Eleazar Eskin, professor of computer science in the UCLA Samueli School of Engineering, has been named one of four 2019 fellows by the International Society for Computational Biology. The fellows program was created to honor members who have distinguished themselves through outstanding contributions to the fields of computational biology and bioinformatics.
Eskin, who is also a professor of human genetics in the David Geffen School of Medicine at UCLA, works on computational problems in human genetics, especially human diseases. He has developed advanced educational programs for computer scientists, biologists and statisticians in computational biology. He has been involved in leadership activities at the National Science Foundation’s Institute for Pure and Applied Mathematics at UCLA and as part of the new UCLA bioinformatics doctoral program.
In 2009, the International Society for Computational Biology board of directors began the fellows program by naming the winners of its accomplishment by a senior scientist award as the first fellows. The program is now in its 10th year. Each year since 2010, the society has sought fellows nominations from the organization’s members, with eligibility restrictions based on selection criteria focused most heavily on the significance of scientific contributions, and service to the field of computational biology and to the organization.
A team of UCLA-led scientists has discovered important clues to what goes wrong in the brains of people with autism — a developmental disorder with no cure and for which scientists have no deep understanding of what causes it.
The new insights involve RNA editing — in which genetic material is normal, but modifications in RNA alter nucleotides, whose patterns carry the data required for constructing proteins.
“RNA editing is probably having a substantial physiologic effect in the brain, but is poorly understood,” said co-author Dr. Daniel Geschwind, UCLA’s Gordon and Virginia MacDonald distinguished professor of human genetics, neurology and psychiatry and director of UCLA’s Institute for Precision Health. “RNA editing is a mysterious area whose biological implications have not been much explored. We know what only a handful of these RNA editing sites do to proteins. This study gives a new critical clue in understanding what has gone awry in the brains of autism patients.”
More than 24 million people worldwide are estimated to have autism. In developed countries, about 1.5 percent of children have been diagnosed with autism spectrum disorder as of 2017. The disorder affects communication and behavior, and is marked by problems in social communication and social interaction, and repetitive behaviors.
“We need to understand how a panoply of genetic and environmental factors converges to cause autism,” Geschwind said. “RNA editing is an important piece of the autism puzzle that has been totally under-appreciated.”
The researchers analyzed brain samples from 69 people who died, about half of whom had autism spectrum disorder (which includes autism and related conditions), and about half of whom did not and served as a control group.
Xinshu (Grace) Xiao, the senior author of the research and UCLA’s Maria R. Ross professor of integrative biology and physiology, and her research team analyzed seven billion nucleotides for each brain sample.
Xiao’s team discovered reduced editing in the group members with autism. Specifically, they identified 3,314 editing sites in the brain’s frontal cortex in which the autism patients had different levels of RNA editing from the control group. In 2,308 of those sites, the individuals with autism had reduced RNA editing, said lead author Stephen Tran, a graduate student in UCLA’s bioinformatics interdepartmental program who works in Xiao’s laboratory. In the 1,006 others, they had increased levels of RNA editing, he added.
In the brain’s temporal cortex, the people with autism had different levels of RNA editing from the control group in 2,412 editing sites, with 1,471 of those sites showing reduced editing levels, Tran said. In the brain’s cerebellum, the autism group members had different levels of RNA editing from control group members in 4,340 sites, of which 3,330 sites in the autistic brain had decreased levels. All three of these brain regions are very important in autism.
Xiao said RNA editing can be thought of as RNA mutations, analogous to the DNA mutations that are linked to many diseases.
“The same piece of DNA can generate multiple versions of RNA, and possibly lead to different protein sequences,” said Xiao, director of UCLA’s bioinformatics interdepartmental graduate program. “RNA editing allows cells to create novel protein sequences that are not written in the DNA.”
Scientists had long assumed that a sequence of RNA is a faithful copy of a gene’s DNA sequence — and that RNA is merely the cellular messenger that carries out DNA’s instructions to other parts of the cell. “This assumption was proved to be wrong when RNA editing was first discovered in the 1980s,” Xiao said, “and we are finding many examples where the genetic codes we inherit from our parents are edited in our cells.”
In another major finding, the researchers identified two proteins, called FMRP and FXR1P, that regulate abnormal RNA editing in autism spectrum disorder. FMRP increases RNA editing and FXR1P decreases RNA editing, Tran discovered. The autism group had reduced editing levels regulated by FMRP, as well as reduced RNA editing overall.
