• RAMPING UP DISCOVERY WITH KIDNEY ORGANOIDS

    By Maya Chaddah | April 4, 2014
    Expert Contributor: Melissa Little, PhD

    Although they conjure up images of science fiction, organoids are actually the quirky new name for mini, lab-grown models of human organs. Scientists are using pluripotent stem cells – the master cells that make any cell in the body – to create small buds of brain, thymus, liver, intestine, eye or kidney tissue that replicate some of the functions we find in these organs.

    Stem Cells in Focus Webcast

    2014-04-04 Little Photo

    Exploring Organoids: Growing a Kidney in a Dish

    Melissa Little, PhD, Institute for Molecular Bioscience, The University of Queensland, Australia

    Learn more about the research and its potential, and pose your questions directly to Prof. Little, during a live public webcastTuesday, April 15 at 5 pm ET (USA).

    There was great excitement in 2013 when Australian scientist, Prof. Melissa Little, at The University of Queensland’s Institute for Molecular Bioscience in Brisbane, Australia saw tiny buds of tissue growing in a dish that looked like embryonic kidneys. Originally a cancer geneticist, she had spent years studying the genes and pathways that lead to the formation of Wilm’s tumor, a kidney cancer found in children. As the connections between abnormal kidney formation during development and kidney dysfunction in children became apparent, she began exploring new ways to help individuals with kidney disease.

    In the 15 years since Prof. Little started focusing on kidney development, renal disease and repair, the rates of chronic kidney disease have skyrocketed globally, due in large part to conditions like diabetes, hypertension (high blood pressure), glomerulonephritis (immune-mediated disease) and cardiovascular disease. Although the adult kidney can repair some damage – for example, after a night of excessive alcohol, a period of dehydration, rapid blood loss, or exposure to chronic toxins – it cannot grow new nephrons, which are vital to its function, after we are born. So chronic kidney damage takes its toll and ultimately leaves individuals on dialysis or awaiting kidney transplants, which are in very short supply.

    The kidney is a very complex organ, comprised of 250,000 to 2 million nephrons that filter the blood (about 5 cups/minute), resorb nutrients and excrete waste. Each nephron is shaped like the head of a wrench leading into a long convoluted tube that bends and winds. Blood is filtered at the head of the wrench and different points along the tube take back what the body needs – ions, amino acids and water. The tube then dumps what the body doesn’t want into a large pipe called the ‘collecting duct,’ which funnels the waste to the bladder for excretion. Any condition that repeatedly affects the ability of the nephrons to filter the blood can lead to a build-up of kidney damage over time.

    Prof. Little’s team was keen to understand kidney development in humans. Because the adult human kidney cannot make new nephrons, they attempted to replicate the process by which nephrons develop in the human embryo, using cultured cells grown in the laboratory. This involved identifying the conditions under which embryonic stem cells – derived from the earliest unspecialized cells in an embryo – can be coaxed to make mesoderm, the layer of cells in the early embryo with the potential to make kidney cells. From there, they developed a very tight, quality controlled method for reproducibly making nephron progenitors, the cells which make nephrons, as well as early nephrons and collecting duct cells.

    What Prof. Little’s team finds amazing is how exactly these types of cells, the nephrons and their progenitors and collecting duct cells, self-assemble into three dimensional structures outside the body, in a totally artificial lab environment. She likens the mystery to when animals are born and immediately just know how to stand up and go to their mothers. The kidney organoids her team can grow right now are only tiny buds of tissue, much smaller than normal kidneys and less complicated, but clearly with the same kinds of cells found in an embryo making a kidney. The next steps are to keep pushing the kidney organoids down the developmental pathway that ends with fully functional organs, and then to investigate whether the nephrons could do their job if given a blood supply.

