There is a quiet revolution going on. While so much media attention is being spent on debating the risks vs benefits of raw milk, the latest outrages from the systematic dismantling of quality science at the CDC and other federal agencies, and by the tsunami of terrible medical science being pushed on social media, science-based medicine marches on. Public awareness of recent medical advances is limited, while so much of their attention is dominated by snake-oil peddlers, science deniers, and rank pseudoscience. Further, trust in authoritative medical information has taken a serious hit due mostly to all this misinformation.
Meanwhile – monoclonal antibody-based medicines are transforming almost every medical discipline. Targeted immune therapy is transforming cancer treatment. And CRISPR and other genetic technologies are ushering in an age of treatments for genetic illnesses. I think it’s important that as we highlight the dangers and false claims of scam medicine, we also showcase the real progress being made by scientific medicine. The contrast is stark.
So here is one more modern medical technology to be aware of – smart drugs. The idea being smart drugs is to have increased control over where drugs go in the body, down to the cellular level. In classic pharmacology, what I learned in medical school and practiced most of my career, drugs are distributed in different compartments in the body. Some essentially bath every cell in the body, while others are kept out of the central nervous system, some distribute more in water and others in fat tissue. But basically, drugs just diffuse throughout the body according to their chemistry, even if there is just one specific cell type that is the intended target of their action.
This “dumb” aspect of drugs is a major contributor to their side effect profile. This is perhaps most true when it comes to chemotherapy – powerful drugs that are highly toxic to cells. Because we are dealing with potentially deadly cancers, a high side effect profile is still worth it, and we use drugs that are optimized to be more deadly to cancer cells than they are to healthy cells, pushing the safe dosing to its limits.
But that was yesterday – today we rely more on targeted therapies like immune therapies that target the host’s own immune cells against their specific cancer. There are also smart drugs, which use a technology called antibody–drug conjugates (ADCs). These use monoclonal antibodies to target a biomarker on a target cell, such as a biomarker of a specific type of cancer. They then deliver a package of drug to cells with those biomarkers. This allows for concentration of the drug on the target cells with lower concentrations reaching healthy cells.
But ADCs have some limitations. They are large (on the molecular level) and so do not penetrate that deeply into solid tumors. They also can carry a limited amount of drug. They are not as selective as we would like, so there is still some off target drug delivery. But still – ADCs are smarter than traditional drugs that just diffuse through tissues unguided.
But now a recent study points the way toward a significant advance – going from merely smart drugs to programmable drugs. This is a proof-of-concept study, so we are not ready for the clinic yet, but the technology is moving fast. Instead of antibody-drug conjugates this technology uses DNA-drug conjugates (DDCs). This is how it works.
DNA strands are used to target desired biomarkers and deliver their payload to the desired cells only, such as cancer cells. However, these DDCs can target multiple biomarkers at once, giving them much higher specificity than ADCs. A DNA initiator strand is split between these biomarkers. When the correct combination of biomarkers are close enough together on the cell surface, the split DNA strands come together in a hybridization chain reaction. This initiates endocytosis into the cell, delivering the package of drugs.
These split DNA strands can act as logic gates that make this system highly modular and programmable. In other words, they can be programmed so that the drug is delivered only when both biomarkers are present. But they can also be programmed to delivery the drug when other combinations of criteria are met – either/or, both, neither, etc.
There are several advantages of existing ADCs (in addition to being more programmable and modular) – they are smaller and can penetrate deeper into solid tumors, they can deliver more drugs, and they have a higher specificity. They can be used to deliver immune therapies in addition to drugs. They also tested mechanisms for amplifying the drug delivery, resulting in even higher concentrations of the desired drug at the desired cells, by a hundred fold.
This technology, while ideal for chemotherapy delivery, is not limited to treating cancer. It can potentially be used to target any drug to a specific cell type, which can result is greater effectiveness with fewer side effects at much lower total doses and therefore toxicity. This also allows for truly personalized and targeted pharmacological treatments.
The main limiting factor at this point is that the unmodified DNA used in the DDCs is not very stable in plasma, which limits its utility. This is a technical issue that will have to be worked out before DDCs are ready for the clinic, but this sounds like a very solvable issue.
This technology could have wide ranging implications for the safety and effectiveness of modern medicine. The idea of just bathing the entire body in a drug in order to affect just one cell population may one day seem hopelessly crude (let’s hope). Also, many potential drugs are extremely effective, but fail because of off-target toxicity. They just don’t have a safe dose range. But if we could use a tiny dose that concentrates 100 times only on the target cells, they could become safe and effective treatments.
Keep in mind – we already have smart drugs. This technology could give us smarter drugs. And even if this specific technique does not work out, researchers are working on many paths to this same outcome. Little by little our drugs are getting smarter and this is quietly transforming medicine.
I just hope people notice among all the noise of pseudoscience and denialism.