“This is the first strong data showing a broad and direct functional role for FMRP and FXR1P in the human brain and autism,” Xiao said.
“Something about what FMRP does is clearly critical to autism pathogenesis,” Geschwind said. “Grace and her team show that these two related proteins are likely responsible for the reduced RNA editing, as well as the occasional increased RNA editing.”
It is currently unknown, he said, whether the changes the people with autism had in RNA editing caused their autism, contributed to the disorder or were a result of it. “We can’t assign causality,” said Geschwind, who praised the research of Xiao’s team as “elegant and brilliant.”
RNA editing may also be disrupted in schizophrenia, bipolar disorder and major depression. The research team plans to continue to study this as well as other brain diseases.
Xiao and Tran replicated their findings by analyzing the frontal cortex from a different group of 22 people who had autism spectrum disorder and a control group of 23 without the disorder. They found the same pattern of editing reduction as they found originally, Tran said.
The researchers found RNA editing alterations in genes of critical neurological relevance to autism, including CNTNAP2 and CNTNAP4, NRXN1 and NRXN3, ANK2, NOVA1 and RBFOX1.
Xiao and Tran used powerful methods of bioinformatics and statistics to identify the RNA editing sites, including a method similar to GIREMI that Xiao designed in 2015 with Qing Zhang, a former postdoctoral scholar in her laboratory.
In searching for causes of diseases, most research has focused on searching for mutations in the DNA. “What was missing, until recently,” Xiao said, “is to look for RNA mutations that are not coded in the DNA. These changes in the RNA could have similar impact as DNA mutations.”
This study may eventually lead to new treatments for autism, but likely not for many years, the researchers said.
Other co-authors are listed in the journal article.
Funding sources for the research include the National Human Genome Research Institute, National Institute of Mental Health (both institutes are part of the National Institutes of Health) and the Simons Foundation Autism Research Initiative.
Lawrence Zipursky, distinguished professor of biological chemistry in the David Geffen School of Medicine at UCLA, will be honored with the 19th Perl-UNC Neuroscience Prize by the University of North Carolina School of Medicine for the discovery of cell-surface proteins that control circuit assembly in the visual system.
Established in 2000, the Perl-UNC Neuroscience Prize is well known among biomedical scientists. Six of its previous winners went on to win the Nobel Prize in physiology or medicine or the Nobel Prize in chemistry.
Zipursky shares the award with Joshua Sanes, the Jeff C. Tarr Professor of Molecular and Cellular Biology and the Paul J. Finnegan Family Director of the Center for Brain Science at Harvard University. The two researchers will visit Chapel Hill in March to deliver a lecture on their work and receive a $20,000 award.
Working with fruit flies, Zipursky discovered the Down Syndrome Cell Adhesion Molecule 1, known as Dscam1, family of cell recognition molecules. The Dscam1 family has thousands of members that can provide individual neurons with a specific surface marker. These proteins allow each type of nerve cell to avoid making connections with itself as it forms connections with other nerve cells. This process of “self-avoidance” has emerged as a key mechanism for determining how patterns form in the neural circuits of both flies and mammals.
“It is incredibly gratifying to have my work acknowledged by the Perl-UNC Prize,” Zipursky said. “I am particularly indebted to the students, postdoctoral fellows, and collaborators whose creativity, hard work and persistence led to the surprising discoveries for which I am being honored.”
Zipursky, the Jerome J. Belzer Chair of Medical Research and a Howard Hughes Medical Institute Investigator, earned his doctorate in molecular biology at the Albert Einstein College of Medicine and conducted postdoctoral work at the California Institute of Technology before joining UCLA in 1985.
This award recognizes Ping’s decades of accomplishments in proteomic sciences, which are the large-scale study of proteins and which represent advances to all of biology. Ping shared the award with Bernd Bodenmiller of the University of Zurich, Switzerland.
Ping is internationally recognized for her expertise in mitochondrial biology, data science, proteomics and computational analytical platforms in cardiovascular diseases. Her team in Ping Research Program at UCLA develops data science methods and analytical approaches to better understand how protein dynamics orchestrate higher physiological functions in normal and diseased hearts.
The Human Proteome Organization is an international scientific organization representing and promoting proteomics through international cooperation and collaborations by fostering the development of new technologies, techniques and training.
Weizhe Hong, an assistant professor of biological chemistry and neurobiology at the David Geffen School of Medicine at UCLA, is one of 18 outstanding young scientists to be awarded the Packard Fellowships for Science and Engineering for 2018.
