On World AIDS Day, December 1, Scripps, Jupiter campus, researcher Susana Valente, Ph.D., delivered the first presentation in this season’s Front Line of Hope series.
Valente, assistant professor in the Department of Infectology at Scripps, has just been awarded a $3.4 million grant from the National Institutes of Health for HIV / AIDS research.
The first recognized cases were 30 years ago, when young men in New York City and Los Angeles, California began developing rare infections and cancers, she said, and at the time, no one knew what this was all about.
It became obvious that these men were suffering from the same syndrome, and by mid-1980s, Luc Montagnier of the Pasteur Institute and Robert Gallo of the National Cancer Institute identified the viral agent and gave it a name, Human Immunodeficiency Virus.
By 1998, scientists who were analyzed older plasma samples from the 1950s, with features of HIV, and thought that HIV had been introduced to the United States in the 1940s and 1950s.
HIV is a part of a group of “slow” viruses, also part of a bigger group, called retroviruses, common in many species. SIV, or Simian Immunodeficiency Virus, is a retrovirus that’s found in apes, and has been around for at least 32,000 years.
HIV-1 and HIV-2, crossed the species barrier to humans. HIV-1 evolved from SIV from a subspecies of chimpanzees and HIV-2 evolved from SIV from white-collared monkeys.
How did that happen? Most likely, while butchering and consuming ape meat, the ape blood got into cuts or wounds of African hunters, Valente explained.
In the 30 years, HIV spread quickly. By 2007, 33-million people are living with HIV/AIDS and 25 million have died. 1.2 million people have HIV/AIDS in the United States, and the third highest concentration of infected people is here in South Florida, right behind New York and California.
For incidences of new infections, (2006 numbers) five of the top 15 cities are in South Florida.
There are 121,000 people with HIV/AIDS in Florida. Last year, 5,200 new cases reported of HIV infection, and 4,400 cases with AIDS and 1,600 have passed away from the disease.
In Florida, half of the HIV population is Black, and that’s a big number, considering that only 14 percent of Florida’s population is Black.
And the group of infected people over 50 years old is a growing number, 27 percent of the total number. Of that group ¾ are male. “That percentage holds true in the United States, and those who died in 2010, 50 percent were more than 50 years old.
HAART (Highly Active Antiretroviral Therapy) was introduced in 1996, and formalized by the FDA in 2001. This therapy targets at least two steps of the life-cycle of the virus.
The problem with HAART is that patients become resistant to the treatment. And because it has side effects (nausea / liver damage), patients fail to take their medication consistently, which is essential for the regimen to work.
And, there are no vaccines, because HIV evolves quickly, making it impossible for an antibody to fight the disease.
Other problems: There are many combinations of the virus, making it hard to be treated by a vaccine. Also, the virus can hide from the immune system, and, finally, for studies and research, there is no animal model that is appropriate.
So, “we need new viruses that target different aspects of viral replication and better safety profiles. There’s lots left to be done,” she said. “A popular approach is to try to find compounds that block the proteins in the cell that the virus needs to replicate. It’s easier if we can target the proteins that the virus uses rather than trying to target the virus itself.”
Here, Valente gave a basic lesson on cells, cell transcription, post-translational modifications, and how and where the virus takes advantage of the cells and those processes.
There are different stages where the virus can be stopped within the cell, and her team is looking for proteins that will do just that.
“We know that certain cells can be infected by the HIV virus, but some cells cannot be infected and those resistant cells can be made or we can make them resistant. A third way, we can give them some signaling molecules that put them in an antiviral state (that’s what happens when we fight any infection). We want to know about the anti-resistant state.
“So, we take the cells that are resistant and see what DNA is making it resistant.
“We have found two cell lines that are very resistant: H1 and H2.”
H1 blocks the RNA of the virus from coming out of the nucleus of the cell into the cytoplasm (so the later viral steps are abolished), and H2 stops the RNA from becoming mRNA.
“We also need to devise chemicals to mimic what those proteins are doing.”
In addition, a new compound that blocks TAT has been discovered.
One of the first proteins produced by the virus is TAT, which pairs up with viral DNA in the nucleus. “It’s like gas for a car. If we can stop TAT from acting, we can control replication of the virus.”
A compound, SV101 (isolated from marine sponges) does the job.
“If we take infected cells and treat them with SV101, we drastically drop the RNA that is expressed. It also changes where TAT is in the cell, excluding it from the nucleus, which is associated with lack of activity.
Front Line of Hope is an educational invitation-only series. To request an invitation or further information on the 2011-2012 Front Lines of Hope program, call (561) 228-2084 or email Philanthropy-Florida@scripps.edu.
copr. 2011 Christine Davis
Recently I wrote a story on the Banner Center of Life Science program headquartered in Palm Beach Gardens (You can read that story here on North County Current).
But in this post here, I wanted to give you an idea about the actual trainings.
I asked the folks at our Banner Center (Elizabeth Handel, Jill Diodato, Douglas Saenz, director of industry and economic relations at Workforce Alliance), if I take part in one of its short one-or-two-day trainings, what kind of job will it prepare me for, and is there one actually waiting for me?
The curricula for the trainings the Banner Center created are based on the feedback they’ve received from bio sciences companies on the skill sets they need their employees to have.
Any prospective (or current) employee can benefit from the trainings, explained Jill Diodato, the center’s program manager. “All workshops are hands-on, industry specific for entry-level, advanced level and skills upgrade.
“Each course has been designed to specifically address industry-accepted competencies. Banner Center for Life Sciences courses are designed by Florida’s life sciences industry for industry to fill jobs where there currently is a need for staff. The purpose behind industry-designed curriculum is to ensure their needs are being met — with the kind of training they want employees to have — and that jobs will be available for the newly-trained workforce.”
