TB is caused by infection with the bacterium M. tuberculosis. In 2011, TB sickened some 8.7 million people and took some 1.4 million lives, according to the World Health Organization. Infections that fail to respond to TB drugs are a growing problem: About 650,000 people worldwide now have multi-drug-resistant TB (MDR-TB), 9 percent of whom have extensively drug-resistant TB (XDR-TB).TB is especially acute in low and middle income countries, which account for more than 95 percent of TB-related deaths, according to the World Health Organization.

The Einstein discovery arose during research into how TB bacteria become resistant to isoniazid, a potent first-line TB drug. The lead investigator and senior author of the study was William Jacobs, Jr., Ph.D., professor of microbiology & immunology and of genetics at Einstein. Dr. Jacobs is a Howard Hughes Medical Institute investigator and a recently elected member of the National Academy of Sciences.

Dr. Jacobs and his colleagues observed that isoniazid-resistant TB bacteria were deficient in a molecule called mycothiol. “We hypothesized that TB bacteria that can’t make mycothiol might contain more cysteine, an amino acid,” said Dr. Jacobs. “So, we predicted that if we added isoniazid and cysteine to isoniazid-sensitive M. tuberculosis in culture, the bacteria would develop resistance. Instead, we ended up killing off the culture— something totally unexpected.”

The Einstein team suspected that cysteine was helping to kill TB bacteria by acting as a “reducing agent” that triggers the production of reactive oxygen species (sometimes called free radicals), which can damage DNA.

“To test this hypothesis, we repeated the experiment using isoniazid and a different reducing agent— vitamin C,” said Dr. Jacobs. “The combination of isoniazid and vitamin C sterilized theM. tuberculosis culture. We were then amazed to discover that vitamin C by itself not only sterilized the drug-susceptible TB, but also sterilized MDR-TB and XDR-TB strains.”

To justify testing vitamin C in a clinical trial, Dr. Jacobs needed to find the molecular mechanism by which vitamin C exerted its lethal effect. More research produced the answer: Vitamin C induced what is known as a Fenton reaction, causing iron to react with other molecules to create reactive oxygen species that kill the TB bacteria.

“We don’t know whether vitamin C will work in humans, but we now have a rational basis for doing a clinical trial,” said Dr. Jacobs. “It also helps that we know vitamin C is inexpensive, widely available and very safe to use. At the very least, this work shows us a new mechanism that we can exploit to attack TB.”

In Macrophages are required for adult salamander limb regeneration, published in the Proceedings of the National Academy of Sciences, researchers from the Australian Regenerative Medicine Institute (ARMI) at Monash University found that when immune cells known as macrophages were systemically removed, salamanders lost their ability to regenerate a limb and instead formed scar tissue.

Lead researcher, Dr. James Godwin, a Fellow in the laboratory of ARMI Director Professor Nadia Rosenthal, said the findings brought researchers a step closer to understanding what conditions were needed for regeneration.

“Previously, we thought that macrophages were negative for regeneration, and this research shows that that’s not the case – if the macrophages are not present in the early phases of healing, regeneration does not occur,” Dr. Godwin said.

“Now, we need to find out exactly how these macrophages are contributing to regeneration. Down the road, this could lead to therapies that tweak the human immune system down a more regenerative pathway.”

Salamanders deal with injury in a remarkable way. The end result is the complete functional restoration of any tissue, on any part of the body including organs. The regenerated tissue is scar free and almost perfectly replicates the injury site before damage occurred.

“We can look to salamanders as a template of what perfect regeneration looks like,” Dr. Godwin said.

Aside from “holy grail” applications, such as healing spinal cord and brain injuries, Dr. Godwin believes that studying the healing processes of salamanders could lead to new treatments for a number of common conditions, such as heart and liver diseases, which are linked to fibrosis or scarring. Promotion of scar-free healing would also dramatically improve patients’ recovery following surgery.

There are indications that there is the capacity for regeneration in a range of animal species, but it has, in most cases been turned off by evolution.

