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book reviews
Gene technology and blood-brain barrier booksreviewed by T. Nelson |
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book reviews
Gene technology and blood-brain barrier booksreviewed by T. Nelson |
Reviewed by T. Nelson
There's a new trend, led by Springer, for publishing scientific books under a Creative Commons license, which means you can either download a copy for free or buy a hard copy. So far it's being led by books that are too short or too fringe-y to become big sellers. It's good for science, and it's good for the publisher, which benefits from measuring interest in emerging or niche topics.
Two examples that I'm reading are Physical (A)Causality: Determinism, Randomness and Uncaused Events by Karl Svozil, and this book, which is a collection of scientific review papers on CRISPR.
By now everyone's heard the fear-mongering about CRISPR. It's a new technology that makes it easy for scientists to perform genome editing on cells. That means they can put human disease-causing genes into a dish of cultured cells to learn how to understand and treat diseases. They can knock out genes easily to see how they work. And, most importantly, they can use them for gene therapy.
An example is the chapter by Bailus, Zhang, and Ellerby, who used CRISPR to learn how common single nucleotide polymorphisms, or SNPs, can be used to treat Huntington's disease. Huntington's disease is a devastating genetic disorder that causes debilititating movement symptoms, psychiatric disturbances, and death. Although people have searched for ways to eliminate the mutant HTT protein or normalize the disturbed biochemical pathways, there is little hope of curing the disease without correcting the mutation. These authors describe how CRISPR could someday be used for gene replacement therapy.
Another example is muscular dystrophy. Doctors have been trying to cure this disease by using harmless viruses like AAV to deliver replacement dystrophin protein. This will never be a permanent cure; only repairing the gene can do that. So researchers are using CRISPR to create specially modified cells, derived from adult stem cells, that can be injected back into the patient to restore normal function. This puts CRISPR in the category not of a threat, but a wonder drug. It's the latest proof that the Human Genome Sequencing project did indeed lead to a revolution in medicine.
may 26, 2018
Reviewed by T. Nelson
The blood-brain barrier, commonly called the BBB, is a coating of cells that surrounds every blood vessel in the brain. It is one of the biggest obstacles to treating neurological diseases: 98% of all small-molecule drugs are unable to cross it. For modern biotherapeutics such as antibodies and DNA molecules, the figure approaches 100%. So there is a major effort to find ways of transporting these molecules into the brain.
Sometimes that effort is ill-conceived. Cancer drugs, for example, kill many normal cells in addition to cancer cells. In the liver, that's no problem—cells just grow back. But a cytotoxic drug that got into the brain would also kill neurons, producing dementia.
But if we could get proteins, antibodies, and siRNA molecules into the brain, it would create a revolution in treatment for genetic diseases and neurodegenerative diseases that we are are currently unable to treat. Unfortunately, progress in the field has been very slow.
This book is a useful collection of review articles on the BBB, all written by Turkish researchers in nearly flawless English. Covers the biology of the BBB, nose to brain delivery, nanoparticles, and in vitro and in vivo models for studying it. The last section discusses targeted strategies for various diseases, including Alzheimer's, Parkinson's, autoimmune diseases, infections, and cancer.
Despite the title, this isn't a protocols book, but a review of the literature. It's nicely published, with color figures, clear diagrams, and lots of refs. One article has 11 pages of text, 1 page of abbreviations, and 9 pages of references. Another has 16 pages of text and 16 pages of refs.
There are only two caveats. First, none of the chapters convey any sense of judgment about what they're covering or the drawbacks of the BBB carriers. Reading this book, you might think that everything works and all the problems have been solved. This is most assuredly not the case. The chapter on in vitro models is an exception, and compares the TEER values of different cell types, including cells derived from iPSCs and immortalized endothelial cells.
Second, caution is advised before accepting any of the numerical figures quoted here, especially if they contain a micro or milli. For example, on page 320, they say a glioma typically contains 1×106 cells and weighs 10 grams (!), but can contain 1×1011 cells and weigh 100 grams before becoming symptomatic. There are many howlers like this throughout the book.
Other than these two issues—lots of the facts are incorrect and the presentation is overly optimistic—this is a good way to get started on the BBB, once you've finished off both of William A. Pardridge's books. These are now out of date, and we're waiting for his next one.
The Blood Brain Barrier and Inflammation (Lyck and Enzmann, eds, Springer,
2017)
This one has lots of photomicrographs and EM images of cells. It's oriented almost exclusively toward the cell biology, with only superficial discussions of pharmacological ways of transporting stuff across the BBB. There are brief discussions of how the BBB is affected by various diseases in which neuroinflammation is involved, such as meningitis, Huntington's disease, and glioma.
The Blood Brain Barrier: Biology and Research Protocols (Nag, ed, Humana,
2003)
This one gives detailed, step-by-step protocols on techniques that were once commonly used back in the time B.C. (before CRISPR). It's divided into six sections:
It's hopelessly out of date (especially the cell culture models and the molecular and genetic techniques), although the surgical, perfusion, and endothelial cell isolation techniques are still used, and those are well illustrated. In fact, I've encountered some labs that still do things this way, even in 2018.
Pharmacology of the Blood Brain Barrier: Targeting CNS Disorders (Advances in
Pharmacology, vol. 71) (TP Davis, ed., Elsevier, 2014)
This is an outstanding compilation of articles by prominent researchers in the field. The BBB's unique function is mostly dependent on its biochemistry, so the chapters on ABC transporters, P-gp, and receptor-mediated transcytosis give a thorough understanding of its function. There are also interesting chapters on PGE2 and sterols. