Curiosity combines with economics and ethics to drive Fragile X research

Dr. Kendal Broadie’s research on Fragile X Syndrome is affected by social, political, and economic factors. Specifically, the financial and ethical interests of the pharmaceutical industry and parent groups play a major role in influencing research.

Dr. Kendal Broadie loves neurons. For years, Broadie has been making advancements on understanding the human brain by studying how the nervous system works. “I am fascinated by how nervous cells talk to each other through the synapse,” said Broadie.

When Broadie was first fully immersed in his journey of neuroscience research in graduate school at the University of Cambridge in England, a group of parents was simultaneously becoming interested in synapses as well. More specifically, they were interested in a disease of synaptic dysfunction, known as Fragile X Syndrome.

“In the brain, synapses connect neurons.  These connections change when you learn and remember things, but Fragile X patients lack the ability of normal synapse change,” said Broadie.

Fragile X, the most common inherited mental impairment disease, affects 1 in 4,000 males and 1 in 6,000 females according to the Center for Disease Control (CDC), and it is the most common known genetic cause for autism. Symptoms of the disease range from hyperactivity to learning disabilities and mental retardation.

Furthermore, 1 in 259 women and 1 in 800 men are carriers of the disease according to the CDC. Carriers exhibit no signs of the disease, but can pass it down to their children or later descendants.

Searching for a treatment and a cure for Fragile X, three parents of affected children founded FRAXA in 1994 to support scientific research. After enormous amounts of fundraising through bake sales, walks, and donations, FRAXA approached the National Institutes of Health (NIH) and proposed to match money on research grants towards Fragile X research.

The NIH consequently sent out an advertisement, seeking researchers interested in studying Fragile X. Broadie responded to the ad, and thus, a new project was born.

“My curiosity combined with a fortuitous circumstance.  Typically, a researcher has a general interest, and then things come together to allow you the resources to do it. Pure curiosity-driven research is starting to decline in favor of research that has a translational purpose,” said Broadie.

The need for resources lies at the root of scientific research. Equipment and employees are fundamental components of a laboratory, and both require a great of money to support.

To sustain their research, scientists nationally and worldwide compete for a strictly limited amount of resources that comes in the form of research funding.

“The chances for getting funding from the NIH are now less than 10 percent in many areas,” said Broadie. This means that a researcher must submit an average of 10+ grants for every one that receives federal funding.

Federal government funding in real terms has been declining over recent years, and its future remains uncertain. The Obama Administration’s stimulus package gave $8.9 billion to scientific research, but Broadie doubts it will remedy the long-term shortage of funds because the money was required to be spent within 24 months.

“Science takes time.  I need money for longer periods of time, for example, to employ people,” said Broadie.

Beyond the ability to attain money to start the research, the potential to receive money from the research influences projects also.  “A lot is based on money. Much research is tied to disease and other issues that are more likely to provide the necessary financial support,” said Broadie.

As Broadie’s lab seeks to discover treatments for Fragile X, the interests of drug companies play a dominating role.

“The way things work in America is that drug companies have to be interested.  Drug companies are concerned with conditions such as obesity, migraines, and heart attacks — things with millions of potential customers. The relatively small number of people affected makes it difficult for Fragile X to receive drug companies’ attention,” said Broadie.

“For genetic diseases, the sad fact is that there aren’t enough patients to produce enough revenue money to garner the interests of the big pharmaceutical companies.  Fragile X is the most common genetic disease, but it still does not affect enough people for drug companies to be interested in finding a cure,” said Broadie.

As a strategy to appeal to more customers, Fragile X researchers try to make developments that could benefit other more common diseases.  “We hope that some of the drugs developed could also help other disorders, such as depression, to expand the market,” Broadie said.

Yet pursuit of a treatment is not solely driven by money. Ethical considerations also enter the scene, as the FDA does not routinely approve drugs for children under the age of six. Furthermore, drug testing on children is usually strictly prohibited.

Dr. Broadie’s lab has found evidence that effective treatments may lie in childhood development, but the inability to test on children deters his research from such a treatment strategy.

“Even though I am convinced childhood is where the problem is, the focus remains on young adults because you can’t do studies on children.  Testing on kids is not and never will be acceptable for moral and ethical reasons,” said Broadie.

As a result, Dr. Broadie and his colleagues have worked to study ways to help treat symptoms in older patients.  “The disease may also affect older patients. In addition, instead of trying to cure the root cause of the disease in childhood, we can try to suppress symptoms and problems at maturity,” said Broadie.

The prevention of testing drugs on children makes it more difficult to search for a cure for Fragile X Syndrome; researchers must often attempt to treat the symptoms of the disease rather than the cause. As a result, Fragile X patients wake up to a daily “cocktail of pills.”

Currently, such treatment often exists in the form of “a huge cocktail of pills,” according to Broadie. “If you are a person with Fragile X, you may wake up to a double handful of pills every morning. Some are symptom directed while others target undesirable side effects. It’s true for a lot of diseases,” said Broadie.

