- Dr. Lipovich lab proving the 'junk' in between genes really matters
In Headlines on September 5, 2012
Leonard Lipovich, Ph.D.
The September 2012 issue of Genome Research includes two articles featuring the work of Leonard Lipovich, Ph.D. and his lab team.
The Encyclopedia of DNA Elements project, or ENCODE, is the international research follow-up to the Human Genome Project.Dr. Leonard Lipovich’s determination to prove genetic matter once deemed “junk” has a place in clinical medicine is bringing the Wayne State University School of Medicine to the forefront of a burgeoning field occupying genome enthusiasts in the United States, Asia and Europe.
The work, on long non-coding ribonucleic acids, or lncRNAs, could lead to new therapeutics for cancer and other diseases.
“Long non-coding RNA genes comprise half of human genes. Most medical, therapeutic work so far has focused on normal, protein-coding genes. So, we – working as part of a multinational team of scientists - have just expanded, twofold, the set of genes that can be therapeutic targets,” he said.
The publication of two groundbreaking articles highlighting results from his lab at WSU’s Center for Molecular Medicine and Genetics is pushing Dr. Lipovich, and his lab’s fellow and graduate students, into the spotlight.
“For many years people pooh-poohed our field, saying that our long non-coding RNAs are either junk, or conventional protein-coding messenger RNAs that we failed to properly understand. We now demonstrate, using an experimental approach, that they are really non-protein-coding (never translated into protein) RNAs in human cells,” said Dr. Lipovich, Ph.D., assistant professor of Molecular Medicine and Genetics and of Neurology.
Dr. Lipovich is a joint last author on a paper on whole-genome translation testing of human lncRNAs, included in the September 2012 issue of Genome Research, the genetics and genomics field’s leading peer-reviewed journal. The September issue is dedicated to the latest phase of results from the Encyclopedia of DNA Elements (ENCODE) Consortium – an international human genomics effort that succeeded the completion of 2001’s Human Genome Project.
The paper sets a new standard for how to integrate RNA data with protein data in a way that has never been done. “My lab, through its computational work here at Wayne, did a vital part of the integration, developing a method that can be used in any future studies that intersect protein and RNA data genome-wide,” Dr. Lipovich said. “Unusual, rare lncRNA-encoded proteins, such as those we found, could be the results of incorrect lncRNA processing by cells in diseased tissues, and hence a huge resource of biomarkers for diagnostics.”
“Long non-coding RNAs are emerging as a huge part of primate, including human-specific, complexity or human phenotypic uniqueness. Yet, they play a critical role in regulating the conserved part of the genome,” said Emily Wood, a WSU Molecular Medicine and Genetics doctoral candidate who served as a second author on the lncRNA translation paper.
“It’s really on the edge of what’s known,” she added, calling the lncRNA field “the wild, wild West” right now.
“There is no unified model of how lncRNAs work,” she said. “We’re really interested in therapeutics in this lab. We’re also not working on a model organism. We’re looking at the activity of the human genome in actual human tissues.”
A National Human Genome Research Institute-funded consortium, international in scope and aided by funding from several countries in Europe and Asia, ENCODE is one of the two major collaborative groups to succeed the completion of the Human Genome Project in 2001, which gave science the ability to read nature's complete genetic blueprint for building a human being.
Abnormal translation – the unusual expression of proteins from RNAs that are not supposed to be protein templates -- clearly has the potential to emerge as a key trend in cancer and autoimmunity research soon, Dr. Lipovich said, and major genomics labs at Harvard Medical School and other top universities are working on complementary aspects of this biological problem.
WSU postdoctoral fellow Hui Jia, Ph.D., in the Lipovich Lab, and WSU Molecular Medicine and Genetics doctoral candidate Will Gundling, during his rotation in the lab last year, also contributed as co-authors of the article, titled “Long noncoding RNAs are rarely translated in two human cell lines.” Dr. Jia is a joint-first author of the paper.
“The energy in the lncRNA community is phenomenal,” Wood said. “It’s a really exciting time to be part of that community. It’s not a science that’s been around forever that we can fine tune. It’s really fun to be a student and be a part of it.”