“Some of these regenerative pathways may still be open to us. We may be able to turn up the volume on some of these processes,” Dr. Godwin said.

“We need to know exactly what salamanders do and how they do it well, so we can reverse-engineer that into human therapies.”

Under the terms of the agreement, BASF will be able to use Dyadic’s patented and proprietary C1 platform technology to develop, produce, distribute and sell industrial enzymes in certain fields for a variety of applications. BASF will fund research and development at Dyadic’s research lab in The Netherlands. In addition to this funding, BASF has agreed to pay Dyadic a $6 million upfront license fee, and certain research and commercial milestone fees, as well as royalties upon commercialization.

“Dyadic’s C1 technology will strengthen BASF’s position in the industrial enzyme industry,” said Dr. Carsten Sieden, Senior Vice President Fine Chemicals and Biocatalysis Research, BASF. “We expect this license agreement with Dyadic to result in promising long-term opportunities.”

Dyadic’s President and Chief Executive Officer, Mark Emalfarb, stated, “Empowering BASF, the world’s leading chemical company, with our C1 technology provides them with access to a commercially-proven industrial enzyme production platform. In using its vast resources to develop, manufacture and sell new products from the C1 platform, BASF will have business opportunities for a variety of markets, including animal and human nutrition. This transaction will have long-lasting effects on the industrial enzyme businesses of both Dyadic and BASF.”

Emalfarb concluded, “Dyadic looks forward to working with BASF and utilizing our C1 technology for the expression of next-generation enzyme products for a range of applications. This collaboration is yet another example of Dyadic’s ability to leverage our technologies in  a variety of industries.”

For the first time, a global team of researchers led by USC Professor Cheng-Ming Chuong has uncovered unique cellular and molecular mechanisms behind tooth renewal in American alligators. “Specialized stem cell niche enables repetitive renewal of alligator teeth” appeared in PNAS.

“Humans naturally only have two sets of teeth — baby teeth and adult teeth,” Chuong said. “Ultimately, we want to identify stem cells that can be used as a resource to stimulate tooth renewal in adult humans who have lost teeth. But to do that, we must first understand how they renew in other animals and why they stop in people.”

Whereas most vertebrates can replace teeth throughout their lives, human teeth are naturally replaced only once, despite the lingering presence of a band of epithelial tissue called the dental lamina, which is crucial to tooth development. Because alligators have well-organized teeth with similar form and structure as mammalian teeth and are capable of lifelong tooth renewal, the authors reasoned that they might serve as models for mammalian tooth replacement.

“Alligator teeth are implanted in sockets of the dental bone, like human teeth,” said Ping Wu, assistant professor of pathology at the Keck School and first author of the study. “They have 80 teeth, each of which can be replaced up to 50 times over their lifetime, making them the ideal model for comparison to human teeth.”

Using microscopic imaging techniques, the researchers found that each alligator tooth is a complex unit of three components — a functional tooth, a replacement tooth and the dental lamina — in different developmental stages. The tooth units are structured to enable a smooth transition from dislodgement of the functional, mature tooth to replacement with the new tooth. Identifying three developmental phases for each tooth unit, the researchers concluded that the alligator dental laminae contain what appear to be stem cells from which new replacement teeth develop.

“Stem cells divide more slowly than other cells,” said co-author Randall Widelitz, associate professor of pathology at the Keck School. “The cells in the alligator’s dental lamina behaved like we would expect stem cells to behave. In the future, we hope to isolate those cells from the dental lamina to see whether we can use them to regenerate teeth in the lab.”

The researchers also intend to learn what molecular networks are involved in repetitive renewal and hope to apply the principles to regenerative medicine in the future.

The authors also reported novel cellular mechanisms by which the tooth unit develops in the embryo and molecular signaling that speeds growth of replacement teeth when functional teeth are lost prematurely.

Co-authors included colleagues from the Louisiana Department of Wildlife and Fisheries, University of Georgia, National Cheng Kung University, National Taiwan University and Xiangya Hospital in China.

