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Ten Breakthroughs in Ten Years

What we’ve learned about stem cells in the past decade

In medicine as in all sciences, the big “eureka” moments are few. Most breakthroughs accumulate slowly over long periods of time. But we live in an age when scientific progress is measured in decades—or even years—rather than in centuries, as was the case for nearly all of human history.

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Just 15 years ago, stem cell research was but a speck on the medical horizon. Today, scientists can grow a beating human heart in a lab using stem cells. They can create pluripotent cells that bypass the need to use human embryos. Study after study suggests that stem cells may be one of the greatest portals we will ever cross in our quest for longer, healthier lives with less illness and suffering than our forefathers could have envisioned.

Much of what has transpired in stem cell research seemed far-fetched only five years ago. Today, investigators hasten to remind us that the field is still in its infancy. The possibilities are dizzying. So are the challenges that remain. But when you read about the work that has already been done, you may want to say, “Eureka!”

1. We Can Turn Back Time 

When induced pluripotent stem cells (iPSCs) first appeared in 2006, investigators quickly saw them as an extraordinary discovery from which a stream of cures and treatments might flow. Using iPSCs helped solve a number of problems, including political and ethical sensitivities regarding the use of human embryos. Because they are derived from adult tissue and then engineered in a lab to revert to an embryonic state, iPSCs negate the need to harvest cells from human embryos.

Just like human embryonic stem cells, iPSCs can be grown into any kind of human tissue, including organs, bones, cartilage, and neurons. This is what makes them so remarkable and so useful. By contrast, adult stem cells, found in our bodies after birth, are specialized and can only develop into the organ or tissue in which they are found. The discovery that adult stem cells could be reprogrammed back to a stage similar to embryonic stem cells won Shinya Yamanaka, MD, PhD, and Sir John Gurdon, PhD, the Nobel Prize in Physiology or Medicine in 2012.

hand-illoThe Cedars-Sinai Regenerative Medicine Institute, directed by Clive Svendsen, PhD, is at the helm of groundbreaking projects that harness the potential of these time-traveling cells. Programs within the Institute focus on developing stem cell therapies for a wide range of conditions affecting the eyes, blood, and bones, as well as specific diseases such as amyotrophic lateral sclerosis (ALS, also known as Lou Gehrig’s disease) and diabetes. The use of iPSCs represents one of the great developments in modern science and may hold the key to battling countless diseases and conditions.

2. Diseases Can Be Recreated in a Dish

No two Parkinson’s patients have the same disease. Neither do any two heart disease sufferers. We know today that the myriad factors that make each of us unique—our genetic makeup, bacterial profile, hormones, and brain chemistry—make our illnesses unique, too. This is the basis for personalized medicine, an approach in which both the diagnosis and the treatment are specifically tailored to the patient. The most valuable player in personalized medicine may well be induced pluripotent stem cells (iPSCs). Using a patient’s own skin cells, researchers can create a replica of the patient’s disease in vitro, a process known as disease modeling.

The patient’s cells are first turned into iPSCs, which are then grown in a lab to become the kind of tissue in which the disease resides. Because the tissue contains the genetic contribution of the donor, investigators can delve into the patient’s unique version of the illness. In addition to offering new insights about the causes of many health conditions, these models allow researchers to screen new drugs and treatments, testing one approach after another without any risk to the patient. Heart disease provides one remarkable example of disease modeling.

Scientists can now successfully grow a beating heart in the lab. The goal: to understand each patient’s unique manifestation of heart disease. “For example, if we have a patient with an arrhythmia, using the patient’s own cells we can create a heart afflicted with the exact same arrhythmia,” explains Dr. Svendsen. “We can try different treatments directly on the lab-grown heart, so the patient is never put at risk. It’s like a virtual clinical trial—we’re doing tests on the diseased heart, though the heart isn’t actually inside the patient.”

Diseases of the central nervous system may also have found their greatest foes in stem cells and disease modeling. In the Regenerative Medicine Institute’s Brain Program, iPSCs are generated from the skin of patients with neurological diseases. The cells are then directed to become various types of brain cells that normally degenerate in the patient—but that now degenerate in the petri dish right before the scientist’s eyes. Dr. Svendsen published the first scientific papers describing the use of this technology to model both spinal muscular atrophy and Huntington’s disease, severe neurological conditions for which no treatment or cure exists. Robert Baloh, MD, PhD, and Joshua Breunig, PhD, are developing iPSC lines from patients with amyotrophic lateral sclerosis (ALS, or Lou Gehrig’s disease) and Alzheimer’s and creating new models of these devastating conditions that may one day lead to breakthrough treatments.

3. We Can Heal a Broken Heart

The human heart is one of the most poignant emblems of life, immortalized in poems, sonnets, and songs. With the advent of stem cell technology, it is now linked to things even more wondrous, such as Dr. Svendsen’s work creating a beating heart in a dish—and the trailblazing efforts of Eduardo Marbán, MD, PhD, director of the Cedars-Sinai Heart Institute.