An additional paper in September’s Genome Research co-written by Dr. Lipovich, “The GENCODE catalogue of human long non-coding RNAs: Analysis of their gene structure, evolution and expression,” presents the most authoritative reference catalog of noncoding-RNA genes ever constructed.
“It will be used by the entire international ENCODE Consortium as a foundation for functional studies linking this exciting new class of RNAs to human health and disease,” said Dr. Lipovich, a middle author on this large, international effort from ENCODE’s Analysis Working Group.
The ENCODE AWG is open to all academic, government and private sector scientists interested in participating in an open process to facilitate the comprehensive identification of the functional elements in the human genome sequence, and who agree to a variety of criteria.
In the GENCODE paper, he and his colleagues found that nearly 5,000 human lncRNAs are not conserved – meaning that there are no similar or identical sequences, in species outside of primates, to these genes. These primate-specific lncRNAs are, hence, absent in mice and other animals. This highlights the limitations of animal models, and the need to study humans to understand human disease, he said. This has major implications for the molecular basis of primate and human uniqueness – which just might be encoded in part by these new RNAs, he said.
Dr. Lipovich also is a member of the Japan-based international research consortium Functional Annotation of the Mammalian Genome, the other leading post-genomic effort. FANTOM, headquartered at the RIKEN (Japan Institute of Physical and Chemical Research) Omics Science Center in Yokohama, analyzes the mammalian transcriptome -- the complete set of all RNA molecules produced in one or a population of cells – using next-generation sequencing.
For FANTOM5, he contributes computational analysis of complex loci and lncRNA network validations. Other member institutions working with RIKEN – and WSU – on this project include Harvard, University of California at Berkeley, Sweden’s Karonlinska Institutet, The Roslin Institute at the University of Edinburgh, Scotland, and the United Kingdom’s Medical Research Council. Dr. Lipovich’s RIKEN collaboration started in 2004, when he joined FANTOM3 while a postdoctoral fellow at the Genome Institute of Singapore.
“WSU earned its ENCODE AWG membership because of the world-class computational genomics that I've been doing in my lab here since 2007 – methods and results that are valued by the FANTOM Consortium in Japan and that through FANTOM exposed us to other valuable collaborators -- such as ENCODE,” Dr. Lipovich said. The Lipovich Lab is the only laboratory in the entire State of Michigan to participate in both FANTOM and ENCODE, a prestigious distinction.
- AMSA presents 'ESCAPE FIRE' documentary Sept. 19
In Headlines on September 5, 2012The Wayne State University School of Medicine chapter of the American Medical Student Association will present an advanced screening of the award-winning documentary “ESCAPE FIRE: The Fight to Rescue American Healthcare” on Sept. 19.
The film will be shown at 5 p.m. in the Margherio Family Conference Center.
“This film has been hailed as ‘An Inconvenient Truth’ for the health care debate, and I’m personally excited about this film because it addresses several fundamental flaws in the current system,” said Taneev Escamilla, a second-year medical student and member of the AMSA’s Community & Environmental Health Action Committee. “This is not a film about political controversy or partisan solutions. It’s about seeking innovation and opportunities to focus on healing patients. If we begin to focus on the health of individuals, at every stage of life, we can change the status of our health care system for good. But in order for this to happen, we need people to understand the issue and the solutions.”
The filmmakers say “ESCAPE FIRE” presents attainable solutions, featuring leaders battling to transform health care at the highest levels of medicine, industry and government.
Food will be served at the halfway point of the movie.
Please RSVP at http://www.surveymonkey.com/s/VCBGYZ7.
For more information about the film, visit http://www.escapefiremovie.com/.
- Researchers say adolescent smoking prevention programs still critical
In Headlines on August 31, 2012
Xinguang Chen, M.D., Ph.D.While many might see the case for programs to prevent adolescent cigarette smoking as already made, a pair of Wayne State University researchers believe that during increasingly challenging economic times policymakers need to be reminded to continue allocating funding for such programs.
