Insights & Outcomes: Skin cells, the 22nd amino acid, and data from wearables
This month, Insights & Outcomes pulls on a warmer lab coat to explore the flexibility of skin cells, the life story of an amino acid, the potential health benefits of wearable digital technology, and a grant for an innovative cancer treatment.
How skin cells find their way
Skin cells die, are shed, and replaced in a multi-step process initiated by stem cells in the epidermis, which give birth to daughter cells that eventually become specialized cells that form different tissues which make up our skin. This process of differentiation of cells was thought to be linear, with each distinct cellular change carefully choreographed after initiation by stem cells.
However, a new study by researchers at Yale and the Karolinska Institute in Sweden describes the process of skin cell differentiation as more of continuous, meandering journey, with changes in cell fate dictated by the environment. “Our skin has figured out how to create needed cells, but with built-in flexibility to respond to different environments and needs,” said co-first author Katie Cockburn, a former postdoctoral fellow in the lab of Valentina Greco, the Carolyn Walch Slayman Professor of Genetics at Yale.
Cockburn, now a faculty member running her own lab at McGill University, and Swedish colleagues used imaging and single cell molecular analysis to track the journey from stem cell to specialized stem cells. They found that daughter cells created from skin stem cells interact with other differentiated cells in the epidermis in a less hierarchal manner than previously believed.
Understanding the process of stem cell differentiation will help scientists develop new treatments for the wide range of skin diseases in which differentiation goes awry, Cockburn says. Maria Kasper is co-senior author and Karl Annusver of Karolinska is co-lead author of the study, published in the journal Nature Cell Biology.
A lab-to-market plan for Modifi Biosciences
The National Cancer Institute has selected a Yale-based start-up, Modifi Biosciences, for a $2.4 million fast-track Small Business Innovation Research (SBIR) Award to bring the company’s precision oncology platform into phase 1 clinical trials.
The co-founders of Modifi Biosciences are Seth Herzon, the Milton Harris ’29 Ph.D. Professor of Chemistry in Yale’s Faculty of Arts and Sciences, and Ranjit Bindra, the Harvey and Kate Cushing Professor of Therapeutic Radiology at Yale School of Medicine and medical director of the Yale Brain Tumor Center at Smilow Cancer Hospital. Herzon and Bindra are also members of the Yale Cancer Center.
Herzon and Bindra have developed a new class of chameleon-like molecules that show favorable, drug-like properties in treating gliomas — one of the deadliest forms of brain cancer. The molecules are active and selective against cancer cells that lack expression of the DNA repair protein O6-methylguanine methyl transferase (MGMT). Loss of MGMT expression is common in other cancers as well, including up to 40% of colon cancers, 35% of small cell lung cancers, and 25% of non-small cell lung cancers, suggesting broad applicability for Modifi Biosciences’ therapeutic strategy in treating various cancers.
“This SBIR grant serves as an independent peer review of the therapeutic potential for our novel approach to leverage direct cancer DNA modification to one day change the treatment paradigm, particularly for patients with brain cancer,” Herzon said.
The National Cancer Institute’s SBIR programs offer funding, mentoring, and networking assistance to help businesses like Modifi Biosciences take research from lab to market.
“The SBIR funding mechanism is essential for the early stages of biotech start-ups, it’s a critical source of non-dilutive capital, which can help us de-risk assets and pass key value infection points quickly,” Bindra said.
A new timeline for an old amino acid
Proteins are essential for all of life’s functions and most organisms rely on 21 amino acids encoded in DNA to construct them. However, a small group of microbes possess a 22nd amino acid called pyrrolysine, which helps determine the ultimate structure of the microbes’ proteins.
While scientists once thought pyrrolysine was a recent evolutionary addition to these microbes’ molecular repertoire, a new Yale-led study suggests it may have existed in common ancestors of all life on Earth.
The Yale team was led by Jeffery Tharp, a postdoctoral research fellow in the lab of Dieter Söll, Sterling Professor of Molecular Biophysics and Biochemistry. Tharp and colleagues compared all known pyrrolysine tRNAs, which carry instructions for insertion of amino acids into proteins, with similar tRNAs from other organisms.
Their analysis showed pyrrolysine emerged before the evolution of all three domains of life — archaea, bacteria, and eukaryotes. The findings not only shed light on the evolution of life, the researchers say, but also suggest ways in which the addition of synthetic amino acids might help create new therapies for disease or the creation of new types of materials.
“This work gives us a better understanding of how the genetic code evolved into its present form, and how the genetic code can be further evolved to accommodate new protein building blocks for applications in synthetic biology and medicine,” said Tharp, now assistant professor at Indiana University School of Medicine.
The research was published in the Journal of Biological Chemistry.
Google gift to analyze benefits of wearables
A recent gift from Google will help Yale researchers analyze how wearable digital devices may be used to improve health.
Harlan M. Krumholz, the Harold H. Hines Professor of Medicine at Yale School of Medicine, Rohan Khera, assistant professor of medicine, and Zhenqiu Lin, senior director of health analytics at the Yale Center for Outcomes Research and Evaluation (CORE), will co-lead the effort.
“With vast numbers of people now wearing devices with sophisticated sensors, the opportunity to observe behaviors, diagnose and monitor diseases, and promote healthy choices has expanded dramatically,” said Krumholz, who is also the director of CORE. “We are hopeful that our work will help propel the development of tools and services that improve patient outcomes and better support their efforts to improve their health.”
The undisclosed gift, which is unrestricted, will be used to pursue transformative work on data that has rarely been part of research at scale. The CORE team will also seek to involve students in the research and engage with data scientists throughout campus.
“Yale is ideally positioned to bring together expertise in clinical medicine, data science, and implementation science to ensure that people fully benefit from the information that these devices are producing,” said Khera, who is the clinical leader of CORE’s Center for Health Informatics and Analytics. “We are just at the beginning of what is possible.” He also noted the relatively untapped benefits of combining the sensor data with other sources of data, such as what is available in the electronic health record.
“This is a great opportunity to apply novel analytic approaches to these multi-modal data and produce novel insights and actionable information,” Lin said. “The ultimate goal is to use data to improve health outcomes.”