If you are job hunting, here’s a list of applicable NIAC codes:
Research and Development in Biotechnology – 541711
Medicinal and Botanical Manufacturing – 325411
Pharmaceutical Preparation Manufacturing – 325412
In-Vitro Diagnostic Substance MFG. – 325413
Biological Product Manufacturing – 325414
Surgical Appliance and Supplies Mfg. – 339113
Other Electronic and Precision Equipment Repair and Maintenance – 811219
When I looked these up, I found that each category included entry-level jobs (like office clerks, sorters and samplers), to higher levels (like supervisors and engineers).
So, for those who are recent high-school grads and for those who are looking for a career change, these trainings are a kind of first step (and might get you in the door). For those who already have a science-related job, the trainings will add skill sets that the bio-science companies are looking for.
Trainings offered by the Banner Center:
Business Basics for Life Science Industry: This two-day workshop provides a basic understanding of business and science components that impact life science businesses. Designed for students, incumbent workers, and scientists in academia, this module provides an overview of business fundamentals of the life science industry. After participating in this workshop, a participant will be able to describe the business aspects of diverse life science companies and explain how science affects business considerations. Topics include: company structure and functions, product development process, funding, legal considerations and business development/licensing. Detailed case studies of Florida and global pharmaceutical, medical device and biotech life science companies will be performed.
Cleanroom Technology: This course will provide fundamentals for working in cleanroom environments including procedures, management and current GMP practices. Topics include facility design and specification, standards and best practices, measurement and instrumentation, environmental monitoring, gowning and product testing. The student will become familiar with ISO, IEST, NIST and ASTM standards.
Medical Device Basics: This two-day workshop provides an introduction to medical device manufacturing and overview of medical device industry regulations. Participants will be able to describe and identify the tools and processes specific to the medical device industry. Topics include GMP systems and procedures, validation and quality Systems. Regulatory Affairs will also be addressed and will include: federal regulations, working with the FDA, assembling and filing an IND, IDE, or 510K application, and clinical trials.
Protein Purification and Characterization: This workshop provides insight into the theory and techniques of monoclonal antibody purification and characterization. Participants learn the theory of antibody separation methods using chromatography and standard characterization methods including quantification using spectroscopy and SDS-Page. Laboratory instruction will include fundamentals of different types of purification strategies and hands-on experience with affinity chromatography and membrane filtration for the production of monoclonal antibodies. This module will include a case study from Meridian Life Science, an industrial monoclonal antibody manufacturer. Lectures will include industrial processing of biological materials from Fermentation to Downstream Purification, Quality Control and Quality Assurance practices.
Cell Culture Methods: This course will introduce students to the components of a tissue culture laboratory, equipment, instruments and aseptic technique. Students will learn how to prepare media, culture and maintain cell lines, perform appropriate documentation, perform cryopreservation, and gain an understanding of biopharmaceutical regulations. The course will involve a case study of Immunosite Technologies, a contract research and testing company focused on discovery and development of immune-based drugs, vaccines and biologics.
Pharmaceutical Basics: This course will provide basic insights into the pharmaceutical industry, drug development process and basic laboratory skills. This module will familiarize participants with basic wet chemistry techniques preparation of buffers, mobile phases, finished product sample and stability samples. This will also include working in a current GMP (cGMP) environment with compendial methods from the United States Pharmacopeia (USP). Students will learn concepts in Quality Assurance including GLP and GMP compliance, SOPs, documentation, and validation.
I took the Protein Purification workshop. A tech for this would fall under the Biological Technician occupational code. In June, there were approximately 75 postitions open in Florida, according to Douglas Saenz, director of industry and economic relations, Workforce Alliance.
Although I don’t have a science background, I could pretty much follow along. About 30 or so people participated (a full class) — and my “classmates” were either science students or lab techs…
and Good Health. Who would have thought?
A team of researchers, led by Scripps scientist Matthew Gill, recently identified a new pathway affecting lifespan. Thanks to what they’ve learned from the lowly worm, there may come a time when we humans may enjoy a healthy old age.
Gill, 38, has been working with worms, (Caenorhabditis elegans – nematodes or roundworms) for more than a dozen years and, for three years, studying the molecule, N-Acylethanolamine (NAE) in worms, and how NAEs relate to diet and lifespan.
“Despite the fact that the worm is only a millimeter long, has 959 cells and lives in the soil, actually its biology and physiology are similar to humans,” Gill said. “So, we can learn important lessons from worms that apply to human physiology.”
For example, worms have two-thirds of the genes known to be involved in human diseases, he explained. “We can look at the worm and try to understand how disease progresses and find therapeutics to address those diseases.”
Two discoveries since the 1980s laid groundwork for possible interventions in the aging process, which, Gill explained, had been considered a difficult prospect since it had so many complex angles.
But then, single gene mutations were discovered in the worm that could double and triple its life span. “Instead of 20 days, it would live 40 days or 60 days,” he said. “This was a major step forward in how we think about aging.”
Then in 1997, came a real breakthrough. “One of those genes was cloned and we found out what the protein was that was being encoded. It turned out to a receptor similar to an insulin receptor that we have in humans.
“This was not just a gene specific to worms, but the same gene affects lifespan across species. Now we have a pathway that seems to be conserved across species that affects lifespan in a profound way.”
Also, researchers had discovered through studying these genes in the worm, fruit fly, yeast and mice, that there are different methods to extend lifespan and one of the most robust ways is through dietary restriction.
For example, if researchers reduced a mouse’s dietary intake, its lifespan was extended and the occurrence of age-related diseases (cancer is a major cause of death in mice) is prevented or delayed.
But, the scientists wanted to know, how do dietary restrictions work and what physiological changes take place that allow the animal to live an extended period of time? Also, many were interested to know whether dietary restrictions extend lifespan in humans.
People are trying to figure that out, too, Gill said. But, in any case, “if we can understand the genes, processes, and pathways involved in making dietary restrictions work in a simple animal, then maybe we can discover key molecules that can act as targets for drug discovery.
