Genetic risk factor for equine eye cancer identified

Squamous cell carcinoma (SCC) is the most common cancer found in equine eyes and the second most common tumor of the horse overall. Thanks to a recent genetic study led by UC Davis, horse owners can now identify horses at risk for ocular SCC and make informed breeding decisions.

In the cover article for the International Journal of Cancer, scientists announced the discovery of a genetic mutation in horses that is hypothesized to impact the ability of damage specific DNA binding protein 2 (DDB2) to carry out its standard role. Normally, the protein conducts DNA surveillance, looking for UV damage and then calling in other proteins to help repair the harm.

“The mutation is predicted to alter the shape of the protein so it can’t recognize UV-damaged DNA,” said Dr. Rebecca Bellone, an equine geneticist at the Veterinary Genetics Laboratory and associate adjunct professor at UC Davis School of Veterinary Medicine. “We believe this is a risk factor because cells can’t repair the damage and accumulate mutations in the DNA that lead to cancer.”

Several equine breeds, including Haflingers, have a higher occurrence of limbal SCC, the form of the disease that originates in the junction between the cornea–the clear surface of the eyeball–and the conjunctiva that covers the white of the eye. A former study, conducted by Bellone and one of her research partners, Dr. Mary Lassaline, found that about 26 percent of SCC-affected horses in a retrospective study were Haflingers.

“The fact that we see this type of cancer in a relatively small breed with a narrow pedigree makes it a good model to study,” said Lassaline, associate professor of clinical equine ophthalmology at the UC Davis School of Veterinary Medicine.

Ocular SCC can lead to vision loss and even loss of the eye. In advanced cases, SCC can be locally invasive and spread to the orbit and eat away at bone and eventually the brain–leading to loss of life. These recent study results offer a huge application in identifying horses at risk for developing SCC on two fronts.

“One, it’s important for the individual horse with a known risk and we can be more vigilant about exams as well as protecting their eyes from UV exposure,” Lassaline said. “If detected early, we can remove the tumor and save the eye. Secondly, that knowledge is important for making informed breeding decisions.”

Scientists at the UC Davis Veterinary Genetics Laboratory were able to develop a genetic test for horses based on the research. The test determines if a horse carries the mutation or has two copies of the risk variant, putting it at highest risk for cancer.

In addition to improving the health of horses, this study may have implications for human health as well. The gene found to be associated with equine SCC is also linked in humans to xeroderma pigmentosum complementation group E–a disease characterized by sun sensitivity and increased risk of cutaneous SCC and melanoma.

“There is an interesting parallel in humans with mutation in this protein,” Bellone said. “Now we have the ability to understand why it’s affecting the eyes of horses as well as the skin of humans.”

Bronchial Thermoplasty Helps Asthma Patients Reduce Severe Attacks, Hospitalizations and ER Visits

In a new study presented at the 2017 American Thoracic Society International Conference, adult asthma patients treated with bronchial thermoplasty (BT) had fewer severe exacerbations and were able to reduce their ER visits and hospitalizations in the two years following treatment.  Approved by the FDA in 2010, BT is a new device-based therapy that uses a series of three radio-frequency treatments to open the airways of adults with severe, persistent asthma whose symptoms are not adequately controlled by inhaled corticosteroids or long-acting beta-agonists.

To date, more than 6,800 patients in 33 countries have been treated with BT.

The “Post-FDA Approval Clinical Trial Evaluating BT in Severe Persistent Asthma” (PAS2 study), which involves hundreds of patients at dozens of research centers, looks at the long-term effects and safety of BT.

“The results of the PAS2 study suggest that after a single series of BT procedures, patients experience long-term improvement in their asthma control,” said lead author Geoffrey Chupp, MD, from Yale School of Medicine.  “These results indicate that BT works across the spectrum of severe asthma patients. We believe BT should be more widely considered as a treatment option in patients with poorly controlled severe asthma.”

Two-hundred eighty four patients were enrolled in the study at 27 centers in the U.S. and Canada.  Two-hundred seventy-nine study subjects had at least one BT procedure, and 271 had all three procedures.  In the 12 months prior to the first BT procedure, 78 percent of subjects had at least one severe exacerbation, 16 percent required hospitalization and 29 percent had ER visits.  In the first year follow up, 50.6 percent had severe exacerbations; 45.4 percent had exacerbations in the second year follow up.  Asthma-related hospitalizations and ER visits also saw significant, continuing reductions:  14.4 percent and 12.7 percent of subjects had hospitalizations, respectively, in

Discovery may offer hope to Parkinson’s disease patients

The finding of a common protein abnormality in these degenerative diseases supports a hypothesis among experts that abnormal deposition of proteins in many neurodegenerative disorders reflects an early change in these proteins.

“We have pinpointed a protein abnormality known as the ‘SOD1 fingerprint’ in regions of neuronal loss in the Parkinson’s disease brain,” said Associate Professor Kay Double who led the research published in Acta Neuropathologica.

“We believe this loss of neurons results from a combination of oxidative stress and a regional deficiency in copper, both of which occur specifically in vulnerable regions of the Parkinson’s disease brain.”

This new finding may offer hope to Parkinson’s disease patients, since therapies targeting abnormal SOD1 protein have resulted in substantial improvements in motor function and survival time in models of ALS, prompting their progression into human clinical trials in this disease. This new finding suggests that such therapies may also be useful to treat Parkinson’s disease.

The discovery that the abnormal SOD1 protein is also linked to nerve cell loss in the Parkinson’s disease brain, suggests coincident degenerative pathways in Parkinson’s disease and ALS.

Alterations in the anti-oxidant enzyme superoxide dismutase (SOD1) underlie around 20 percent of familial (f)ALS cases, where mutations to the sod1 gene result in functional and/or structural defects, including misfolding of the protein and loss of copper binding capacity. The aggregation of mutant SOD1 is believed to underlie motor neuron death in these ALS patients.

Researchers take an important step toward an HIV vaccine

Vaccines are an essential tool for preventing and treating serious infectious diseases such as polio, chicken pox and measles. But so far it has not been possible to develop vaccines capable of contributing to the treatment and prevention of chronic infectious diseases such as HIV and hepatitis C.

This new research paves the way for vaccines that, as opposed to conventional methods, boosting the parts of the immune system attacking the viral genes, which are the least active during the infection. This prolongs the resistance of the immune system to the virus.

Traditional vaccines typically cause a strong stimulation of the parts of the immune system, that are most responsive to the specific virus. But the reaction to the vaccine and the infection is often so intense that the immune system ‘loses momentum’ and consequently is not able to completely eliminate the virus. Researchers have therefore designed a vaccine which boosts the cells of the immune system responsible for the less exposed parts of the virus. As a result, the cells are able to distribute the ‘work load’ and retain the defense against the virus attack for a longer period of time. This gives the immune system time to build a more efficient defense, which may then defeat the remaining of the virus.

“We’re presenting an entirely new vaccine solution. Our vaccine supports the work of the immune system in developing an effective combating mechanism against the virus, rather than immediately combating the toughest parts of the virus. In combination with other vaccines, this approach can prove to have a highly efficient effect,” says Research Team Leader and Associate Professor Peter Holst of the Department of Immunology and Microbiology.

In 2008, the research team decided to develop a new vaccine strategy, which generates so-called strong immune responses against weak immunostimulatory parts of viruses. Research initially focused on experiments on mice and later on monkeys.

Now, the results of the research team show, that this technology can control the SIV virus infection (simian immunodefiency virus) in monkeys. SIV is a chronic infectious disease and a highly realistic representation of HIV. The results are an important step toward developing a vaccine against HIV and other chronic infections.

“The next phase of our work is to build virus control in all infected animals and later in humans. We’re convinced that it’s possible to identify further improvements in our experiments and thus achieve a well-functioning vaccine, initially against HIV, but also against other chronic infections,” says Peter Holst.

Epilepsy drug therapies to be improved by new targeted approach

New research from the University of Liverpool, in collaboration with the Mario Negri Institute in Milan, published today in the Journal of Clinical Investigation, has identified a protein that could help patients with epilepsy respond more positively to drug therapies.

Epilepsy continues to be a serious health problem and is the most common serious neurological disease. Despite 30 years of drug development, approximately 30% of people with epilepsy do not become free of fits (also called seizures) with currently available drugs.

New, more effective drugs are therefore required for these individuals. We do not fully understand why some people develop seizures, why some go onto develop epilepsy (continuing seizures), and most importantly, why some patients cannot be controlled with current drugs.

Inflammation

There is now increasing body of evidence suggesting that local inflammation in the brain may be important in preventing control of seizures. Inflammation refers to the process by which the body reacts to insults such as having a fit. In most cases, the inflammation settles down, but in a small number of patients, the inflammation continues.

The aim of the research, undertaken by Dr Lauren Walker while she was a Medical Research Council (MRC) Clinical Training Fellow, was to address the important question of how can inflammation be detected by using blood samples, and whether this may provide us with new ways of treating patients in the future to reduce the inflammation and therefore improve seizure control.

The research focused on a protein called high mobility group box-1 (HMGB1), which exists in different forms in tissues and bloodstream (called isoforms), as it can provide a marker to gauge the level of inflammation present.

Predicting drug response

The results showed that there was a persistent increase in these isoforms in patients with newly-diagnosed epilepsy who had continuing seizure activity, despite anti-epileptic drug therapy, but not in those where the fits were controlled.

An accompanying drug study also found that HMGB1 isoforms may predict how an epilepsy patient’s seizures will respond to anti-inflammatory drugs.

Dr Lauren Walker, said: “Our data suggest that HMGB1 isoforms represent potential new drug targets, which could also identify which patients will respond to anti-inflammatory therapies. This will require evaluation in larger-scale prospective trials.”

Innovative scheme

Professor Sir Munir Pirmohamed, Director of the MRC Centre for Drug Safety Science and Programme lead for the MRC Clinical Pharmacology scheme, said: “The MRC Clinical Pharmacology scheme is a highly successful scheme to train “high flyers” who are likely to become future leaders in academia and industry.

“Dr Walker’s research is testament to this and shows how this innovative scheme, which was jointly funded by the MRC and Industry, can tackle areas of unmet clinical need, and identify new ways of treating patients with epilepsy using a personalised medicine approach”.

Stem Cell Trial for Stroke Patients Suffering Chronic Motor Deficits Begins at UTHealth

A clinical trial to evaluate the safety and efficacy of a stem cell product injected directly into the brain to treat chronic motor deficits from ischemic stroke has begun at McGovern Medical School at The University of Texas Health Science Center at Houston (UTHealth).

McGovern Medical School at UTHealth is the only site in Texas and the central south portion of the country to open enrollment for the multi-institutional, phase 2B study – the first in the U.S. for chronic stroke. Surgeries will be conducted at Memorial Hermann-Texas Medical Center.

“This trial is one of the first randomized, sham-controlled studies to test the efficacy of administering adult-derived stem cells in patients disabled with a chronic stroke,” said Sean I. Savitz, M.D., professor and the Frank M. Yatsu Chair in Neurology at McGovern Medical School and director of the UTHealth Institute for Stroke and Cerebrovascular Disease. “We were chosen as one of only a handful of referral centers in the nation and patients from all over the country will be referred to our center for this trial. Overall, the study adds to our growing regenerative medicine program for patients with neurological disorders.”

In the double-blind, sham-surgery controlled study, patients randomized to the study intervention will receive a stem cell product made by SanBio and patients must have chronic motor deficits from an ischemic stroke to be eligible for the study. The product, administered through tiny holes bored into the skull and placed near the site of the damage, came from the bone marrow of two healthy adult donors. Enrollment is limited to patients who are between six and 60 months post-stroke and have a chronic motor neurological deficit.

Results of a phase 1/2A study of the stem cell product, presented at the International Society of Stem Cell Research Meeting and published in the journal, Stroke, showed statistically significant improvements in motor function and no safety concerns.

The UTHealth Stroke Program at McGovern Medical School, led by Savitz, is one of the most active research and clinical programs in the country. It was one of the lead sites in the National Institute of Neurological Disease and Stroke’s (NINDS) tPA stroke study; was one of eight centers in the country funded by the NIH to conduct specialized translational research to develop novel acute stroke therapies; and receives NINDS fellowship funding to train the next generation of academic leaders in cerebrovascular disease.

Trigger for autoimmune disease identified

Researchers at National Jewish Health have identified a trigger for autoimmune diseases such as lupus, Crohn’s disease and multiple sclerosis. The findings, published in the April 2017 issue of Journal of Clinical Investigation, help explain why women suffer autoimmune disease more frequently than men, and suggest a therapeutic target to prevent autoimmune disease in humans.

“Our findings confirm that Age-associated B Cells (ABCs) drive autoimmune disease,” said Kira Rubtsova, PhD, an instructor in biomedical science at National Jewish Health. “We demonstrated that the transcription factor T-bet inside B cells causes ABCs to develop. When we deleted T-bet inside B cells, mice prone to develop autoimmune disease remained healthy. We believe the same process occurs in humans with autoimmune disease, more often in elderly women.”

Autoimmune diseases occur when the immune system attacks and destroys the organs and tissue of its own host. Dozens of autoimmune diseases afflict millions of people in the United States. Several autoimmune diseases, including lupus, rheumatoid arthritis and multiple sclerosis strike women two to 10 times as often as men. Overall, about 80 percent of autoimmune patients are women. There is no cure for autoimmune disease.

