A Fungus with a Deadly Sweet Tooth

By: Kristen Kocher

severe brain swelling caused by a Cryptococcal infection

As it turns out, humans aren’t the only ones with a sweet tooth. According to an article published last week (April 5, 2010) in mBio online microbiology journal, a certain species of fungus, Cryptococcus, were found to thrive and reproduce through consumption of a sugar, inositol, which is commonly found in the human brain and spinal cord.

Joseph Heitman, M.D. and Ph.D. and his team of researchers who have been studying Cryptococcus at the Duke Department of Molecular Research believe they have identified a set of almost a dozen genes that code for sugar transport molecules. Sugar transport molecules are important in borrowing sugars from parts of the body to use where they are needed. Normal fungi have only two genes that code for these sugar transport molecules. It is therefore hypothesized that because of the increased number of genes coding for sugar transport molecules in Cryptococcus, this fungus is able to more quickly gather sugars to consume. According to Heitman, “Inositol is abundant in the human brain and in the fluid that bathes it (cerebral spinal fluid), which may be why this fungus has a predilection to infect the brain and cause meningitis. It has the machinery to efficiently move sugar molecules inside of its cells and thrive.” Meningitis is a serious health problem that involves the swelling of the area around the brain, causing a build up of fluid, which can have negative effects on brain function. Meningitis is a medical emergency because it occurs quickly and often results in permanent brain damage or death.

Before it was able to infect the brain, it is believed that Cryptococcus originally localized itself on plants. Plants are rich in inositol and most likely caused Cryptococcus to adapt and change its genome to produce more sugar transport molecules in order to survive and replicate. Because the brain and spinal cord naturally have very high concentrations of inositol it makes sense that Cryptococcus would target the brain as a niche.

Furthermore, it has been found that inositol stimulates sexual reproduction in Cryptococcus, so in areas of plentiful inositol concentrations, such as the brain, reproduction occurs often and rapidly.


Chaoyang Xue, Ph.D., formerly a postdoctoral research associate in the Heitman lab and now an assistant professor at the Public Health Research Institute at the University of Medicine and Dentistry of New Jersey, comments, “A connection between the high concentration of free inositol and fungal infection in the human brain is suggested by our studies. Establishing such a connection could open up a new way to control this deadly fungus.”

While Cryptococcus’ love for sugar may seem only beneficial, it turns out that because the fungus relies so heavily on inositol for nutrition, scientists have found a way to essentially put the fungus on an “Atkin’s-esque low-carb diet”. This “diet” would greatly reduce the ability of Cryptococcus to multiply, thus lessening its effects on the human brain.

Original Press Release

Check out mBio online microbiology journal for more articles and other information on this research.

Click here information on the Heitman lab

Discoveries in Diabetes, Depression, and Dementia

By Shelly Hwang

Diabetes, Depression, and Dementia are three of the most common medical conditions among Americans today. A recent study released on March 5 by a group of researchers at the University of Washington (UW) revealed that depression in diabetic patients doubles the risk of developing dementia, a finding that may affect the way that depression is screened and treated in order to prevent the development of other diseases.

Dementia is the gradual loss of cognitive and reasoning abilities, including memory loss, wandering, inability to do basic math, and forgetting familiar things or people.  Depression is a mental disorder marked by low mood and poor concentration. Diabetes is a medical condition in which a person has a high blood sugar level. While both diabetes and major depression have been shown to be separate risk factors for dementia, the effect of both diabetes and depression on dementia has not been studied. It turns out that adults with both conditions are twice as likely to develop dementia, compared with adults with only diabetes.

This project, led by Dr. Wayne Katon, a professor of psychiatry and behavior sciences at UW, is a part of the Pathways Epidemiological Follow-Up study, which examines adults from the Group Health Cooperative’s diabetes registry. Patients from nine clinics in western Washington State were studied for five years. 163 of 3,382 (4.8%) patients with diabetes alone developed dementia, while 36 of 455 (7.9%) of the diabetes patients with major depression were diagnosed with dementia. This presents a 2.7 fold increase of dementia in diabetic patients with depression.

Depression is common among individuals with diabetes. Previous studies found depression increases mortality rate among diabetes patients, in addition to health complications. However, the way the two diseases interact is unknown. Perhaps they interact by genetics, increasing stress levels, or resulting in unhealthy behaviors such as smoking, lack of exercise, and over-eating, which raise the risk of dementia. Diabetes is a known risk factor for dementia because it causes blood vessel problems, tissue damage, and increased blood sugar levels, which all increase odds of developing dementia. Although the link between depression, diabetes, and dementia is still not understood, it is useful for doctors to screen and treat for depression as a preventive measure against the development of cognitive deficits or dementia in diabetic patients.

Original Press Release

VA Puget Sound Health Care System Clinical Research Unit

Info on Dementia

The Sea Squirt: An Answer to Alzheimer’s?

Ciona intestinalis

By Kelly Lohr

The newest breakthrough in Alzheimer’s research is coming from an unlikely source–a sea squirt.  Just this week (March 2, 2010) Mike Virata and Bob Zeller of San Diego State University believe that Ciona intestinalis, known commonly as the sea squirt, may be the perfect model organism for this disease.

The brains of Alzheimer’s patients are typically filled with tangles and plaques made of the protein fragment beta-amyloid.  Alzheimer’s disease affects nearly 4 million Americans and an estimated 27 million people worldwide. It is the most common form of age-related dementia and has no cure. Current drug regimens only relieve symptoms and cannot halt the progression of the disease. Research in the scientific community is currently  aimed at slowing the disease through drugs such as Aricept and Namenda which are focused on decreasing plaque accumulation.

