Last night, I headed down to the beautiful Bell House, in the Gowanus section of Brooklyn, for this month's Secret Science Club lecture, featuring cell biologist Dr Elaine Fuchs of The Rockefeller University and the Howard Hughes Medical Institute. This month's lecture was the annual Secret Science Club collaboration with The Lasker Foundation.
Dr Fuchs began her lecture by telling the audience that this was a first for her, she had never lectured an audience in a bar. Welcome, my good doctor, to the Secret Science Club experience. She noted that her main subject of study is adult stem cells, and posed the question: what are stem cells? Biologist Ernst Haeckel coined the term 'stem cell', which was popularized by E.B. Wilson) to describe the cells in an embryo which give rise to the cells of the body. Stem cells were discussed exclusively in terms of embryology. In 1909, cytologist Alexander Maximow isolated cells from bone marrow and found undifferentiated cells which give rise to blood cells. Biologists Ernest McCulloch and James Till introduced a single stem cell into an irradiated mouse which had its marrow cells destroyed, and demonstrated that a single cell could rebuild an entire hematopoietic, blood forming, system. Dr Fuchs noted that not all groundbreaking research wins a Nobel Prize.
She then shifted to topic to culturing cells, and the distinction between embryonic and adult stem cells. Embryonic stem cells are pluripotent, they give rise to all of the tissues of an organism. Adult stem cells are more restricted, limited to giving rise to a narrower range of cell types. Adult stem cells are used to repair tissues when they are subject to wear and tear- wound healing is a prime example of adult stem cells at work. Dr Fuchs summed up the distinction elegantly: we can't develop without embryonic stem cells and we can't survive without adult stem cells.
Dr Fuchs then delivered a crash course in emryology- a fertilized egg forms a structure known as a blastocyst, the outer layer of which forms the placenta of placental mammals, and the inner cell mass of which produces embryonic stem cells, which produce the embryo. Blastocysts can survive outside of the womb, they can be generated in vitro. Regenerative medicine can be achieved using embryonic stem cells to repair damaged tissue (for instance, nerve damage caused by Parkinson's disease). Cultured embryonic stem cells can be transformed into any cell type- adjusting growth factors can be used to derive the desired cell type. Dr Fuchs specifically mentioned the growth of heart muscle cells in a petri dish. In one experiment, stem cells were introduced into the severed spinal cord of a rat in order to restore hind limb movement:
Dr Fuchs noted that human neurons introduced into mouse don't make it any smarter, though the percentage of neurons is kept low due to ethical concerns (I'd like to interject that nobody wants murine supervillains).
Due to ethical concerns, techniques for reprogramming adult stem cells to induce pluripotency have been developed. Transcription proteins such as KLF4 (KLF3AM is not a protein), OCT-4, SOX2, and c-myc are used in this process. The types of therapies made possible by the use of reprogrammed stem cells are myriad, with treatments for Parkinson's disease, Huntington's disease, cardiomyopathies, Alzheimer's disease, type 1 diabetes, and macular degeneration being within reach.
A lot of knowledge in developmental biology is needed to produce specific cell types. There is a need to push development of cell types such as the pancreatic islet cells needed to treat type one diabetes. One particular researcher produced 'buckets' of these cells which ere attacked by the immune system of the lab animal into which they were introduced- the environment of stem cells is as important as stem development itself. Ultimately, it is an engineering problem- how do we make a 'cage' in which stem cells can develop? What is important has to be determined. In Japan, clinical trials to combat macular degeneration are entering a second stage. The eyes are an immune privileged site. In other treatments, genetic differences must be minimized so treatments can go forward.
Dr Fuchs noted that we need to know how different cell types emerge. How do normal tissues develop? How do tissues 'put away' stem cells until needed for repair? How do adult stem cells sit in quiescence until they are needed? If they are mobilized unnecessarily, tumors can develop as a result. How do stem cells cope with stress, such as conditions in which their microenvironment isn't right? Basic science research is integral to developing regenerative medicine.
Dr Fuchs then displayed a collage of photos of various animals, and noted that there were many manifestations of skin types, with various furs and feathers existing. She joked that she would rather study the beautiful surfaces of animals than their ugly internal organs. She noted that you can never solve equations in biology, questions answered invariably lead to new questions. Biologist Howard Green was a pioneer of stem cell culturing, and compared cultures of skin cells to actual human skin. He was able to expand skin cells into sheets which could be grafted onto burn patients. Only a few purified stem cells were needed for a near-whole body skin replacement- regenerative therapy could be used to save children who were burned over 90% of their bodies.
