Our lab tries to understand the role that stem cells play in normal development and disease. Stem cells have the dual potential to self-renew and give rise to mature cells. They play key roles in development, during tissue homeostasis and following injury in the adult. Moreover, stem cells have been experimentally shown to be the cells of origin in certain types of cancer. To understand the biology of stem cells and to exploit their use for therapy, it is critical to identify and characterize the factors that control the decision between their self-renewal and differentiation under normal physiological conditions and in disease.
We are particularly interested in the biology of embryonic stem (ES) cells which are derived from early embryos and retain the ability to give rise to all cell types of the body, an ability referred to as pluripotency. The pluripotency of ES cells is dependent upon a set of genes whose elimination results in the inappropriate commitment of ES cells into specialized cells. Interestingly, some of the pluripotency genes are also active in rare adult cells, however their function in the adult remains poorly understood. This observation suggests a common origin of these cell types and indicates similarities between embryonic and adult stem cells. We are interested in studying the biology of these cells in order to determine whether they originate from a common precursor, whether they can serve as the cells of origin in cancer, and whether these cells have an increased ability to convert back into embryonic stem cells when manipulated experimentally.
We use cell culture and animal model systems to further characterize the role of pluripotency genes. Specifically, we employ gene targeting in ES cells, mouse transgenesis, and nuclear transfer as tools to address the fundamental questions of where stem cells come from, what similarities and differences there are between different types of stem cells and what role they play in tumor formation. Ultimately, studying these questions may lead to novel strategies to expand adult stem cells and convert one cell type into another therapeutically relevant cell type, goals of regenerative medicine, and could help to fight cancer more effectively by targeting tumor cells at their roots.
About Konrad Hochedlinger
ooking back, Konrad Hochedlinger can't believe he considered giving up when his Ph.D. project ran into trouble. He had joined Rudolf Jaenisch's lab at the Massachusetts Institute of Technology in 2000, intent on creating a mouse from "scratch" by transferring DNA from mature mouse cells into egg cells stripped of their DNA—a scientific feat that no one had yet accomplished. After working for 18 months without success, Hochedlinger fought the urge to quit. He decided to scrap his original plans and begin trying new approaches
The goal was worthy of the effort because the experiments could help answer longstanding questions about the developmental potential of mature cells. But try as he might, Hochedlinger could not produce cloned mice by the simple act of transferring nuclei from adult immune system cells into mouse egg cells.
After many failed attempts, in 2002 he finally cloned a mouse derived entirely from the nucleus of a mature lymphocyte."That was a big moment in my career. It led me to stay in science."
Today at Massachusetts General Hospital, Hochedlinger continues to enhance development of genetically reprogrammed cells. He is developing safer and more efficient methods, with a long-term aim of generating custom-tailored cells for treating and understanding disease.
After receiving his Ph.D. in 2003, Hochedlinger was invited to stay on in Jaenisch's lab to tackle another big problem. Two years earlier, President George W. Bush had announced that the U.S. government would fund research only with human embryonic stem cell lines created before August 9, 2001. Researchers could not apply for National Institutes of Health (NIH) grants, or any other federal funds, to support development of new human embryonic stem cells, nor could they use equipment funded by federal grants to work with newer stem cell lines. Jaenisch and others were working furiously to determine whether mature cells could somehow be coaxed into reverting to stem cells. With Hochedlinger's help, Jaenisch's group found that when an embryonic gene called Oct-4 is activated in adult tissues, it blocks their maturation and causes cancer. While these experiments did not yield stem cells from adult cells, they demonstrated that Oct-4 activation has a strong effect on the differentiation of adult cells, making it a likely candidate gene for attempts to convert mature cells directly into stem cells.
In 2006, a new finding energized the world of stem cell research. Japanese scientist Shinya Yamanaka converted skin cells into stem cells by using a nontraditional approach—employing viruses to insert four specific genes, including Oct-4, into the cell's DNA. Hochedlinger, who was in the midst of setting up his own lab at Massachusetts General Hospital, quickly reproduced the results and showed that the reprogrammed cells, called induced pluripotent stem (iPS) cells, are functionally similar to embryonic stem cells. He also improved on Yamanaka's technique by using a harmless adenovirus that disappears after its job is done. Yamanaka and others employed retroviruses to shuttle the genes into the mature somatic cells. Retroviruses, however, can integrate into the host genome and set the stage for the development of cancer.
Since then, Hochedlinger has been studying the mechanisms behind iPS cell development. "We know that sticking these four genes into an adult cell transforms the cell into an embryonic-like cell, but what's actually going on inside the cell? What happens to the modification of DNA as you turn an adult cell into an embryonic cell? What genes are turned on and what genes are turned off? Does it matter whether the cell is a skin cell or a neural cell or a pancreas cell in terms of what it can do? How similar are reprogrammed cells to embryonic stem cells from an embryo? These are all questions that we are interested in addressing."
The answers could have major medical implications, and Hochedlinger is exploring the possibilities with colleagues at MGH and elsewhere. Reprogrammed adult cells could reveal the genetic mechanisms behind common diseases and possibly lead to therapies in which a person's cells could be converted to stem cells and used to grow replacement tissues.