The Sanford Burnham Prebys scientist discussed the Cre-loxP recombination system, which continues to be a mainstay genetic engineering technology.
“Techniques come and go with new technology, it’s just like night and day.” said Jamey Marth, PhD, professor and director of the Immunity and Pathogenesis Program at Sanford Burnham Prebys during his interview with The Scientist regarding his lab’s contributions to a genetic engineering technique that has stood the test of time.
“So, when you have a technique that’s lasted 30 years with no replacement technology, I think that’s kind of remarkable.”
Marth was interviewed about the Cre-loxP recombination system, which acts as a molecular genetic editor for controlling mutations in the genome. It was initially investigated by Drs. Nat Sternberg and Brian Sauer in the 1980s in tests to manipulate the genes of yeast and mammalian cells.
Marth wanted to use the technique for conditional mutagenesis in animal studies that would enable temporal and cell-type specific genetic models to better investigate biological systems and more effectively model human diseases. He and his team advanced the Cre-loxP system for use in laboratory mice and demonstrated the ability to efficiently delete DNA sequences in specific T cells in 1992.
The Cre-loxP recombination system continues to be a mainstay technology today and some scientists are exploring ways to combine it with the clustered regularly interspaced short palindromic repeats (CRISPR) and CRISPR-associated nuclease, Cas9, to gain the advantages of both genetic engineering techniques.
Richard Altmann (1852-1900) was a German prosecutor-turned-anatomy professor who focused on advancing microscopy techniques in his day. Using a new staining technique, he observed filaments in nearly every cell type he viewed. These filaments developed from granules, which Altmann deduced were elementary living units.
He called them “bioblasts.”
His conclusions were not well-received by peers.
These days, it’s believed Altmann was describing mitochondria, a term coined by Carl Benda in 1898 replaced Altmann’s “bioblasts.” And no one disputes the significance of Altmann’s original observations.
Mitochondria are cellular organelles that covert fuel into energy, the so-called “powerhouses of the cell.” They have many responsibilities and notably, possess their own genes apart from the cell’s nucleus. This fact supports the hypothesis that mitochondria were originally free-living prokaryotic cells lacking a nucleus that permanently fused with eukaryotic cells in the distant past.
Given their fundamental and expansive importance, mitochondria are the focus of much research. At Sanford Burnham Prebys, Peter Adams, PhD, with collaborators elsewhere, are exploring the role they play in cellular aging and immune responses, and particularly how they may affect the connection between aging and liver cancer.
About the art: Odra Noel is a medical doctor and PhD in basic science, with additional degrees in aesthetics and music. Her silk paintings focus primarily on human biology, often informed by microscopy. Wellcome Collection.
A colorized scanning electron micrograph of a human brain cancer stem cell. Cell bodies are in orange; nuclei in green. Cancer stem cells possess characteristics of normal stem cells, specifically the ability to give rise to all cell types found in a particular cancer sample. That makes them a particularly enticing target for developing cancer therapies, especially those prone to metastasis or recurrence.
Image courtesy of Izzat Suffian, Pedro Costa, Stephen Pollard, David McCarthy & Khuloud T. Al-Jamal.
Institute News
A Conversation About Aging and Cancer at Sanford Burnham Prebys
Event recording now available for panel discussion with scientists held on October 9, 2024
David A. Brenner, MD, president and CEO of Sanford Burnham Prebys, welcomed attendees to the launch of a new community engagement program called “A Conversation About” in the institute’s Victor E. LaFave III Memorial Auditorium on October 9, 2024.
The initial panel discussion in the A Conversation About series focused on the connection between aging and cancer and included information about a current breast cancer research collaboration. A recording of the event is available online.
Reena Horowitz, the founder of Group of 12 and Friends at Sanford Burnham Prebys, provided introductory remarks. Brooke Emerling, PhD, director of the Cancer Metabolism and Microenvironment Program, moderated the discussion among three featured panelists:
Peter Adams, PhD, director of the Cancer Genome and Epigenetics Program, Sanford Burnham Prebys
Xiao Tian, PhD, assistant professor in the Degenerative Diseases Program, Sanford Burnham Prebys
Kay Yeung, MD, PhD, associate clinical professor in the Division of Hematology-Oncology, University of California San Diego Health
By bringing together community collaborators and clinicians with Sanford Burnham Prebys researchers, A Conversation About offers a unique perspective on how clinical research and practice can be used to inform fundamental and translational science.
