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An easier (and safer) route to stem cell therapies

by Bruce Lieberman on October 31, 2011 at 9:32 am | 0 Comments

Chao-Shun Yang, graduate student in Dr. Tariq Rana's lab and first author of the study

Many research labs around the world are focused on finding the most effective ways to reprogram an adult cell (a skin cell, for example) into induced pluripotent stem cells (iPSCs)—that is, cells that have the ability to develop into other tissues in the body. These cells not only offer researchers powerful tools to study a particular patient’s individual disease, but they have the potential to therapeutically replace diseased or damaged tissue in the patient from whom the cells originated.

Most experiments to reprogram adult cells employ viruses as vehicles to carry four particular genes—called reprogramming factors—into the nucleus of a cell. But genetic engineering carries its own risks, including the chance that these cells will continue replicating, eventually forming a tumor. What’s more, scientists are not exactly sure what the reprogramming factors do, on the molecular level, to promote the generation of iPSCs.

Could there be a safer and more predictable way to alter the expression of genes in cells, thereby reprogramming their DNA so they revert to their earlier, more malleable state?

How cells sense nutrients and fuel cancer cell growth

by Heather Buschman, Ph.D. on October 6, 2011 at 10:52 am | 0 Comments

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Dr. Maria Diaz-Meco (left), professor and senior author, and Dr. Angeles Duran, research assistant professor and one of the study’s first authors

In cancer, genes turn on and off at the wrong times, proteins aren’t folded properly, and cellular growth and proliferation get out of control. Even a cancer cell’s metabolism goes haywire, as it loses the ability to appropriately sense nutrients and use them to generate energy. One particular piece of cellular machinery that is known to malfunction in a number of cancers is a group of proteins called mTORC1. This master control center coordinates many cellular functions by sensing external signals such as nutrients and growth factors and telling cells how to respond.

Now, in a paper published October 7 in Molecular Cell, Sanford-Burnham scientists have identified a new member of the mTORC1 team—a protein called p62—that is crucial to the cell’s response to dietary amino acids. This finding provides new information about mTORC1 and its role in cellular metabolism in both normal cells and cancer cells. What’s more, it provides scientists with a new therapeutic target for cancers in which mTORC1 malfunctions.

Fighting fat with fat

by Heather Buschman, Ph.D. on October 4, 2011 at 9:00 am | 0 Comments

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Loss of orexin impairs brown fat function and promotes obesity in mice. The leaner mouse with functional brown fat (left) dissipates considerable amounts of energy as heat. The orexin-deficient mouse (right) lacks fat fuel and active mitochondria, thus storing energy as fat instead of burning it. (Image by Peter Allen, UCSB)

The fat we typically think of as body fat is called white fat. But there’s another type—known as brown fat—that does more than just store fat. It burns fat. Scientists used to think that brown fat disappeared after infancy, but recent advances in imaging technology led to its rediscovery in adult humans. Because brown fat is so full of blood vessels and mitochondria—that’s what makes it brown—it’s very good at converting calories into energy, a process that malfunctions in obesity.

In a study published October 5 in Cell Metabolism, Sanford-Burnham researchers discovered that orexin, a hormone produced in the brain, activates calorie-burning brown fat in mice. Orexin deficiency is associated with obesity, suggesting that orexin supplementation could provide a new therapeutic approach for the treatment of obesity and other metabolic disorders. Most current weight loss drugs are aimed at reducing a person’s appetite. An orexin-based therapy would represent a new class of fat-fighting drugs—one that focuses on peripheral fat-burning tissue rather than the brain’s appetite control center.

“Our study provides a possible reason why some people are overweight or obese despite the fact that they don’t overeat—they might lack the orexin necessary to activate brown fat and increase energy expenditure,” explains Dr. Devanjan Sikder, senior author of the study and assistant professor in Sanford-Burnham’s Diabetes and Obesity Research Center, located in Orlando’s Medical City at Lake Nona.