The research breakthrough, led by Shoukhrat Mitalipov, Ph.D., a senior scientist at ONPRC, follows previous success in transforming monkey skin cells into embryonic stem cells in 2007. This latest research will be published in the journal Cell online May 15 and in print June 6.

The technique used by Drs. Mitalipov,Paula Amato, M.D., and their colleagues in OHSU’s Division of Reproductive Endocrinology and Infertility, Department of Obstetrics & Gynecology, is a variation of a commonly used method called somatic cell nuclear transfer, or SCNT. It involves transplanting the nucleus of one cell, containing an individual’s DNA, into an egg cell that has had its genetic material removed. The unfertilized egg cell then develops and eventually produces stem cells.

“A thorough examination of the stem cells derived through this technique demonstrated their ability to convert just like normal embryonic stem cells, into several different cell types, including nerve cells, liver cells and heart cells. Furthermore, because these reprogrammed cells can be generated with nuclear genetic material from a patient, there is no concern of transplant rejection,” explained Dr. Mitalipov. “While there is much work to be done in developing safe and effective stem cell treatments, we believe this is a significant step forward in developing the cells that could be used in regenerative medicine.”

Another noteworthy aspect of this research is that it does not involve the use of fertilized embryos, a topic that has been the source of a significant ethical debate.

The Mitalipov team’s success in reprogramming human skin cells came through a series of studies in both human and monkey cells. Previous unsuccessful attempts by several labs showed that human egg cells appear to be more fragile than eggs from other species. Therefore, known reprogramming methods stalled before stem cells were produced.

To solve this problem, the OHSU group studied various alternative approaches first developed in monkey cells and then applied to human cells. Through moving findings between monkey cells and human cells, the researchers were able to develop a successful method.

The key to this success was finding a way to prompt egg cells to stay in a state called “metaphase” during the nuclear transfer process. Metaphase is a stage in the cell’s natural division process (meiosis) when genetic material aligns in the middle of the cell before the cell divides. The research team found that chemically maintaining metaphase throughout the transfer process prevented the process from stalling and allowed the cells to develop and produce stem cells.

“This is a remarkable accomplishment by the Mitalipov lab that will fuel the development of stem cell therapies to combat several diseases and conditions for which there are currently no treatments or cures,” saidDr. Dan Dorsa, Ph.D., OHSU Vice President for Research. “The achievement also highlights OHSU’s deep reproductive expertise across our campuses. A key component to this success was the translation of basic science findings at the OHSU primate center paired with privately funded human cell studies.”

One important distinction is that while the method might be considered a technique for cloning stem cells, commonly called therapeutic cloning, the same method would not likely be successful in producing human clones otherwise known as reproductive cloning. Several years of monkey studies that utilize somatic cell nuclear transfer have never successfully produced monkey clones. It is expected that this is also the case with humans. Furthermore, the comparative fragility of human cells as noted during this study, is a significant factor that would likely prevent the development of clones.

“Our research is directed toward generating stem cells for use in future treatments to combat disease,” added Dr. Mitalipov. “While nuclear transfer breakthroughs often lead to a public discussion about the ethics of human cloning, this is not our focus, nor do we believe our findings might be used by others to advance the possibility of human reproductive cloning.”

The human studies were funded by OHSU and a grant from Leducq Foundation. The nonhuman primate studies were funded by the following grants from the National Institutes of Health: HD063276, HD057121, HD059946, EY021214 and OD011092.

• $2,850,000 from the General Revenue Fund is provided to the James and Esther King Biomedical Research Program.

• $500,000 from the Biomedical Research Trust Fund is provided to maintain the statewide Brain Tumor Registry Program at the McKnight Brain Institute.

• $5,000,000 from the General Revenue Fund is provided to the William G. “Bill” Bankhead, Jr., and David Coley Cancer Research Program.

• $2,050,000 from the General Revenue Fund is provided to the H. Lee Moffitt Cancer Center and Research Institute.

• From the funds in Specific Appropriation 474A, $2,050,000 from the General Revenue Fund and $5,000,000 from the Biomedical Research Trust Fund are provided to the Shands Cancer Hospital.

