Chemistry Meets Biology: How UT Southwestern Scientists Are Creating Tomorrow's Medicines
At the crossroads of disciplines, researchers are translating molecular insights into real-world treatments, leveraging tools from chemical synthesis to cellular biology to tackle some of medicine's most persistent challenges.
Explore the ScienceImagine a world where cancer metastases can be prevented before they form, where dangerous side effects of powerful drugs can be predicted in advance, and where targeted therapies precisely eliminate diseased cells without harming healthy ones. This isn't science fiction—it's the daily work of scientists at UT Southwestern Medical Center who specialize in the dynamic interface between chemistry and biology.
At UT Southwestern, this interdisciplinary approach isn't just encouraged—it's embedded in the institution's DNA. With more than 6,000 research projects annually and over 500 specialized labs, the medical center has cultivated an environment where chemists don't just hand off compounds to biologists, but rather work side-by-side to understand disease at a fundamental level 1 .
The Interdisciplinary Approach: Why Chemistry Needs Biology and Vice Versa
Chemistry's Role
Chemistry gives researchers the ability to create precise molecular tools to probe biological systems, design novel compounds, and develop targeted therapies that interact with specific cellular components.
Biology's Role
Biology reveals the complex cellular contexts in which these chemical tools must function, providing insights into disease mechanisms, cellular pathways, and the biological effects of chemical interventions.
"Through a variety of training activities and interactions with fellow colleagues and faculty, students in the Biological Chemistry Graduate Program experience and learn how to do good science," explains Dr. Glen Liszczak, Program Director of the Biological Chemistry Ph.D. program at UT Southwestern 2 .
Training the Next Generation of Scientific Integrators
Recognizing the critical importance of this interdisciplinary approach, UT Southwestern has established specialized training programs to equip scientists with skills in both domains. The Chemistry-Biology Interface (CBI) predoctoral training program, led by Dr. Margaret Phillips, embodies this mission by preparing young scientists to "tackle challenging diverse problems in biomedical research" 9 .
Integrated Skill Development in CBI Training Program
Key Research Areas and Breakthrough Discoveries
Preventing Cancer's Deadly Spread: The Metastasis Cascade
One of the most impactful examples of chemistry-biology integration at UT Southwestern involves understanding and preventing cancer metastasis—the process that makes cancer so deadly. A team led by Dr. Rolf Brekken has discovered a key signaling cascade that promotes metastasis in pancreatic, breast, and other cancers .
Their research revealed that proteins called AXL, TBK1, and AKT3 work together in a sequence to stabilize proteins in the cell nucleus that regulate what's known as epithelial-to-mesenchymal transition (EMT). During EMT, cancer cells transform to become more mobile and invasive, allowing them to spread throughout the body.
The collaboration extended beyond UT Southwestern to include researchers in Norway who developed the first AKT3-specific molecule inhibitor. When the team used this chemical tool to block AKT3 in models of pancreatic and breast cancer, they observed a dramatic decrease in metastases without affecting the primary tumor size .
Metastasis Signaling Cascade
Key Proteins in the Metastasis Signaling Cascade
| Protein | Function in Cancer | Therapeutic Potential |
|---|---|---|
| AXL | Cell surface receptor that initiates EMT | Already under investigation as cancer target |
| TBK1 | Drives EMT process inside cells | Potential target for metastatic disease |
| AKT3 | Specific AKT family member that promotes metastasis | Newly identified druggable target; potential biomarker |
Safer Immunotherapy: Predicting Side Effects
A UT Southwestern-led team analyzed blood samples from 162 patients before and after immunotherapy, identifying three key immune features linked to higher risk of side effects 3 .
This discovery offers a path toward blood tests that could predict which patients are most likely to experience complications from immunotherapy, allowing doctors to tailor treatments accordingly.