Blistering skin disorders can be treated by identifying the major proteins expressed by epidermal skin cells. Mutations in epidermal skin cells can be repaired through homologous replication. By 2012, whole body regeneration using corrected epidermal stem cells was possible. Stem cell therapy can also be used to repair burns of both the skin and chemical burns of the corneas.
The skin's stem cells are found in hair follicles, sebacous glands, sweat glands, and throughout the interface of the dermis and epidermis, which is full of growth factors. Stem cells are surrounded by many cell types, such as nerve cells, which are derived from the same progenitors in the blastocyst. The 'cross-talk' between different cell types influences what stem cells do and when they do it. A bucket of stem cells, lacking feedback from other cell types, cannot develop properly... stem cells have niches and understanding of these niches is needed.
Stem cells lie in quiescence until they are needed for tissue repair. Inhibitory messages from neighboring cells keep them in quiescence, but when repair is needed, an override signal takes over and the stem cells form short-lived progenitor cells which produce tissue. The on-signal for producing hair follicles has been studied in mice. An on-signal without an off-signal produces tumors... quiescence is important. BMP signaling kicks off a cascade of proteins such as SMAD1, ID1, ID3, and XCL to produce tissue growth. Stem cell numbers remain high throughout an organism's life, but stem cell activity wanes with age. Hair graying is dependent on melanocyte stem cells which occupy the same nice as follicle stem cells. These melanocytes inject melanin into hair. On researcher, looking for a 'fountain of youth', intercepted the BMP signal, but this resulted in sparser gray hair appearing more quickly... the hair conundrum is probably more environmental rather than stem-cell based.
Stem cells are equipped to cope with many different signals- each stem cell has many surface receptors to make needed repairs possible. Chromatin dynamics form the signal-receiving switchboard within stem cells. Wounds and inflammation are different stresses and these different stresses cause different signals. Chronic inflammatory skin diseases such as psoriasis and atopic dermatitis cause epidermal cells to proliferate, and the skin to thicken. They tend to recur in the same spot and new flare-ups tend to worsen. Stem cells retain the memory of inflammation in their chromatin, and this memory might be cumulative. Changes in the chromatin can be apparent six months later. If the problem of cytosine memory can be figured out, the use of immunosuppressant drugs to treat these conditions might be unnecessary. The skin is also affected by other diseases, such as squamous cell carcinomas. TGF beta signals effect tumor growth, and sometimes tumor relapse can occur if stem cells are invasive.
Dr Fuchs ended her lecture by noting that the skin is the largest organ of the human body, and the primary interface between the organism and the environment, keeping fluids in and microbes out... she joked that, in some few cases, 'building a wall' was necessary.
The lecture was followed by a Q&A session, but I must confess that my bursting bladder overrode my burning curiosity, so I didn't manage to get a question in. Other audience members took up the slack, though... One question regarded the microbiome, and Dr Fuchs joked that, though the gut microbiome is pretty well known, researchers are just 'scratching the surface' regarding the skin microbiome. Regarding autoimmune diseases, the basis of autoimmune problems is not well known, but tumor antigens might play a role... the 'cross-talk' between stem cells and immune cells needs to be better known, especially as the skin milieu changes with inflammation. Regarding the study of diseases such as papilloma viruses, Epstein-Barr, and herpes, the complexity of tissues is not usually taken into account in culture studies. Human skin contains 65 different cell types, all of which might not be represented in a tissue culture. The final question involved the ways in which stem cells can go awry and form tumors- Dr Fuchs noted that there are many ways in which this can happen and quipped 'Mother Nature has seen it all'.
Dr Fuchs delivered a fantastic lecture, involving a nice embryology refresher course, a good overview of emerging regenerative medical techniques, and a fantastic discussion of an often overlooked part of the body. Kudos to her, to Margaret and Dorian, and the staffs of the beautiful Bell House and the lovely Lasker Foundation for another top notch Secret Science Club lecture.
For additional information, here's a video, first in a series, of Dr Fuchs discussing stem cells:
Pour yourself a tasty beverage and soak in that SCIENCE!!!