• From the funds in Specific Appropriation 474A, $2,050,000 from the General Revenue Fund and $5,000,000 from the Biomedical Research Trust Fund are provided to the Sylvester Cancer Center at the University of Miami.

• From the funds in Specific Appropriation 474A, $3,000,000 from the General Revenue Fund and $2,600,000 from the Biomedical Research Trust Fund are provided to the Sanford-Burnham Medical Research Institute.

• From the funds in Specific Appropriation 474A, $3,000,000 in nonrecurring funds from the Biomedical Research Trust Fund is provided to the Torrey Pines Institute for Molecular Studies.

• $10,000,000 in nonrecurring funds from the General Revenue Fund is provided to the following institutions for the establishment of an endowed cancer research chair. This funding is contingent upon the passage of Senate Bill 1660, or similar legislation, becoming law:
- Shands Cancer Hospital at the University of Florida………3,333,333
- H. Lee Moffitt Cancer Center and Research Institute………3,333,333
- Sylvester Cancer Center at the University of Miami……….3,333,334

• From the funds in Specific Appropriation 529, $1,000,000 from the General Revenue Fund is provided for the department to contract with the Brain Injury Association of Florida (BIAF) to identify and link resources to traumatic brain injury patients.

• From the funds in Specific Appropriation 529, $1,000,000 in nonrecurring funds from the General Revenue Fund is provided to the Bitner/Plante Amyotrophic Lateral Sclerosis Initiative of Florida.

• GRANTS AND AIDS – MOFFITT CANCER CENTER
AND RESEARCH INSTITUTE
FROM GENERAL REVENUE FUND . . . . . 10,576,930
Funds in Specific Appropriation 141 may be transferred to the Agency for Health Care Administration and used as state matching funds for Moffitt’s participation in the Low Income Pool or the application of Medicaid inpatient and outpatient rate adjustments applied to the H. Lee Moffitt Cancer Center and Research Institute and other Medicaid reductions to its rates up to the actual Medicaid inpatient and outpatient costs. In the event that enhanced Medicaid funding is not implemented by the Agency for Health Care Administration, these funds shall remain appropriated to the H. Lee Moffitt Cancer Center and Research Institute to continue the original purpose of providing research and education related to cancer.

• The Florida Hospital/Sanford-Burnham Translational Research Institute is designated as a State of Florida resource for research in diabetes diagnosis, prevention and treatment. The Florida Sanford-Burnham Translational Research Institute may coordinate with the Department of Health on activities and grant opportunities in relation to research in diabetes diagnosis, prevention and treatment.
APPROVED SALARY RATE 10,652,414
460 SALARIES AND BENEFITS POSITIONS 230.50
FROM GENERAL REVENUE FUND . . . . . 1,921,862

• From the funds in Specific Appropriation 472, $100,000 in nonrecurring funds from the General Revenue Fund is provided to the Scripps Research Institute for the Nicotine Addiction Drug Treatment Evaluation Grant Program.

• University of Florida – Chemistry/Chemical Biology Bldg….. 15,000,000

• University of South Florida – Heart Health Institute…….. 12,500,000

SECURITY – BIOTERRORISM ENHANCEMENTS -
HEALTH AND HOSPITALS
FROM FEDERAL GRANTS TRUST FUND . . .28,146,674

“The opportunity to participate in ground-breaking research is extremely valuable for our students, giving them an unprecedented advantage for employment and graduate school,” said Casey Lunceford, Dean of Arts and Sciences at IRSC.  “To earn a paycheck and scholarship as well is truly exceptional, and we are very thankful for Torrey Pines’ support.”

Student salaries and scholarships are funded by Torrey Pines with students earning $10 per hour and working 19 hours per week.  The scholarship provides tuition for a semester, fees or textbooks.  New students are selected each semester and students can also reapply on a semester-by-semester basis.