Xinguang Chen, M.D., Ph.D., professor of Pediatrics in the WSU School of Medicine, and Feng Lin, Ph.D., professor of Electrical and Computer Engineering in the College of Engineering, have found a way to provide policymakers with hard evidence.
Most adult smokers in the United States report trying their first cigarette before age 18, according to government statistics, with more than 80 percent of established smokers starting before high school graduation. Earlier initiation has been associated with greater smoking frequency and number of cigarettes smoked per day.
Only about 5 percent of established smokers ever quit completely, Dr. Chen said, making prevention in adolescence a critical and strategic priority for tobacco control.
“The number of smokers year to year at any given time is an accumulation of past experience,” he said. “Our methodology has the power to glean that information from one cross-sectional survey, overcoming the limit to track people over time.”
School-, community- and family-based prevention programs have been effective, he said, but evaluating their success at the national level has been a challenge because of the high cost associated with longitudinal data collection and blank groups for comparison.
“We get so much national survey data every year, but we cannot see the real impact of these programs, or get a feeling for the accumulation and meaning of smoking prevention knowledge they pass along,” Dr. Chen said.
In “Exposure to School and Community Based Prevention Programs and Reductions in Cigarette Smoking Among Adolescents in the United States 2000-08,” supported by funding from the National Institute on Drug Abuse of the National Institutes of Health (grant No. R01 DA022730) and published recently in the journal Evaluation and Program Planning, Drs. Chen and Lin describe a methodology and an analytical approach capable of extracting longitudinal information from cross-sectional survey data. Based on a probabilistic discrete event system, the method requires just one wave of data to assess behavior progression. It treats individuals in multi-year cross-sectional surveys as a series of snapshots of a stable system, overcoming the challenges to previous methods.
The research team examined data on children and teens ages 12 to 17 from the National Survey on Drug Use and Health. They found that fewer of those exposed to prevention programs started smoking, more of them quit if they did start and fewer ex-smokers resumed the habit.
WSU researchers also found that state funding cuts in smoking prevention programs from 2003 to 2005 affected those numbers adversely, Dr. Chen said, possibly because less money meant fewer new school and community personnel were trained in how to conduct smoking prevention programs.
Researchers noted a time lag of one to two years between the funding cuts and behavior reversals.
The latter point takes on renewed importance with the beginning of an economic recovery, Dr. Chen said.
Because state spending on prevention has increased slowly since the time of the cuts, he expects smoking startup, quit and relapse numbers to reverse course.
Dr. Chen realizes that policymakers have a number of health-related issues to consider in the funding allocation process, but he said that given the demonstrated, widespread ill effects of smoking on rates of cancer and heart disease, smoking prevention should remain at the top of the priority list because of the health care costs that can be avoided.
“It’s an investment,” he said. “Given the financial difficulties the nation is facing, policymakers should consider the potentially powerful impact offered by relatively low-cost nationwide substance use prevention campaigns.”
- Cancer investigators secure grants through American Cancer Society
In Headlines on August 31, 2012
Aliccia Bollig-Fischer, Ph.D.
Lydia Choi, M.D.
Guojun Wu, Ph.D.
Nicholas Szerlip, M.D.Four Wayne State University researchers have obtained American Cancer Society – Institutional Research Grants of $30,000 each for one year to help fund their research.
The grants are provided annually to four researchers at the School of Medicine and the Barbara Ann Karmanos Cancer Institute.
This year’s winners and their research project titles include:
Aliccia Bollig-Fischer, Ph.D., assistant professor of Oncology, for “Characterization of 5-hydroxymethyl-cytosine in breast cancer.”
Lydia Choi, M.D., breast surgeon and assistant professor of Surgical Oncology, for “Ultrasound tomography for breast imaging.”
Nicholas Szerlip, M.D., assistant professor of Neurosurgery, for “Therapeutic implications of the SUR1/TRPM4 complex: and inducible mechanism of cell death in glioblastomas.”