B cells are important players in autoimmune disease. The National Jewish Health research team, led by Chair of Biomedical Science Philippa Marrack, PhD, previously identified a subset of B cells that accumulate in autoimmune patients, autoimmune and elderly female mice. They named the cells Age-associated B cells, or ABCs. Subsequent research showed that the transcription factor T-bet plays a crucial role in the appearance of ABC.

Transcription factors bind to DNA inside cells and drive the expression of one or several genes. Researchers believe that T-bet appears inside cells when a combination of receptors on B-cell surfaces — TLR7, Interferon-gamma and the B-cell receptor — are stimulated.

Through breeding and genetic techniques the research team eliminated the ability of autoimmune-prone mice to express T-bet inside their B cells. As a result, ABCs did not appear and the mice remained healthy. Kidney damage appeared in 80 percent of mice with T-bet in the B cells and in only 20 percent of T-bet-deficient mice. Seventy-five percent of mice with T-bet in their B cells died by 12 months, while 90 percent of T-bet-deficient mice survived 12 months.

“Our findings for the first time show that ABCs are not only associated with autoimmune disease, but actually drive it,” said Dr. Rubtsova.

ABCs have attracted increasing interests since their discovery in 2011. Dr. Rubtsova and her colleagues at National Jewish Health have expanded their study of ABCs beyond autoimmune disease and are looking at their involvement in sarcoidosis, hypersensitivity pneumonitis and chronic beryllium disease.

Researchers Uncover Key Role for MicroRNA in Inflammatory Bowel Disease

An international team of researchers has discovered that a microRNA produced by certain white blood cells can prevent excessive inflammation in the intestine. The study, “Myeloid-derived miR-223 regulates intestinal inflammation via repression of the NLRP3 inflammasome,” which will be published May 9 in The Journal of Experimental Medicine, shows that synthetic versions of this microRNA can reduce intestinal inflammation in mice and suggests a new therapeutic approach to treating patients with Crohn’s disease or ulcerative colitis.

Inflammatory bowel disease (IBD), including Crohn’s disease and ulcerative colitis, affects almost 2 million people in the US. Although IBD is caused by a complex mix of genetic and environmental factors, it is thought to be initiated by an excessive immune response against bacteria in the gut. This immune response involves the recruitment of various white blood cells, such as neutrophils and monocytes, into the intestine and the activation of a protein complex in these cells known as the inflammasome. The inflammasome, in turn, activates the proinflammatory signaling molecules IL-1β and IL-18, which stimulate the further influx of white blood cells.

MicroRNAs are small RNA molecules that can bind and repress protein-coding messenger RNAs. An international team of researchers led by Eóin McNamee at the University of Colorado-Anschutz Medical Campus found that IBD patients showed increased levels of a microRNA called miR-223 during active bouts of inflammation. This microRNA was also elevated in laboratory mice with colitis.

miR-223 is produced by neutrophils and monocytes and has previously been shown to repress the messenger RNA encoding NLRP3, a key component of the inflammasome. McNamee and colleagues found that mice lacking miR-223 expressed higher levels of NLRP3, causing increased IL-1β production and enhanced susceptibility to intestinal inflammation.

In contrast, mice treated with lipid nanoparticles containing synthetic RNA molecules that mimic miR-223 showed lower levels of NLRP3 and IL-1β and were accordingly protected from experimentally induced colitis.

“Our study highlights the miR-223–NLRP3–IL-1β regulatory circuit as a critical component of intestinal inflammation,” McNamee says. “miR-223 serves to constrain the level of NLRP3 inflammasome activation and provides an early brake that limits excessive inflammation. Genetic or pharmacologic stabilization of miR-223 may hold promise as a future novel therapy for active flares in IBD.”

First-In-Human Clinical Trial Aims to Extend Remission for Children and Young Adults With Leukemia Treated With T-Cell Immunotherapy

Phase 1 pilot study utilizes T-cell antigen presenting cells to prolong the persistence of cancer-fighting chimeric antigen receptor (CAR) T cells, reduce the relapse rate

After phase 1 results of Seattle Children’s Pediatric Leukemia Adoptive Therapy (PLAT-02) trial have shown T-cell immunotherapy to be effective in getting  93 percent of patients with relapsed or refractory acute lymphoblastic leukemia (ALL) into complete initial remission, researchers have now opened a first-in-human clinical trial aimed at reducing the rate of relapse after the therapy, which is about 50 percent. The new phase 1 pilot study, PLAT-03, will examine the feasibility and safety of administering a second T-cell product intended to increase the long-term persistence of the patient’s chimeric antigen receptor (CAR) T cells that were reprogrammed to detect and destroy cancer.

The research team, led by Dr. Mike Jensen at the Ben Towne Center for Childhood Cancer Research at Seattle Children’s Research Institute, is exploring this strategy after discovering that of the patients who relapse in the PLAT-02 trial, about half of them have lost their CAR T cells. Lasting persistence of the CAR T cells is critical in combating a recurrence of cancer cells.

“While it’s promising that we’re able to get these patients who are very sick back into remission, we’re also seeing that the loss of the CAR T cells in some patients may be opening the door for the cancer to return,” said Dr. Colleen Annesley, an oncologist at Seattle Children’s and the lead investigator of the PLAT-03 trial. “We’re pleased to now be able to offer patients who have lost or are at risk of losing their cancer-fighting T cells an option that will hopefully lead to them achieving long-term remission.”

In the PLAT-03 trial, patients will receive “booster” infusions of a second T-cell product, called T antigen-presenting cells (T-APCs). The T-APCs have been genetically modified to express the CD19 target for the cancer-fighting CAR T cells to recognize. Patients will receive a full dose of T-APCs every 28 days for at least one and up to six doses. By stimulating the CAR T cells with a steady stream of target cells to attack, researchers hope the CAR T cells will re-activate, helping to ensure their persistence long enough to put patients into long-term remission.

PLAT-03 is now open to patients who first enroll in phase 2 of Seattle Children’s PLAT-02 trial and who are also identified as being at risk for early loss of their reprogrammed CAR T cells, or those who lose their reprogrammed CAR T cells within six months of receiving them.

The PLAT-03 trial is one of several trials that Seattle Children’s researchers are planning to open within the next year aimed at further improving the long-term efficacy of T-cell immunotherapy. In addition to the current T-cell immunotherapy trial that is open for children with neuroblastoma, researchers also hope to expand this promising therapy to other solid tumor cancers.

