Author: The Wistar Institute

Recently, Wistar had the great honor of bestowing its annual Women & Science’s Helen Dean King Award upon Dr. Mary-Claire King, one of the most esteemed and productive scientists of our time, in recognition of her seminal contributions to science and human health.

King needs no introduction as the impact of her work in human genetics speaks volumes: She established the hereditary nature of breast cancer and identified mutations in the BRCA1 gene as the culprit of the phenomenon, shifting the view of the role of genes in cancer.

She also put her expertise at the service of humanitarian efforts around the world, applying genomic sequencing to identify victims of human rights abuses by, for example, reuniting more than 100 children who were kidnapped during the “Dirty War” in Argentina with their biological families.

After the award ceremony, with extreme clarity and verve King presented a fascinating overview of how an evolutionary biologist by training, she took on the task of deciphering the mystery of breast cancer heredity, from the first observations in the pre-genetics era through the Human Genome Project revolution, to the functional studies of the BRCA1 protein and the current options for prevention and targeted therapy.

King traced the beginning of the story back to the 1860s, when French surgeon and pathologist Paul Broca described familial breast cancer for the first time in medical history and postulated the existence of “unknown dispositions of the body which precede the first appearance of certain tumors.” Boca didn’t know genetics but based his conclusions on the study of family trees and autopsy cancer tissues. Later, in the 1970s, Broca’s hypothesis was formalized with statistical and epidemiological studies showing that women with a first-degree relative affected by breast and ovarian cancer had a higher risk of developing the disease.

This is when King entered the field of cancer epidemiology and genetics and began her “hunt” for what turned out to be the genetic origin of breast cancer. At that time, cancer research mainly focused on the role of viruses as the cause of cancer, so King’s working hypothesis of a genetic transmission of breast cancer was regarded with strong skepticism. Thanks to her background in evolutionary biology, she approached the question by building mathematical and statistical models to search for parameters that could explain the patterns of breast cancer in some families. She became convinced that the alteration of a single gene was the answer.

As King recalls, a lucky coincidence happened in the early 80s when the National Cancer Institute (NCI) was conducting a large epidemiological study to analyze the relationship between the use of oral contraceptives and breast cancer. King asked Dr. Frank Rauscher Jr., then NCI director, to include a question to study participants regarding family history of breast cancer. This resulted in data from more than 1,500 women, which King compared with her mathematical predictions, confirming her model of genetic transmission of breast cancer risk and existence of a breast cancer gene.

This model postulated that women and men in high-risk families inherit mutations in one of their two copies of this gene in all the cells of their body. These individuals remain healthy until a second mutation, referred to as “second hit,” alters the other copy in breast and ovarian cells, completely removing the gene function in these tissues. This pattern of transmission, known to geneticists as autosomal dominant, explains why mutation carriers have a much higher risk of cancer and, at the same time, why cancer doesn’t occur in 100% of the cases, requiring a second mutation event.

A few years later, in the mid 90s, similar studies conducted on the Eastern European Ashkenazi Jewish population confirmed King’s results on a completely different set of families, showing that women carrying mutations in breast and ovarian cancer susceptibility genes had a 70-80% risk of developing breast cancer, the same King estimated in the 70s with her mathematical model.

In the late 80s, however, the existence of a breast cancer gene was still a theory. To prove it, King had to find it or, as she said, “hold the gene in her hands.” Without the molecular biology technologies available today, it took a total of 17 years of hard and diligent work to finally hunt down the gene, later named BRCA1 and map it to chromosome 17. The results of this long effort, published in 1990 in Science, initiated a race to sequence BRCA1, eventually won by Myriad Genetics in 1994.

Soon after, another gene named BRCA2 was discovered, whose mutations are transmitted in the same pattern as BRCA1. It only took one year to sequence the full BRCA2 gene because at that point the Human Genome Project was underway and thanks to new technologies that had become available.

Thanks to King’s pioneering work, it is now well established that women who carry mutations in BRCA1 have more than 60% and close to 40% risk of developing breast and ovarian cancer, respectively, before age 70. For carriers of a BRCA2 mutation, the risk is around 45% for breast and 25% for ovarian cancer. More breast cancer genes have also been identified.

King is a fierce advocate for prevention in at-risk women and those in the general population, as in some cases, when family history is not available or the mutation is inherited from fathers who didn’t develop cancer, identifying women at risk can be challenging.

In a Journal of the American Medical Association (JAMA) commentary in 2014, King maintained that every woman should be offered genetic screening of breast cancer susceptibility genes by age 30 as a routine practice, so that carriers can opt to undergo risk-reducing surgery to remove their breasts and ovaries or remain under strict surveillance for early cancer detection.

“Every BRCA mutation detected after diagnosis is a missed opportunity to prevent cancer,” said King in closing her talk. “No women should die of breast or ovarian cancer, because these diseases can be preventable with the right screening approach.”

Along with warmer temperatures and the beautiful blossoming across the city, spring has become synonymous with the Philadelphia Science Festival, a staple and model for similar initiatives in other cities, that continues to grow each year.