Recently, research has shown the need for an improved model organism to aid  in understanding the pathology of the disease.  Currently, genetically modified strains of mice have been the organism of choice in the research of this disease. However, there are limitations in the use of mice including an extremely long waiting period for plaque development like those seen in Alzheimer’s brains. Also, these mice do not contain the same genetic mutations linked to hereditary risk of Alzheimer’s disease.  Mice are also more costly to purchase and maintain for research.

Sea squirts are tunicates, marine organisms with a hard outer tunic and a soft body. They live on underwater structures and are filter feeders that eat small plant material. It has been suggested that sea squirts are actually our closest invertebrate relatives.  As far as research benefits, sea squirts share nearly 80% of our genes and resemble vertebrates in their immature form.  These animals are inexpensive to house and contain all of the genes needed for the development of Alzheimer’s plaques in humans.

An immature sea squirt.

Virata and Zeller found that by giving the immature sea squirt amyloid precursor protein, a mutant protein linked to hereditary Alzheimer’s, sea squirts developed brain plaques in a single day.  Further, these plaques and the behavioral deficits seen in these animals were able to be reversed using a drug meant to remove plaques.  Such techniques have been ineffective in all other invertebrate models, including the commonly used nematode, C. elegans.  Now, investigators can be freed from genetic, time, and financial constraints.  These findings provide a resource for an entirely new take on Alzheimer’s research…all because of a sea squirt.

For more information, click here.

Making new connections: Stem cells as treatment for ALS

By Kelly Lohr

The motor cortex in the human brain is mapped to match specific body parts. Body parts with more devoted cortex area are generally more sensitive or have finer motor control.

              Imagine slowly losing control of your muscles, first with a few twitches in your arms and legs or a slurred word here or there. Muscle failure will continue until it eventually stops your ability to move, speak, and breathe.  This is the life of a patient suffering from amyotrophic lateral sclerosis (ALS) also known as Lou Gehrig’s disease, a progressive neurodegenerative disorder.  Currently, there is little treatment for the rapid course of this disease, but James Weimann, PhD, of Stanford Medical School provides a new hope.

            Weimann is part of a team of neuroscientists using transplanted neurons grown from embryonic stem cells to replace damaged cells in young animals.  This finding is the first of its kind in that the stem cells can be directed to take on the jobs of specific brain cells while also making the correct connections with other cells. Weimann’s cells transmit information from the cortex, the neural tissue that is outermost part the mammalian brain, specifically areas needed for motor function.

             Up until this point, the issue of stem cell transplantation in the brain was making the proper neuronal connections.  As an adult organism, creating the accurate connections in the nervous is extremely complex.  During development, superfluous neural connections deteriorate with lack of use. Only the pathways with the most activity remain in adulthood.  The chemical or physical signals that once lead the way in development are no longer present.  Without such cues, it is difficult for neurons to reach their target areas. For example, the stem cells created in Weimann’s lab must make connections with motor cortex in order to be an effective treatment for disorders like ALS or a traumatic brain injury.  Incorrect connections could result in further erratic brain function.

A step in the processing of human embryonic stem cells.

           While Weimann’s work holds a lot of potential for further progress and treatments, the studies have involved transplantation in young animal models.  Since the majority of neurodegeneration takes place in older adults, the next step will be to explore stem cell transplantation in adult animals.  Weimann and his team are hopeful that these newest findings will soon be used in treatment of neurons that are lost or damaged due to spinal cord injuries or diseases like ALS.

Not Your Average Fairytale

By Kristen Kocher                        February 4, 2010

Numerous genetic diseases, especially hereditary brain diseases, are untreatable therefore subjecting many individuals to a life of endless pain and suffering. However, in recent years with the development of the technique of gene therapy, new hope has been brought to life in those diagnosed as “terminally ill” with the promise of the “happily ever after” ending that everyone deserves.

Gene therapy is still not used as a mainstream medical technique because much of the process is still in the developmental stages. Recently, geneticists have been desperately working to perfect the successful transport of therapy genes into brain cells. In many cases, the diseases are caused by a single gene or protein mutation but can cause devastating affects, which normally result in the loss of brain cells and fatality.

A recent scientific breakthrough has finally made it possible for therapy genes to be inserted into brain cells and cure certain genetic diseases.  Before this discovery, therapy genes were only administered through the use of viruses, predominantly the herpes virus, HSV-1. While HSV-1 has the ability to effectively transport large genes into the nucleus of the targeted cells, once the genetic information enters the nucleus it is unable to be integrated into the mammalian, host genome. This proves to be unhelpful as the therapeutic information is quickly silenced and within a few days the effects of gene therapy are no longer visible.  

Another molecule used for gene therapy transport is known as “Sleeping Beauty”. The aforementioned molecule is named as such because it is innately a silent gene that was activated, or “awakened”, by scientists. The discovery of this molecule is beneficial because it has the ability to take the target gene intended for therapy into the nucleus and integrate it directly into the mammalian genome.  The genes transported by Sleeping Beauty, however, must be relatively small, roughly 15 to 30 times less than the amount of DNA carried by HSV-1. This is unfortunate because the genes that are used for treatment of diseased brain cells are predominately large and cannot be carried by Sleeping Beauty.

So, where does the happy ending come in? These two molecules individually have characteristics that make them useful in therapy gene transport but separately cannot aid in the treatment of brain disease. However, thanks to the research of William Bowers, Ph.D. and graduate student Suresh de Silva, this blockade has been removed. With the creation of a hybrid molecule made up of both HSV-1 and Sleeping Beauty, geneticists have been able to successfully integrate large therapy genes into the mammalian genome, which, though current experiments, have resulted in long-term therapeutic gene expression. The creation of this hybrid therapy gene transport molecule promises a bright future and “happy ending” for those suffering from terminal, genetic disease.

Original Press Release

Find out more about the projects going on in Bowers Laboratory