“And this leads to the idea put forth by a number of people to discover a calorie restriction mimetic. This would be a drug that would give you the benefits of calorie restriction but without you reducing food intake.
“It’s not about living longer, but delaying the onset of age-related disease.”
So, Gill’s study focuses on the molecules N-acylethanolamnes (NAEs) and endocannabinoids. These signaling molecules act between cells to coordinate a cell’s response to a particular input, and they are involved in response to food. Their levels change when an animal or person has low food or high food, and the molecules can control energy use in animals, “so we thought they would be a good candidate for response in dietary restriction and also, if they were involved in dietary restriction, they may have an impact on lifespan.”
The researchers set out to find these molecules, and they found that the worm has at least 6 NAEs, two of which are similar to endocannobinoids in mammals, and that the levels of these molecules change with food availability.
“When the researchers feed the worms bacteria (its food), the levels of those molecules are high. But when they reduce the levels of food, the NAEs drop down. If they add food back, the levels go back,” he said.
“We saw these molecules are responsive to food.”
“But, if we made an animal that’s deficient in NAEs, we found that the worm was long lived, so there was a correlation between low NAEs and an extended lifespan.”
Then, with one of the worms deficient in NAEs, they added back one of the NAEs, “with exciting results,” he said.
“Just adding one of these molecules back to this worm suddenly shortened its lifespan dramatically. Instead of living 25 or 30 days. Now it was living 15 days.
“Usually with these dietary restrictions, there would be a reduced level of those molecules and that would signal to the animal that food is low, and it needs to change its physiology to use nutrients more efficiently.
“But that one molecule added back in, tricked the worm into thinking it was in an environment where there was plenty of food.”
The worm can manage up to a certain point, but then it reaches a crisis, he said. “ It tries to live its normal lifespan of 25 days, but it crashes and burns. After 15 days, it can’t go any further.
“The implication, in terms of relevance to humans: this is a pretty well known signaling pathway in response to food, but it never had been demonstrated that it had impact an aging.
This study adds another pathway and set of molecules that scientists know are involved in dietary restriction, and, therefore, potentially another target for drug discovery. “If we can manipulate the NAE pathway with a small molecule, then maybe we can find something that will act with one of these dietary restriction mimetics.”
Now, the aim at Scripps is two-fold, he said. “One is to go into more details in the mechanism of how these molecules affect lifespan in a worm, and exactly how they work. Secondly is a discovery angle. NAEs are known to interact with certain receptors in humans but we don’t know the receptors in worms, and if we find these new receptors in the worm, it might lead us to find a new receptor in humans. A new receptor in humans becomes a new target for drug discovery.
“And given the role of these pathways in food sensing, energy balance and aging, there’s a potential in the long term that we can find something that has profound impact on obesity, diabetes, age-related diseases and aging itself.”
Corinne Lasmezas, DVM, PhD, and a team of researchers at The Scripps Research Institute’s Department of Infectology, are working to find cures for prion diseases as well as age-related brain disorders. These all are fatal neurodegenerative diseases. Included in this group of neurodegenerative diseases are Alzheimer’s disease, Parkinson’s disease, Huntington’s disease and Fronto-Temporal Dementia.
There are no cures, Lasmezas said. “For Alzheimer’s, there are five FDA-approved drugs, but although they can delay the symptoms, they don’t cure the disease.”
However, the Scripps researchers have identified one blocking neuroprotective compound and four suppressing compounds that hold promise.
In humans, Creutzfeldt-Jakob Disease is a rare prion disease that is inherited, can occur for no known reason or through exposure to contaminated products. Kuru is another prion disease. It was found in young men, women and children in a tribe in Papua New Guinea who ate human brain as part of a funerary rite.
In animals, prion diseases include Mad Cow Disease, scrapie found in sheep and goats, and chronic wasting disease found in deer and elk.
Lasmezas, whose work provided the proof that Mad Cow Disease had been transmitted to humans in 1996, explained that there is a similarity in prion diseases and age-related brain disorders – they have types of proteins that misfold.
“Prion diseases are transmissible, but we didn’t know what the infectious agent causing these diseases was. This was an enigma,” Lasmezas said.
“Usually, we get infectious diseases through bacteria or a virus. Sometimes, diseases are caused by parasites or fungi. But none of these diseases were caused by any of these agents.”
Finally, she explained, scientists found dark plaques in brain matter consisting of fibers made of protein. “The infectious agents turned out to be proteins,” and, hence, they were called prions, (proteinaceous infectious particles). Later, Dr. Charles Weissmann, chair of Scripps Department of Infectology, found that the prion proteins were produced in the cells. But, how, the scientists wanted to know, is it possible that a protein, produced by our cells, can be infectious and harmful?
“Every protein has a shape. When a protein changes its shape, it can’t perform its function and it can become harmful. This is what happens in prion diseases. The protein changes shape (misfolds), induces other proteins to change shape, forms chains and then forms plaque. This process is harmful to the brain.”
When a neuron gets sick, she explained, it retracts its extensions, so it can’t communicate anymore. Its overall metabolism slows down and the neuron accumulates junk, which it tries to contain in little pockets, called vacuoles.
“If at this point, we could intervene, we could revert that fate and go back to having healthy neurons. Otherwise, the neuron loses its extensions; it becomes full of vacuoles and dies. Like prion diseases, in most age-related neurodegenerative diseases, proteins (other than the prion protein) also change shape.”
To understand how these misfolded proteins kill the neurons, Lasmezas’ team engineered a normal protein. “We put them on neurons, and they were fine. If we cooked the protein for 15 minutes, though, the protein changed its shape and started making a chain (oligomers) and if we put that on neurons, it was very toxic.”
Then, the researchers found a method to produce the toxic protein.
They took healthy neurons and put them in a culture. When a normal form of the protein was added to a culture, nothing happened to the neuron. But when they put the toxic form on the neurons, the neurons lost their extensions, became full of vacuoles and died.