    Prof. Little sees a few ways that functional kidney organoids could open new avenues of discovery in the near future:

    1. Kidney organoids are made with human cells, so they mimic early human kidney development more closely than mouse models, allowing researchers to better study the organ and its diseases
    2. Kidney organoids promise a more patient-specific way to model what goes wrong in disease. If researchers are able to accurately and quickly replicate the types of mutations found in particular patients, they can better treat them (eventually leading to more directed treatments)
    3. Kidney organoids could become test beds for assessing whether experimental drugs are toxic to the kidney – lack of adequate testing models is one of the main reasons that drug development fails and incurs such enormous costs

    Because the kidney is such a large, complex organ, it is unlikely that scientists will be able to grow life-sized kidneys for the purpose of transplantation. But in the distant future, even tiny kidney organoids might provide enough functional filtration to benefit patients. There is still a long, long way to go, but just being able to make kidneys organoids is bringing scientists like Melissa Little one step closer to helping people with chronic kidney disease.

  • Making Sense of Disease – In a Dish

    By Maya Chaddah | March 6, 2014
    Expert Contributor: Kevin Eggan, PhD

    Stem cell research is revolutionizing the way scientists study human disease in many ways. One of the most fascinating, is through the creation of human “diseases in a dish,” which are giving scientists a better way to study disease biology and test new drugs.

    Stem Cells in Focus Webcast

    Disease Modeling with iPS Cells: Diseases in a Dish Explained

    Kevin Eggan, PhD, Harvard Stem Cell Institute, USA

    Learn more about the research and its potential, and pose your questions directly to Dr. Eggan, during live public webcast, Thursday, March 13 at 2 pm ET (USA).


    Many of the current advancements in disease modeling stem from Dr. Shinya Yamanaka’s discovery of induced pluripotent stem cells (iPS cells) in 2006. He and others figured out that they could turn adult skin cells into embryonic-like stem cells, capable of creating all the different organs and tissues in the adult body. Since that time, iPS cells have been used to model diseases outside the human body, allowing scientists, who previously relied on testing in animals, a much better canvas on which to study disease and potential treatments.

    Dr. Kevin Eggan, from the Harvard Stem Cell Institute, studies amyotrophic lateral sclerosis (ALS), an incurable neurological condition, and psychiatric disorders such as schizophrenia, through the use of iPS cells. In 2008, his lab showed that it was possible to turn iPS cells from people with ALS into motor neurons, the cells that are damaged during the course of the disease. Dr. Eggan is hoping this will help him to solve the mystery of how different causes can lead to the same disease in different patients or how the same mutation can cause a very different disease altogether.

    For example, patients with ALS can have mutations in any one of 20-30 different genes. Instead of going through the laborious and expensive process of making mouse models that emulate every one of those mutations, he can instead make iPS cells from human patients with different mutations, and turn them into motor neurons to study how particular mutations can affect disease biology and change its trajectory. These iPS models are equally as valuable in patients with psychiatric disorders, such as schizophrenia and autism, where many genes may be involved together.

    The process of exploring disease and then developing and testing treatments, often referred to as clinical translation, is lengthy and complicated. It requires rigorous pre-clinical testing in animals and then multi-phase clinical trials in humans. Using iPS disease models allows scientists to explore drug discovery with diseased human cells, in addition to animal testing, which leads to a more efficient clinical translation process.

    In addition to ALS and schizophrenia, researchers have also developed iPS cell disease models for many other diseases, including heart, blood and eye diseases, Alzheimer’s disease, diabetes and spinal muscular atrophy.

    With iPS cell technology, the research community now has an incredible opportunity to model human disease in a dish and also to test candidate drugs on the actual cells that get sick. As scientists learn better ways to turn human-derived iPS cells into distinct cell types, and grow them in large numbers, they should have a steady supply of diseased cells to study, bringing clarity to the individuality of disease and identifying new approaches for treatment.
  • Exploring Endogenous Heart Repair and Regeneration

    By Maya Chaddah | February 13, 2014
    Expert Contributor: Deepak Srivastava, MD

    For the millions of people who suffer from heart attacks every year, the aftereffects are literally scarring. When the heart muscle dies from lack of blood, it is replaced by scar tissue, since the heart has very little regenerative capacity. While better medical care and timely management of heart attacks have decreased the number of early deaths, survivors face an increased risk of chronic heart failure as they develop even more scarring. This grim prospect is what stem cell scientists, like Dr. Deepak Srivastava, Director of Cardiovascular Disease and the Stem Cell Center at the Gladstone Institutes in San Francisco, are hoping to change. 