Under Dr. Marbán’s leadership, a team at the Heart Institute completed the world’s first injection of cardiac stem cells in 2009. Since then, additional research at the Heart Institute has shown that an infusion of cardiac stem cells helps damaged hearts regrow healthy muscle. “This has the potential to revolutionize how we treat heart attack patients,” says Dr. Marbán.

The findings, first published in The Lancet, show that heart attack patients who received stem cell treatment had a significant reduction in the size of the scar on the heart muscle. With support from the California Institute for Regenerative Medicine, the Heart Institute team is planning further clinical trials using stem cells to treat advanced heart disease.

4. Bugging Your Cells

Currently, one of the major challenges of induced pluripotent stem cells is that some harbor genetic defects, which can cause problems such as tumors when the cells are transplanted.

Surprisingly, one solution may be gleaned from research on leprosy, a disease almost entirely limited to the developing world, where 200,000 new cases occur every year. While studying the bacterium that causes the neurodegenerative disease, investigators noticed something unexpected. The bacterium appears to cause a change in supporting cells within the nervous system—known as Schwann cells—by switching on a set of genes that transform them into stem cells with migratory properties. This gives the leprosy bacterium a clever way to propagate throughout the host’s body: It hitches a ride with the altered cells, which develop into a variety of tissues such as muscle, bone, and cartilage—allowing the disease to move and take root throughout the body.

Why might this be a revelation for stem cell research? Because the leprosy bacterium reprograms the host cell without entering the nucleus at all—and therefore without causing any genetic mutations. While scientists at Cedars-Sinai now use similar techniques to create stem cell lines, this crafty bacterium may pave the way for doing so more efficiently.

5. Sweet Surprise

Because rates of Type 2 diabetes are sharply on the rise, Type 1 diabetes gets much less press. But in America alone, 800,000 people suffer from the disease, having been born unable to produce enough insulin to survive without intervention. Patients with Type 1 diabetes require several injections of insulin every day, or an insulin infusion pump, to control their blood glucose. Even with treatment, patients remain at risk of serious long-term health problems.

Enter stem cells. The pancreas contains specialized cells whose job it is to produce insulin. In patients with Type 1 diabetes, these cells are defective. Investigators at the Maxine Dunitz Neurosurgical Institute at Cedars-Sinai derived stem cells from bone marrow and modified them, resulting in the creation of new and healthy insulin-producing cells—and in the reversal of the disease in animal models.

Similarly, at the Pancreas and Liver Program, Donald Dafoe, MD, and Vaithilingaraja Arumugaswami, MVSc, PhD, are working on transforming ordinary adult skin cells to the same end: creating insulin-producing cells to treat diabetes and hepatocytes to treat diseases of the liver.

Although the work is not ready for trials on humans, it suggests that pancreatic regeneration may be possible—a potentially revolutionary approach to treating diabetes.

6. Insight On Eyesight

To date, the most successful work involving stem cells has occurred in the field of ophthalmology. Last year, The Lancet published the results of a project in which scientists used human embryonic stem cells to create cells in the back of the eye that are able to support a dying retina.

magnifying-illoThey successfully injected them into the eyes of two legally blind patients—an elderly woman struck by macular degeneration and a younger patient suffering from Stargardt’s, an inherited disease that causes light-sensitive cells in the retina to deteriorate, resulting in the loss of central vision. Within a few months of treatment, not only did the progression of the diseases slow, but new cells also began to grow, and both women reported slight improvements in their eyesight.

While these are very preliminary results—and investigators are quick to caution that the treatment does not cure blindness in these advanced stages—it may slow the degeneration and prevent blindness from occurring in the first place.

In the Regenerative Medicine Institute’s Eye Program, Shaomei Wang, MD, PhD, Alexander Ljubimov, PhD, and Yaron Rabinowitz, MD, are part of this revolution, working with various types of stem cells to treat age-related macular degeneration and other blinding conditions that are notoriously difficult to combat, such as retinitis pigmentosa, keratoconus, corneal scarring, and eye disease caused by diabetes.

7. Pass the Tissues

While examining a man with throat cancer who had previously undergone surgery and radiation, a doctor in Sweden had a radical idea. Instead of continuing with conventional treatment, the medical team—specialists in a field known as tissue engineering—conducted a procedure that made global headlines: They made the patient a brand-new windpipe out of plastic and his own stem cells and successfully implanted it in June 2011.

Tissue engineering is markedly different than the process that creates artificial hearts. Artificial hearts are essentially machines, while tissue engineers work entirely in the human realm, using cells, blood vessels, and nerves. To date, only simple, hollow organs such as windpipes and bladders have been built, but working with stem cells, investigators believe the day will come when they will be able to grow even complex organs.

