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DSB Retreat
Members of the Dennis Vitkup Lab, from l to r: Konstatine Tchourine, German Plata and Jon Chang (Credit: Sandra Squarcia); Photo Gallery of the retreat.

Innovative research projects were highlighted at the Department of Systems Biology’s annual retreat, held October 5, at Wave Hill Public Garden and Cultural Center in Riverdale, NY. The retreat, attended by 160 faculty, staff, post-doctoral scientists, students and guests, also provided an opportunity for young investigators to showcase their work during a poster competition. 

Andrea Califano , Dr., chair of the department, opened the day’s sessions with welcome remarks, as the retreat also served as a site visit by the National Cancer Institute for the Columbia University Center for Cancer Systems Therapeutics (CaST) . CaST, co-directors Drs. Califano and Barry Honig , vice-chair of the department, was established in 2016 as one of the key centers in the NCI’s Cancer Systems Biology Consortium (CSBC). The initiative behind CSBC is heavily grounded on innovation—bringing together interdisciplinary teams of clinical and basic cancer researchers with physical scientists, engineers, mathematicians and computer scientists who collaborate to tackle major questions in cancer biology from a novel out-of-the-box point of view. 

October 10, 2018

Q+A with Dr. Laura Landweber

Oxytricha

Oxytricha. (Credit: Bob Hammersmith)

Laura Landweber, PhD, loves a challenge. So it’s no surprise that she has built a scientific career unraveling the hows and whys of a unique single-cell organism known for its biological complexity.  

An evolutionary biologist whose work sits at the interface of genetics and molecular biology, Dr. Landweber, for nearly 20 years, has focused much of her research on Oxytricha trifallax , a microbial organism that is prevalent in ponds, feeds on algae and has a highly complex genome architecture, making it an attractive, albeit challenging, model organism to study. Compared to humans, with 46 chromosomes containing some 25,000 genes, Oxytricha is known to comprise many thousands of chromosomes, in the ballpark of 16,000 tiny “nanochromosomes”. Yet not only is it complex in sheer numbers of chromosomes but the information carried in those individual chromosomes can be scrambled, like information compression, and the process of development in Oxytricha must descramble this information so that it can be converted into RNA and proteins.

“DNA can be flipped and inverted in Oxytricha and the cellular machinery actually knows how to restore order,” says Dr. Landweber. “Hence, it’s this wonderful paragon for understanding genome integrity and the maintenance and establishment of genome integrity.” 

Even more perplexing, in cell division, Oxytricha reproduces asexually when it wants to produce more in number, and it reproduces sexually when it needs to rebuild its genome. It also has the ability to “clean up” its genome, so to speak, eliminating nearly all of the non-coding DNA, or so-called junk DNA. Much of why Oxytricha presents such an intricate genomic landscape remains a mystery, and for Dr. Landweber, the leading expert on this single-celled protist, that wide-open field for potential discovery is what got her hooked. 

Scientists stunted the puberty of male worms by starving them before they underwent sexual maturation. In the study, published in Nature and led by Oliver Hobert,PhD, researchers suggested that stress from starvation even days before sexual maturation prevented normal changes in the wiring patterns of key neuronal circuits, which caused adult male worms to act immature.

“We found that environmental stress can permanently and profoundly impact the connectivity of a developing nervous system,” said Dr. Hobert, professor of biological sciences at Columbia University and a faculty member of the Department of Systems Biology.

The researchers’ results also suggested that these responses to stress were, in part, controlled by serotonin, a neurotransmitter associated with depression in humans.

Initially, Emily Bayer, a graduate student in the Hobert Lab and co-author of the work, stressed out immature worms when she accidentally left them unattended for a few weeks. This caused the worms to pause their normal growth and enter what scientists call a “dauer state.”

Eventually, Bayer returned the worms to their normal environment and let them grow into adults. After examining the nervous systems of stressed worms, she noticed something unusual. Normally, some of the neuronal connections in the males’ tails are eliminated, or pruned, during sexual maturation. Instead, she found that immature connections in the stressed worms remained. Follow-up experiments suggested that this was strictly caused by starvation and no other forms of stress – such as heat – could have caused the dauer state.