Next, the researchers developed a test to find drugs to prevent neuron death in prion disease and Alzheimer’s disease. “We tested a small collection of compounds and through that test, we found a neuroprotective compound.
“Then we repeated the culture experiment using the toxic prion protein, and the neurons started losing extensions and accumulate vacuoles. But when we added the neuroprotective compound, the neurons started resuming their shape in three hours and in two days they were perfectly happy. They grew back their extensions.
“This showed us that we can find neuroprotective compounds that can block the toxic protein and also revert neurons that were going to die. It was a strong signal of hope that we can find cures for those neurodegenerative diseases.”
To make sure, the researchers adopted a second strategy, based on a finding of Scripps Research scientist Charles Weissmann in 1993, that mice that don’t have the prion protein couldn’t be infected by prion disease. “So the elimination of the prion protein is protective against prion disease,” she explained.
“Recently, a researcher at Yale found that not having prion protein protected against Alzheimer disease. The aggressive form of the Alzheimer’s protein only attacks the neuron with the prion protein. We wanted to verify this finding.
“What we did, we took a cell line that expresses a prion protein at its surface and infected it with the destructive toxic Alzheimer’s protein, and the neurons died.
“Then with neurons without the prion protein, we added the toxic Alzheimer’s protein and nothing happened.”
Lasmezas and Weissmann teamed up to develop a screening test to find drugs that eliminate the prion protein from the neuronal surface to cure prion disease and Alzheimer’s. “At Scripps, we have a great drug discovery platform led by Peter Hodder. There is a robot that can screen a hundred thousand compounds per day.”
“We did a preliminary screening using a drug collection of 1,280 compounds, followed by a whole battery of tests and ended up finding four compounds that suppress the prion protein.”
The researchers now have one neuroprotective compound and four compounds that suppress prion proteins, and they are actively investigating their therapeutic effect in prion and Alzheimer’s disease models.
Equally important, the researchers also have two high throughput screening tests that can be adapted to screen for other neurodegenerative diseases.
AND AS A SIDE NOTE:
In addition to asking Scripps scientist Corinne Lasmezas about toxic prion proteins, the culprit in Mad Cow Disease, let’s ask her to get to the meat of the matter.
What cuts of beef are ok to eat? Lasmezas, whose work provided the proof that Mad Cow Disease had been transmitted to humans in 1996, said these days, any cut is ok. “It was beef brain that caused the disease (brain used to be in sausages, ground meat and even baby food), but that’s prohibited. Brain is not mixed into foods anymore,” she said.
A type of protein that misfolds like prion protein is also the culprit in Alzheimer’s Disease. So, here’s a second quick question for Lasmezas. Is there anything we can do to guard against getting Alzheimer’s?
A healthy lifestyle reduces the risk, she said. “The brain needs energy and you need to have a healthy cardiovascular system to bring the brain oxygen and nutrients.”
The brain needs exercise, too.
“The more you exercise your brain, you make new networks and increase your cognitive reserve. Exercise does influence how the brain ages.”
In addition, Lasmezas drinks green tea. “It has EGCG in it, which has been found to slightly decrease the production of the Alzheimer’s protein,” she said
for palm 2 jupiter
It’s no longer debatable: for treatment of wet age-related macular degeneration (AMD), the inexpensive Avastin (at $50 a dose) is just as good as Lucentis (at $2,000 a dose), according to the report from the Comparison of AMD Treatments Trials (CATT), which was published online in the New England Journal of Medicine on Sunday, May 1.
Doctors are being incentivized to use the more expensive drug, remember? Medicare reimburses physicians 6 percent of the sales price for the drug they use. On top of that, Genentech started a rebate program for high-volume Lucentis users.
In an earlier issue of Palm 2 Jupiter, Bascom Palmer ophthalmologist, Philip Rosenfeld pointed out the money side of this debate, as well as outlining research phases with these two drugs. At that time, he said he was anxiously awaiting the CATT results.
And here they are: Results from the first year of the two-year clinical trial, funded by the National Eye Institute, showed that Avastin, a drug approved to treat some cancers and that is commonly used off-label to treat AMD, is as effective as the Food-and-Drug-Administration-approved drug, Lucentis, for the treatment of AMD.
Wet AMD, the leading cause of blindness of the elderly, occurs when certain proteins (vascular endothelial growth factor or VEGF) cause abnormal blood vessel growth in the back of the eye. As the blood vessels grow, they can leak blood and fluid, which damage the macula—the part of the retina that lets one see color and fine detail.
Rosenfeld, who was the lead investigator in phase 1 trials for Lucentis in 2001, said that Lucentis was revolutionary. “The way Lucentis works, it binds to VEGF, stopping the growth of abnormal blood vessels. It changed everything. Rather than simply showing down vision loss, we got dramatic vision improvement in a day or two. Patients were seeing better.”
Then, in 2003, Rosenfeld who also has a Ph.D. in genetics, began studying Genentech’s literature on Avastin, a drug that also blocks abnormal blood vessel growth.
“Both Avastin and Lucentis are derived from the same molecule, which was a mouse antibody. The mouse antibody was then humanized (made to look like a human antibody) and then Lucentis was made as a fragment of the antibody. So, both Avastin and Lucentis bind VEGF exactly the same way, only Avastin is a larger molecule and Lucentis is a fragment of this larger molecule.”
He suggested to Genentech that Avastin could be used systemically for AMD, but the company was not interested, so he raised money for a trial. He found that Avastin used systemically was effective, but had a 1-percent risk for heart attacks and strokes that he and his colleagues did not want to take.
“Then we had a Eureka moment.” Rosenfeld said. “We realized that if we injected the same amount of Avastin as Lucentis, we would have the same amount of inhibitory activity, and it worked.
“We presented this to meetings and it spread all over the world, and Avastin was ready before Lucentis was available.”