“We are pleased to be at a pivotal point where we are now looking at several new strategies to further improve CAR T-cell immunotherapy so it remains a long-term defense for all of our patients,” said Dr. Rebecca Gardner, Seattle Children’s oncologist and the lead investigator of the PLAT-02 trial. “We’re also excited to be working to apply this therapy to several other forms of pediatric cancer beyond ALL, with the hope that T-cell immunotherapy becomes a first line of defense, reducing the need for toxic therapies and minimizing the length of treatment to only weeks.”

To read about the experience of one of the patients in the PLAT-02 trial, please visit Seattle Children’s On the Pulse blog.

The T-cell immunotherapy trials at Seattle Children’s are funded in part by Strong Against Cancer, a national philanthropic initiative with worldwide implications for potentially curing childhood cancers. If you are interested in supporting the advancement of immunotherapy and cancer research, please visit Strong Against Cancer’s donation page.

For more information on immunotherapy research trials at Seattle Children’s, please call (206) 987-2106 or email immunotherapy@seattlechildrens.org.

Biomarker Test for Lou Gehrig’s Disease Useful in Diagnosing Canine Neurodegenerative Disease

Mizzou researchers seek clinical trial participants for further treatment study

In 2009, Joan Coates, a veterinary neurologist, along with other researchers at the University of Missouri and the Broad Institute at MIT/Harvard, found a genetic link between degenerative myelopathy (DM) in dogs and amyotrophic lateral sclerosis (ALS), or Lou Gehrig’s disease in people. Now, MU researchers Coates and Michael Garcia, an associate professor in the Division of Biological Sciences, have found that a biomarker test that helps diagnose ALS also can assist with determining a diagnosis for degenerative myelopathy.

Coates is seeking clinical trial participants to evaluate a treatment for canine DM.

In dogs, DM is an older adult onset disease that can eventually lead to paralysis. The neurodegenerative disease has been confirmed in more than 30 pure bred dog breeds, such as Pembroke Welsh corgis, German Shepherd Dogs and boxers, as well as mixed breed dogs. The current genetic test for DM can be useful to breeders and veterinarians in identifying risk for the disease; however, it has limitations when diagnosing DM.

“DM is a diagnosis of exclusion, meaning that veterinarians must rule out all other diseases that mimic it before coming to a final diagnosis,” said Coates, a professor in the MU Department of Veterinary Medicine and Surgery. “This requires expensive diagnostic procedures such as MRIs of the spinal cord. Now that we know that DM and ALS are related, we are studying ways to diagnose and measure disease progression with similar diagnostic modalities used in ALS patients.”

ALS can be tested using phosphorylated neurofilament heavy proteins (pNF-H) that are released into spinal fluid and blood in humans with ALS. These biomarkers are released during the degeneration of spinal tissues making them a good indicator that ALS is present. Coates and co-principal investigator Garcia tested whether the diagnostic tool could be used in canines.

“I was very excited by the idea that there could be another model that might have many more strength than the existing models,” Garcia said. “So this was a natural fit for me.”

Cerebrospinal fluid and blood samples were collected from DM-affected dogs, including dogs that had a confirmed diagnosis as well as dogs in early stages of the disease. pNF-H concentrations from those samples were compared to samples from age-matched normal dogs and dogs with mimicking diseases.

“We found a significant difference in the DM affected dogs,” Coates said. “pNF-H levels were increased in the cerebrospinal fluid of the DM-affected dogs relative to the control groups, indicating that the human ALS test could be used to diagnose DM. These results will enable us to ‘scale up’ the test to make it more accessible to veterinary community.”

Collecting cerebrospinal fluid from patients is more complicated than a blood test, but is less expensive compared to an MRI to make a presumptive DM diagnosis, Coates said. Nonetheless, pNF-H may serve as a diagnostic tool for diagnosis of DM.

Coates also is conducting clinical trial research for treatment of DM. The goals of the therapies being tested is to slow the progression of neurologic signs of DM and improve quality of life. These therapies are in collaborations with other ALS researchers and funded by the ALS Association and National Institutes of Health. The clinical trials are taking place at the MU Veterinary Health Center (VHC) Small Animal Hospital. To inquire about enrolling a dog, contact Coates at coatesj@missouri.edu.

Collaborations among human health and veterinary clinicians and researchers highlights the multidisciplinary, One Health/One Medicine initiative at Mizzou. The concept is a worldwide strategy for expanding interdisciplinary collaborations and communications in all aspects of healthcare for humans and animals where biomedical research discoveries and expanding the scientific knowledge base lead to faster improvements benefitting both humans and our pets.

The study, “Cerebrospinal Fluid Levels of Phosphorylated Neurofilament Heavy as a Diagnostic Marker of Canine Degenerative Myelopathy,” was published in the Journal of Veterinary Internal Medicine. Christine Toedebusch, a veterinary neurology resident and doctoral candidate, was lead author on the study. The study was funded in part by the American Boxer Charitable Foundation and the American Kennel Club Canine Health Foundation (Grant #2165). The content is solely the responsibility of the authors and does not necessarily represent the official views of the funding agencies.

Engineering Researcher at MSU Helps Design Artificial Lung Device

Children with chronic lung diseases often must wait months or even years for a transplant, while large, immobile hospital equipment that could help them breathe easier actually may worsen their condition by overtaxing already damaged lungs.

Additionally, the required bed confinement can bring about a decline in these young patients’ overall physical and mental states.

At Mississippi State, Greg Burgreen is part of a team at the university’s Center for Advanced Vehicular Systems helping address these critical issues. With a grant from the National Institutes of Health, the associate research professor is working with colleagues at the University of Pittsburgh to develop a more portable breathing device.

Regularly referred to by its acronym, CAVS is a member research center of the university’s High Performance Computing Collaboratory (HPC2) and has developed a global reputation for interdisciplinary education and research to expand and enhance the design, technology, production and infrastructure necessary for sustainable mobility. At HPC2, Burgreen also has access to one of the world’s most advanced supercomputers.

In the project with Pittsburgh, the CAVS team is using computational prototyping to develop digital models of a device called thePediatric Paracorporeal Assist Lung. When fully developed, P-PAL, as it’s known, will be about the size of an average adult fist.

Like larger devices for oxygenating blood cells while removing carbon dioxide, P-PAL will involve tubes connected to the body via either the femoral artery or jugular vein. Though invasive, it will enable patients to be mobile during treatment and enjoy a better quality of life while awaiting lung transplants.

A doctoral graduate in mechanical engineering from Old Dominion University, Burgreen came to CAVS shortly after it opened. Previously, he spent nearly a decade with a Pittsburgh medical research team involved in a national research effort to develop an artificial heart small enough for use in infants and children.

Historically, biomedical devices have been designed and tested using physical models that have been both expensive and time-consuming to create. The rise of computer-based prototyping has made possible significantly faster and cheaper ways to develop a device and simulate operation.