Nanoparticles seek and destroy glioblastoma in mice

by Heather Buschman, Ph.D. on October 3, 2011 at 12:00 pm | 0 Comments

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Erkki Ruoslahti, M.D., Ph.D., distinguished professor in both Sanford-Burnham’s NCI-designated Cancer Center in La Jolla and the Center for Nanomedicine, a Sanford-Burnham collaboration with the University of California, Santa Barbara

Glioblastoma is one of the most aggressive forms of brain cancer. Rather than presenting as a well-defined tumor, glioblastoma will often infiltrate the surrounding brain tissue, making it extremely difficult to treat surgically or with chemotherapy or radiation. Likewise, several mouse models of glioblastoma have proven completely resistant to all treatment attempts.

To overcome this hurdle, Sanford-Burnham scientists and their collaborators at the Salk Institute developed a method to combine a tumor-homing peptide, a cell-killing peptide, and a nanoparticle that both enhances tumor cell death and allows the researchers to image the tumors. When used to treat mice with glioblastoma, this new nanosystem eradicates most tumors in one model and significantly delays tumor development in another. These findings were published the week of October 3 in the Proceedings of the National Academy of Sciences of the USA.

“This is a unique nanosystem for two reasons. First, linking the cell-killing peptide to nanoparticles made it possible for us to deliver it specifically to tumors, virtually eliminating the killer peptide’s toxicity to normal tissues. Second, ordinarily researchers and clinicians are happy if they are able to deliver more drugs to a tumor than to normal tissues. We not only accomplished that, but were able to design our nanoparticles to deliver the killer peptide right where it acts—the mitochondria, the cell’s energy-generating center,” says Dr. Erkki Ruoslahti, senior author of the study and distinguished professor in both Sanford-Burnham’s NCI-designated Cancer Center in La Jolla and the Center for Nanomedicine, a Sanford-Burnham collaboration with the University of California, Santa Barbara.

Using stem cells to treat Parkinson’s disease

by Heather Buschman, Ph.D. on September 26, 2011 at 7:13 am | 1 comment

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Neurons derived from embryonic stem cells

When neurons that make a chemical called dopamine are slowly destroyed, nerve cells in that part of the brain cannot properly send the messages that would normally control muscle function. As the damage gets worse with time, a person experiences tremors and movement becomes difficult. This is Parkinson’s disease.

In short, Parkinson’s patients need more dopamine. Or, better yet, new neurons that produce dopamine on their own. In a paper published August 25 in the journal PLoS ONE, a team led by Dr. Stuart Lipton, director of Sanford-Burnham’s Del E. Webb Center for Neuroscience, Aging, and Stem Cell Research, demonstrates how this therapeutic approach might be possible.

Oncothyreon helps bring potential cancer drug from lab to patients

by Heather Buschman, Ph.D. on September 15, 2011 at 10:17 am | 0 Comments

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Dr. Maurizio Pellecchia

Sanford-Burnham has entered an agreement with Oncothyreon Inc that will allow the biotechnology company to develop sabutoclax, a chemical discovered as a result of research in the laboratories of Dr. Maurizio Pellecchia and Dr. John Reed, into a potential new anti-cancer drug. Sabutoclax inhibits a family of proteins called Bcl-2, which helps cells avoid self-destructing in a process known as apoptosis. By tempering Bcl-2, sabutoclax shows great promise in blocking cancer cell growth.

“Overexpression of one or more members of the Bcl-2 family of proteins is common in most human cancers,” said Dr. Scott Peterson, Vice President of Research and Development at Oncothyreon. “This overexpression prevents the type of cell death known as apoptosis, resulting in resistance to many frequently used cancer treatments. By blocking Bcl-2 protein function, sabutoclax induces apoptosis in tumor cells and increases the activity of chemotherapy. Sabutoclax inhibits all of the Bcl-2 protein family members, which may prove advantageous when compared with other compounds directed at these targets.”