In 2004, the FDA approved Avastin for the systemic treatment of metastatic colon cancer. Also that year, some doctors started to give Avastin systemically as an intravenous infusion.
In 2005, ophthalmologists began injecting AMD patients with low doses of Avastin, due to its similarity to Lucentis and its availability. Many physicians saw a beneficial treatment effect and Avastin’s use grew rapidly. In 2006, two Genentech-sponsored clinical trials established Lucentis as highly effective for the treatment of wet AMD.
Ophthalmologists used Avastin primarily as needed when there was evidence of active disease. Also, most clinicians adopted as needed dosing for Lucentis, which was a departure from FDA-approved labeling and the monthly dosing schedule evaluated in the Genentech-sponsored clinical trials.
In 2008, the National Eye Institute decided to fund CATT to compare the two drugs. “Over 250,000 patients are treated each year for AMD, and a substantial number of them receive Avastin. Given the lack of efficacy data regarding Avastin for AMD treatment, the NEI had an obligation to patients and clinicians to conduct this study,” said Paul A. Sieving, M.D., Ph.D., director of the NEI.
The CATT study has now reported results for 1,185 patients treated at 43 clinical centers in the United States. AMD Patients were randomly assigned and treated with one of four regimens for a year. They received Lucentis monthly or as needed, or Avastin monthly or as needed.
Patients in the monthly dosing groups received an initial treatment and then had an injection every 28 days. Patients in the as needed groups received an initial treatment and were then examined every 28 days to determine medical need for additional treatment. The as needed groups received subsequent treatment when there were signs of disease activity, such as fluid in the retina.
Change in visual acuity served as the primary outcome measure for CATT. Some of the main findings are as follows:
● Thus far, visual acuity improvement was virtually identical for either drug when given monthly. Also, when each drug was given on an as needed schedule, there also was no difference between drugs. As needed dosing required four to five fewer injections per year than monthly treatment and overall visual results were still excellent.
● Adverse events indicate development or worsening of a medical condition. They may or may not be causally associated with the clinical trial treatment, but they are always monitored and reported in any clinical trial. The median age of patients in CATT was over 80 years, and a high rate of hospitalizations might be anticipated as a result of chronic or acute medical conditions more common to older populations.
● Serious adverse events (primarily hospitalizations) occurred at a 24-percent rate for patients receiving Avastin and a 19-percent rate for patients receiving Lucentis. These events were distributed across many different conditions, most of which were not associated with Avastin in cancer clinical trials where the drug was administered at 500 times the dose used for AMD. The number of deaths, heart attacks, and strokes were low and similar for both drugs during the study. CATT was not capable of determining whether there is an association between a particular adverse event and treatment. Differences in serious adverse event rates require further study. Investigators in the CATT study will continue to follow patients through a second year of treatment. These additional data will provide information on longer-term effects of the drugs on vision and safety.
The outcome of this study will not sway doctors one way or the other, Rosenfeld said. “They had already made up their minds. And these results won’t make a difference to Medicare, which does not have a mandate to recommend treatments based on cost. But, thank goodness, we now have two excellent AMD drugs.
“”However, if we had rerun the phase 3 Lucentis trials and replaced Lucentis with Avastin, the results would have been identical,” Rosenfeld said. “The frustrating part is this: Avastin could have been available for clinical trials in 2000. We could have run the trials with Avastin and, no doubt the FDA would have approved it for AMD for 2003 and 2004. Just think of all the blindness we could have prevented.”
Greg Marion, 47, a general contractor who owns Marion Construction in Jupiter, said his mother, Earline, 81, had been doing fine up until a few years ago. But then he found out that she had been writing checks to a fraudulent sweepstakes charity that was taking advantage of her. Marion took over her finances and moved her into the house next door to him. “She was very disoriented, confused and uncomfortable. I thought that maybe the move was traumatic for her, but, after she settled in, she started repeating herself every few minutes.” Their doctor suggested that she see a neurologist at Premiere Research Institute at Palm Beach Neurology in West Palm Beach.
“At first, she didn’t want to go to another doctor, but then she admitted to me that she was having symptoms consistent with Alzheimer’s.
“So, we went to see Dr. Walter Martinez (the institute’s co-director) and she had some initial review tests and MRIs, and, at that point, she was diagnosed with early onset Alzheimer’s and he explained the disease to us.” Earline was given prescriptions for an Excelon patch (which decreases the chemical, acetylcholine) and Namenda (a drug that regulates the activity of the chemical, glutamate) and she is taking part in a clinical trial with Bapineuzumab (a vaccine that appears to bind to amyloid and neutralize its toxic effects).
“We noticed within a couple of weeks that she stopped repeating herself,” Marion said.
Six years ago, Mickey Rodriguez of Stuart noticed that her husband, Frank, 75, was becoming forgetful. “He’d ask me the same thing over and over, and say, ‘I saw that before,’ when I knew he had not.”
She took her husband to Premiere Research Institute to have him tested, and “they found that he fits into the Alzheimer’s category,” she said.
Although she and her husband knew that there is no cure for the disease, they decided that he would take part in clinical trials. “I thought if I could get him into treatment early, we could stall it, or, who knows, maybe it will help our grandchildren, at least,” Rodriguez said.
All in all, Frank has taken part in four clinical trials at the institute, three with varying dosages of Aricept (a drug that decreases the chemical, acetylcholine) and one in combination with an injection of Bapineuzumab. He did best, Mickey felt, when he was taking 23 milligrams of the Aricept. “He did very well on that dosage. Years ago, he used to paint. He started again and was better at it than ever. He thrived on that drug.”
But, when the trial was over, the FDA put a hold on that drug dosage because of side effects that some of the patients experienced. “So we weren’t given the drug for free, which usually happens for people who take part in the study,” Rodriguez explained.
“But, since then, the FDA has lifted the hold, and I’m hoping that our doctors will arrange for him to get a prescription for 23 milligrams of Aricept because it really helped him,” she said.