Meanwhile, Dan Gazit, MD, PhD, and Zulma Gazit, PhD, at Cedars-Sinai are learning to regenerate skeletal tissue lost to trauma or degenerative disease. There is currently no way to reverse spinal disc degeneration, a common aspect of aging. And when bones are fractured as a result of osteoporosis, patients have few options other than pain medication and bed rest. With stem cells, new solutions are on the horizon.

After isolating adult stem cells from bone marrow or adipose (fat) tissue, scientists can activate unique genes within those cells that trigger the formation of the desired tissue. These modified stem cells are then injected into the injured area along with parathyroid hormone, which helps target the cells to the site of the fracture, such as a vertebra. That’s not all. Using therapeutic ultrasound as well as genes that form specific bones, the Regenerative Medicine Institute’s investigators have been able to target stem cells inside damaged bone, helping the bone regenerate faster and more efficiently in the laboratory than once seemed possible.

8. Baby Steps

Infertility affects more than 6 million women in the U.S.—about 12 percent of the reproductive-age population—at some point in their lives. In 2012, for the first time, researchers were able to extract stem cells from human ovaries and make them generate egg cells, signaling a potential breakthrough in the future of reproductive biology.

The key to this new research is a special protein that marks the surface of reproductive cells such as eggs and sperm. Using a cell-sorting machine that distinguishes the marked cells, researchers obtained reproductive cells from ovaries and demonstrated that the cells could generate viable egg cells that could be fertilized and produce embryos.

In addition, men who lose the ability to produce sperm following chemotherapy—a common side effect of the treatment—may one day be able to regain their fertility. Scientists have been able to reverse such infertility in male primates using an injection of stem cells taken from the animals prior to chemotherapy treatment.

While the new findings won’t translate into infertility treatments overnight, they open the door to a radically new way of approaching a problem that currently leaves would-be parents searching for solutions and finding far too few.

9. Stem Cells as Trojan Horses

Sometimes, stem cells are the therapy, becoming healthy tissue that scientists use to replace damaged parts. Other times, they act as carriers, ferrying therapeutic treatments to injured areas of the body. With amyotrophic lateral sclerosis (ALS, or Lou Gehrig’s disease), scientists are finding that stem cells can play both roles, paving the way for better, longer lives—and one day, perhaps, a cure.

“At the very least we hope we can slow down this horrific disease,” says Dr. Svendsen. “It’s a nightmare and it often affects young, otherwise healthy people.”

With a $17.8 million California Institute for Regenerative Medicine grant, Dr. Svendsen and his team are planning the world’s first human trial using stem cells that have been modified to release a powerful growth factor. When implanted into the spinal cords of animal models of ALS, these cells act as Trojan horses, turning into support cells that slow the degeneration of dying neurons—a hallmark of the disease in which nerve cells in the spinal cord die, slowly halting movement and breathing.

10. Stem Cells Can Be Put in the Bank

The Regenerative Medicine Institute recently moved to the Advanced Health Sciences Pavilion to be at the center of Cedars-Sinai’s growing biomedical community. To conduct all of the projects described in this article, and to help support the scientific community at the Medical Center and throughout the world, the Institute houses a facility dedicated to deriving, expanding, and characterizing induced pluripotent stem cells (iPSCs) using the latest reprogramming techniques.

Directed by Dhruv Sareen, PhD, the iPSC Core Facility uses cutting-edge technologies to create iPSC cells from all types of adult human tissue and to develop new ways to turn iPSCs into specific cells such as blood, brain, and bone.

The Core Facility’s laboratory houses a tissue-culture suite with three rooms and six cabinets for cell cultures. The state-of-the-art equipment includes microscopes that allow for viewing live cultures and the manipulation of stem cells, along with other sophisticated instruments that perform functions such as extended real-time cell imaging and genetic analysis.

As part of its mission, the Core Facility stores a variety of control and diseased iPSC lines available for use by all of Cedars-Sinai’s investigators and clinicians.

Challenges in Check

Before the full potential of induced pluripotent stem cells (iPSCs) can be harnessed, scientists must overcome a challenge that arises from the way the cells are engineered. Typically, iPSCs are created using viruses that integrate themselves into the host cell’s chromosome. “Unfortunately, that process can prompt a genetic mutation, making it impossible to safely transplant the cells into humans because they could cause tumors to develop,” explains Dr. Svendsen.

Investigators have produced a strain of virus that does not enter the nucleus, allowing them to generate iPSC lines free of genetic mutations—a major breakthrough in iPSC creation.

Investigators also face the question of how to create iPSCs more efficiently. The cells are usually generated in laboratories, where scientists may start with thousands of skin cells and end up with only a few iPSCs. To address this limitation, they are taking a closer look at chemical compounds that block the activity of kinases—enzymes responsible for various aspects of cell communication, survival, and growth. When added to starter cells, it seems that kinase inhibitors help generate a far greater number of iPSCs— almost more than the dishes can hold. The work is preliminary but, like so much in the world of stem cells, it is exciting and highly promising.

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