Discover how a molecular biologist with a passion for puzzles transformed our understanding of epigenetic inheritance
In the intricate world of the cell, DNA doesn't tell its story openly. Its secrets are wrapped around proteins, folded and modified in complex ways that determine which genes are active and which remain silent. For decades, scientists struggled to read this hidden code—until a molecular biologist with a passion for puzzles transformed the field.
Henikoff's work focuses on how cells pass on information without changing their DNA sequence.
Recipient of the prestigious 55th Lewis S. Rosenstiel Award for Distinguished Work in Basic Medical Research 4 .
His work spans mammals, fruit flies, worms, yeast, and plants 1 .
Henikoff's path to scientific prominence was anything but conventional. His scientific curiosity was first sparked not in a laboratory, but in a darkroom, where he discovered the thrill of discovery through the chemistry of photography 6 .
Chemistry of photography sparked initial scientific interest 6 .
Drafted during Vietnam War era but assigned to Germany instead of Vietnam 6 .
Joined Harvard University's graduate program and worked with Matt Meselson 6 .
Found perfect environment to pursue high-risk, high-reward science 6 .
"The idea is that you will make fundamental discoveries if you let the science dictate your next step" 6 .
This approach led to groundbreaking methods that transformed genomic research.
One of Henikoff's most significant contributions came from addressing a fundamental limitation of chromatin immunoprecipitation (ChIP-seq), the traditional method for studying how proteins interact with DNA 3 7 .
| Method | Resolution | Cells Required | Background Noise | Key Advantages |
|---|---|---|---|---|
| Traditional ChIP-seq | 200-500 bp | 10,000-1,000,000 | High | Established protocol; widely used |
| CUT&RUN | Base-pair level | 100-1,000 | Very low | Low sequencing depth; high resolution; works on rare cells |
| CUTAC | Base-pair level | Compatible with FFPE samples | Low | Works on archived clinical samples; simple protocol |
The true power of Henikoff's methods becomes evident in their practical applications, particularly in cancer research. In a recent collaboration with Dr. Eric Holland, a brain cancer researcher at Fred Hutch, Henikoff adapted his CUT&Tag method to work on formalin-fixed, paraffin-embedded (FFPE) tissue samples .
Most clinical samples are preserved as FFPE blocks—a standard practice in pathology departments worldwide. As Holland notes, "Every pathology department in every hospital is full of these" .
Unfortunately, the formalin preservation process makes chromatin nearly unreadable using conventional methods.
Henikoff discovered that a gentle heating process could melt away the paraffin and reverse the bonds between DNA and proteins without damaging the DNA .
His method picks up the short "open" sections of DNA that lie between DNA packaging proteins.
"We can do retrospective studies that link tumor biology with patient outcomes using samples already collected and stored," Holland explains .
This could dramatically accelerate the development of precision oncology approaches that tailor treatments to individual patients.
| Reagent/Method | Function | Applications |
|---|---|---|
| pAG-MNase fusion protein | Antibody-targeted nuclease for precise DNA cleavage | CUT&RUN enables mapping of protein-DNA interactions |
| INTACT system | Isolation of nuclei from specific cell types | Cell-type-specific gene expression and chromatin profiling |
| BLOSUM matrices | Scoring protein sequence alignments | Evolutionary analysis and protein function prediction |
| CUTAC | Mapping accessible chromatin in FFPE samples | Cancer research using archived clinical samples |
| AutoCUT&RUN | Automated high-throughput chromatin profiling | Clinical epigenomic studies |
Henikoff's commitment to the scientific community extends beyond his own research. He has made his methods and reagents readily available to other researchers, distributing materials to more than 600 laboratories worldwide and maintaining an open-access protocol site for user questions and answers 3 .
Materials distributed to 600+ laboratories worldwide 3
Collaborating to teach high school students about gene regulation
Henikoff remains a passionate advocate for what he calls "small-lab science"—the kind of research where principal investigators work side-by-side with their trainees at the bench 4 .
This collaborative, hands-on approach has been a hallmark of his career since he joined Fred Hutch in 1981, and he values that this culture has persisted despite trends toward larger, more impersonal research operations 4 .
| Innovation | Field Impact | Clinical Relevance |
|---|---|---|
| CUT&RUN | Revolutionized chromatin profiling; enabled high-resolution mapping with low cell numbers | Potential for diagnostics using limited clinical samples |
| FFPE Adaptation (CUTAC) | Made vast archives of clinical samples accessible for chromatin studies | Enables retrospective cancer studies; links biology with patient outcomes |
| INTACT | Enabled cell-type-specific nuclear isolation without FACS or microdissection | Understanding cell-type-specific changes in disease |
| BLOSUM Matrices | Became standard tool for protein sequence analysis and evolutionary studies | Used in predicting functional consequences of genetic variants in disease |
As Steven Henikoff continues his work, the potential applications of his methods continue to expand. He plans to explore ramped-up transcription in cancer and examine developmental processes using intestinal stem cells grown in three-dimensional cultures .
Reflecting on the significance of the Rosenstiel Award, Henikoff sees it as validation of an approach to science that values fundamental discovery and methodological innovation.
"That kind of science was kind of unusual at the time," he recalls. "It's amazing to me we can still do that even today—small-lab science" 4 .
Through his combination of technical ingenuity and scientific vision, Steven Henikoff has not only transformed how we study the genome but has provided the tools that may eventually unlock the deepest secrets of how life encodes its intricate instructions—from the earliest stages of development to the complex changes that drive diseases like cancer.
As his methods continue to spread through the scientific community, the promise of truly understanding and manipulating the epigenetic code comes increasingly within reach.