“We are confident that we have found a strong development partner in the Oncothyreon team that is dedicated to advancing sabutoclax into the clinic for patients battling with cancer,” said Dr. Reed, who has extensively published on the role of Bcl-2 proteins in cancer and also serves as Sanford-Burnham’s CEO.

10 years of science & counterterrorism

by Communications Staff on September 11, 2011 at 6:41 am | 0 Comments

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Crystal Structure of Anthrax Lethal Factor complexed with a small molecule inhibitor

As the United States pauses to observe the 10th anniversary of the September 11th terrorist attacks, we reflect on the research advances that contribute to new counterterrorism measures—understanding anthrax, for example—and the health of our soldiers in Iraq and Afghanistan, including under-studied conditions such as traumatic brain injury (TBI) and post-traumatic stress disorder (PTSD). Here are a few examples, and these only cover discoveries made at Sanford-Burnham since September 11, 2001. Can you think of more? Please share your thoughts in the comments below.

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Glucose uptake relies on newly identified protein

by Heather Buschman, Ph.D. on September 7, 2011 at 10:50 am | 0 Comments

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Dr. Zhen Jiang

All cells need glucose (sugar) to produce the energy they need to survive. High glucose levels in the bloodstream (such as occur after a meal), trigger the pancreas to produce insulin. In turn, muscle and fat cells respond to insulin by moving GLUT4, a glucose transporter, from intracellular storage out to the cell surface. There, GLUT4 can take up the glucose the cell needs from the bloodstream.

A team led by Dr. Zhen Jiang recently identified the protein—called CDP138—responsible for ensuring that GLUT4 is properly inserted in the cellular membrane. This finding provides a new understanding of glucose metabolism—an important finding considering that impaired insulin action and glucose metabolism contribute to the development of type 2 diabetes.

“This is a newly identified protein that’s involved in an important step in glucose uptake,” said Dr. Jiang, assistant professor in Sanford-Burnham’s Diabetes and Obesity Research Center, located in Orlando’s Medical City at Lake Nona.

Recycling fat to live longer?

by Heather Buschman, Ph.D. on September 6, 2011 at 9:00 am | 0 Comments

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Germline-less C. elegans nematodes with an autophagy marker shown in green. (Image courtesy of the Hansen lab)

Aging is generally accepted as a universal fact of life, but how do humans and other organisms age at the molecular level?

At Sanford-Burnham, a team led by Dr. Malene Hansen uses a type of worm called Caenorhabditis elegans to work out the molecular underpinnings of the aging process. Recently, they found that two cellular processes—lipid metabolism and autophagy—work together to influence worms’ lifespan. Autophagy, a major mechanism cells use to digest and recycle their own contents, has become the subject of intense scientific scrutiny over the past few years, particularly since the process (or its malfunction) has been implicated in many human diseases, including cancer and Alzheimer’s disease. (See Autophagy 101.)

The Hansen group’s latest study, published online September 8 in Current Biology, provides a more detailed understanding of the roles autophagy and lipid metabolism play in aging.

“The particular worm model we used in this study is known to live longer than normal worms, but we didn’t completely understand why,” said Dr. Hansen, assistant professor in Sanford-Burnham’s Del E. Webb Center for Neuroscience, Aging, and Stem Cell Research and senior author of the study. “Our results suggest that increased autophagy has an anti-aging effect, possibly by promoting the activity of a fat-digesting enzyme. In other words, it seems that recycling fat is a good thing—at least for worms.”

How to make new neurons

by Bruce Lieberman on August 31, 2011 at 9:55 am | 0 Comments

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Neurons (Image courtesy of the Lipton lab)

Imagine the ability to take skin cells from a patient with Alzheimer’s disease, convert them directly into brain cells, and then study how the disease progresses in those cells—which still contain the patient’s DNA—all in the lab, with minimal invasiveness on the part of the patient. Then imagine taking those same brain cells and testing novel but risky drugs that could cure the devastating disease—again, in the safety of a dish in the lab.

