Every day, care teams at Memorial Sloan Kettering (MSK) treat people with cancer in the hope of destroying their disease. Behind the front lines, biologists, chemists, and other scientists doing basic research are seeking the most elemental understanding of how the human body works — and using those discoveries to improve the treatment of cancer and other diseases.
“Basic research” means just that: scientific inquiry that focuses on illuminating the secrets of natural systems. “Basic biomedical research investigates the fundamental processes that drive biology and that can cause diseases, including cancer,” says Joan Massagué, PhD, director of the Sloan Kettering Institute (SKI), MSK’s research arm. “This provides the foundation for translational research, which is aimed at turning this knowledge into cures for disease.”
That solid footing serves as a platform for the next generation of discoveries. In the more than 70 years since SKI was founded, its basic science investigators have pioneered more targeted cancer drugs, better ways of detecting disease in the body, and a clearer understanding of the immune system, among other advances.
“Although many investigators pursue basic research with an eye toward having an impact in the clinic, basic investigators must be free to pursue whatever their instinct tells them will provide the most penetrating insights into the unknown,” Dr. Massagué says. A basic scientist himself, Dr. Massagué works on the signals that control tissue growth and tumor metastasis.
We spoke with three of SKI’s leading researchers about what brought them to MSK and how curiosity and vision drive their work. Their investigations — in the fields of structural biology, developmental biology, and molecular biology — represent just a few of the areas in which basic research is expected to have a profound impact on all forms of disease in the coming years.
PEERING INSIDE THE CELL
Structural biologists seek to visualize the three-dimensional shapes of biological molecules. “Knowing the structure of DNA, RNA, proteins, lipids, and other macromolecules enables us to do experiments that address many of the fundamental problems of biology and medicine,” says investigator Dinshaw Patel, PhD, who came to MSK in 1992 to help initiate structural biology research there.
This foundational knowledge advances cancer science by identifying the structure of macromolecules, which is critical to understanding how they function. They often interact with other molecules based on their shapes, like keys fitting into locks. When mutations cause the molecules to change, it can trigger events that may result in cancer and many other diseases.
“If you can get a molecular view of the protein and how it interacts in the cell, you can gain an understanding of what that protein does, both when it’s performing its proper function and when it isn’t,” says Dr. Patel. “This can indicate why the mutation has medical consequences and how you might correct its harmful impact by gene editing and/or designing drugs against it.”
By collaborating with other investigators at MSK and elsewhere, Dr. Patel has become a world leader in several fields of biological research, including epigenetics — the study of biochemical changes that affect which genes are turned on in a cell. The field is becoming increasingly important to cancer research, as well as an important initiative at MSK.
His work relates to the study of proteins called histones, which act like a spool for DNA to wrap around and enable it to be packaged inside a cell. Access to this wrapped-up DNA is critical and impacts which genes are able to make proteins.
Collaborating with David Allis, a professor and researcher at Rockefeller University, Dr. Patel’s team has made fundamental discoveries about the proteins that ‘read,’ ‘write,’ and ‘erase’ the chemical tags at specific sites on histones that instruct genes which proteins to turn off and on. Their work has helped clarify how changes in histone readout may contribute to cancer.
“I’m different from many of my colleagues, most of whom focus on a single area of research,” he explains. “Because so much of my work over the years has focused on collaborations with other researchers, we have been able to publish our findings in a number of leading journals in many different fields.”
Currently, Dr. Patel is excited about MSK’s acquisition of a cryoEM machine, which will enable him and other investigators to study large, multicomponent biological systems with greater precision than ever before. His group is applying cryoEM to study CRISPR-Cas complexes involved in gene editing.
Reflecting on his tenure at MSK, Dr. Patel says, “We are very fortunate to be at an institution with incredibly talented and visionary leadership, both at SKI and MSK, who understand the importance of basic, translational, and clinical research.”
DECIPHERING EMBRYONIC CELLS
In the field of developmental biology, researchers are studying how a single fertilized egg is able to divide and generate all of the diverse cells and tissue types that make up the human body.
The discipline is vital to MSK’s research mission because in addition to answering fundamental questions about how we all develop, it has important implications for cancer. Understanding genes’ normal function is essential to then uncovering what happens when they go awry and lead to cancer. To figure out the process, we need to understand how genes’ normal genetic programming builds the organs and tissues in our bodies.