Hong’s laboratory seeks to understand how animals, including humans, exhibit a broad range of complex social interaction that are crucial to their survival and well-being. Hong and colleagues use optogenetics, imaging, genomics and machine learning to study how networks of neurons in the brain control social behaviors and how those networks become disturbed in disorders such as autism spectrum disorder.
Packard fellowships, which are presented by the David and Lucile Packard Foundation, enable the nation’s most promising early-career professors to pursue science and engineering research with few funding restrictions and limited reporting requirements.
“By providing the freedom for brilliant young scholars to pursue new frontiers in science, this prestigious award will allow Weizhe Hong to further explore and expand our understanding of how the brain works,” said Dr. Kelsey Martin, dean of the Geffen School of Medicine. “This type of scientific exploration can eventually lead to the development of new treatments for a range of neurological and psychiatric disorders.”
The fellowships, which were established in 1988, are among the nation’s largest non-governmental fellowships. Nominees are put forward by 50 university presidents, and recipients are chosen by an advisory panel of scientists and engineers reviews. The grants are worth $875,000 over five years.
Hong joined UCLA in 2016 after completing a Helen hay Whitney postdoctoral fellowship at the Caltech and earning a doctorate from Stanford University. He also has received a Klingenstein-Simons Fellowship Award, in 2018; and a Searle Scholar Award and Alfred P. Sloan Foundation research fellowship, both in 2017; among other honors.
“It really is amazing to see what brilliant researchers can do when given the room to take big risks,” said Frances Arnold, chair of the Packard Fellowships advisory panel, in a statement. “And I’m not only talking about their impressive contributions to their fields — I’m also talking about building entirely new disciplines and giving back to the next generation of scientists.”
Xinshu Grace Xiao is the new Director of the Bioinformatics Interdepartmental Ph.D. Program, appointed by the Deans of Life Science and the School of Medicine. Grace has an impressive record combining computational and experimental approaches to study fundamental problems in RNA processing and regulation. Her long-standing commitment to the Bioinformatics IDP and her interdisciplinary training and research make her an exceptional choice to lead the program.
Grace received her undergraduate degree from Tsinghua University, an M.S. in Mechanical Engineering from M.I.T. and a Ph.D. from the Division of Health Sciences Technology at M.I.T. Following postdoctoral research in the Department of Biology at M.I.T., she joined the Department of Integrative Biology and Physiology here at UCLA where she is now a full professor. She has been an integral member of the Bioinformatics IDP, serving on the Executive Steering Committee, the Curriculum Committee, and as a member and Chair of the Student Advising Committee.
Grace takes over leadership of a program that has grown to become a major Bioscience Ph.D. program at UCLA, nationally recognized for integrated training in big data at the interface of computer science, mathematics, statistics, biology, and biomedicine. Under the prior Directors, Chris Lee and Yi Xing, the program has become a pillar of the vibrant and growing data science community at UCLA. Grace brings interdisciplinary experience and vision to build on this foundation and advance the Bioinformatics IDP as a premiere training program.
On April 12, 2018, Johnson & Johnson named the six winners of their Women in STEM²D Scholars Award. This award “supports women at significant points in their research careers in the disciplines of Science, Technology, Engineering, Math, Manufacturing and Design (STEM²D)”.
UCLA Bioinformatics IDP Faculty Member, Jingyi Jessica Li was announced as the winner in the field of Math. We are very proud to have her as part of the Bioinformatics IDP faculty and congratulate her on this accomplishment.
On Wednesday, June 7, faculty, staff, and undergraduates began a new tradition for the UCLA Bioinformatics Minor Program. Prof. Eleazar Eskin, chair of the Minor Program, hosted the first annual Bioinformatics Minor End-of-Year Celebration to recognize and celebrate undergraduates who completed the requirements for the Minor.
This year, Bioinformatics IDP PhD students Kikuye Koyano and Artur Jaroszewicz organized the retreat at the University of Southern California’s Wrigley Marine Science Center in Two Harbors, 20 miles offshore from Los Angeles.
During the 3-day retreat, Bioinformatics IDP graduate students presented research papers and held forums on applying for fellowships, writing letters of intent, managing graduate school funding packages, and using campus mental health resources. In addition to science, faculty and students enjoyed hiking the chaparral hills, kayaking in the bay, snorkeling in the kelp forest, and enjoying dinner overlooking the beach in Two Harbors.