The Nobel Prize-winning tool helping scientists rewrite biology textbooks, one molecule at a time
Think about the last time you enjoyed a delicious, nutritious meal. The fats from that avocado, olive oil, or piece of salmon didn't just magically turn into energy and building materials for your body. They embarked on an incredible microscopic journey, passing through complex pathways into your cells.
But here's the astonishing part: scientists still don't fully understand how our cells actually take in these essential fatty acids.
For decades, biologists have debated a fundamental question: do fatty acids simply diffuse through cell membranes like water through a sieve, or do they need specialized "doors" - protein transporters - to let them in? The answer could revolutionize how we treat conditions like obesity, diabetes, and heart disease.
Now, thanks to an ingenious laboratory technique nicknamed "click chemistry," we're finally getting clear answers. This revolutionary approach, which earned the 2022 Nobel Prize in Chemistry, is letting researchers spy on fatty acids in ways never before possible, challenging long-held beliefs about how these essential nutrients enter and are processed by our cells 1 5 .
The 2022 Nobel Prize in Chemistry was awarded to Carolyn R. Bertozzi, Morten Meldal, and K. Barry Sharpless for developing click chemistry and bioorthogonal chemistry.
How do long-chain fatty acids cross cell membranes? Is it passive diffusion or protein-mediated transport?
Fatty acids aren't just dietary components - they're fundamental to life itself. They form our cellular membranes, store energy for later use, and serve as signaling molecules that help coordinate complex biological processes. Long-chain fatty acids - those with 12 or more carbon atoms - are particularly important as they're abundant in our diets and crucial for health 6 8 .
The scientific controversy has centered on whether proteins like FadL in bacteria and CD36 in mammals act as genuine transporters that actively shuttle fatty acids across the otherwise impermeable cell membrane, or if they simply facilitate a process that could happen without them 1 4 .
Traditional methods for studying this process, like growth experiments, provided indirect and often ambiguous evidence. Tracking the movement of tiny, hydrophobic fatty acid molecules through even smaller cellular structures presented a monumental technical challenge - until click chemistry entered the scene.
Click chemistry describes a class of chemical reactions that are reliable, easy to perform, and work well in water - including the watery environments inside living cells. The most famous example, copper-catalyzed azide-alkyne cycloaddition (CuAAC), works like molecular Lego: an azide group (N₃) clicks together with an alkyne group (C≡C) to form a strong, stable connection 3 7 .
R-N₃ + R'-C≡C → R-N-N-R' (triazole)
Azide + Alkyne → Stable Triazole Linkage
What makes this so powerful for biology is that scientists can create fatty acid molecules with tiny, harmless azide tags. These "azido fatty acids" behave almost identically to regular fatty acids in biological systems. When researchers want to track where these tagged fatty acids have gone, they simply add a fluorescent or other detection molecule containing the matching alkyne group, and they click together - making the invisible journey of fatty acids through cells suddenly visible 1 3 .
Fatty acids freely diffuse through the lipid bilayer without assistance
Specific transporter proteins facilitate fatty acid entry
A complex interplay of both mechanisms with activation as the key driver
In 2015, researchers set out to resolve the fatty acid transport debate using the precision of click chemistry. They designed an experiment to answer a straightforward question: what happens to fatty acid uptake when we remove suspected transporter proteins? 1
The experiment focused on two key bacterial proteins: FadL, thought to transport fatty acids across the bacterial outer membrane, and FadD, an enzyme that activates fatty acids for degradation by attaching a coenzyme A (CoA) molecule. While the system was bacterial, the findings had implications for understanding similar processes in human cells.
The research team followed a meticulous process to ensure their results would be unambiguous:
They created "azido-fatty acids" - fatty molecules with an attached azide group that could later be detected using click chemistry.
They introduced these tagged fatty acids to different bacterial strains: normal bacteria, those lacking the FadL transporter, and those lacking the FadD activation enzyme.
After giving the bacteria time to take up and process the fatty acids, the researchers used the click chemistry reaction to attach fluorescent tags specifically to the azido-fatty acids and their metabolic products.