“I was fortunate to have had Work-Study opportunities during my education.” said Dr. Richard Houghten, Founder, CEO, & President of Torrey Pines Institute.  “My Work-Study experiences profoundly influenced my future pathway as a scientist.  We are extremely pleased with the quality of IRSC Work-Study students currently receiving hands-on experience in our biology and chemistry laboratories.  We were able to match each student’s interests with the many difference areas of research being conducted at Torrey Pines Institute.”

“It was an amazing opportunity, and I couldn’t have asked for anything better,” said Jennifer Davis, 21 of Hobe Sound.  A junior majoring in biology, Davis is working in Dr. Gregg Fields’ lab on peptide synthesis related to the study of multiple sclerosis and rheumatoid arthritis.  Eric Dorn, 28, of Fort Pierce, a sophomore interested in a nursing career, is developing insight into the causes of Alzheimer’s through study of the plaques that cause the disease in the laboratory of Dr. Madepalli Lakshmana.

Melissa Williams, 23, of Port St. Lucie is working with cells under the direction of Dr. Akihiko Ozawa to understand how cancer is caused by different types of proteins in the body. “It’s awesome to take what I have learned in college and use it here in the lab – I’m always learning,” Williams said.

Students selected for the program must be at least 18 years old, have reliable transportation, and must complete specific biology and chemistry courses with a C or higher before applying.  They should also submit a written letter of recommendation from a full-time IRSC Biology or Chemistry faculty member and complete an employment application for Torrey Pines Institute of Molecular Studies.  For more information, contact the Arts and Sciences Depart at IRSC at 772-462-7503.

New technique developed by researchers at FIU uses magneto-electric nanoparticles to deliver a significantly higher level of the anti-HIV drug AZTTP to the brain.

Researchers from FIU’s Herbert Wertheim College of Medicine describe a new technique they have developed that can deliver and fully release the anti-HIV drug AZTTP into the brain. Externally controlled on-demand release of anti-HIV drug using magneto-electric nanoparticles as carriers is published in Nature Communications.

Madhavan Nair, professor and chair, and Sakhrat Khizroev, professor in HWCOM’s Department of Immunology, used magneto-electric nanoparticles (MENs) to cross the blood-brain barrier and send a significantly increased level of AZTTP—up to 97 percent more —to HIV-infected cells.

For years, the blood-brain barrier has stumped scientists and doctors who work with neurological diseases. A natural filter that allows very few substances to pass through to the brain, the blood-brain barrier keeps most medicines from reaching the brain. Currently, more than 99 percent of the antiretroviral therapies used to treat HIV, such as AZTTP, are deposited in the liver, lungs and other organs before they reach the brain.

“This allows a virus, such as AIDS, to lurk unchecked,” said Nair, an HIV/immunology researcher.

The patent-pending technique developed by FIU binds the drug to a MEN inserted into a monocyte/macrophage cell, which is then injected into the body and drawn to the brain. Once it has reached the brain, a low energy electrical current triggers a release of the drug, which is then guided to its target with magnetoelectricity. In lab experiments, nearly all of the therapy reached its intended target. It will soon enter the next phase of testing.

Potentially, this method of delivery could help other patients who suffer from neurological diseases such as Alzheimer’s, Parkinson’s, epilepsy, muscular dystrophy, meningitis and chronic pain. It could also be applicable to diseases such as cancer.

“We see this as a multifunctional therapy,” said Khizroev, who is an electrical engineer and physicist by training.

Multi-disciplinary efforts that combine principles of those fields with immunology enabled the project to move forward.

“The success of our nanotechnology is derived from the fact that nature likes simplicity,” Khizroev said.

This free event from 9:30 a.m. to 1 p.m. is hosted by the Northeast Chapter of BioFlorida and will feature more than 70 scientific and other vendors, an expanded bus tour of Progress Corporate Park and a brief program to celebrate the successes of the local biotechnology industry over the past year. The 204-acre park is home to 30 biotechnology companies.

Florida has seen a 60 percent growth of the biotechnology industry over the past five years. Furthermore, University of Florida’s Sid Martin Biotechnology Incubator, located in the park, was recently awarded the Randall M. Whaley Incubator of the Year for overall excellence, topping incubators more than twice its size, such as the Hong Kong Science and Technology Parks Corporation. These accomplishments and more will be highlighted during this year’s celebration.