Both the Rodriguez family and the Marion family couldn’t be happier with the care they’ve received at the research institute. And while they hope that their taking part in clinical trials will slow down the progression of their disease, they also want to contribute to research that might produce new medicines that can help others in the future.
Dr. Carl Sadowsky, co-director of research at Premiere Research Institute, has been conducting trials for more than 25 years. He is also medical director of the Memory Disorders Center at St. Mary’s Hospital, a clinical associate professor, Division of Neurology, at Nova Southeastern University and a board member of the Southeast Florida Alzheimer’s Association.
“Frank and Earline are on one of the disease-modifying therapies,” Sadowsky said.
“We are using antibodies to try to reduce the amyloid burden in the brain.”
Amyloid, a sticky protein that damages the neurons is the real culprit with Alzheimer’s and the time to treat the elevated amyloid is before it causes damage, he said. “To illustrate, think about cholesterol.
“We don’t wait until a person has a stroke. If a person’s cholesterol reading is high, we put them on drugs because we know that cholesterol will cause damage.
“There are a whole group of treatments to lower amyloid.”
For some trials, an antigen is given to the patients so they can develop their own antibodies and researchers are also working on multiple ways to remove amyloid from the brain using immune therapy, he explained.
Sadowsky said he and his team are able to recruit for trials because they have good ongoing relationships with the people they treat. “We take care of our patients,” he said. “Just this year, a patient I cared for will be involved in a study of General Electrics. He has a life expectancy of less than one year.
“The study requires a brain donation.”
“We will scan his brain now, and compare it to a scan taken post mortem, looking for amyloid.
“This is not an easy thing to talk about with people as you can imagine,” he said. “It’s very hard to advertise for a study like that. It’s easier if you have a good relationship with your patients.”
But these are critical tests, he said. “We need to treat Alzheimer’s patients earlier before the disease becomes severe.
“Alzheimer’s is becoming the epidemic of the 21st century – 5.3 million Americans have Alzheimer’s. If you make it to age 85, your chances of getting it are 40-50 percent.
“The longer you live, the greater the risk. It’s expensive, devastating and if we don’t get a better handle on it, it will overwhelm us financially and medically.”
In the last five years, researchers have made progress in understanding the disease, which was recognized in 1907 by Dr. Alois Alzheimer, he said.
“The Alzheimer’s vaccine by Pfizer/Wyeth, Bapineuzumab, looks promising – an antigen is given so that the patients develops their own antibodies.”
Patients undergoing trials at his institute are counseled about the benefits and risks and they don’t pay for treatment. “They are given a small stipend for their time and to cover some of the gasoline for their travel. That’s important because they are donating their time and effort.
“If the requirements for the trial are too difficult, they won’t participate. We have to be cognitive of what the patient and family wants.”
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TrialMatch program helps pair patients and trials
TrialMatch, a service offered by the local chapter of the Alzheimer’s Association, can help patients and caregivers find appropriate clinical trials. “There are lots of trials out there, but they have specific criteria for inclusion,” said Lauren Young, LCSW, the association’s helpline coordinator. “It can get frustrating to figure out and we can help.”
Research, she said, is important not only to look for future cures and treatments for Alzheimer’s Disease, but also for discovering new ways to cope with the disease from the emotional and social perspectives. “Trials listed on TrialMatch are approved research studies that are ethical and government regulated to protect the safety of the patient to whatever extent that is required,” she explained. Another service provided by the Alzheimer’s Association is the 24-hour helpline at (800) 272-3900. “Caregivers and patients can call the helpline to explore whether participating in a clinical trial is a good fit for the patient, or to ask questions about the process of participating in clinical studies. We can provide publications about the process, as well,” she said.
Premiere Research Institute at the Palm Beach Neurology Center in West Palm Beach and Palm Beach Neurological Center in Palm Beach Gardens conduct trials locally.
“And if we can’t find an appropriate trial, patients can get help at the memory disorders centers at either St. Mary’s Medical Center (West Palm Beach) or Florida Atlantic University (Boca Raton). They bring together neurology, psychiatry, nursing and social work to meet the needs of the patients and their families.”
The Alzheimer’s Association is a national organization that offers a myriad of programs. “Our chapter has the second largest call volume of all the association’s chapters in the country,” she said. “We offer supportive counseling, a 24-hour helpline, an identification program for patients who wander, in-depth community education, professional training, support groups and an annual conference.
“We also promote research. We are the second largest private funder of research internationally, after the U.S. Government.”
Subsidized caregiver support programs, such as daycare and homecare, are limited and have waiting lists, she said, while there are many good private programs available. “We advocate through public policy initiatives for enhancing programs for care services within our community.”
To find out about clinical trials through TrialMatch, go to www.alz.org and click on TrialMatch or call (800) 272-3900.
A Life After Diagnosis
Alzheimer’s Community Care is a not-for-profit organization founded in 1996 that serves Palm Beach, Martin and St. Lucie Counties and offers specialized care to Alzheimer’s Disease-and-related-disorders patients and their caregivers. Services include adult day service centers, family nurse consultants, 24-hour Alzheimer’s crisis line, support groups, case management, education, training and advocacy. The organization has eleven specialized Alzheimer’s adult day service programs and seven family nurse consultant offices in fifteen locations throughout the three counties.
Written for Palm2Jupiter
Don’t feel too bad if you don’t have a clue how your brain works. After all, scientists, whose business it is to know about such things, admit that they are in the beginning stages of this study. They start by taking “simple” processes, in the hopes that these will throw light on the more complicated workings of our minds.
Scientist David Fitzpatrick, who was named CEO of Max Planck’s Jupiter campus in December, heads up the institute’s Functional Architecture and Development of Visual Cortex department. Recently, Fitzpatrick shared with us an inside look at his work and of one of the research projects he oversees.
In the process, he used an analogy, comparing the circuity in the human brain to computer circuitry, and also, by waving his arms around, explained that thanks to specific neurons in our brain, we are able to see that motion.