Using sensitive detection methods, they precisely quantified how much fatty acid each bacterial strain had taken up and degraded 1 .
This elegant approach provided something previous methods couldn't: a direct, unambiguous measurement of fatty acid metabolism, not just indirect inferences.
The findings challenged conventional wisdom about fatty acid transport:
| Bacterial Strain | Fatty Acid Uptake | Fatty Acid Degradation | Scientific Implications |
|---|---|---|---|
| Normal bacteria | Normal | Normal | Baseline for comparison |
| Missing FadL transporter | Still occurred | Still occurred | FadL not absolutely essential for transport |
| Missing FadD activator | Significantly reduced | Blocked | Activation essential for uptake and degradation |
The most striking finding was that bacteria lacking the FadL transporter could still take up and use fatty acids, just at a reduced efficiency. This suggested that while FadL facilitates the process, it isn't absolutely essential - fatty acids can still enter cells through other means, possibly including passive diffusion 1 .
In contrast, bacteria lacking the FadD activation enzyme showed severely impaired fatty acid uptake and could not degrade fatty acids at all. This pointed to activation as the crucial step that drives the entire process forward 1 .
The high sensitivity of the click chemistry method allowed the team to detect these subtle differences that previous, less precise methods had missed.
The power of click chemistry comes from a versatile toolkit of specialized molecules that researchers can mix and match for different applications.
| Reagent Type | Role in Research | Key Features | Applications |
|---|---|---|---|
| Azides | "Clickable" tags attached to fatty acids | Small size minimizes disruption to natural biological processes | Metabolic labeling of proteins, lipids 3 |
| Alkynes | Partner molecules that react with azides | Can be linked to detection markers like fluorescent dyes | Detection of azide-tagged molecules 3 |
| DBCO/BCN | Advanced alkynes for copper-free reactions | No copper required, better for living cells | Live cell imaging, in vivo studies 3 |
| Copper Ligands (TBTA, BTTAA) | Protectors that stabilize copper catalyst | Reduce copper toxicity, improve reaction efficiency | Enabling click reactions in biological environments 3 5 |
Recent innovations continue to improve this toolkit. In 2025, researchers at Northeastern University developed "InCu-Click," a novel copper-chelating ligand that makes click chemistry safe for live cells by neutralizing copper's toxic effects while maintaining reaction efficiency - opening the door to watching biological processes in real time 5 .
The click chemistry findings in bacteria align with fascinating research in mammalian systems. A 2020 study published in Nature Communications revealed that in fat cells, the transporter CD36 doesn't just sit statically in the membrane waiting for fatty acids. Instead, fatty acids trigger a dynamic process where CD36 is internalized through a process called endocytosis, effectively carrying fatty acids into the cell in membrane-bound vesicles 4 .
This discovery that CD36 facilitates fatty acid uptake through dynamic palmitoylation-regulated endocytosis suggests a more complex transport mechanism than previously imagined - not simple diffusion nor straightforward gated transport, but an active cellular ingestion process 4 .
The impact of click chemistry extends far beyond basic fatty acid research:
Researchers are using click chemistry to create more complex drug candidates, particularly "middle molecules" that have been difficult to synthesize using traditional methods 2 .
Scientists at Biogen and the Karolinska Institute have developed a click chemistry method to track the distribution of potential brain drugs using PET imaging, critical for developing treatments for neurological disorders like Alzheimer's and Parkinson's diseases 7 .
The simple "click" of molecules joining together has provided unprecedented clarity in the long-standing mystery of how cells acquire fatty acids. By allowing direct observation of these fundamental processes, click chemistry has revealed that fatty acid transport is more complex and nuanced than the either-or debate of diffusion versus protein-mediated transport suggested.
As these tools become even more sophisticated and accessible, particularly with innovations that make them safer for use in living cells 5 , we can expect many more biological mysteries to be solved. Each click reaction not only connects molecules but connects ideas, helping piece together the intricate puzzle of life at the molecular level.
The rewriting of biology textbooks continues, one click at a time.