    Stem Cells in Focus Webcast

    An Introduction to Endogenous Heart Repair

    Deepak Srivastava, MD, Gladstone Institutes, USA

    Learn more about the research and its potential, and pose your questions directly to Dr. Srivastava, during a live public webcast, Thursday, February 20 at 2 pm ET (USA).

    They plan to fix the heart from the inside – a strategy called endogenous (self) repair – by stimulating resident heart cells to generate new cardiomyocytes, the specialized heart muscle cells that keep our hearts beating.

    But why does the heart need help regenerating in the first place? Well, scientists used to think that our heart muscle cells were with us for life. It turns out, by the time we reach the age of 50, approximately half of all the cells in the heart aren’t the ones we were born with. While this is welcome proof that the heart can regenerate enough to maintain itself, the slow rate of turnover – about 0.5 to 1% per year – is far too low to repair damaged heart muscle. 

    The source for new muscle cells for heart turnover is still a black box. There might be a pool of heart stem cells that slowly churn out new muscle cells. Or that might be the role of stem cells circulating in the blood that set up shop in the heart. Or there may be unknown factors that trigger existing heart muscle cells to multiply. These theories are all being explored.

     One of the reasons that scientists have turned to endogenous repair for answers, is that clinical trials transplanting adult stem cells from a variety of sources have not panned out as hoped. While the safety profiles have been encouraging, the level of heart recovery has been minimal at best. Scientists are not yet sure why, but they are exploring the possibilities around increasing stem cell survival, expanding the numbers of patient-derived stem cells, and finding agents that can attract stem cells to damaged heart tissue for future trials. 

    But is there any evidence for endogenous repair of the heart? This area of research is in early days, but the answer seems to be yes: there are internal switches that can kick start heart muscle cells in newborn mice; there are heart cells in newly born mammals that look like they might be able to make new heart muscle; and there are experiments showing how non-muscle cells in the heart can be coopted to become heart muscle cells.

    An example of a heart muscle cell that was created from a reprogrammed fibroblast. A protein specific to heart muscles is visualized by the green fluorescence.

    The last example brings us back to Dr. Srivastava’s approach. His team is the first to show that fibroblasts, structural support cells found throughout the body, can be directly converted, or reprogrammed, into heart muscle cells. Figuring out the conversion process was no simple task. First, they identified a pool of 14 different factors known to be used by nature to make a heart in an embryo. Then they painstakingly whittled the number down to three essential factors. Finally, they introduced the factors into fibroblasts by way of a virus delivery system and found that the three factors were enough to convert the fibroblasts into cells that looked very much like heart muscle. In mice with heart damage similar to a heart attack in humans, the three factors not only created new muscle, but also improved the pumping of the heart. This reprogramming process is novel because it triggers the conversion of one specialized cell directly into another specialized cell, without first being forced to become a stem cell.

    Having shown that it’s possible to directly reprogram mouse fibroblasts (in a dish and in adult hearts) and also human heart fibroblasts in a dish, Dr. Srivastava’s group is testing the recipe in pigs, whose heart size and physiology is closer to our own.

    So what are some of the pros and cons of direct reprogramming? A big plus is that this represents a new way to fix damaged heart tissue - and since the heart is over 50% fibroblasts, there are ample cells to reprogram. The major issue is safety: there is always the chance of causing tumors when using virus delivery systems. Many researchers are trying to find ways around this; one possibility is identifying small drug-like molecules that could replace the reprogramming-factor / virus delivery combination. Dr. Srivastava’s main concern is the risk of irregular heartbeats that could happen if the newly made heart muscle cells, located in patchy, scarred areas of the heart, start beating out of sync because they are not able to connect with existing heart muscle cells.

    In the best of all worlds, Dr. Srivastava estimates the direct reprogramming approach might reach clinical trials within five years. The first trials would primarily assess safety but would also begin to probe what really happens inside a human heart, perhaps through testing in patients scheduled for heart transplantation, allowing scientists to study their old hearts post-transplant. While such trials are well into the future, the possibility of repairing the heart via direct reprogramming does offer some much needed hope for all those who face the prospect of heart failure.

