Tycko Investigates Genetic-Epigenetic Interactions Across Multiple Human Diseases
The discovery of the DNA double helix completely changed human understanding of biology, and progress since then has highlighted the importance of chemical modifications that are overlaid onto our DNA in specific patterns to turn genes on or off.
Delving into such epigenetic patterns to understand inter-individual differences in disease risks and disease progression is where the work of Benjamin Tycko, M.D., Ph.D., thrives. As reflected in nearly 200 publications, his laboratory has produced foundational papers, including work showing how variations in the primary DNA sequence (genetics) between different individuals can lead to major differences in the methylation patterns on their DNA (epigenetics).
“The emphasis in my lab has always been on tissue-based research - meaning clinical human tissue,” said Tycko, member of the Hackensack Meridian Center for Discovery and Innovation (CDI). “We want to better understand the relationship between genetic and epigenetic factors - most recently by probing how this relationship can help us pinpoint specific genetic variants that lead to altered expression of disease-related genes and thereby influence a person's risk of developing some of the most common types of human diseases.”
“Ben Tycko is a remarkable scientist,” said David Perlin, Ph.D., chief scientific officer and executive vice president of the CDI. “His work in understanding these fundamental biological interactions pushes our science forward - not just in his lab but in those of his collaborators, as well.”
Autopsies to Epigenetics
Tycko is trained as both a researcher and a pathologist. After a Princeton University biochemistry undergraduate degree, he received his dual M.D. and Ph.D. from New York University School of Medicine. It was followed by stints as resident and fellow at Stanford University Hospital, and as an instructor in Pathology at Harvard University.
All that led to more than 20 years at Columbia University. He was ultimately a professor of Pathology and Cell Biology at the school, running a research lab while also directing the autopsy service at New York-Presbyterian Hospital.
His work delving into the origin of disease was at the vanguard of the explosion of DNA science. The topic that firmly set him toward his current path was Wilms tumor, a pediatric kidney cancer which is the fourth-most-common cancer in children currently, according to federal health statistics. It’s also perhaps the first tumor type identified in which the earliest molecular changes are epigenetic, not genetic - with altered methylation of a particular DNA region, known as an imprinting center, on human chromosome 11 leading to the Beckwith-Wiedemann syndrome of fetal overgrowth and a high risk of Wilms tumor formation. This was described in a landmark series of papers - featured in Nature Genetics, including the inaugural issue of that journal in 1992.
Tycko also conducted fundamental imprinted gene discovery in the role of placental and fetal growth. Between 1997 and 2013, he and his colleagues identified and determined the function of the imprinted gene PHLDA2, which controls placental growth, both in mouse models and in humans, where it has been implicated in the important obstetrical condition of fetal intrauterine growth restriction. Highlighting an increasingly recognized connection between placental growth and the growth of cancers, this same gene and similar genes such as PHLDA3, have now been implicated as regulating cancer cell proliferation.
A Web of Diseases
Tycko left Columbia and joined the CDI in 2019, right at the inception of the new institution. His work continues to focus on methylation - the process by which methyl groups are added to the DNA molecule - thereby muffling the expression of the DNA sequence. This can be for “good” - or it can tend toward disease.
Using the latest tools including the Nanopore at the CDI, Tycko and his team are looking for the slightest methylation changes in expression across entire chromosomes - and down to the level of single alleles, to find the clues for genetic variants that cause diseases like cancer and others.
“The Nanopore has the unique advantage of whole genome sequencing, and it produces long-sequencing reads, which allow detection not only of mutations and other genetic variants, but also chromosome translation, and DNA methylation without any pre-modification of the DNA,” he said. “We can directly score DNA methylation using the tool for projects such as one that involves correlating genetic variants with local DNA methylation patterns, which is our project for the Tycko Lab.”
CRISPR approaches are also used to test the predictions based on their detailed mapping of these microcosmic changes - which can lead to a world of difference for patients. It adds up to “post-genome-wide association studies” (post-GWAS) which are a global way of looking at genetic dynamics - and targeting minute changes which may be the culprit for huge changes in phenotype.
A milestone publication for the laboratory was a 2020 Genome Biology paper which showed that inherited DNA single-nucleotide polymorphisms (SNPs) produce methylation in the immediate vicinity when these SNPs create or destroy binding sites for transcription factors. This finding can therefore hugely narrow down the search for genetic culprits in disease.
“Thus, a finding of (allele-specific DNA methylation) centered on a given SNP elevates that SNP to strong candidate status for being functional (i.e., not neutral) and thereby conveying an increased or decreased disease risk,” said Tycko.
These interlocking techniques are piecing out the puzzles of a variety of conditions, including multiple myeloma, kidney and brain tumors, Crohn’s and celiac diseases, Type 2 diabetes, and Down syndrome, among other conditions.
Tycko has formed collaborations with key experts at Hackensack Meridian Health and beyond: Kathryn E. Hamilton, Ph.D., of the Children’s Hospital of Philadelphia, and Kevin Tong, Ph.D. of the CDI, for the Crohn’s and gastrointestinal work; for kidney cancer he works with Michael Stifelman, M.D., chair of Urology and director of Robotic Surgery at Hackensack University Medical Center; David Siegel, M.D. and Rena Feinman, Ph.D., for the research into blood cancers; for ongoing brain tumor science there are colleagues Claire Carter, Ph.D. of the CDI and George Kaptain, M.D., FAANS, surgical director of Neuro-Oncology, Skull-Base Surgery and Radiosurgery at the John Theurer Cancer Center at Hackensack University Medical Center; other collaborations are with Florian Thomas M.D., Founding Chair & Professor in the Department of Neurology, Colette Knight, M.D., Director of the HUMC Diabetes Center, and many others.
The ongoing data collection on these many disease pathways - and the many papers forthcoming - point the way toward the commonalities of disease. This phenomenon is especially key in terms of genetic expression, and the resulting inflammation which can trigger the genesis of a condition. For instance, the risk of getting multiple myeloma is increased substantially by having Type 2 Diabetes.
“The same gene, the same genetic variant, is connected,” said Tycko. “We’re studying that gene and others with CRISPR. So it is really tied together - through the famous obesity-cancer connection.”
Similar connections are observed in Down syndrome, also called Trisomy 21, caused by a genetic disorder caused by extra genetic material from chromosome 21, and in which the Tycko group has shown widespread changes in DNA methylation patterns. Autoimmune inflammatory diseases are markedly increased in Down syndrome, as Tycko’s work continues to demonstrate and explore. For instance, Down syndrome persons have a 20- to 50-fold increase in celiac disease - but interestingly the same syndrome shows a much lower incidence of solid tumors, including breast cancers.
“So there’s some tumor suppressor pathway linked to chromosome 21 that has to be linked - but nobody yet knows exactly what the key genes are. It’s still speculative, but maybe there is a connection between increased autoimmunity and decreased cancers - via increased immune surveillance against cancer cells in people with this syndrome” said Tycko.
Work-Life Balance and Future Goals
Tycko grew up in the New York area, and apart from the stints at California and Massachusetts institutions, has been a lifelong Metro Area resident. His father was a physicist and a computer scientist in the earliest days of the machines, and his son has an already well developed career in science, interestingly also focused on gene regulation. What free time he has is spent fishing, including at the Jersey Shore when the traffic congestion allows.
His ultimate career goal, at this stage, is to further the research projects underway - and to help usher in the next generation of scientists, he said.
“A key goal at this stage of my career is to try to bring in more participation by the clinicians, and make the links to the hospitals which will drive the research forward,” he said. “Developing those connections and bringing in younger faculty members is the way to improve medical research and keep it going in the long term.”