Protein Disposal Systems: Cancer Treatment
Using cryo-electron microscopy (cryo-EM), researchers determined the structure of a protein called midnolin that's crucial to the survival of malignant cells in certain blood cancers 8 .
Midnolin functions as a ferry service for proteins, carrying them to cellular disposal units called proteasomes. Drugs that specifically block midnolin could offer a safer alternative to broader proteasome inhibitors 8 .
A Closer Look: Mapping the Midnolin Protein
The Experimental Approach
Genetic Discovery
The journey began with the Beutler Lab's pioneering use of automated meiotic mapping (AMM) in mice. Researchers discovered that mutations in the Midn gene protected mice genetically predisposed to developing B-cell leukemias and lymphomas 8 .
Functional Characterization
Further experiments revealed midnolin's role in B cells—ferrying proteins to proteasomes for disposal without requiring ubiquitin tags. This raised the fundamental question: How does midnolin accomplish this unusual feat? 8
Structural Analysis
Using UT Southwestern's Cryo-Electron Microscopy Facility, the researchers obtained three-dimensional images of midnolin bound to proteasomes at nearly atomic-level resolution 8 .
Midnolin-Proteasome Interaction
Results and Significance: A Molecular Look at Protein Disposal
The cryo-EM images revealed midnolin's structural secrets, particularly one portion with a shape surprisingly similar to ubiquitin. This "molecular mimicry" allows midnolin to open the same gateway in proteasomes that proteins must cross for their disposal—essentially tricking the proteasome into accepting its cargo without the usual ubiquitin tag 8 .
New Pathway Discovered
Reveals a previously unknown pathway for protein disposal in cells
Drug Development
Provides a structural basis for developing drugs that might block midnolin's function
Experimental Techniques
| Technique | Information Gained |
|---|---|
| Automated Meiotic Mapping | Genetic basis for midnolin's importance in disease |
| Cryo-Electron Microscopy | Near-atomic resolution structure of the protein complex |
| Genetic Manipulation | Confirmed protein's role in B-cell survival and cancer |
The Scientist's Toolkit: Essential Resources for Interfacial Research
The groundbreaking discoveries emerging from UT Southwestern's chemistry-biology interface are supported by sophisticated tools and resources that enable researchers to answer complex questions.
Cryo-Electron Microscopy
Determines 3D protein structures at near-atomic resolution for visualizing molecular interactions.
High-Throughput Screening
Tests thousands of compounds for biological activity to identify potential drug candidates.
Proteomics Core
Analyzes protein expression, interactions, and modifications to understand disease mechanisms.
Immunology Patient Registry
Biorepository of samples from immunotherapy patients for identifying predictive biomarkers 3 .
Chemical Biology Tools
Develops chemical probes to investigate biological processes and monitor cellular activities 7 .
Research Support Teams
Assist scientists in their work, fostering collaboration to accelerate discovery 1 .
Research Impact Distribution
Conclusion: The Future of Medicine at the Interface
The interdisciplinary work happening at UT Southwestern Medical Center represents a paradigm shift in how we approach disease treatment. By leveraging tools from chemistry to understand and manipulate biological systems, researchers are developing more precise, effective, and safer therapies for some of medicine's most challenging conditions.
Precision
Targeted therapies that specifically address disease mechanisms
Safety
Reduced side effects through better prediction and targeting
Innovation
Novel approaches to previously untreatable conditions
As Dr. Brekken notes about his team's discovery of AKT3's role in metastasis, "This research defines a new target for fighting metastatic disease" . Similarly, the midnolin structure determination provides insight into a protein disposal process "that could have significant implications for cancer and immune-related diseases" 8 .
The future of this interdisciplinary approach appears bright at UT Southwestern, with training programs specifically designed to equip the next generation of scientists with skills in both chemistry and biology 9 . As these students and fellows mature into independent researchers, they'll carry forward the collaborative spirit that defines science at the interface, ensuring that the molecules they study today become the medicines of tomorrow.
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