However, drug test regulations alone are not the sole reason research continues on treatment for older patients.

“The hope that it is a disease that can be treated at any age fuels some of the research. The last thing parents want to be told is that we can’t do anything for their kids as they grow up,” said Broadie.

Optimism combines with ethical considerations, markets of drug companies, and the need for resources to influence Fragile X research. Broadie’s curiosity is just one component of the circular path of overlapping factors that led to the developments his lab has achieved.

Looking under the microscope: An explanation of Dr. Broadie’s research

Fragile X Syndrome is caused by a mutation in the Fragile X Mental Retardation 1 (FMR1) gene, which is located on the X chromosome.  This singular cause of the disease gives more hope for finding a cure, as it can be specifically targeted.

The mutation in the FMR1 gene leads to a lack of the Fragile X Mental Retardation Protein (FMRP).  FMRP is a protein that binds to RNA, which regulates whether other proteins will be made or not. It is involved in reading and directing proteins in synapses, which are connections of neurons in the brain. The full function of the protein remains unknown.

Therefore, discovering the exact role of FMRP lies at the foundation of Dr. Broadie’s research.  Currently, Dr. Broadie’s lab is trying to determine whether Fragile X is a developmental disease, a plasticity disease or some combination of both.

A developmental disease is one that occurs during a certain time in development. If the problem could be attributed to a specific period of time, an effective treatment would need to correct the problem during that specific time period in brain development.

A plasticity disease, on the other hand, occurs continually. The problem exists in some sort of constant interaction between cells, and a treatment would be able to solve the problem at any time.

The scientific community has not reached a concrete conclusion about the temporal requirements for FMRP.

“There is debate whether the disease affects children, or is a learning and memory disease with dysfunction that happens all the time,” said Broadie.

Evidence found in Broadie’s lab supports that the disease is developmental, suggesting a true cure would need to come during a certain stage of development.

“My view is that there is a window of time in which the primary problem occurs, and it is during that time in which treatment needs to be targeted,” said Broadie.

Dr. Broadie together with Research Associate Dr. Cheryl Gatto developed this idea using the genetic engineering Gene-Switch (GS) method, in which FMRP can be selectively turned on and off in different regions of the brain at different times to determine when the protein is used.

His lab conducts experiments using the Drosophila genetic model, one of four existing types of animals used as genetic models.

“All animal genetic research is done on either worms, flies, fish or mice. We need genetic systems that supply large populations that can reproduce really quickly,” said Broadie.

Dr. Broadie’s lab developed the Drosophila genetic model of Fragile X Syndrome after years of research. The mutant fruit flies expressed similar defects in the brain and in behavior that occur in humans with Fragile X Syndrome, indicating that tests on these flies would provide insight into how the disease functions in humans.

“Placing the human FMR1 gene into fruit flies rescues all the mutant defects, proving functional conservation with the human condition,” said Broadie.

With the GS method, Broadie found that neurological problems occurred more during a specific stage in brain development.

“FMRP is expressed at very high levels during a window of time during late brain development and at much lower levels at other times.  We look at defects at cellular levels in animal models, and those defects are more severe during the window of time when the protein is most highly expressed,” said Broadie.

Thinking of the disease as developmental, however, defies common logic. “Learning and memory formation is something we think of as happening currently in the moment. If you have a problem, and you can’t learn well, the tendency is to think that problem is occurring right now,” said Broadie.

“If something happened in the development of your brain at five years old that affects how you learn now, it’s hard to test, and it’s not intuitive to think that’s the case,” said Broadie.

Nevertheless, the learning problems that persist in the present could in fact be traced back to the past. “If the connections in your brain don’t form correctly, that means it is a development problem,” said Broadie.

However, the protein continues to be expressed after developmental stages, making the evidence of Fragile X as a solely developmental disease less definitive.

“It is not clear-cut because a lower level of the protein continues in the adult brain. It’s complicated by the fact that we know human patients have this ongoing problem,” said Broadie.

Since the protein continues to exist, and problems continue to arise, Fragile X may be a plasticity disease as well. Dr. Broadie’s lab tries to understand how the protein is used even after development by studying its connection to brain activity.

“Most people believe the Fragile X protein controls the synthesis of other proteins.  It may help move RNA messages, or it may help stabilize RNA and prevent degradation,” said Broadie.

Dr. Broadie’s lab looks at how the protein reads and responds to activity in the brain. “We are trying to understand the connection between brain activity and Fragile X. We do that by changing levels of activity in the brain, in the presence or absence of the Fragile X protein. By determining how these two factors depend on each other, we are trying to understand the exact role of Fragile X in relation to activity-dependent brain development,” said Broadie.

In summary, Dr. Broadie’s lab is constantly combining ideas about the developmental and plasticity characteristics of the FMRP protein to develop potential treatments for the Fragile X disease.

Clinical trials are currently ongoing as a result of ideas supported through their work. The ultimate goal is to produce with a drug that will treat Fragile X Syndrome.