Wow. That gives a whole new definition to the term, “being wired.”
So, to start: Max Planck Florida Institute is a basic research society.
“The Florida institute is focused on the brain,” Fitzpatrick said. “Specifically, we are exploring neural circuits, the complex synaptic networks of the brain. We want to understand how they are organized, how they function, and how they develop. This requires bringing together scientists with expertise in different levels of analysis — genetic, molecular, cellular, circuit and behavioral — and developing new technologies that make cutting-edge scientific discoveries possible.”
Brain circuits are the synaptic networks of neurons that interact to create movement, perception, thought, memory and emotions. You can think of them this way, he said.
“The brain is an incredibly complex biological computer, and neural circuits are like what’s running inside your computer,” he said. “The circuits that make the computer able to register the keys that are being pushed, that’s the sensory side. And the output, that’s what pops up on the screen. We want to understand how the circuits work, how they transform sensory input into a motor output and how these circuits are constructed during development. This information is critical for understanding a wide range of brain disorders.”
One area that is of particular interest to the scientists in Fitzpatrick’s lab is the role that experience plays in the development of neural circuits. Most of the synapses (the connections between neurons) in the cerebral cortex (the outer portion of the brain that’s responsible for movement, perception, thought and memory) are formed at a time when experience can influence their formation.
“After birth, there’s a huge increase in the density of synapses in the cortex, and we now know that patterns of neural activity driven by experience with the outside world influences how these circuits form,” Fitzpatrick said. “We are interested in understanding how that comes about. How is it that experience can influence the formation of these circuits?”
This is an important issue to address considering that there are many neuro-developmental disorders, the most well-known being autism. These disorders are likely to reflect alterations in the way that experience influences the development of neural circuits.
The visual cortex is used as a model system to explore these questions in his lab, he said, because it’s an easy system to manipulate. Scientists can control the visual information coming in, and they can ask how visual information influences the formation of circuits.
“We have been studying a property in the visual cortex that emerges with experience, and this property is known as selectivity for direction of motion,” he said. “If I wave my arm, you see my hand move in a certain direction. The reason that you are able to recognize its direction of motion is because you have neurons in your cerebral cortex that are sensitive to movement in a certain direction. Some neurons are sensitive to movement upwards, others to movement downwards, left and right. Our research has shown that the selective responses of cortical neurons to motion direction is acquired through experience with visual motion at an early stage in development.”
What the scientists don’t understand is the mechanism responsible for that, he said.
“We don’t understand which parts of the neural circuits that make up the cerebral cortex are being altered by visual experience, and how these alterations generate direction selectivity,” he said. “But we think that if we can understand the mechanisms that are responsible for building up this response property, we will have a better understanding of the fundamental mechanisms by which experience influences the formation of neural circuits. We are interested in how it is that neural circuits get built and how our interaction with the world around us influences the construction of these circuits.”
Progress all comes down to the tools that the scientists have to address these questions.
“And in the last five years, there’s been an explosion of new techniques that are allowing us to visualize circuits in the brain and control their activity with light in ways that we couldn’t have dreamed of,” Fitzpatrick said. “So quite literally, we can visualize neurons in living brains, we can visualize their structure, and we can visualize their activity.”
To explain, “activity,” he said that neurons communicate with each other through synapses and the synapse involves a chemical transmission from one neuron to another, but the basic mode of communication is electrical. So a neuron generates an electrical signal that travels down its axon where it reaches a synapse, releases a neurotransmitter, and that neurotransmitter causes an electrical event in the dendrite, the receiving part, of the next neuron.
He gives an idea of some of the complexity: “One neuron in the cerebral cortex receives between 5,000 to 12,000 synapses onto its dendrite, and it is the specificity in the patterns of connections between neurons that is responsible for selectivity in neuronal responses, such as selectivity for direction of motion. We are still far from understanding the ‘wiring diagram’ that defines cortical circuits and how experience influences the patterns of connections that form between different neurons. This is what we are after.”
Back to the tools, with the newest technologies, scientists are now in the position to use light to see the neuron and its connections in a living brain, to visualize the activity in the neuron, and even to control its activity.
“We are developing a powerful set of tools for ‘interrogating’ neural circuit function,” he said. Their goal, he explained, “is to be able to really understand the structure of the neurons, the way the synapses are arranged, and the way in which experience shapes those connections.”
So, the scientists can go into the brain and control the activity of neurons and see how controlling their activity impacts the response of the neuron to motion selectivity, he said.
“Using these new techniques, we can begin to understand how all the inputs that come into a neuron contribute to its function,” he said.
Based on the idea that neuro-development disorders reflect alterations in how experience builds circuits, if the scientists can understand the basic mechanism through which experience builds circuits, than they can begin to understand these disorders.
“I mentioned autism, because it emerges as the child develops, it’s very profound, and increasing in terms of the number of people impacted,” he said. “Children appear to be normal and then begin to exhibit the symptoms of autism. It’s very likely that what’s going on here is some alteration in the way experience shapes the development of brain circuits.”
To be clear, Fitzpatrick addressed a problem faced by basic scientists: “People need to appreciate that we still know very little about neural circuits and the mechanisms that are responsible for their development. Even with the discoveries that these new techniques are making possible, the complexities of the brain make translating this knowledge into effective treatments a difficult process.
“But, it’s fundamental, basic science research that holds the key to understanding the normal mechanisms of brain development, and it’s that information that ultimately is crucial for in understanding disorders that reflect alterations in normal circuit development,” he said.
The scientists literally are going to the basics and asking: What are these circuits? They are saying: Let’s define them. Let’s map out what the circuits are and understand how these circuits produce this remarkable degree of selectivity.
The work in Fitzpatrick’s lab addresses a relatively simple question: How is it that neurons in the brain respond selectively to the direction of a moving stimulus?
