|T H E N I H C A T A L Y S T||M A R C H A P R I L 2004|
(First in an occasional series)
What Drives NIH Scientists?
A NEED TO KNOW THE ORIGINS OF CANCER SPARKS A CAREER PATH
Katherine Calvo remembers that "as a young girl I wanted to become either a scientist, a doctor, or a constitutional lawyer."
Two out of three, as they say, isnt bad, especially when the two she has succeeded in becoming put Calvo at the cutting edge of research that is revolutionizing the diagnosis and treatment of cancer.
In a sense, motherhood almost derailed the pursuit of those aspirations and then, unexpectedly, it helped define them.
It was her sons illness that sparked her resolute journey through a rigorous MD/PhD program at the University of California, San Diego, and into an NCI residency, where for the past year, she has engaged in clinical pathology training while preparing for the research that for years she thought would remain a dream.
As a resident in the Laboratory of Pathology, Calvo will be using proteomics to map out the specific molecular pathways that are deranged in individual patients tumors. She and her colleagues hope eventually to use cocktails of molecularly targeted inhibitors tailored for individual tumors.
"It is my dream that in the futurethe treatment of cancer will be as easy as taking antibiotics to cure an infection," Calvo says.
Calvo observes that she didnt exactly follow the paths of her two childhood idolsMadame Curie and Mother Theresawhen she opted to concentrate on international relations at Reed College (in Portland, Ore.) and then married and had two children.
It was through her husband, Ahmed, a physician and the CEO of a primary care IPA, as well as the president of the AlamedaContra Costa AAFP (American Academy of Family Physicians) in California, that she was initially connected to the field of medicine.
"I was happy being a mom at home," she recalls, "but I still had a desire to be part of the world, to be an active participant." When her older child, Sean, was three, Calvo decided she wanted to practice medicine. She enrolled at Stanford University in Stanford, Calif., and "essentially started college all over again" in science to fulfill premed requirements.
Two years later, during a vacation to Disneyland, Sean became uncharacteristically lethargic and complained of pain when walking. His sister Leah, two years younger, showed no signs of fatigue. That evening, the Calvos noticed a bruise on Seans shoulder. "I thought he might have gotten hurt while playing," but Ahmed insisted they see a pediatrician the next morning, Calvo recounts.
Although the pediatrician thought Sean had nothing more serious than a cold, Ahmed insisted that blood be drawn. The next day, while Calvo took a final exam on cancer in the oncology section of her human biology class, the pediatrician came to the Calvos home and told Ahmed that a group of pediatric oncologists at the University of California at San Francisco were waiting to see Sean. Ahmeds suspicion that Sean had leukemia, which he had withheld from his wife, had been confirmed.
The Calvos were directed to the pediatric oncology ward at UCSF, where Sean was diagnosed with acute lymphoblastic leukemia with myeloid markers and a 1:19 chromosomal translocation.
Because Seans prognosis was poor, the Calvos accepted their doctors suggestion that Sean participate in a research study with an experimental chemotherapy protocol. Consents and waivers signed, Sean was given the first dose of pills, liquids, and shots. IV infusions, spinal taps, injections, bone marrow aspirations, biopsies, and more blood tests would follow.
Over the next several months, five-year-old Sean pleaded not to be taken to chemo, and Calvo questioned whether she ought to pursue her career. She credits her sons physician with teaching her bedside manner and with urging her to continue her studies. She went to school in the morning three days a week while friends and family stayed with Sean. During his hospital stays, she slept on a cot next to his bed.
The first two months passed. Sean became so pale his skin was translucent; his hair fell in large patches; he spiked fevers and had bouts of neutropenia. His parents feared potentially fatal infections and monitored his neutrophil count. But they also wanted Sean to live as normal a life as possible and enrolled him in kindergarten at a Berkeley school reputed for its academic excellence and its progressive attitude.
Their experiences at the school fell a bit short of the schools reputation, however: Some parents objected to Seans presence for fear their children would soon have to deal with the death of a schoolmate, and a group of older children, third-graders, actually ganged up on Sean during one recess, removing his cap and laughing at his baldness.
Over time, education improved the understanding of parents and students, and the situation improved considerably; the lessons learned were indelible.
"I wanted to find out what had happened to (my son) on a molecular level."
the Road to Recovery
In the ensuing three and a half years, Sean completed chemotherapy and regained his health and energyand Calvo completed biochemistry and biology courses at Berkeley, applied to medical school, and was accepted into the UCSD MD/PhD program.
During her first year, she joined a lab at the Scripps Research Institute in La Jolla to delve into the mechanisms of programmed cell death. She also arranged to rotate through a leukemia lab.
"I decided I needed to know and do more," Calvo recalls. "The pressure of watching my son and other children suffer from cancer intensified my desire to go deeper into medicine and research. I wanted to understand what had happened to him on a molecular level."
She was captivated by the science of dissecting the oncogenic mechanisms of the transcription factors that induced the aberrant gene expressions that drove cells toward cancer.
Down to Basics:
As a student in the Molecular Pathology Graduate Program, she worked simultaneously on several different projects: the structural biochemistry of E2a-Pbx1, homo- and heterodimerization properties, and the functional domains required for oncogenesis in a mouse marrow immortalization system; the cooperation of HoxA9 and Meis 1 in orchestrating blockage of cell differentiation and self-renewal in cytokine-specific contexts; and the mechanisms of oncogenesis by Nup98-HoxA9 in myeloid leukemia.
Her thesis work addressed the oncogenic mechanisms of homeobox genes that are targets of chromosomal translocation in leukemias.
After completing her PhD in molecular pathology, Calvo took the final two years of medical school and began applications for her residency. "My biggest dilemma at the time was whether I would go into pathology or hem/onc [hematology/oncology]," she says.
"And I wanted more than anything to visit the NIH (pathology residency program) . . . . I never dreamed Id be here."
"You Can Do that Here"
What she had wanted to do, she relates, was to be able to map the specific proliferative, differentiation, and apoptotic pathways that become altered in cells in the progression to a cancerous phenotype.
With the understanding that each type (and subtype) of cancer probably has a unique combination of altered proteins in key pathways, she reasoned thatusing a combination of genomics and proteomicsearly diagnosis could be based on identifying the specific altered pathways in each individual patients tumor. The design of cocktails of specific molecular inhibitors to fight each individual cancer could then follow.
This was the sort of research she dreamed of pursuing, but she was not sure then that the dream was realistic. When she described her ideas to Lance Liotta, chief of the NCI Laboratory of Pathology and head of the pathology residency program, he looked at her and said simply, "You can do that here."
"I was blown away; Im still blown away," she says, laughing.
At the Threshold
Sean has been in remission since 1993. Leah, now 15, moved from California to Bethesda when Calvo accepted her residency with NIH and attends high school in the area. Ahmed and Sean will move later this year when Sean graduates from high school. Ahmed is now busy recruiting his replacement as chief medical officer for the San Ysidro Health Center in San Diegoand Sean, who is drawn to bioengineering and medical school, is applying to colleges on the East Coast.
"My greatest hope," Calvo says, "is to make a difference in the lives of patients by advancing the fields of cancer diagnostics and treatment. We need more dedicated research to reach a point where cancers are diagnosed at the earliest stages and treated individually for the specific protein network of pathways that have gone awry."
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