“I was totally surprised. In fact, I never thought stressing the worms out would matter,” said Bayer. 

She also found that starvation before sexual maturation caused male adult worms to act immaturely during behaviors known to be controlled by these circuits. Unlike normal adult males, the stressed worms were highly sensitive to a noxious chemical called SDS. Stressed worms swam away from SDS while normal males barely responded. The stressed worms also had problems mating. Specifically, they spent much less time in contact with hermaphrodite worms than normal males.

Judith in the lab
Judith Kribelbauer

As a child growing up in a small town in Germany, Judith Kribelbauer excelled in science, counting chemistry and mathematics as her two favorite subjects from grade school through high school. After high school graduation, she attended the Ruprecht-Karls University in Heidelberg to pursue a bachelor’s degree in chemistry, which she completed in 2012. 

Becoming more serious about pursuing scientific research, Kribelbauer, who is graduating this May with a PhD in the Systems Biology Integrated Program, moved to the U.S. to work as a graduate exchange student at the University of North Carolina-Chapel Hill (UNC) before enrolling at Columbia University in 2013. At UNC, using SHAPE-MaP sequencing technology, she researched the structural basis of the HIV-1 RNA frame-shift element, a sequence that causes ribosomes to shift reading frames, therefore producing truncated proteins.  

Columbia’s collaborative environment—the chance to work with researchers spanning areas from biology to chemistry and physics to computer science—is what drew her to the University and ultimately to concentrating in systems biology. 

“Thanks to this unique environment, I could realize my dream research project—combining both experimental and computational approaches,” says Kribelbauer. “This comprehensive training allowed me to conduct my thesis research in two labs, with both PhD advisers having appointments in Systems Biology.”

Harmen and Tuuli
Harmen Bussemaker (left) and Tuuli Lappalainen

Harmen Bussemaker, PhD, and Tuuli Lappalainen, PhD, have received an inaugural Roy and Diana Vagelos Precision Medicine Pilot Award for a collaboration that will bridge quantitative genetics and mechanistic biology to obtain a mechanistic understanding of regulatory effects of genetic variants in humans.

Drs. Bussemaker and Lappalainen, both faculty in Columbia’s Department of Systems Biology, represent one of three winning proposals out of a pool of 56 applications. Their project titled, “Elucidating the tissue-specific molecular mechanisms underlying disease associations through integrative analysis of genetic variation and molecular network data”, will help to advance Columbia University’s efforts in precision medicine basic science research. 

As reported by Columbia Precision Medicine, the investigators’ research objectives include: to dissect the molecular mechanisms underlying tissue-specificity of genetic regulatory variants and to map network-level regulatory variants that cause protein-level transcription factor (TF) activity to vary between individuals. The investigators will infer TF activity based on DNA binding specificity models of human TFs, and use it as a tissue-specific parameter of the cellular environment. They will also map trans-acting genetic variants that affect TF activity (coined ‘aQTLs’ by one of the investigators) in each tissue. The investigators hope to elucidate which transcription factors are driving the functional impact and tissue specificity of any particular eQTL, genomic loci that contribute to variation in gene expression levels. 

Faculty

Laura Landweber

Professor, Biochemistry and Molecular Biophysics, and Biological Sciences

Professor, Biochemistry and Molecular Biophysics, and Biological Sciences

Faculty

Guy Sella

Associate Professor, Department of Biological Sciences

Associate Professor, Department of Biological Sciences

Faculty

Molly Przeworski

Professor, Department of Biological Sciences

Professor, Department of Biological Sciences

Faculty

Brent Stockwell

Professor, Departments of Biological Sciences and Chemistry
Co-director, High-Throughput Screening

Faculty

Harmen Bussemaker

Professor, Department of Biological Sciences

Professor, Department of Biological Sciences