  • Newly Discovered STAP Cells Explained

    By Carl Wonders | January 31, 2014

    You may have heard the news this week about exciting new developments in the field of stem cell research, published in the January 30 issue of Nature. A Japanese scientist, Dr. Haruko Obokata, and her colleagues demonstrated a new way to reprogram specialized stem cells from a newborn mouse to a “pluripotent” state; which is to say, the cells gained the ability to turn into any sort of cell in the body, much the same way embryonic stem cells can.

    Pluripotent cells have attracted considerable attention from stem cell researchers around the world. In fact, human pluripotent cells are a valuable tool for understanding how our bodies work. They provide opportunities to study many different diseases and conditions-- such as heart disease, diabetes, Parkinson’s disease and spinal cord injury-- and to develop new methods for diagnosis and therapy.

    Dr. Obokata’s primary finding is that she can cause a specialized cell from a newborn mouse to revert back to a pluripotent state. But as striking as this is, she is not the first to create a pluripotent stem cell from a specialized cell. In 2006, Shinya Yamanaka discovered how to generate “induced pluripotent stem cells,” or iPS cells, through genetic manipulation of fully mature, specialized cells. This discovery was groundbreaking and challenged the way we think about how our tissues form and how we can influence this process both inside and outside of the body. In recognition of this work, Dr Yamanaka was co-recipient of the 2012 Nobel Prize in Physiology or Medicine.

    What makes Dr. Obokata’s newly discovered cells, called “Stimulus-Triggered Acquisition of Pluripotency,” or STAP cells, so remarkable is that they are created, not by genetic manipulation, but through exposure to a more acidic environment. Incredibly, this suggests that cells possess the ability to be reprogrammed without any outside changes to their genetic code. While it is exciting, the full potential of this research will be unknown until the results can be duplicated in other labs and replicated with older tissues and within other species, including humans.

    There is still much to be learned about stem cells, cellular reprogramming and pluripotency. The stem cell research community hopes that as more is understood about STAP cells, they will join embryonic stem and iPS cells as another reprogramming tool for use in their collective quest to understand and treat human disease. 

    Hear ISSCR President Janet Rossant discuss the new research with Feature Radio News

  • Introducing "Stem Cells in Focus"

    By Janet Rossant, ISSCR President | January 16, 2014

    Happy New Year from the International Society for Stem Cell Research (ISSCR) and welcome to our very first "Stem Cells in Focus" post.

    The ISSCR is an independent nonprofit organization with over 4,100 members in 55+ countries. Our community is composed of researchers, clinicians and industry professionals working to advance stem cell research with the goal of finding or improving treatments for blood disorders, cancers, eye diseases, heart failure, multiple sclerosis, Parkinson’s disease, spinal cord injury, stroke and other currently intractable diseases and injuries.

    As we welcome 2014, the ISSCR is deepening its commitment to public education and outreach through a broad-based effort to share our science. We look forward to bringing you regular updates from the front lines of stem cell research and to sharing our excitement in the progress being made. Many of you have questions about what stem cell research is, the timeline and potential for treatments, specific diseases impacting you or loved ones and the validity of certain therapies. We will do our best to provide answers and guidance.

    This blog is just one part of our commitment to you. Each month, we will work with our members and experts to highlight different advancements in stem cell research, such as heart repair and regeneration, disease modeling and drug discovery and personalized stem cell medicine. We will explain the importance of each topic and discuss its potential to improve human health.

    If you have questions about topics, you may pose them directly to our experts via another new feature – regular and live public webcasts. Additional information from the ISSCR will be available to you 24/7 via ISSCR.org and A Closer Look at Stem Cells, both of which will be expanded in the months ahead.

    Please visit "Stem Cells in Focus" each month and follow our more regular updates on the ISSCR Facebook page. Thank you in advance for your feedback and engagement, and we hope we can count on your interest in and support of stem cell research for years to come.