“We are not talking about how the brain represents thoughts or emotions,” he said. “These are much more complicated issues. But if we can take something simple — how do neuron circuits represent the direction of a moving stimulus, if we can understand how that happens, and how experience with moving stimuli builds that representation, then we can take what we learn and apply it to these other, far more complicated processes.”
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Here is a link to a video presentation on the NIH VideoCasting site where Fitzpatrick speaks about his work.
Might want to think twice before you swat that fruit fly buzzing around your kitchen, suggests Ronald Davis, Ph.D., chairman of the neuroscience department at Scripps Florida in the Jupiter campus, who is researching the genes required in learning and memory.
Consider this, Davis said: “The fly has 15,000 genes. Humans have 25,000 genes, so we are not that different.”
But, thank goodness (for the researchers), the fruit fly’s brain is smaller.
“The human brain has 100 billion neurons – that’s about as many stars in the Milky Way,” he said. “On top of that, each neuron makes 10,000 connections. That’s an amazing social network of cells.”
Meanwhile, the brain of the fruit fly has 100,000 neurons.
“Its brain is a million times less complex than the human brain,” Davis said. “Even 100,000 neurons is hard to grasp, but we can start working with that.”
Figuring out how memories are formed and learning takes place are monumental tasks, when you think about it – even if all those 100 billion neurons fired at once.
“The human brain, a three-pound mass of tissue, captures memories across our lives – many, if not all, of our episodes and stories in a biological form — and recalls them, and we don’t know how that happens,” Davis said.
“We can’t understand how the brain forms and encodes memories,” he continued. “Our brain is too complex a network to wrap our brains around. So, to simplify, we use the fruit fly. It is an incredible model to understand the subset of genes in memory formation because its genes are conserved (there are similar genes in the fruit fly, mouse, rat and humans), so hopefully, the principles we learn from the fruit fly can be applied to other organisms, including humans.”
To meet that challenge, the scientists introduced a strategy to identify the genes involved in memory.
Step one: “We can teach flies simple tasks,” Davis said. “We present them with an odor and give them a mild electric shock. They learn quickly and run away. Or, we give them a positive stimulus, and they run toward it.”
The second major step in the strategy is to isolate the mutant flies that can’t learn or remember.
“We can identify sets of genes or mutant strains in those mutant animals, and pull those genes out of the flies and study them on the DNA level,” he said. In addition, “genes encode proteins, so we can then deduce what brain proteins that gene makes and how it is involved in memory formation.”
The scientists’ final overall strategy is to identify each gene in a fly that has to do with memory formation.
“Out of 15,000 genes in a fly’s DNA, there are 400 or 500 genes that are important to learning and memory,” Davis said. “We have about 100 genes that we know about right now.”
Once the scientists have a handle on that, they hope to reconstruct how the molecular machinery within neurons for memory works.
That may sound complicated, but machinery is machinery, he explained.
“It’s a little like a ’63 Stingray,” he said. “Without knowing anything about the car, you can disassemble it and deduce what different parts do.”
Same with isolating genes. If you are missing the gene equivalent of the car starter, you can’t learn. If you are missing the equivalent of the spark plug, you’ll start, but you won’t hit on all eight cylinders.
If you take something like the radiator out, the car (or you) will run great, but only for five minutes.
“The radiator would be the equivalent to a maintenance function,” he said.
The headlights, however, don’t affect the running of the car, one way or another, and you still can function with your eyes closed.
“In the same way, we can identify mutants in fruit flies that can’t learn like “normal” flies, or we can identify flies that can learn, but can’t maintain or remember,” he said.
“An amazing aspect — something that surprises a lot of people — fruit fly genes are conserved – if we isolate a fruit fly gene, there’s 99 percent certainty that we can identify that same gene in humans, and it is involved in human behavior, at least.
Take the gene, dunce, for example. When it is mutated in fruit flies, they have a learning deficiency. The human counterpart of dunce is involved in regulating mood. In the last five years, scientists have found that humans who carry a certain variation of the human dunce gene have an increased susceptibility to schizophrenia.
Another example: When the gene NF1 is mutated in fruit flies, they can’t learn. Humans with the condition, neurofibromatosis type 1, have a mutation of NF1, and about half of them have difficulty in learning or attention deficiency.
And here’s an example of an ongoing study with humans: The scientists obtained DNA from 2,000 subjects with bipolar disorder, and they took 80 fruit fly and mice genes that are involved in memory. Then, they studied those 80 genes in the individuals with bipolar disorder, as well as comparing those genes relative to a control group with no history of psychiatric disease to see whether there were unique changes, variations or mutations.
“So far, we’ve hit a few novel genes,” Davis said. “If we find a change in a fair fraction in the bipolar group in some gene, and we don’t find it in the normal population, that leads to the conclusion that changes in that gene in the DNA might confer an increased probability that an individual will be subject to bipolar disorder.”
The goal of memory and learning research is to better understand the disorders that impact memory and learning, he said.
“Memory issues form a common thread in major neurological and psychiatric illnesses and so has profound medical importance,” he said.
Alzheimer’s disease, which affects 5 million people and is hereditary, is the obvious disease that comes to mind, but people with schizophrenia, which affects one percent of the population, have a deficiency in forming memories. People with autism spectrum disorder have problems learning complex tasks. Drug addicts have memory problems – going back to the place where they shoot up, for example, leads to relapse — as well as people suffering from mood disorders, like bipolar and depression.
People with Attention Deficit Hyperactivity Disorder and those who have suffered brain trauma have memory problems. And, then, there are the memory problems that come along with normal aging – where are those car keys?
“The end game has to be to solve these diseases,” he said. “Just imagine if we took all the genes involved in memory behavior, and through Scripps’ drug-discovery program, if can we find drugs that can tweak the activity of those proteins involved (in memory and learning) and make them work better, these drugs would be cognitive enhancers. Right now, we need as many cognitive enhancers as we can get.”
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