Friday, April 06, 2012

Book Review: "The Quest for the Cure" by B.R. Stockwell

The Quest for the Cure: The Science and Stories Behind the Next Generation of Medicines
By Brent R. Stockwell
Columbia University Press (June 1, 2011)

As a particle physicist, I am always amazed when I read about recent advances in biochemistry. For what I am concerned, the human body is made of ups and downs and electrons, kept together by photons and gluons - and that's pretty much it. But in biochemistry, they have all these educated sounding words. They have enzymes and aminoacids, they have proteases, peptides and kineases. They have a lot of proteins, and molecules with fancy names used to drug them. And these things do stuff. Like break up and fold and bind together. All these fancy sounding things and their interactions is what makes your body work; they decide over your health and your demise.

With all that foreign terminology however, I've found it difficult to impossible to read any paper on the topic. In most cases, I don't even understand the title. If I make an effort, I have to look up every second word. I do just fine with the popular science accounts, but these always leave me wondering just how do they know this molecule does this and how do they know this protein breaks there, fits there, and that causes cancer and that blocks some cell-function? What are the techniques they use and how do they work?

When I came across Stockwell's book "The Quest for the Cure" I thought it would help me solve some of these mysteries. Stockwell himself is a professor for biology and chemistry at Columbia university. He's a guy with many well-cited papers. He knows words like oligonucleotides and is happy to tell you how to pronounce them: oh-lig-oh-NOOK-lee-oh-tide. Phosphodiesterase: FOS-foh-dai-ESS-ter-ays. Nicotinonitrile: NIH-koh-tin-oh-NIH-trayl. Erythropoitin: eh-REETH-roh-POIY-oh-ten. As a non-native speaker I want to complain that this pronunciation help isn't of much use for a non-phonetic language; I can think of at least three ways to pronounce the syllable "lig." But then that's not what I bought the book for anyway.

The starting point of "The Quest for the Cure" is a graph showing the drop in drug approvals since 1995. Stockwell sets out to first explain what is the origin of this trend and then what can be done about it. In a nutshell, the issue is that many diseases are caused by proteins which are today considered "undruggable" which means they are folded in a way that small molecules, that are suitable for creating drugs, can't bind to the proteins' surfaces. Unfortunately, it's only a small number of proteins that can be targeted by presently known drugs:
"Here is the surprising fact: All of the 20,000 or so drug products that ever have been approved by the U.S. Food and Drug Administration interact with just 2% of the proteins found in human cells."
And fewer than 15% are considered druggable at all.

Stockwell covers a lot of ground in his book, from the early days of genetics and chemistry to today's frontier of research. The first part of the book, in which he lays out the problem of the undruggable proteins, is very accessible and well-written. Evidently, a lot of thought went into it. It comes with stories of researchers and patients who were treated with new drugs, and how our understanding of diseases has improved. In the first chapters, every word is meticulously explained or technical terms are avoided to the level that "taken orally" has been replaced by "taken by mouth."

Unfortunately, the style deteriorates somewhat thereafter. To give you an impression, it starts more reading like this
"Although sorafenib was discovered and developed as an inhibitor of RAF, because of the similarity of many kinases, it also inhibits several other kinases, including the patelet-derived growth factor, the vascular endothelia growth factor (VEGF) receptors 2 and 3, and the c-KIT receptor."

Now the book contains a glossary, but it's incomplete (eg it neither contains VEGF nor c-KIT). With the large number of technical vocabulary, at some point it doesn't matter anymore if a word was introduced, because if it's not something you deal with every day it's difficult to keep in mind the names of all sorts of drugs and molecules. It gets worse if you put down the book for a day or two. This doesn't contribute to the readability of the book and is somewhat annoying if you realize that much of the terminology is never used again and one doesn't really know why it was necessary to use to begin with.

The second part of the book deals with the possibilities to overcome the problem of the undruggable molecules. In that part of the book, the stories of researchers curing patients are replaced with stories of the pharmaceutical industry, the start-up of companies and the ups and downs of their stock price.

Stockwell's explanations left me wanting in exactly the points that I would have been interested in. He writes for example a few pages about nuclear magnetic resonance and that it's routinely used to obtain high resolution 3-d pictures of small proteins. One does not however learn how this is actually done, other than that it requires "complicated magnetic manipulations" and "extremely sophisticated NMR methods." He spends a paragraph and an image on light-directed synthesis of peptides that is vague at best, and one learns that peptides can be "stapled" together, which improves their stability, yet one has no clue how this is done.

Now the book is extremely well referenced, and I could probably go and read the respective papers in Science. But then I would have hoped that Stockwell's book saves me exactly this effort.

On the upside, Stockwell does an amazingly good job communicating the relevance of basic research and the scientific method, and in my opinion this makes up for the above shortcomings. He tells stories of unexpected breakthroughs that came about by little more than coincidence, he writes about the relevance of negative results and control experiments, and how scientific research works:
"There is a popular notion about new ideas in science springing forth from a great mind fully formed in a dazzling eureka moment. In my experience this is not accurate. There are certainly sudden insights and ideas that apear to you from time to time. Many times, of course, a little further thought makes you realize it is really an absolutely terrible idea... But even when you have an exciting new idea, it begins as a raw, unprocessed idea. Some digging around in the literature will allow you to see what has been done before, and whether this idea is novel and likely to work. If the idea survives this stage, it is still full of problems and flaws, in both the content and the style of presenting it. However, the real processing comes from discussing the idea, informally at first... Then, as it is presented in seminars, each audience gives a series of comments, suggestions, and questions that help mold the idea into a better, sharper, and more robust proposal. Finally, there is the ultimate process of submission for publication, review and revision, and finally acceptance... The scientific process is a social process, where you refine your ideas through repeated discussions and presentations."