Researchers are on their way to achieving this remarkable milestone. Dr. Stuart Lipton at Sanford-Burnham, Dr. Sheng Ding at the Gladstone Institutes, and their collaborators recently figured out how to reprogram skin cells directly into functioning neurons. The study was published online July 28 in the journal Cell Stem Cell.

“This technology should allow us to very rapidly model neurodegenerative diseases in a dish by making nerve cells from individual patients in just a matter of days, rather than the months required previously,” Dr. Lipton says in a statement released by the Gladstone Institutes.

The paper is one of several recent studies that are all zeroing in on a long-sought-after advance in stem cell science: the potential to obtain unlimited numbers of brain cells from an easily accessible tissue such as the skin.

Normal in development, abnormal in cancer

by Bruce Lieberman on August 19, 2011 at 5:16 am | 0 Comments

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Dr. Danielle Murphy (right)

It’s an amazing and frightening thought: some of the same genetic signaling that shapes the development of an embryo also drives the spread of cancer. But that’s what a new study by Dr. Sara Courtneidge’s lab suggests.

Dr. Courtneidge’s lab primarily studies cancer metastasis—the spread of cancer from a tumor to another part of the body. Cancer cells do this by moving from the tumor through the vasculature and into the extracellular matrix, which provides structural support for tissues and organs. A few years ago, Dr. Courtneidge’s lab showed that cancer cells rely on a protein called Tks5 to form invadopodia, structures on the surface of cells that enable cancer cells to “walk” from one place in the body to another.

Cell migration, of course, is not a process unique to cancer and occurs during other normal and disease states. For example, cells move to the site of a wound during healing, during angiogenesis when new blood vessels form in response to injury, and during an immune response to infection. Cell migration is also crucial during embryonic development. So the Courtneidge lab decided to unravel Tks5’s role in development using the tiny zebrafish as an experimental model.

Getting to the root of Alzheimer’s disease

by Heather Buschman, Ph.D. on August 17, 2011 at 5:47 am | 0 Comments

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Dr. Stuart Lipton

Alzheimer’s disease is characterized by abnormal proteins that stick together in little globs, disrupting cognitive function (thinking, learning, and memory). These sticky proteins are mostly made up of beta-amyloid peptide. A better understanding of these proteins, how they form, and how they affect brain function will no doubt improve the diagnosis and treatment of Alzheimer’s disease.

To this end, a research team led by Dr. Stuart Lipton‘s group found that beta-amyloid-induced destruction of synapses—the connections that mediate communication between nerve cells—is driven by a chemical modification to an enzyme called Cdk5. The team found that this altered form of Cdk5 (SNO-Cdk5) was prevalent in human Alzheimer’s disease brains, but not in normal brains. These results, published August 15 in the Proceedings of the National Academy of Sciences of the USA, suggest that SNO-Cdk5 could be targeted for the development of new Alzheimer’s disease therapies.

Cdk5 is an enzyme known to play a role in normal neuronal survival and migration. In this study, Dr. Lipton and colleagues found that beta-amyloid peptides, the hallmark of Alzheimer’s disease, trigger Cdk5 modification by a chemical process called S-nitrosylation. In this reaction, nitric oxide (NO) is attached to the enzyme, producing SNO-Cdk5 and disrupting its normal activity.

How fat and obesity cause diabetes

by Heather Buschman, Ph.D. on August 15, 2011 at 5:08 am | 23 Comments

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Overnutrition in many countries has led to epidemics of obesity and type 2 diabetes. (Image by Peter Allen, UCSB)

Overnutrition in many countries has led to an epidemic of type 2 diabetes. (Image by Peter Allen, UCSB)

Newly diagnosed type 2 diabetics tend to have one thing in common: obesity. Exactly how diet and obesity trigger diabetes has long been the subject of intense scientific research. A new study published online August 14 in Nature Medicine reveals a pathway that links high-fat diets to a sequence of molecular events responsible for the onset and severity of diabetes.