Established in 2011 by The Franklin Institute as one of the first of its kind in the country, the Festival is a celebration of science, technology and education in everyday places — parks, libraries, museums, restaurants, and bars. More than 200 partners, including the major academic, research and educational institutions in the area, collaborate to produce a nine-day series of science, technology, engineering, and mathematics (STEM)-focused events for adults and children alike.  

The Festival aims to engage the community and inspire the next generation of scientists and engineers by creating homegrown citizen scientists. 

Wistar is proud to be a partner and to have served on the advisory council for the Festival from the beginning. This year, a team of Wistar volunteers will participate in Festival events with hands-on, educational activities designed to inform the public about basic cancer and infectious diseases and spread awareness about Wistar science. Wistar’s commitment to the Science Festival aligns with its mission of educating new generations of scientists and engaging the community in its work to improve human health. 

The Festival culminates in the free, daylong Science Carnival on the Ben Franklin Parkway on May 4 from 10:00 a.m. until 4:00 p.m. A group of Wistar scientists, trainees and staff will share their passion for science with Festival attendees at the Wistar booth in zone 6/Blue. Volunteers work hard each year to explain vaccine development or how a cell functions, but they are rewarded by the enthusiasm and curiosity of those that visit the Wistar tent. 

For more info and full Festival program, visit www.fi.edu/psf.

Each year in early May, representatives from Wistar and fellow institutions who are part of the Pennsylvania Cancer Alliance engage legislators to reinforce the importance and impact of CURE funding.

The Commonwealth Universal Research Enhancement Program (CURE), which funds health research across Pennsylvania, was established in 2001 with money received by the state from the Tobacco Master Settlement Agreement in 1998.

This was the largest civil settlement in U.S. history and came as the result of a lengthy legal battle to get tobacco companies to admit to the well-established causal relation between cigarette smoke and cancer and other health conditions.

The settlement was historic and far-reaching. Tobacco companies agreed to pay $206 billion to 46 states and the District of Columbia over the first 25 years. They also agreed to end marketing to kids and to provide annual payments indefinitely to cover some of the healthcare costs of smoking-related illnesses.

The states involved in the settlement agreed to devote their payments to reduce tobacco use. Pennsylvania is one of the few states that have invested 100% of settlement proceeds in health-related enterprises.

A few years after the settlement, then-governor Tom Ridge signed the Tobacco Settlement Act into law. The act allowed the Department of Health (DOH) to use settlement money to establish the CURE program with the goal of supporting research that can improve the health of Pennsylvanians.

CURE provides funding to universities, hospitals and nonprofits for broad-based health research, tobacco use prevention and cessation programs, and hospital uncompensated care programs. There are two types of grants:

• Formula — Institutions that receive funding from the National Institutes of Health or the National Cancer Institute (NCI) are eligible for these non-competitive grants.
  
• Non-formula — These competitive grants are distributed by the DOH, which each year assigns a priority for these grants. The 2018-2019 priority is collaborative research on opioid abuse and the overdose crisis.

Through the CURE Program, 39 organizations across the state, including Wistar, have received funding, and more than 85 patents have been filed for commercial use because of CURE-sponsored research. The settlement money has also generated more than 1,000 healthcare jobs in Pennsylvania.

Sustainable funding for CURE is essential because not only does it improve the economy, but it also provides Pennsylvania citizens with significant health benefits through research and health advances.

CURE Funding at Work at Wistar

At The Wistar Institute, pilot CURE funds were essential for Dr. Louise Showe, a preeminent researcher focused on identifying novel predictive cancer biomarkers, to advance research that has subsequently been translated into a new minimally invasive blood test that will help clinicians to distinguish benign lung nodules from cancerous lung nodules in high-risk populations. This test, developed with a for-profit research and development partner, is expected to be commercially available soon. Without CURE funding, Showe’s research would have taken much longer to complete and with limited preliminary data, it would have been impossible to attract a partner to assist with the further development and commercialization of a diagnostic test.

Wistar also uses CURE money to underwrite research by junior investigators at the start of their independent research careers. National Institutes of Health (NIH) grants are highly competitive and are generally not awarded to investigators until they have significant progress in their chosen area of inquiry. As a consequence, institutions must find support for their young investigators until they become competitive for NIH funding.

In addition to jump-starting biomedical research careers, CURE money is used to accelerate the translation of new discoveries into future potential products that may change the way cancer and infectious diseases are diagnosed and treated. For example, Drs. Alessandro Gardini, Kavitha Sarma, and Jessie Villaneuva have been able to elucidate novel mechanisms underlying tumor initiation and treatment resistance in ovarian cancer, glioblastoma and melanoma, respectively, with the support of CURE funding. Drs. Luis Montaner, Zachary Schug, Joseph Salvino, and Farokh Dotiwala have applied CURE funds towards the research and discovery of novel small molecule inhibitors useful for treating ovarian, colorectal cancers, gliomas and antibiotic-resistant microorganisms including tuberculosis, respectively.

CURE funds are critical for seeding transformative discoveries that can lead to the next generation of effective therapies.