“There is a lot to celebrate at this year’s event,” said Patti Breedlove, associate director of Sid Martin Biotechnology Incubator and a member of BioFlorida’s board of directors. “We are excited to share the successes of our local biotechnology companies and research institutions with life sciences stakeholders and the general public.”

Since the release of the second edition of Florida’s BioPulse, the biotechnology industry in Florida has experienced additional growth with Nanotherapeutics — a privately held biopharmaceutical company located in Progress Corporate Park and graduate of the Sid Martin Biotechnology Incubator — being awarded a $135 million contract with the U.S. Department of Defense to develop manufacturing processes for drugs to treat bioterrorism and radiological threats. The company is expanding to land adjacent to Progress Corporate Park. Moreover, RTI Biologics is expanding its presence in Progress Corporate Park, by building a 41,165-square-foot Logistics and Technology Center that is expected to open in early 2014.

Jim Talton, CEO of Nanotherapeutics, will be at the celebration to discuss the Department of Defense contract that is expected to provide 150 new employees with an average salary of $90,000. Guests can take a narrated bus tour around Progress Corporate Park and surrounding areas, exploring the Sid Martin Biotechnology Incubator, RTI Biologics’ Logistics and Technology Center and Santa Fe College’s Charles R. and Nancy V. Perry Center for Emerging Technologies, and the site of Nanotherapeutic’s new manufacturing facility.

For those interested in continuing education and training programs, Santa Fe College will highlight the school’s biomedical and biotechnology programs that educate and train the talent needed for the growing life sciences industry in the Gainesville area, and Florida.

Lunch will be for sale and provided by Gator Dominos, KB Kakes and Govinda’s from the Hare Krishna Temple. Guests will also have the chance to win door prizes.

“We’ve created a ‘smart’ system that is injected into the body and responds to changes in blood sugar by releasing insulin, effectively controlling blood-sugar levels,” says Dr. Zhen Gu, lead author of a paper describing the work and an assistant professor in the joint biomedical engineering program at NC State and UNC Chapel Hill. “We’ve tested the technology in mice, and one injection was able to maintain blood sugar levels in the normal range for up to 10 days.”

When a patient has type 1 diabetes, his or her body does not produce sufficient insulin, a hormone that transports glucose – or blood sugar – from the bloodstream into the body’s cells. This can cause a host of health effects. Currently, diabetes patients must take frequent blood samples to monitor their blood-sugar levels and inject insulin as needed to ensure their blood sugar levels are in the “normal” range. However, these injections can be painful, and it can be difficult to determine the accurate dose level of insulin. Administering too much or too little insulin poses its own health risks.

The new, injectable nano-network is composed of a mixture containing nanoparticles with a solid core of insulin, modified dextran and glucose oxidase enzymes. When the enzymes are exposed to high glucose levels they effectively convert glucose into gluconic acid, which breaks down the modified dextran and releases the insulin. The insulin then brings the glucose levels under control. The gluconic acid and dextran are fully biocompatible and dissolve in the body.

Each of these nanoparticle cores is given either a positively charged or negatively charged biocompatible coating. The positively charged coatings are made of chitosan (a material normally found in shrimp shells), while the negatively charged coatings are made of alginate (a material normally found in seaweed).

When the solution of coated nanoparticles is mixed together, the positively and negatively charged coatings are attracted to each other to form a “nano-network.” Once injected into the subcutaneous layer of the skin, the nano-network holds the nanoparticles together and prevents them from dispersing throughout the body. Both the nano-network and the coatings are porous, allowing blood – and blood sugar – to reach the nanoparticle cores.

“This technology effectively creates a ‘closed-loop’ system that mimics the activity of the pancreas in a healthy person, releasing insulin in response to glucose level changes,” Gu says. “This has the potential to improve the health and quality of life of diabetes patients.”

Gu’s research team is currently in discussions to move the technology into clinical trials for use in humans.