In studies spanning mice and humans, a research team at the Center for Nanomedicine, a collaboration between Sanford-Burnham and the University of California, Santa Barbara, discovered a pathway to disease that is activated in pancreatic beta cells, and then leads to metabolic defects in other organs and tissues, including the liver, muscle and adipose (fat). Together, this adds up to diabetes.

“We were initially surprised to learn how much the pancreatic beta cell contributes to the onset and severity of diabetes,” says Dr. Jamey Marth, director of the Center for Nanomedicine and senior author of the study. “The observation that beta cell malfunction significantly contributes to multiple disease signs, including insulin resistance, was unexpected. We noted, however, that studies from other laboratories published over the past few decades had alluded to this possibility.”

Marching to the same beat

by Ana Miletic Sedy on August 4, 2011 at 11:23 am | 0 Comments

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heart muscle in a fruit fly (image courtesy of the Bodmer lab)

Heart disease is the leading cause of death in the United States, accounting for more than 25 percent of all deaths each year. While many factors work together to contribute to heart disease—including environment, lifestyle, and genetics—we only have control over the first two. To address the third factor (genetics), researchers at Sanford-Burnham recently turned to fruit flies.

Fly and human genes are so closely related that the sequences of newly discovered human genes, including many that contribute to disease, can often be matched up with fly counterparts. Since fruit flies are relatively easy to work with (they’re small, breed quickly, and don’t require a lot of maintenance), they often give scientists clues to the functions of human genes and helps them develop drugs that target them.

As Dr. Rolf Bodmer, director of Sanford-Burnham’s Development and Aging Program, explains in the Journal of Cell Biology, “We use fruit flies to learn about the fundamental genetic mechanisms that are important for the development and function of the heart.”

Dr. Bodmer himself discovered early in his career that flies lacking Tinman, a protein that regulates the expression of other genes, fail to develop heart tissue during embryonic development. If Tinman is removed later during fly development, the flies’ hearts don’t function properly.

Now researchers in Dr. Bodmer’s lab, led by postdoctoral researcher Dr. Li Qian, uncovered a genetic network that controls heart development and function in fruit flies and mice, with additional clues that it might also play a role in human heart health.

Taste receptors…in the gut?

by Bruce Lieberman on August 1, 2011 at 5:58 am | 0 Comments

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Let’s suppose your summer backpacking trip takes a disastrous turn and you’re lost, out of food, and desperate. You think those berries look OK so you swallow them down—even though they’re as bitter as anything you’ve eaten before. It’s not long before you regret ignoring your taste buds and suspect you’ve eaten something poisonous.

Unless you’re a molecular biologist, you’re probably not thinking at that moment about the biochemistry churning in your gut. But a cacophony of cellular signals is actually assembling a second line of defense to keep your digestive system from absorbing toxins into your bloodstream.

Of course, your body doesn’t always win. But Dr. Timothy Osborne’s lab at Sanford-Burnham’s Lake Nona campus has outlined how bitter taste-sensing receptors on enteroendocrine cells in the gut, called T2Rs, automatically kick into gear when confronted with bitter-tasting substances. You might disregard the taste buds in your mouth, but your digestive system knows better and tries to make up for your recklessness.

An easier (and safer) route to stem cell therapies

How cells sense nutrients and fuel cancer cell growth

Fighting fat with fat

Nanoparticles seek and destroy glioblastoma in mice

Using stem cells to treat Parkinson’s disease

Oncothyreon helps bring potential cancer drug from lab to patients

10 years of science & counterterrorism

Glucose uptake relies on newly identified protein

Recycling fat to live longer?

How to make new neurons

Normal in development, abnormal in cancer

Getting to the root of Alzheimer’s disease

How fat and obesity cause diabetes

Marching to the same beat

Taste receptors…in the gut?

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