Even with progress made possible by advanced computer-based technologies, Burgreen said the P-PAL project still faces major challenges. “One of the hardest things in this type of research is trying to mimic the sophistication and efficiency of human physiology without causing mechanical damage to blood,” Burgreen said.

Though clinical use by patients remains years away, Burgreen said all involved on the project in Mississippi and Pennsylvania believe P-PAL can be a major therapeutic improvement, if not a full treatment, for children with lung diseases.

“Mississippi State University is helping to improve and prolong the lives of children suffering from lung diseases,” he said.

Three-Week Radiation Therapy Treatment Given Post Mastectomy Is Safe and Effective

Rutgers Cancer Institute of New Jersey research shows low toxicity in shorter treatment course

A shorter course of radiation therapy given to breast cancer patients following mastectomy is safe and effective and cuts treatment time in half. That is according to data from a phase II clinical trial conducted by Rutgers Cancer Institute of New Jersey investigators and other colleagues who examined a hypofractionated regimen given over three weeks versus the traditional six week course of treatment. The work appears in the current online edition of the Journal of Clinical Oncology (http://ascopubs.org/doi/full/10.1200/JCO.2016.70.7158).

When there is a concern that cancer cells may remain in the chest wall and lymph node regions following a mastectomy, a patient may be given targeted radiation over a five to six week period to further treat the breast cancer. “Receiving radiation for that long of a period becomes a quality of life issue for many patients. This includes the inconvenience of frequent travel to the treatment facility, as well as fatigue and other common side effects that can cause lost time at work and other challenges,” notes the work’s senior investigator Bruce G. Haffty, MD, professor and chair, Department of Radiation Oncology at Rutgers Cancer Institute, Rutgers Robert Wood Johnson Medical School and Rutgers New Jersey Medical School.

Researchers explored an accelerated course of radiation that cut treatment time in half. Currently, there is limited data supporting this type of treatment in this patient population.

From 2010 to 2014, 67 eligible patients with stage II to IIIa breast cancer were enrolled at Rutgers Cancer Institute of New Jersey and Huntsman Cancer Institute at the University of Utah. A dose of 36.63 Gy (a unit of radiation measurement) was given in 11 fractions of 3.33 Gy each.  The fractions were delivered over a three-week period to the chest wall and area lymph nodes.  The treatment also allowed for an optional four fractions (3.33 Gy each) of radiation to the chest wall at the mastectomy scar area, resulting in a total of 15 treatments over three weeks.

The aim was to not have any reported treatment toxicities of grade three or above. After a median follow up of 32 months, no grade three toxicities or higher were reported. There were 29 grade two toxicities reported, with a majority being skin rash followed by fatigue, similar to what may be experienced with the longer five to six week course of treatment. The estimated three-year survival rate of the cancer not coming back to the breast area was 89.2 percent.  The estimated three-year survival rate for the cancer not coming back and spreading beyond the breast was 90.3 percent.

“While shorter courses of radiation therapy have been adopted in patients receiving radiation therapy to the breast alone after lumpectomy, there has not been adoption of shorter courses of treatment to the chest wall and lymph nodes after mastectomy. This trial demonstrated the safety of this shorter course approach in a prospective phase II study,” notes Dr. Haffty.

Based on this study, a larger post-mastectomy randomized trial has been developed through the Alliance Cooperative Group with Haffty and current study investigators Matt Poppe of the Huntsman Cancer Institute and Atif J. Khan of Memorial Sloan Kettering Cancer Center leading the effort.  In this phase III trial, a shorter course of radiation in the post-mastectomy, post-reconstruction setting will be compared to the more conventional five to six week course of treatment.

Antidepressant May Enhance Drug Delivery to the Brain

NIH rat study suggests amitriptyline temporarily inhibits the blood-brain barrier, allowing drugs to enter the brain.

New research from the National Institutes of Health found that pairing the antidepressant amitriptyline with drugs designed to treat central nervous system diseases, enhances drug delivery to the brain by inhibiting the blood-brain barrier in rats. The blood-brain barrier serves as a natural, protective boundary, preventing most drugs from entering the brain. The research, performed in rats, appeared online April 27 in the Journal of Cerebral Blood Flow and Metabolism.

Although researchers caution that more studies are needed to determine whether people will benefit from the discovery, the new finding has the potential to revolutionize treatment for a whole host of brain-centered conditions, including epilepsy, stroke, human amyotrophic lateral sclerosis (ALS), depression, and others. The results are so promising that a provisional patent application has been filed for methods of co-administration of amitriptyline with central nervous system drugs.

According to Ronald Cannon, Ph.D., staff scientist at NIH’s National Institute of Environmental Health Sciences (NIEHS), the biggest obstacle to efficiently delivering drugs to the brain is a protein pump called P-glycoprotein. Located along the inner lining of brain blood vessels, P-glycoprotein directs toxins and pharmaceuticals back into the body’s circulation before they pass into the brain.

To get an idea of how P-glycoprotein works, Cannon said to think of the protein as a hotel doorman, standing in front of a revolving door at a lobby entrance. A person who is not authorized to enter would get turned away, being ushered back around the revolving door and out into the street.

“For example, as good as vegetables are for us to eat, they have molecules that could be toxic if they slipped into the brain,” Cannon said. “They don’t get in, because of P-glycoprotein, but this same protector also keeps out helpful therapeutics.”

Cannon and his NIEHS colleagues initially found that amitriptyline significantly reduced P-glycoprotein’s pump activity in brain capillaries from wild-type rats. Later, they saw amitriptyline had the same effect in brain capillaries from genetically modified rats designed to mimic human ALS. In both rat models, amitriptyline turned off P-glycoprotein within 10-15 minutes. When amitriptyline was removed, P-glycoprotein pump activity returned to full-strength.

NIEHS postbaccalaureate fellow David Banks is lead author on the paper and described amitriptyline’s action on P-glycoprotein as rapid and reversible. It’s these advantages that make the therapy so appealing.

“Most inventions developed at the bench don’t make it to the clinic, but I’m hopeful that our findings will translate into better treatment options for doctors and their patients,” Banks said.

Cannon anticipates that administering amitriptyline along with a lower dose of an opioid could relieve pain and reduce the negative side effects, such as constipation and addiction, usually seen with higher doses of prescribed opioids.

“As our nation faces increases in Alzheimer’s disease, autism, and opioid abuse, we’re hopeful that this discovery will help address these serious health challenges,” said NIEHS Director Linda Birnbaum, Ph.D.