He also writes in a moderate dose about his own research and experience with the pharmaceutical industry.

The proposals that Stockwell has how to deal with the undruggable proteins have a solid basis in today's research. He isn't offering dreams or miracle cures, but points out hopeful recent developments, for example how it might be possible to use larger molecules. The problem with large molecules is that they tend to be less stable and don't enter cells readily, but he quotes research that shows possibilities to overcome this problem. He also explains the concept of a "privileged structure," structures that have been found with slight alterations to bind to several proteins. Using such privileged structures might allow one to sort through a vast parameter space of possible molecules with a higher success rate. He also talks about using naturally occurring structures and the difficulties with that. He ends his book by emphasizing the need for more research on this important problem of the undruggable proteins.

In summary: "The Quest for the Cure" is a well-written book, but it contains too many technical expressions, and in many places scientific explanations are vague or lacking. It comes with some figures which are very helpful, but there could have been more. You don't need to read the blurb to figure out that the author isn't a science writer but a researcher. I guess he's done his best, but I also think his editor should have dramatically sorted out the vocabulary or at least have insisted on a more complete glossary. Stockwell makes up for this overdose of biochemistry lingo with communicating very well the relevance of basic research and the power of the scientific method.

I'd give this book four out of five stars because I appreciate Stockwell has taken the time to write it to begin with.


Phil Warnell said...

Hi Bee,

Undrugable proteins, this realization alone has made the reading of this piece worthwhile, for it’s a word that like many you described as contained in this book even my spell checker would reject. For instance it would have it to be “unarguable” proteins. I also agree with you when you say we should commend Stockwell for even making the attempt to demystify this increasingly complex field of science and I as such I might consider reading it just for the vernacular exposure. However as it is I’m still attempting to finish a coupled of books you’ve previously prompted me to read and as such it might have to wait for a while. Then again in the end I’m still hopeful physics might solve all these problems as having it possible that when one becomes seriously ill to have a previous record of one’s total state able to be exactly duplicated and then have its brain uploaded with all one has experienced since. That is in other words instead of being cured we will be simply recreated and rebooted.

“Death is not an event in life: we do not live to experience death. If we take eternity to mean not infinite temporal duration but timelessness, then eternal life belongs to those who live in the present. Our life has no end in just the way in which our visual field has no limits.”

- Ludwig Wittgenstein “Tractatus Logico-Philosophicus - 6.4311” (1921)



PTMR said...

If you want to understand more about cell biology I strongly recommend "Molecular Biology of the Cell" by Bruce Alberts and "Biochemistry" by Lubert Stryer.

They are THE books on the subject, very well written, with great illustrations, start from the basics and explain everything clearly and in detail. A great investment imo.

Plato Hagel said...

In a way you could say your physics view is an "expansionary view" of the universe and the subject is an formative expression of it.

So where did it all begin?

Hmmm.... the way in which we can look at things?:)


Uncle Al said...

"...the human body is made of..." Stereochemistry at all scales, Bee, physical chirality - the non-superposability of mirror images. Looking glass milk is not good to drink. Physics willfully excludes a testable vacuum interaction toward massed fermions explaining why non-classical gravitations fail (hey, Green's theorem + GR = nothing) and SUSY is a cesspool.

Protein therapeutics could be replaced by "simple" organic scaffolds performing the same chemistry inside, with site selectivity obtaining outside. Not likely. Protein is remarkably good at specificity, as COX-2 inhibitors lethally are not. Viagra was sloppy, Cialis less so but still.

"nuclear magnetic resonance" discovered by physics, enobled by chemistry, impenetrable without knowing a boat load of stuff irrelevant to each alone. If you press the "diagonal" key on a Bruker NMR keyboard, the NMR lady screams, then you.

An antibody masses 150,000 daltons. Cocaine base masses 303.35 daltons. Innoculating a person against a gram of cocaine requires 500 g of circulating antibody. It was generously funded. Blödsinn!

Bee said...


Thanks for the references. I've put that on my wishlist. They're quite expensive! Best,


Bee said...

Hi Phil,

I have the impression that Stockwell's motivation to write the book is partly political. He is making a case that this research is relevant and needs continued funding. The graph that he starts with, that I mentioned, it actually shows not only that the number of drug approvals is dropping but that it's dropping despite the R&D funding increased. You can see the graph on Amazon Search Inside. It's on page 5.

So I think a major part of the target group of his book are policy makers who want to know what's the matter and what's next. Best,


Kay zum Felde said...

Hi Bee,

I had chemistry as a "Leistungskurs" in school, and we have biochemistry one half-year. There're only a few chemical reactions, that rule biochemistry. Unfortunately this is such a long time ago, that I don't remember all that stuff. The names of the biochemical molecules are also given by some structure. I don't know exactly, what book to recommend, so I try with , but the best is to look for yourself.

Best, Kay

Kay zum Felde said...

Hi Bee,

that was not entirely correct, what I was posting before. We had one half-year organic chemistry in school. And there exist only a few reactions. And as you know biochemistry is based on organic chemistry. I cannot recommend a book, but a book based on organic reactions should serve your needs.

Best, Kay