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5. Rational Drug Design

A continuation of essays regarding George Whiteside's work: DOI 10.1002/anie.201410884

Rational drug design is a myth. And it's not from lack of trying.

The study of drug chemistry is valid and the biological scientists that study mechanisms of action for different chemical substrates serve an important purpose. However, rational drug design is not answered by any of these people. This is not because these scientists are not good enough. Not because they are dumb. Rational drug design simply does not exist.

The reason for this is simple: life is complicated. While understanding an amino acid sequence can then be used to calculate a tertiary structure and the associated active sites of a protein, this only answers a small question regarding drug design. We can only sequence the proteins that we can observe, those that are in sufficiently high concentration that their biochemical roles are in some way known or predicted. What if a protein is simply unknown to science--how then can we predict a drug that will alter its behavior? What if the protein that is actually active in an enzymatic reaction is actually not the protein that is suspected, but a minor sub-population of mutants? All of these questions regard molecular biology.

However, cells do not come as equals, nor do organisms. In single cell sorting, it has been made clear that there is a pesky relationship between cells, between different mutations of cells, and the interaction within. Furthermore, on the organism level, things are not consistent. If you implant a tumor model into one mouse and inject a drug that accumulates selectively within tumors, it will only sometimes work. Despite a consistent quality of drug, purity of mouse model lineage, and method of tumor implantation, it simply does not consistently work.

Regardless, 5. does not deserve to be struck from the list. As George noted, there may be a missing piece that ties everything together. However, the study of biology goes back hundreds of years and drug development a not so different amount of time; so, is there really a missing piece or is it just an oversimplification to ask whether a single molecule will consistently improve a condition across a multitude of different patients, each with unique biology that varies with time?

20. Death

A continuation of essays regarding George Whiteside's work: DOI 10.1002/anie.201410884

"From that fateful day when stinking bits of slime first crawled from the sea and shouted to the cold stars, 'I am man!,' our greatest dread has always been the knowledge of our mortality. But tonight, we shall hurl the gauntlet of science into the frightful face of death itself. Tonight, we shall ascend into the heavens. We shall mock the earthquake. We shall command the thunders, and penetrate into the very womb of impervious nature herself." -Dr. Frankenstein (Young Frankenstein, 1974)

Like many young children, I had a great curiosity with death. In my childish thinking, I observed that children would suddenly become insufferable adults and eventually vanish from life, with only cemetery stones that others kept in their memory. My mother maintained a book of notes as each of her children grew up, from birth to four years old. Reading through her notes on those years, I found that I had consistently asked, "how do you die?". Apparently, I asked her over and over, again.

Frankly, I have no good answer to my own questions, some twenty years later. I have learned bits and pieces of the science that goes into death. I realize that breaking some biochemical processes leads to an ultimate breakdown of the mandatory processes that enable life. I understand that once these processes are halted, the damage irreversible. Apart from relatively trivial cases of near-death, where the heart has stopped beating or a liver begins to fail, in which medical intervention can prevent imminent death, there are few other ways to prevent this finality of life.

Here, I want to make clear that I an discussing death, not aging. Issues in aging can stem from telomere shortening among other things, which I may address in a follow-up post.

Death is one of the best quantifiable measures of the quality of a drug for the pharma industry. While arguments can be made for improvement of quality of life, the FDA often seeks that a new drug offers a statistically significant extension to the life of patients as opposed to the current standard of care. As a result, drugs are often directed towards pushing the maximum age of patients, but not directly solving any issues associated with processes that lead to (or prevent) death. Here, industry often trumps science, where the mechanism/nature by which a drug helps to extend life is much less important than the fact that it simply works, meaning it successfully extends life.

So where can chemistry come in? Obviously, biochemistry seeks to understand the complex chemical processes in the body, following up by attempting to obstruct or enhance certain pathways to incur a medical benefit. This avenue of research is vital, but it is not the way to prevent or understand death via chemistry.

Chemists must study the chemical process that occurs when death takes place by a variety of conditions. When signals cease from the brain, what is the chemical pathway that is first obstructed? Could a long-circulating promoter of that particular pathway, serving to keep the chemical cycle operational, delay death? What about death from lack of oxygen? It may not be possible to easily reverse the damage that oxygen-deprivation has on the brain, but surely the remaining intact pieces of the body can be sustained and maintained independent of the brain?

Chemistry should begin treating the body like the machine that it is, with complicated wiring and responsive pathways. The more information that can be gathered during the process of death might prove fruitless in its reversal, but it might just serve as a means for its prevention.


"That life is simply molecular behavior is disconcerting; that human thought is more of the same is even more so." -George Whitesides

DOI 10.1002/anie.201410884

Being a young scientist, I have invested most of my time pursuing the practice of chemistry and have only begun to dabble in its study. My initial efforts into research focused on improving previous literature reports, making small modifications, and then studying the output. I still do this, but I used to, too. However, I did not initially consider which scientific questions warranted more attention than others. In "Reinventing Chemistry", the history of scientific problems over the past 100 years or so are explored, while predictions about the future of chemistry-based research are made.

Dr. Whitesides highlights a number of evolving characteristics of Chemistry as a field: the blending of fields of study, the lessening need for chemical synthesis methods for the chemical industry, and the omnipresence of chemistry in many (if not all) large-scale issues that mankind faces. After introducing 24 topics as "New Classes of Problems", the reader is left with an overwhelming feeling that there is work to be done--a lot of work.

Though this Essay was published in 2015, I do not feel that the topics have aged; though, more topics related to gene editing might be warranted with new discoveries since its publication. Dr. Whitesides noted the brevity employed in each of the topics he presented so I will attempt to expand on each topic on a weekly basis--an exercise for me to better understand science and the subtleties that take a thought from being an interesting topic to a revolutionary idea.