T cells are a type of white blood cell (lymphocytes) that develop from stem cells in bone marrow and are part of the adaptive immune system, which constantly monitors the body for threats. They help protect the body from infection and may help fight cancer. Each T cell is unique, designed to fight only one type of intruder.
At Sanford Burnham Prebys, Linda Bradley, PhD, Jennifer Hope, PhD, and colleagues are working to help revive exhausted T cells to tackle immunotherapy-resistant cancers—a major emphasis in cancer research.
Meanwhile, Kelly Kersten, PhD, is studying how T cells fundamentally interact with cancer cells and the microenvironment, looking for ways to improve immunotherapies and reduce the likelihood of treatment resistance, which is common in many types of cancer.
About the art: Odra Noel is a medical doctor and PhD in basic science, with additional degrees in aesthetics and music. Her silk paintings focus primarily on human biology, often informed by microscopy. Wellcome Collection.
A colorized scanning electron micrograph of a natural killer cell from a human donor. NK cells are a type of white blood cell critical to the innate immune system. They provide rapid responses to virus-infected cells, stressed cells, tumor cells and other intracellular pathogens based on signals from several activating and inhibitory receptors.
Image courtesy NIAID.
Institute News
Two Sanford Burnham Prebys scientists selected for American Cancer Society postdoctoral fellowships
Alicia Llorente Lope, PhD, is a postdoctoral associate in the lab of Brooke Emerling, PhD, director of the Cancer Metabolism and Microenvironment Program at Sanford Burnham Prebys. Ambroise Manceau, PhD, is a postdoctoral associate in the lab of Cosimo Commisso, PhD, interim director and deputy director of the institute’s NCI-Designated Cancer Center.
Funds will support Alicia Llorente Lope and Ambroise Manceau who study breast and pancreatic cancer
Alicia Llorente Lope, PhD, and Ambroise Manceau, PhD, were awarded 2024 Postdoctoral Fellowships from the American Cancer Society (ACS). These prestigious awards provide more than $65,000 per year for up to three years to support early career scientists studying cancer.
“I was so excited when I heard the news,” said Llorente. “It is a privilege to have this award, and it feels very validating to know that someone saw enough potential in my research to deem it worthy of funding.”
Tackling treatment-resistant breast cancer
Llorente joined the lab of Brooke Emerling, PhD, director of the Cancer Metabolism and Microenvironment Program at Sanford Burnham Prebys, nearly three years ago after beginning her breast cancer research career as a doctoral student.
“I was first interested in breast cancer because my grandmother died of the disease, and I wanted to contribute to finding new therapeutic opportunities for cancer patients,” said Llorente. Llorente’s ACS-funded research project focuses on HER2-positive (HER2+) breast cancer.
Roughly one in five breast cancer tumors have elevated levels of the HER2 protein. While these tumors tend to grow quickly, drugs targeting the HER2 protein are usually effective at first. However, HER2+ tumors often are able to adapt and develop resistance to these drugs over time, leaving patients with few if any remaining treatments options.
Llorente has found evidence that a form of the protein phosphatidylinositol-5-phosphate 4-kinase (PI5P4K) plays a role in breast cancer tumors becoming resistant to HER2 drugs.
Brooke Emerling, PhD
“We’ve revealed a strong connection between elevated levels of PI5P4K gamma and reduced survival rates in patients with HER2+ breast cancer,” explained Llorente. “I plan to explore whether targeting both HER2 and PI5P4K gamma in breast cancer cells may provide a path to overcoming treatment resistance.” Llorente also will study the functions of PI5P4K gamma in breast cancer cells to see why these cells cease to respond to HER2-targeting drugs.
“I am incredibly proud of Alicia for spearheading this groundbreaking project targeting the lipid kinase PI5P4K gamma,” said Emerling. “Her insightful analysis of breast cancer datasets, which uncovered a correlation between elevated expression of PI5P4K gamma and worse outcomes in HER2+ patients, has set the stage for vital research aimed at overcoming the significant challenge of resistance to targeted therapies in HER2+ tumors.”
Cosimo Commisso, PhD
Powering down pancreatic cancer
Manceau is in the second year of his postdoctoral training in the lab of Cosimo Commisso, PhD, interim director and deputy director of the institute’s NCI-Designated Cancer Center. During his doctoral program, Manceau studied how abnormal cells die in a programmed series of steps called apoptosis, a process known to go awry in cancer and neurodegenerative diseases.
