Five VP&S Scientists Receive Schaefer Scholar Awards

Five scientists at Columbia University Vagelos College of Physicians and Surgeons have received awards from the Schaefer Research Scholars Program, made possible through a bequest from Dr. Ludwig Schaefer. Each award consists of a $50,000 cash prize and up to $200,000 in direct research support.

Two awardees are full-time VP&S faculty and three are visiting faculty who are collaborating with VP&S faculty:

• Chao Lu, PhD, assistant professor of genetics & development, Columbia University Vagelos College of Physicians and Surgeons
• Mijo Simunovic, PhD, assistant professor of chemical engineering, Columbia Stem Cell Initiative
• Jacqueline M. Gulbis, PhD, laboratory head and senior research scientist, Walter and Eliza Hall Institute of Medical Research, Australia
• Tomer Hertz, PhD, associate professor of microbiology, immunology & genetics, Ben-Gurion University of the Negev, Israel
• Robert Tampé, PhD, professor of biochemistry and biophysics and director of the Institute of Biochemistry, Goethe University, Germany

Each year the Schaefer Scholars program presents awards to research scientists who have distinguished themselves in the science of human physiology and whose current work is of outstanding merit with significant academic distinction.

The new Schaefer Scholars, along with previous recipients, will be honored at a reception on June 21.

Read below for project descriptions.

Chao Lu, PhD

Project: "Reversal of the epigenetic clock for anti-aging therapy"

Biological age and chronological age are not always equal, with some individuals showing the effects of age years earlier than others with the same birthdays.

In the past decade, the epigenetic clock (a measurement of age-related DNA methylation changes) has become a popular marker of biological aging and is used in several clinical trials. However, it is still unknown if a faster epigenetic clock causes biological aging, due in large part to the lack of experimental methods to perturb the clock.

Recent findings by Chao Lu's group suggest that NSD1, one of the proteins that regulate DNA methylation, is a major determinant of the epigenetic clock and can be manipulated to control the pace of the clock for the first time.

In his Schaefer project, Lu will first determine if loss of NSD1, which is expected to accelerate the epigenetic clock, has any effect on biological aging and, if so, will attempt to slow the biological aging by increasing NSD1 levels through genetic and pharmacological approaches.

The work, in collaboration with two other VP&S investigator (Chaolin Zhang, PhD, and Yousin Suh, PhD), may unveil a new therapeutic approach for aging and age-related diseases.

Mijo Simunovic, PhD

Project: "Modeling embryogenesis with stem cells: a new frontier in studying human development"

The first days of mammalian development are veiled in mystery because the process cannot be observed. Mijo Simunovic has begun to make inroads and was among the first to use pluripotent stem cells to create an experimental model of post-implantation development, taking part in shaping a new field of stem cell research.

However, early development critically depends on the placenta-uterine crosstalk and currently no experimental system exists that mimics the implantation interface. Simunovic has recently developed a way to model the human endometrium in vitro by combining stem cell biology with tissue engineering, setting the stage for the development of a novel organoid platform that models uterine implantation.

Simunovic's organoid platform will help open a mechanistic window into early post-implantation development, accelerate our understanding of how the placenta forms, and hopefully allow investigators to map the molecular signatures of the first stages of pregnancy.

If successful, the simplified in vitro system will offer a visual glimpse of the long-elusive embryo-maternal first contact and may lead to a better understanding of placental and uterine impairments that are the leading causes of infertility, recurrent pregnancy loss, and many other serious obstetric disorders.

Jacqueline M. Gulbis, PhD

Host: Henry Colecraft, PhD, Department of Physiology & Cellular Biophysics

Project: "A pathway from discovery to treatment of Kir4.1-linked disease"

In aggressive brain cancer (glioblastoma multiforme), cancer cells escape the primary tumor and rapidly infiltrate both hemispheres of the brain to seed new tumors.

At Columbia, Jacqueline M. Gulbis will build on her previous research to test a way of impeding the migration of brain cancer cells that could improve the effectiveness of surgery and radiation, the mainstays of current treatment.

The work centers on Kir4.1 potassium channels that are central to the invasiveness of brain cancer cells. When Kir4.1 currents are reduced, the cell membranes depolarize. This drives invasion by increasing the capacity of cancer cells to migrate and also allows the cells to pass more readily through brain tissue.

Recent work by Gulbis on Kir channels has transformed understanding of K+ channel control mechanisms and is opening doors to the development of therapeutics for brain cancer.

Gulbis, with the help of a technology pioneered by Colecraft and the expertise of Columbia's Center of Membrane Protein Production and Analysis, will test a strategy to reinstate the resting cell membrane potential in brain cancer cells, a critical first step in restoring normal physiology and reducing invasive behavior.

The findings also may lead to new treatments for epilepsy and other neurological disorders involving impaired Kir4.1 channels.

Tomer Hertz, PhD

Host: Donna Farber, PhD, chief of the Division of Surgical Sciences, Department of Surgery

Project: "Characterizing tissue specific antibody repertoires"

Individuals generate varied immune responses to vaccine and natural infections that can have critical effects on clinical outcome.

Upon exposure to a pathogen, the immune system's B cells are activated to produce antibodies, and memory B cells are generated to respond to future exposures of the same pathogen. B cells are found in multiple tissue sites, including lymphoid organs (lymph nodes, spleen) and mucosal sites such as lungs and intestines, but it is unclear if B cells at one site are specific against certain pathogens that are unique to a site or if B cells are disseminated across multiple tissues and the circulation.

Tomer Hertz will utilize the tissue repository created by Donna Farber and apply his novel antibody profiling technology to answer this question across different human tissues in adults and children.

These studies will elucidate how the B cell response is localized within and across tissues and how antigen exposures and age shape the immune repertoire.

The findings will have important implications for future vaccine design.

Robert Tampé, PhD

Host: Filippo Mancia, PhD, Department of Physiology & Cellular Biophysics

Project: "Conformational landscape of ER transport machineries under altered physiological conditions"

The biogenesis of membrane proteins in the endoplasmic reticulum (ER) is critical for cell function and immune defense. The adaptive immune system relies on a sophisticated interplay of membrane transport and quality control orchestrated by the multi-unit peptide-loading complex (PLC) in the ER membrane. In the final step, antigens are released from the PLC and shipped to the cell surface, where they are recognized by T cells that mount an immune response.

Given its fundamental role, this PLC machinery is targeted by many pathogens and tumors that attempt to evade immune surveillance. But despite recent breakthroughs, how the multiple units work together in the complex remains poorly defined.

To decipher the mechanistic network, structural data of different conformational states are essential, but obtaining these states is often limited. Robert Tampé aims to use new technology to reconstitute and analyze the membrane complexes in a wide range of conformational states and study the conformational dynamics and assembly of membrane complexes with time-resolved cryogenic electron microscopy, a major advance in structural biology.

The research may lead to new ways to boost the immune system against pathogens or cancer.