Guojun Wu, Ph.D., assistant professor of Oncology and the Breast Cancer Biology Program, for “The role of PDGFRs in Foxq1 induced stem cell states and breast cancer metastasis.”
American Cancer Society ACS-IRG funds provide seed money to support junior faculty members with an interest in cancer research who do not have national grant support. Investigators must be an assistant professor or equivalent and must be within six years of their first independent faculty appointment to be eligible for the grants.
- Dr. Kim named Educator of Year by Association of Radiation Oncology Residents
In Headlines on August 30, 2012
Harold Kim, M.D., receives the AROR Educator of the Year award from his residents.The Association of Radiation Oncology Residents has named Harold Kim, M.D., associate professor of Radiation Oncology for the Wayne State University School of Medicine, an Educator of the Year for 2012.
“Because I have the utmost respect for my peers and hold them in the highest regard, I am humbled to accept the honor of Educator of the Year by the Association of Radiation Oncology Residents,” said Dr. Kim, who joined the School of Medicine in 1995.
Nominations for the award were submitted by residents in radiation oncology programs around the country. A total of 49 recipients were selected.
“As a teacher, I most enjoy watching the residents grow professionally and develop confidence in their knowledge and ability to treat patients,” Dr. Kim said.
Members of the Radiation Oncology residency program presented the award to Dr. Kim during the June 8 resident graduation dinner.
“Dr. Kim is a dedicated faculty member and has mentored a number of students this year to successful national presentations as well as first author peer-reviewed publications,” said Andre Konski, M.D., M.B.A., M.A., F.A.C.R., professor and Chair of Radiation Oncology, and winner of the same award in 2010.
- Dr. LoRusso featured in Sept. 7 Stand Up To Cancer primetime fundraiser
In Headlines on August 29, 2012
Dr. LoRusso with Karmanos melanoma patient Hillary Kind.
Filming a segment at the Karmanos Cancer Center for the Sept. 7 Stand Up To Cancer primetime special are Dr. LoRusso; Lawrence Flaherty, M.D.; and Cynthia Marsack, M.S.N., R.N.Patricia LoRusso, D.O., professor of Oncology at Wayne State University School of Medicine and director of Phase I Clinical Trials and the Eisenberg Center for Experimental Therapeutics at the Barbara Ann Karmanos Cancer Institute, will be featured in the Stand Up To Cancer primetime fundraising telecast airing live Sept. 7, from 8 to 9 p.m.
Dr. LoRusso is co-leader of the Stand Up To Cancer-Melanoma Research Alliance Melanoma Dream Team.
SU2C is a program of the Entertainment Industry Foundation, the 501(c)(3) not-for-profit organization that serves as the collective philanthropy for the television and film businesses. EIF has distributed hundreds of millions of dollars to support programs addressing critical health, education and social issues. EIF created SU2C, a collaboration to build public support for groundbreaking translational research accelerating the delivery of new therapies to patients, getting them from the “bench to the bedside” as quickly as possible. The scientific partner of SU2C is the American Association for Cancer Research, the world’s largest professional organization dedicated to advancing cancer research. SU2C brings together scientists from different disciplines across the nation’s various institutions to collaborate on innovative cancer research.
Dr. LoRusso co-leads the SU2C-Melanoma Research Alliance Melanoma Dream Team with Jeffrey Trent, Ph.D., of Translational Genomics Research Institute in Phoenix, Ariz. They’re developing personalized therapies for individuals with highly aggressive BRAF wild-type metastatic melanoma. There are few current treatment options for patients with this disease.
Dr. LoRusso will be among the Dream Team leaders attending the Sept. 7 SU2C primetime special in Los Angeles. It will air nationally, commercial-free and simultaneously, on ABC, CBS, FOX and NBC, as well as on numerous cable networks both nationally and internationally. Dr. LoRusso and some of her patients, along with Karmanos staff, will be showcased in an inspirational segment during the television program.
This is the third SU2C primetime special since 2008. It will be viewed in approximately 190 countries and involve numerous celebrities/performers who are donating their services for this global fundraising event. All donations received will go toward cancer research.