“It began as a basic science project about the molecular processes around cell death, and over time it led to possible therapeutic implications,” said Manceau. “I learned that I like to study fundamental biology and then try to find an application for it, and I saw in the Commisso lab an opportunity to do just that in pancreatic cancer.”
Manceau’s fellowship project focuses on pancreatic ductal adenocarcinoma (PDAC) — the most common form of pancreatic cancer with only a 13% five-year survival rate — and its ravenous pursuit of energy. Because of PDAC cells’ constant need for fuel to sustain their rampant growth, they adapt by reshaping the surface of their cells to snatch extra nutrients from the jelly-like substance between cells.
Commisso and others have shown that cutting off the extra power supplied by this process — known as macropinocytosis — reduces tumor growth. Manceau has studied the contents taken by contorted pancreatic cell surfaces in pockets called macropinosomes. By analyzing every single protein in this scooped goop, he found that calcium transporter proteins present in macropinosomes also are required for macropinocytosis.
“During the fellowship, I will work to understand how these transporter proteins affect macropinocytosis,” said Manceau. “These proteins have never been targeted before in pancreatic cancer, so our long-term goal is to use this strategy to cut the nutrient supply to tumors and see if we can inhibit tumor growth.”
“By disrupting the cancer cells’ ability to feed themselves through macropinocytosis, we can potentially starve tumors and inhibit their growth,” added Commisso. “Ambroise’s research aims to target key proteins involved in this process, opening up new possibilities for treatments that could significantly improve outcomes for patients battling pancreatic cancer.”
Despite decades of research, heart disease is still the leading cause of death in the industrialized world. The human heart beats roughly 100,000 times a day pushing 2,000 gallons, or about five quarts a minute. Disorders that affect the abilities of cardiac muscle to beat normally are called cardiomyopathies. They can affect people of any age, race or sex, and are often inherited. Cardiomyopathy poses a significant health risk, leading to heart failure. More than half of all heart transplants are due to cardiomyopathies.
Among the most common of cardiomyopathies is atrial fibrillation or AFib, a form of cardiac arrhythmia in which the heart beats abnormally: usually too fast and irregularly. More than 5 million people in the U.S. have AFib, which in 2021 was cited in 232,030 death certificates and named as the underlying cause of death in 28,037. The risk of developing AFib is increased by congenital defects, heart attacks, high blood pressure, pneumonia, viral infections and sleep disorders. The biggest risk factor is age with roughly 10% of people over age 65 developing AFib. How genetics, age and other risk factors interact to cause AFib is unknown.
At Sanford Burnham Prebys, researchers are investigating the gene networks that result in AFib. Recently, Alexandre Colas, PhD, and Karen Ocorr, PhD, with colleagues elsewhere, published findings that describe a multi-model platform for identifying causative genes for AFib, a major step toward finding new treatments.
About the art: Odra Noel is a medical doctor and PhD in basic science, with additional degrees in aesthetics and music. Her silk paintings focus primarily on human biology, often informed by microscopy. Wellcome Collection.
Sections of a rat heart are shown using fluorescence microscopy imaging. The muscle cells of the heart, called cardiomyocytes, are stained in green; cell nuclei are counterstained in blue; and proliferating cells are labeled in green.
Neurons or nerve cells are the main components of nervous tissue in all animals except sponges and placozoans. Plants and fungi don’t have nerve cells. They are characterized by the ability to fire electric signals called action potentials across a neural network, either in the brain or through the central and peripheral nervous systems.
There are three basic types of neurons based on function. Sensory neurons respond to stimuli, such as touch, sound or light. They trigger messages to the spinal cord or brain. Motor neurons receive signals from the brain and spinal cord to control everything from muscle contractions to glandular output. Interneurons connect multiple neurons to create neural circuits.
There are approximately 100 billion neurons in a mature human brain. Each can make connections with more than 1,000 other neurons, creating approximately 60 trillion total neuronal connections.
Given their profound and fundamental importance to every aspect of life, the roles of neurons in both health and disease has long been a matter of intense study. At Sanford Burnham Prebys, that effort has often focused on the fate of neurons in neurodegenerative diseases like Alzheimer’s and in the processes of aging. By 2050, the number of Alzheimer’s patients age 65 and older may nearly triple from 5 million to 13.8 million.
About the art: Odra Noel is a medical doctor and PhD in basic science, with additional degrees in aesthetics and music. Her silk paintings focus primarily on human biology, often informed by microscopy. Wellcome Collection.
