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Beth Thomas

Advancing Discoveries to Relieve the Suffering Caused by Psychiatric and Neurodegenerative Disorders

For as long as she can remember, Beth Thomas has been fascinated with how the brain works. This passion has guided her career as a neuroscientist, where she is driven by a prevailing goal to alleviate the suffering caused by psychiatric and neurological disorders. As an undergraduate biochemistry student at the University of California, Berkeley, in the late 1980s, the mentally ill homeless people that Beth saw on the street every day reinforced her interest in studying pharmacology and the effects of anti-psychotic drugs, which are used to treat psychiatric illnesses. As a postdoctoral fellow at Scripps Research in the 1990s, her research interests expanded to include neurodegenerative disorders, when a colleague in her lab discovered she was at risk for Huntington’s disease.

Today, as an Associate Professor at Scripps Research on the California campus, Beth continues to work diligently to investigate the role of genes in brain-destroying diseases, such as schizophrenia. Her research aims to understand the nature of gene dysfunction in these disorders in order to provide a basis for improved therapeutics and disease prevention.

The debilitating psychiatric disorder, schizophrenia, which means “fragmented mind,” usually begins in the late teens or early adulthood. Symptoms include delusions, hallucinations, bizarre behavior, depression, social withdrawal, apathy, and poor communication skills. These symptoms make affected individuals unable to function in society, resulting in a huge community burden.  It is a common mental illness, affecting close to 1% of the general population. While the outcome varies among individuals, the course of illness is one of frequent relapse and persistent dysfunction that lasts throughout one’s lifetime.

“In general, schizophrenia remains a poorly diagnosed, poorly understood, and inadequately treated illness, one that is especially heartbreaking because it strikes people in their teens and early 20s. It’s a horrible disease for individuals and their families that can often end in suicide at an early age,” says Beth. “Many genes contribute to the cause of the disease, making it extremely complex to study, and better pharmaceuticals are needed – the pharmaceuticals for schizophrenia today are generally no better than those developed fifty years ago.”

Researchers are actively working to identify the direct causes of schizophrenia, likely rooted in interactions between genes and the environment resulting in abnormal gene expression in the central nervous system.  Scientists have been studying expression changes in schizophrenia on an individual gene basis, yet this strategy has explained only a portion of the genetic risk.

In recent work, Beth and her team of researchers took a novel approach to this problem, performing a gene network-based analysis using microarray technology that enables analysis of up to 40,000 genes at once. The work revealed surprising new insights into how gene regulation and age play a role in schizophrenia and how schizophrenia may develop.

The group analyzed gene expression from the prefrontal cortex, a region of the brain associated with schizophrenia, and sampled post-mortem from normal individuals and schizophrenia patients ranging from 19 to 81 years old, some who only had the illness for two or three years. However, instead of just looking at genes individually, Beth and her colleagues considered interactions between genes, as well as groups of genes that showed similar patterns of expression, to identify dysfunctional cellular pathways in schizophrenia.

“Once gene co-expression networks are identified,” said Beth, “we can then ask how they are affected by factors such as age or drug treatment, or if they are associated with particular cell types in the brain. The most surprising finding was a significant link between aging and gene expression patterns in schizophrenia, especially genes related to brain development, a process which continues throughout late adolescence.

Beth explained that these findings help to refine the developmental hypothesis of schizophrenia, which states that one or more pathogenic “triggers” occur during a critical period of development to increase risk for the disease. Specifically, this work indicates that abnormal gene expression in developmentally related genes might be a significant pathogenic trigger, occurring over a broader time-scale than expected. “Rather than a pathological trigger occurring at a critical developmental time point,” said Beth, “the trigger is ongoing throughout development and aging. This suggests a bigger window of opportunity for early treatment”. She added, “Although it is clear that identifying new drugs to treat schizophrenia is essential, these studies reveal how the mode of treatment may improve outcome”.

Studies have shown that treatment soon after initial diagnosis of schizophrenia results in good outcome. Although prophylactic treatment in schizophrenia is controversial, it is possible to identify those individuals at a high risk for developing the disease, based on family history and particular symptoms that appear several years prior to disease onset. Beth noted that the new study supports early intervention and treatment of schizophrenia prior to official diagnosis, in which therapeutic approaches would be aimed at averting gene expression changes occurring early on. “Our studies underscore the idea that early intervention is critical and could alter the course of disease,” Beth says.