Researchers Explore Innovative Therapy for Treatment-Resistant Multiple Myeloma

New clinical trial investigates targeted treatment for incurable form of cancer

A new clinical trial at Baylor Scott & White Research Institute is exploring a novel treatment option for patients with multiple myeloma, a type of cancer formed in bone marrow plasma cells that is considered incurable.

The phase I trial will evaluate Actimab-M, developed by Actinium Pharmaceuticals, Inc., in treating patients with multiple myeloma who are unresponsive to available therapies. Actimab-M targets the CD-33 antigen commonly found on blood cells of myeloid lineage, both malignant and normal. The drug is an antibody that is bound to Actinium 225, a potent radioisotope. It delivers a focal dose of radiation to the target without affecting surrounding cells and tissues.

“Interestingly, we have found aberrant expression of this marker on some lymphoid cancers, including myeloma,” said Yair Levy, MD, director of hematolgic malignancies research at Baylor University Medical Center at Dallas and principal investigator of the trial. “Research has shown its presence in cancer cells of 25 to 35 percent of all multiple myeloma patients, making it a possible target for treatment. In addition, it also predicts for a more aggressive course of disease.”

In this new trial, Actimab-M will be used in patients whose myeloma expresses CD33, and who have progressing disease after at least three prior multiple myeloma therapies.

“Treatments for multiple myeloma have progressed tremendously in the past decade,” Dr. Levy said.  “Unfortunately most patients’ cancer recurs with current treatments and the disease is considered incurable at this time. We are examining the genetic behavior and tendencies of this cancer to hopefully identify new targets for treatment for these patients who experience disease progresses on our current therapies. This is the first trial in the U.S. to open using this method of treatment, taking bench research into the clinic. I am excited to lead the development of this novel approach.”

New Progress Toward Finding Best Cells for Liver Therapy

Study shows transplanted fetal rat liver cells multiply and give rise to new cells in injured adult liver.

In a new study, researchers demonstrate successful transplantation of fetal rat liver cells to an injured adult rat liver. The work is an important step toward using transplanted cells to treat liver failure, which currently requires an organ transplant.

Jennifer Sanders, PhD, assistant professor of pediatrics at Brown University, will present the new research at the American Society for Investigative Pathology annual meeting during the Experimental Biology 2017 meeting, to be held April 22–26 in Chicago.

“There are too few donor livers, so many people die of liver diseases such as hepatitis and cirrhosis without ever getting a transplant,” said Sanders. “Understanding the behavior of fetal liver cells may lead to ways to select the best cells for transplantation into people whose livers are failing.”

In the new study, the researcher removed liver cells from a rat fetus near the end of gestation and transplanted them into an injured adult rat liver. In the new liver, the transplanted cells multiplied for a long period and gave rise to new hepatocytes—the main cell type found in the liver—as well as the cells that form the bile ducts and line the blood vessels. Adult rat liver cells cannot multiply and differentiate after transplantation.

“Most previous studies have used very immature fetal rat cells and have not attempted to characterize the cell population prior to transplantation,” said Sanders.  “We are using late-gestation fetal rat hepatocytes that can carry out many of the functions of adult liver cells, and we characterized the cells based on expression of markers on their surface.”

To better understand how fetal and adult hepatocytes differ, the researchers examined proteins called histones that regulate DNA structure. They identified histone differences that may allow the fetal cells to grow and survive when transplanted into an injured adult liver.

“Our prior studies have shown that fetal rat hepatocyte proliferation, growth and gene-expression regulation are different than in adult rat hepatocytes,” said Sanders. “This has led us to believe that maintenance of DNA structure is very important for the behavior of fetal rat hepatocytes and the ability of these cells to repopulate an injured adult liver.”

In addition to this work’s implications for cell-based liver therapies, better understanding of how DNA structure, gene expression and protein function are regulated together in the normal fetal liver cell could help scientists understand the events that lead to liver cancer.

As a next step, the researchers are working to determine how the adult liver environment affects transplanted fetal cells. They want to find out whether transplanted fetal cells differentiate in a way that makes them indistinguishable from normal adult hepatocytes.

Maternal High-Fat Diet May Increase Offspring Risk for Liver Disease

Research could uncover who is most at risk for nonalcoholic fatty liver disease and lead to new treatments for this increasingly common condition

Nonalcoholic fatty liver disease, a condition where fat builds up in the liver, is now the most common chronic liver disease diagnosed in adults and children. Although the disease is linked with obesity, scientists don’t fully understand why some people develop it and others don’t. Findings from a new mouse study suggest that exposure to a high-fat diet in the womb and immediately after birth may change the liver in a way that promotes more rapid progression of nonalcoholic fatty liver disease later in life.

Michael Thompson, MD, PhD, pediatric endocrinology fellow at Nationwide Children’s Hospital, will present the new research at the American Society for Investigative Pathology annual meeting during the Experimental Biology 2017 meeting, to be held April 22–26 in Chicago.

“Complications of obesity are a significant cost burden for the medical system, especially given the prevalence of obesity,” said Thompson. “Understanding how maternal exposures impact obesity-related disease such as nonalcoholic fatty liver disease will allow us to develop lower cost preventative therapies to utilize up front rather than awaiting complications down the road.”

In the new study, the researchers found that the offspring of pregnant mice that consumed a high-fat diet developed liver fibrosis, a type of tissue scarring that is a sign that more serious disease will develop. The offspring weaned to a low-fat diet after maternal high-fat diet exposure developed fibrosis in adulthood. The livers of these mice also had signs of fat accumulation and inflammation.

The findings showed that developmental exposure to a high-fat diet can produce changes in the liver that last into adulthood, even with consumption of a low-fat diet after birth. These findings could have implications for people who are not obese themselves but who had obese mothers.

Additional analysis showed that bile acid levels and genes involved in bile-acid regulation were changed in the offspring exposed to the maternal high-fat diet. This finding suggests that the offspring may have a liver disease called cholestasis, which occurs when the normal flow of bile is impaired.

“If human offspring from obese mothers have a similar risk for developing fibrosis as we see in mice, we may be able to predict who is going to develop more serious disease,” said Thompson.  “Knowing who is most at risk for more serious disease will guide us on which patients should be treated more aggressively. Furthermore, understanding the biological mechanisms involved in this increased risk could lead to preventative therapies.”

The researchers are now working to further understand the mechanisms involved in the risk for disease progression. They also plan to use their mouse model of developmental high-fat diet exposure to evaluate preventative therapies that could be administered during pregnancy or to the offspring.