Developmental biologist Anna-Katerina (Kat) Hadjantonakis, PhD, combines two research approaches — genetics and imaging — in her lab to study the role that genes play in various stages of normal embryonic development. By inducing genetic mutations in mouse embryos and studying their effects at the level of single cells within a population, her team is able to learn what these genes do.
“We’re able to look at every single cell among a population of hundreds or thousands and ask which genes are active, and then in turn look at the cells’ movements and shapes, and how all of these factors play into normal development,” she says. They use fluorescent molecules to label different proteins within mouse embryos, enabling them to study the communication between different types of cells in real time.
“Many of the genes that we study in the context of the early embryo are also critical for tumor metastasis and cancer invasion,” she says. “How do cells divide, and what regulates that? What genes control what they become? How do they move and talk to one another to form specific organs? These are all questions we ask about both embryo development and cancer.”
Her research also has applications for understanding stem cells. Pluripotent embryonic stem cells, which have the potential to develop into any type of cell, show promise for regenerative medicine, which is searching for ways that new tissues and organs could be grown in the lab to replace those lost to injury or disease.
She adds that being in an environment like SKI has enabled her to explore and develop many avenues of cutting-edge research. “MSK is truly cross-disciplinary, and all of the labs — from basic to clinical — are very collaborative,” she says. “My colleagues are truly the best group of people working in my field in any institution, anywhere in the world.”
ILLUMINATING DNA REPAIR
When DNA is damaged, it can cause genetic mutations that accumulate and lead to diseases such as cancer. Repairing these DNA breaks is essential for any organism, including humans, to function normally. Molecular biologist Scott Keeney, PhD, investigates how cells identify and fix this damage.
One way he and his lab are gaining insight into DNA repair is by studying meiosis, the process by which cells divide to create reproductive cells (eggs and sperm). Most cells in the body have two copies of each chromosome. As meiosis proceeds, these pairs are separated so that the reproductive cells receive half the number of chromosomes. This ensures that when a sperm and egg cell later unite, the embryo will have one copy of every chromosome from each parent.
The researchers are focusing on how the cells keep track of their chromosomes during meiosis. It gets tricky because the original cells deliberately damage their own chromosome segments and then repair them as a way to keep the chromosome pairs properly sorted.
This particular form of severe DNA damage is a significant contributor to the formation of cancers when it occurs outside of meiosis. Clarifying how cells repair these DNA breaks — or fail to — is critical to understanding how cancer develops and finding strategies to stop or reverse it.
This breaking and reassembling of DNA fascinated Dr. Keeney as a young scientist, and his interest in the intricate process continues to propel his research. He emphasizes that harnessing scientists’ fervor for understanding how things work at their simplest level is the best way to produce important discoveries.
“What gets me up in the morning and keeps me working well into the night is my fascination with this really small slice of things,” Dr. Keeney says. “An essential aspect of what drives science is people’s curiosity and excitement about what they’re doing.”
“This is also why the basic science being explored at MSK provides outstanding opportunities to train the next generation of biomedical researchers,” he continues. “The graduate students and postdoctoral fellows who do the lion’s share of the day-to-day work at the lab bench are on track to be the new leaders in their fields.”
As a postdoctoral fellow at Harvard University, Dr. Keeney discovered that a protein called SPO11 creates these double-strand breaks in DNA during meiosis. His laboratory is now trying to get a clearer picture of how SPO11 is regulated — understanding how a cell ensures that the protein breaks DNA only at the right time and place, so the chromosomes can pair with each other without shattering the genome.
Notably, the Patel and Keeney laboratories have recently begun a collaborative effort to understand the molecular basis underlying SPO11 regulation. This joint effort has already successfully determined the structure of a key complex, thereby providing an improved understanding of the effect of mutations that disrupt this regulatory pathway.
Ultimately, insight into this process could lead to more effective therapies. That’s why basic science is so important, Dr. Keeney explains: So much remains to be understood about a complicated organism like humans.
“The reason I think a place like MSK has long recognized the importance of basic research is because we can’t predict where those discoveries are going to come from,” he says. “The best investment is to pick smart people and let them do the things they’re passionate about.”