkable 50 percent of human cancers. Berger, the Daniel S. Och University Professor and a Penn Integrates Knowledge University Professor at Penn, and colleagues found that the most common mutations in p53, the tumor suppressor protein encoded by that gene, led to inappropriately increased levels of several key epigenetic enzymes which drive rapid uncontrolled growth—the hallmark of cancer. By decreasing the amount of these epigenetic enzymes, Berger and colleagues were able to inhibit the proliferation of cancer cells. These results suggest that a broader understanding of how epigenetic changes drive proliferation of cancer cells, and thus cancer’s progression, could lead to novel targeted therapeutic approaches—in fact, Berger noted, a handful of epigenetic therapies are already used clinically to treat cancer.
Berger has directed the Penn Epigenetics Program since its inception in 2009. The Penn Epigenetics Institute, one of the leading epigenetics programs in the country, is co-directed with Berger by Marisa Bartolomei, PhD, and Gerd Blobel, MD, PhD.
Cell-based Analyses Fuel Precision Medicine
At Penn’s Flow Cytometry and Cell Sorting Resource Laboratory, Jonni Moore, PhD, oversees an instrument that she describes as the cutting edge of cell-based analytics: A 48-color flow cytometer, the only one outside of the National Institutes of Health. The instrument provides an additional tool to explore cytomics—the molecular analysis of cellular systems—to analyze cells across multiple dimensions. Cytomics was pioneered by the late Carleton Stewart, PhD, who came to Penn as Nowell’s first postdoctoral fellow in 1966.
“We wouldn’t have that instrument here if Peter hadn’t encouraged me and others early on that looking at the genomic level is important, but looking at the cell-based level is really where the rubber meets the road,” Moore said, because even more important than what gene is expressed are the effects that expression has on the cell. “It is at the level of the cell that we find the integration of genetic, proteomic and environmental causes of disease,” she said.
Cytomics has fueled the development of precision medicine by enabling physicians to apply advanced computational algorithms to identify signature biomarkers of disease status from cell samples. By providing actionable information for diagnosis, disease progression, and treatment response, Moore said, this information allows physicians to make patient-specific decisions.
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