The “Geneva Signature” Measures the Safety and Efficiency of a Vaccine Against Ebola Virus Disease

An international team based at Geneva University Hospitals (HUG) and at the University of Geneva (UNIGE), Switzerland, has succeeded in defining a “signature” composed of a small number of inflammatory markers that can be monitored in order to understand how a promising anti-Ebola virus vaccine stimulates the immune system. The researchers inoculated 115 volunteers with either a high dose or a low dose of the rVSV-ZEBOV anti-Ebola vaccine, or with placebo. By analyzing the differences between the three groups, they found that it is sufficient to monitor only 5 substances that are naturally present in the blood in order to define immune responses to the vaccine. The “Geneva rVSV-ZEBOV signature” is published in a scientific paper, in Science Translational Medicine. It’s an easy-to-use equation adding up the concentrations of these 5 substances or markers, most of which are mediated by monocytes, a class of white blood cells known to be active in combatting Ebolavirus in infected individuals. The signature is also expected to inform investigations of safety and immunogenicity of other emerging vaccines.

The 2014–2015 Ebola epidemic affected several countries in West Africa, leading to the death of more than 11’000 people. Although this epidemic of Ebolavirus disease is over, there is no knowing if, when or where another may strike. It is therefore more important than ever to find a reliable vaccine against this deadly disease. Research on vaccines, which was ongoing during the epidemic in West Africa, is now yielding promising results.

Important progress in understanding the vaccine

In an article published on April 12, 2017, in Science Translational Medicine[1], a team from the HUG and the UNIGE, working in collaboration with researchers and clinicians in several other countries in Europe and Africa, has defined a formula that measures the reliability and efficiency of vaccines that might help prevent or limit future outbreaks.

The rVSV-ZEBOV vaccine (recombinant vesicular stomatitis virus–vectored Zaire Ebola vaccine) had already been shown to stimulate the immune system in human volunteers; and in a field trial in 2015 it successfully protected people who had been exposed to Ebola patients from contracting the disease themselves. Yet concerns had been raised during the Geneva trial regarding side effects. What the Geneva team has now published is a detailed examination of the blood plasma of 115 healthy volunteers from Geneva, some of whom received either a low-dose or a high dose of vaccine, while others received a placebo vaccine.

When a vaccine enters the bloodstream, dozens of inflammatory markers that are naturally present see their concentrations change over the next few days. The researchers investigated 15 of them (different varieties of chemokines or cytokines). They found that 1-3 days after the vaccine was administered, the concentration of 6 of these 15 markers had measurably increased. Using a statistical procedure known as principal components analysis, the Geneva team succeeded in producing a simple score that makes the activity of the vaccine much easier to monitor. This “signature” contains only 5 of the 6 markers most likely to change in the presence of the rVSV-ZEBOV vaccine: together, they account for over two-thirds (68%) of the variation in blood cytokine/chemokine activity.

The Geneva Signature found in Gabon

The signature was found to be stronger in volunteers who received the higher dose than in those who got the lower dose.

Importantly, the “Geneva signature” was applied to blood samples from a similar trial that took place in Lambaréné, Gabon, where healthy volunteers had also received the rVSV-ZEBOV vaccine. The same markers were elevated and correlated with side effects and later immunity in the same way.

The 5 markers in the signature are: monocyte attractant protein 1 (MCP-1), the interleukin-1 receptor antagonist (IL-1Ra), tumor necrosis factor (TNF-alpha), interleukin-10 and interleukin-6. Several of these are produced by monocytes or are known to interact with them, so the results imply that monocytes play a critical role in the efficacy and safety of the rVSV-ZEBOV vaccine.

In the case of many other vaccines, such as one recently developed against H1N1 influenza, the chemical markers mostly belong to another category of white blood cells: lymphocytes. Taken together, these signatures help understand how vaccines stimulate the immune system in very different ways to tackle various types of virus. This latest discovery therefore opens up encouraging perspectives for investigating the safety, efficacy and mechanisms of other emerging vaccines.

Study Finds Association Between Specific Gut Bacteria and Colorectal Cancer

Researchers identify less invasive method to detect colorectal cancer

Specific strains of bacteria in the gut are significantly associated with colorectal cancer, according to a new study by researchers at The University of Texas Health Science Center at Houston (UTHealth) School of Public Health. The study, which also identified a less invasive and less expensive way to screen for colorectal cancer, was recently published in the journal Gut.

Colorectal cancer is the second leading cause of cancer-associated death in the U.S., according to the American Cancer Society. Previous studies have found associations between gut bacteria and colorectal cancer, but this is the first to link several studies to identify specific strains and species that are associated with the disease: Parvimonas micra ATCC 33270, Streptococcus anginosus and multiple members of the phylum proteobacteria.

First author Manasi Shah, Ph.D., examined the raw data from nine previous studies of colorectal cancer and the gut. The study cohorts were ethnically diverse, recruited between 2012 and 2016 and the scientists conducting each study used non-uniform laboratory methods. Despite these challenges, Shah established that across the cohorts, specific bacteria were frequently and significantly found in stool samples from patients with colorectal cancer.

“Although previous studies have found associations between the gut microbiome and colorectal cancer, there was little agreement between the results. To our knowledge, our study is the first attempt to gather existing microbial marker gene data and reprocess it uniformly.  Despite differences in cohort demographics, laboratory protocols and downstream analysis, which are known to influence microbiome outcomes, it is encouraging that we found bacterial signals that are consistently and significantly associated with colorectal cancer,” said Shah, who completed the research while she was a doctoral student at UTHealth School of Public Health.

Identifying the bacteria that could serve as biomarkers for the disease is a new method that could be used to screen for colorectal cancer using stool samples, Shah said. This new approach could be less invasive and less expensive than a colonoscopy, which is the most commonly used screening method.

“Microbiome studies offer tremendous potential for advancing diagnostics and therapeutics. For some diseases and conditions, identifying microbiome-based associations has been relatively simple. For the majority, however, the research community is still sifting through a lot of data and a lot of noise as we seek to understand how the microbiome contributes to disease onset, progression and our ability to provide rapid, accurate diagnoses,” said Emily Hollister, Ph.D., senior author and assistant professor of pathology and immunology at Baylor College of Medicine. “The identification of consistent patterns across studies of the colorectal cancer-associated microbiome represents a big step forward in these efforts.”

Microbial markers by themselves could accurately detect colorectal cancer 80 percent of the time. For a subset of the data, when combined with a home-based diagnostic fecal occult to test for blood in the stool, as well as a patient’s age and gender, the new biomarker method could accurately detect colorectal cancer 91 percent of the time.

“In order to discover improved biomarkers and therapeutics based on the microbiome, you must have a strain-focused computational platform able to detect changes in abundance as a disease progresses,” said Todd DeSantis, co-author and vice president of informatics at Second Genome. “This study demonstrated that our platform was unique in that it enabled the identification of important microbiome-based biomarkers.”