Another important finding from her recent studies is that the aging process in schizophrenic patients appears to be quite different from normal subjects. In particular, Beth found that genes related to inflammation were expressed differently in older patients compared to young patients and that this age difference was not found in normal subjects. “This may translate into a simple application of personalized medicine, which could be to specifically tailor medications to the age of the patient” says Beth. These findings have enormous implications with regards to anti-inflammatory treatments, which have recently emerged as important adjuncts to standard antipsychotic drug therapy. Anti-inflammatory agents may prove to be very useful to young patients with schizophrenia, but not older patients with chronic illness. This approach, she added, could be applied to several other neurological disorders as well.

Beth’s group was the first in the world and is still the only group to tease apart schizophrenia on a molecular level according to stage of illness and age. Using the post-mortem brains of schizophrenia patients allowed Beth to study various aspects of early-stage illness, as well as chronic disease, in the central nervous system itself where the disease is actually happening, as opposed to looking at blood samples. Post-mortem brain samples from younger subjects are often difficult to obtain as these patients often suffer a tragic death or suicide, meaning the parents are less willing to donate their sons or daughters brains to science. This is the main reason that most studies in the past have focused on subjects with chronic illness.

Beth’s interest in Huntington’s disease – which is characterized by progressively worsening involuntary movements, loss of intellectual faculties, emotional disturbances and premature death – was initially piqued by a Scripps Research friend and colleague who was at significant risk because her mother had passed away from the disease.

Accompanying her friend to support group meetings only intensified Beth’s resolve to study Huntington’s disease, the most common inherited neurodegenerative disease. About one in 10,000 Americans has Huntington’s disease and 150,000 people are believed to be at risk, meaning that one of their parents inherited the disease, giving them a 50 percent chance of developing it as well.

“It was unbelievably moving to witness how Huntington’s disease rips apart those who have the disease, those at risk, and their families,” says Beth. “I felt I had to do whatever I could to help better understand this terrible disease that strikes people when they are relatively young – in their 40s or even younger, and still in the prime of their lives.”

There is no cure for Huntington’s disease, or even treatments that can reverse or slow progression of the devastating movement deficits and cognitive dysfunction that occur with the condition. But Beth and her colleagues have developed an agent that has shown dramatic therapeutic efficacy in experimental mice, and with minimal toxicity.

Beth and her colleagues work with “transgenic” mice – those whose DNA has been altered so that the mouse exhibits the characteristics of Huntington’s disease – to try to understand the genetic basis for the disease. Using microarray technology, as in her schizophrenia studies, she has identified many genes expressed in the striatum of the transgenic mice that seem to be involved in both early and late stage neurodegeneration.

Because the brains of these Huntington’s disease transgenic mouse models show high levels of abnormal gene expression, Beth, in collaboration with Scripps Research Professor Joel Gottesfeld, has made progress in testing novel compounds that alter gene expression in these mice. In particular, they have focused on one drug candidate that was highly effective in preventing disease symptoms in Huntington’s disease mice. “The benefit seen was surprising, and immensely exciting, because it suggests this compound could form the basis of a truly relevant therapeutic treatment for Huntington’s disease,” says Beth.

Beth notes that without the generous philanthropy of an anonymous donor, as well as donor funding of summer interns, the work would not have been possible. Beth and her colleagues have now received additional funding, based on the discovery in mice, from the federal government to further explore the relevancy of these novel compounds for humans use.

Beth spends countless hours in her lab on the research motivated by the hope that one day her efforts may result in better lives for people with neurological diseases. “In the end, nothing would make me happier as a scientist than to have a role in making it possible for people with schizophrenia to be able to function better in society, and to contribute to a possible cure for Huntington’s, allowing patients to live a full life,” Beth says.

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“In general, schizophrenia remains a poorly diagnosed, poorly understood, and inadequately treated illness, one that is especially heartbreaking because it strikes people in their teens and early 20s,” says Associate Professor Beth Thomas.