In a study published online in Nature, the lab of Dmitry I. Gabrilovich, M.D., Ph.D., Christopher M. Davis Professor and leader of the Immunology, Microenvironment and Metastasis Program, identified a critical step that happens when parts of the immune system switch sides and work for the tumor.

Myeloid derived suppressive cells (MDSCs) are a bone marrow-derived cell population that becomes pathologically activated in cancer patients and hinders the body’s antitumor immune response. They are associated with poor prognosis and resistance to immunotherapy.

“We need to better define how these cells work and what pathways are important, so that we can devise strategies to keep them at bay,” said Gabrilovich. “Our study represents an important step forward in that direction.”

They found that a gene that encodes for a protein called FATP2 is expressed at much higher levels in MDSCs isolated from tumor-bearing mice than in the corresponding cell population derived from healthy mice. They also described how FATP2 converts normal neutrophils into immunosuppressive cells in the presence of a tumor.

This study opens new opportunities for specific therapeutic targeting of MDSCs to inhibit tumor growth and enhance the anticancer activity of other immunotherapies. READ MORE

David B. Weiner, Ph.D., executive vice president and director of Wistar’s Vaccine & Immunotherapy Center, and W.W. Smith Charitable Trust Professor in Cancer Research, and his collaborators described a new approach for delivery of DNA-encoded monoclonal antibodies (DMAbs) for protection against Zika virus (ZIKV) infection.

In this study, published in Molecular Therapy, the lab engineered a synthetic DNA plasmid encoding a previously identified potent anti-ZIKV monoclonal antibody. When injected intramuscularly in mice and non-human primates, these DMAbs resulted in antibody presence in circulating blood for several weeks to months and provided long-term protection against infection in both small animals and, for the first time, non-human primate preclinical models.

“These properties, coupled with the ease of production and storage, support further development of DMAbs as a possibly ideal approach during infectious disease outbreaks to provide rapid protection to at-risk individuals and, in the case of Zika, to their offspring as well,” said Weiner. READ MORE

A study by researchers in Wistar’s Vaccine & Immunotherapy Center, published online in JCI Insights, led to the creation of a novel synthetic DNA approach for patient-specific production of cancer-targeting molecules called bispecific T cell engagers (BiTEs).

BiTEs are a type of artificial monoclonal antibody that directly binds to tumor targets, while at the same time binding to and activating killer T cells. In doing so, BiTEs act as a bridge between killer T cells and tumor cells, making sure that T cells see and specifically kill tumors with high accuracy.

BiTE production is difficult and they have a short duration in the bloodstream, requiring patients to be continuously infused for up to seven days for the treatment to be effective.

Teams led by Weiner and Kar Muthumani, Ph.D., assistant professor in the Vaccine & Immunotherapy Center, developed DNA-encoded bispecific T cell engagers (dBiTEs) that, when injected into the muscle in mouse models, provided the genetic instruction for muscle cells to make and launch the novel molecule directly into the bloodstream to seek and destroy tumors.

They designed dBiTEs specific for HER2, a cancer antigen found on breast and ovarian cancer cells, and tested them in mouse models of ovarian cancer. HER2 dBiTEs were highly expressed after just a single injection and were able to attract T cells that were activated to kill the tumor cells. Importantly, the tumor-killing activity persisted for more than a month.

“These results showed that dBiTEs are much more potent than traditional monoclonal antibodies. Not only did treatment extend survival of tumor-bearing mice, but also 80% of the animals treated with dBiTE were cured – a high bar to reach in this animal model,” said Muthumani. “Our results show that further exploration of the dBiTE approach for therapeutic development is warranted.” READ MORE

For two decades, Wistar’s Biomedical Technician Training (BTT) pre-apprenticeship program has injected biomedical talent into the region’s life sciences workforce by ushering class after class of promising Community College of Philadelphia (CCP) students to attain the skills and experience required to become part of a growing biomedical science workforce. Director of the Pennsylvania Apprenticeship and Training Office Eric Ramsey and the PA Department of Labor & Industry officially recognized the BTT Program as a state-credentialed, non-traditional, biomedical pre-apprenticeship program.

“Across the nation, states look to strengthen their pipeline of skilled workers and on-the-job training opportunities to keep talent and jobs local,” said Brian Keith, Ph.D., Wistar dean of biomedical studies. “Within Pennsylvania, Wistar’s BTT Program has been providing students with highly competitive skills that prepare them for success as research assistants in the burgeoning life sciences workforce.”

Through learn-and-earn classwork and on-the-job laboratory training, CCP students from diverse backgrounds embark on an alternative to the traditional coursework track. Taught by experienced mentor-scientists, they learn biomedical techniques and skills while bringing out-of-the-box problem solving skills and a strong work ethic from diverse perspectives to enhance the STEM/biomedical workforce.

“What started as a commitment to developing a pipeline of research lab technicians for the burgeoning life sciences region in Philadelphia has become much more than the sum of its parts,” said William Wunner, Ph.D., Wistar director of outreach education, technology training and academic affairs. “In the BTT Program, I see the growth potential of our students—some are looking to break into the life sciences industry and some are setting their sights on attaining further education degrees and pushing beyond. Either choice makes the region stronger.”