Immunotherapy for Glioblastoma Well Tolerated; Survival Gains Observed

A phase one study of 11 patients with glioblastoma who received injections of an investigational vaccine therapy and an approved chemotherapy showed the combination to be well tolerated while also resulting in unexpectedly significant survival increases, researchers at the Duke Cancer Institute report.

Patients treated with the study drug (dose-intensified temozolomide and vaccines) were continuously monitored for toxicity and adverse events. Study patients experienced known side effects with temozolomide, including nausea, lymphopenia, thrombocytopenia and fatigue.

There were no treatment limiting adverse events and no adverse events related to the cellular portion of the vaccine. One patient developed a grade 3 vaccine-related allergic reaction to the GM-CSF component of the vaccine. The patient was able to continue vaccinations in which the GM-CSF was removed and had no subsequent adverse events.

Although the trial was small and not designed to evaluate efficacy, four of the 11 study patients survived for more than five years following treatment with a combination of vaccine and the drug temozolomide, a first-line chemotherapy drug for glioblastoma. That outcome is uncommon for glioblastoma, a lethal brain cancer that has a median survival of nearly 15 months when treated with the current standard of care.

“This is a small study, but it’s one in a sequence of clinical trials we have conducted to explore the use of an immunotherapy that specifically targets a protein on glioblastoma tumors,” said Duke’s Kristen Batich, M.D., Ph.D., lead author of a study published online April 14 in the journal Clinical Cancer Research. “While not a controlled efficacy study, the survival results were surprising, and they suggest the possibility that combining the vaccine with a more intense regimen of this chemotherapy promotes a strong cooperative benefit.”

Batich and colleagues–including senior author John Sampson, M.D., Ph.D., chair of Duke’s Department of Neurosurgery — treated 11 patients as part of a single arm study to test the safety of using a dose-intensified regimen of temozolomide along with a dendritic cell vaccine therapy that selectively targets a cytomegalovirus (CMV) protein. CMV proteins are abundant in glioblastoma tumors, but are absent in surrounding brain cells.

In earlier clinical trials, the researchers used the dendritic cell vaccine to teach T-cells to attack tumor cells, and their data suggested these vaccines could be enhanced when primed by an immune system booster. A separate clinical trial found that higher-than-standard doses of temozolomide, combined with an immune-stimulating factor, also primed the immune system and enhanced the response of a different vaccine target.

The researchers built on those findings in the current study. They used a combination of the dendritic cell vaccine therapy and the immune-stimulating factor, which was administered as injections following dose-intensified regimens of temozolomide. The 11 patients received at least six vaccine treatments.

“Our strategy was to capitalize on the immune deficiency caused by the temozolomide regimen,” Batich said. “It seems counter-intuitive, but when the patient’s lymphocytes are depleted, it’s actually an optimal time to introduce the vaccine therapy. It basically gives the immune system marching orders to mount resources to attack the tumor.”

Batich said the approach significantly slowed the progression of patients’ tumors. Typically, glioblastoma tumors begin to regrow after standard treatment at a median of eight months, but for study participants, recurrence occurred at a median of 25 months.

“These are surprisingly promising clinical outcomes,” Sampson said. “However, it is important to emphasize that this was a very small study that used historical comparisons rather than randomizing patients to two different treatments, but the findings certainly support further study of this approach in larger, controlled clinical trials.”

The research team has received approval to launch a new study that will compare the standard dose of temozolomide vs. the dose-intensified regimen along with the vaccine in glioblastoma patients.

New Method for Tapping Vast Plant Pharmacopeia to Make More Effective Drugs

Cocaine, nicotine, capsaicin.

These are just three familiar examples of the hundreds of thousands of small molecules (also called specialized or secondary metabolites) that plants use as chemical ammunition to protect themselves from predation.

Unfortunately, identifying the networks of genes that plants use to make these biologically active compounds, which are the source of many of the drugs that people use and abuse daily, has vexed scientists for years, hindering efforts to tap this vast pharmacopeia to produce new and improved therapeutics.

Now, Vanderbilt University geneticists think they have come up with an effective and powerful new way for identifying these elusive gene networks, which typically consist of a handful to dozens of different genes, that may overcome this road block.

“Plants synthesize massive numbers of bioproducts that are of benefit to society. This team has revolutionized the potential to uncover these natural bioproducts and understand how they are synthesized,” said Anne Sylvester, program director in the National Science Foundation’s Biological Sciences Directorate, which funded the research.

The revolutionary new approach is based on the well-established observation that plants produce these compounds in response to specific environmental conditions.

“We hypothesized that the genes within a network that work together to make a specific compound would all respond similarly to the same environmental conditions,” explained Jennifer Wisecaver, the post-doctoral fellow who conducted the study.

To test this hypothesis, Wisecaver – working with Cornelius Vanderbilt Professor of Biological Sciences Antonis Rokas and undergraduate researcher Alexander Borowsky – turned to Vanderbilt’s in-house supercomputer at the Advanced Computing Center for Research & Education in order to crunch data from more than 22,000 gene expression studies performed on eight different model plant species.

“These studies use advanced genomic technologies that can detect all the genes that plants turn on or off under specific conditions, such as high salinity, drought or the presence of a specific predator or pathogen,” said Wisecaver.

But identifying the networks of genes responsible for producing these small molecules from thousands of experiments measuring the activity of thousands of genes is no trivial matter. That’s where the Vanderbilt scientists stepped in; They devised a powerful algorithm capable of identifying the networks of genes that show the same behavior (for example, all turning on) across these expression studies.

The result of all this number crunching – described in the paper titled “A global co-expression network approach for connecting genes to specialized metabolic pathways in plants” published online Apr. 13 by The Plant Cell journal – was the identification of dozens, possibly even hundreds of gene pathways that produce small metabolites, including several that previous experiments had identified.

Vered Tzin from Ben-Gurion University’s Jacoob Blaustein Institutes for Desert Research in Israel and Georg Jander from Cornell University’s Boyce Thompson Institute for Plant Research in Ithaca, NY, helped verify the predictions the analysis made in corn, and Daniel Kliebenstein from the Department of Plant Sciences at the University of California, Davis helped verify the predictions in the model plant system Arabidopsis.

The results of their analysis go against the prevailing theory that the genes that make up these pathways are clustered together on the plant genome. “This idea comes from the observation in fungi and bacteria that the genes that make up these specialized metabolite pathways are clustered together,” said Rokas. “In plants, however, these genes appear to be mostly scattered across the genome. Consequently, the strategies for discovering plant gene pathways will need to be different from those developed in the other organisms.”

The researchers argue that the results of their study show that this approach “is a novel, rich and largely untapped means for high-throughput discovery of the genetic basis and architecture of plant natural products.”

If that proves to be true, then it could help open the tap on new plant-based therapeutics for treating a broad range of conditions and diseases.