Appendix 1: Genetically speaking, what is Fragile X?

Within the nucleus of a cell, sections of DNA strands hold instructions for how to make proteins.  Each section of DNA that instructs for a certain protein is called a gene. Once proteins are made, they organize into a specific shape, which determines their function around the cell.

The FMR1 gene holds instructions for producing FMRP. People who are not affected by Fragile X Syndrome produce FMRP in some cells.  The production of the protein is regulated, so it exists in the places it is needed.

1 in 4,000 males struggle with Fragile X syndrome, a mutation on the X chromosome caused by the repeated codon cytosine-guanine-guanine (CGG). Dr. Kendal Broadie’s lab researches Fragile X in hopes that there will one day be an effective cure.

Towards the beginning of the FMR1 gene, there is usually a series of around 30 repeats of the amino acid sequence: cytosine-guanine-guanine (CGG). The long repeats of CGG set in motion methylation, which turns off the gene that produces the protein FMRP.  Too many repeats will cause too much methylation, turning off more genes and decreasing FMRP production.  When the production decreases to zero, a lack of FMRP triggers Fragile X.

The location of the mutation on the X chromosome makes it more common for women to be carriers. Women have two X chromosomes, so they have two copies of the FMR1 gene.  Even if a female has a full mutation on one X chromosome, FMRP is still produced by the other X chromosome.

Males have one X and one Y chromosome, so males with the mutation do not produce the protein at all. Males with a pre-mutation make lessened amounts of FMRP.

In the case of a pre-mutation, there are around 55-200 repeats of CGG in one’s DNA. The full mutation occurs when there are more than 200 CGG repeats.  Thus, a person may have 100 repeats and not show symptoms of the syndrome because FMRP will still be produced. The repeats may continue to grow through generations until a person has over 200 repeats and stops producing FMRP.  A person lacking FMRP will be affected by the syndrome.

Though the genetic cause can be explained on a molecular level, the role of FMRP cannot. Uncovering this role is the basis of Dr. Broadie’s research as it is key to the discovery of a cure.

Appendix 2: How does the federal funding process work?

The main source for federal funding of medical research is the National Institutes of Health (NIH), which is a sector of the U.S. Department of Health and Human Services.  The NIH consists of 27 specialized institutes, and Broadie’s Fragile X research receives most of its support from the Institute for Child Health and Human Development.

Every year, the NIH invests $30.5 billion in medical research to help American people, according to its website.

Federal funding does not come as a continuous flow, but rather in the form of grants that fund projects for a given period of time.  “The average lab will have about one to two grants that run for four years on average,” said Broadie.

Thus, scientists must continue to apply for grants as their research progresses. To write a grant, researchers must outline specific aims of their projects, detail ways in which they plan to experiment, and provide support that indicates the project is promising.

“I begin by making outlines of about three major aims for each grant, and I write my ideas for each different aim. Then, I talk to the people who work in my lab for their input and to see their ideas. It’s a process of constant revision,” said Broadie.

The NIH has three major deadlines per year, for which scientists from around the world submit grants based on their own interests and personal histories. There is no limit to the number of grants a researcher may submit; however, the same grant may not be submitted multiple times.

Though grants can be submitted for any idea, the intense competition requires a researcher to have significant knowledge, as a basis to indicate that the research will be promising.

“You can submit a grant for anything under the sun, but you will only get funded on something you are an expert on” said Broadie.  This produces difficulties for new scientists trying to upstart labs and projects.

-Michelle C., Laura D., Katherine N.

~ by lauradolbow on April 26, 2010.

4 Responses to “Curiosity combines with economics and ethics to drive Fragile X research”

  1. Fascinating stuff. The part about the drug companies makes me a little sick to my stomach. Everything is about the bottom line instead of trying to cure this condition. Disappointing but I guess that’s reality. You’ve got to play the game in order to get funding etc. I wonder if that wears on these researchers after all.

    • Those were my thoughts exactly when Broadie first mentioned the drug company influence. It is upsetting, and I’m sure it hurts the researchers’ mentalities.. but like you said, it’s the reality. Very thought-provoking about society.

  2. I thought this was a really great presentation today. I loved the multi-media the effect of the combination of research and art. We have talked about the clash between humanities and science in class all semester. I think this project was a great way to show that the two can really go hand in hand. I though the art work gave emotional meaning to the research and gave the concepts depth. Before taking this class I always associated genetics with iron and clad science. However, I learned that behind each genetic formulation and equation is a story, implication, or greater meaning. Your project reiterates this feeling.

    Also, I am truly impressed that this project will be published. How cool! I really admire all of your hard work and dedication. Great job!!
    – Zoe

  3. I really enjoyed your presentation of all three genres, art, science, and journalism. Led to a very dynamic project. I know you mentioned Dr. Brodie’s use of fruit flies as opposed to mice. Do you know why he chose fruit flies over mice or the other mentioned “fast reproducing” species? Has he ran into any issues with fruit flies and their demonstrated traits of fragile x?

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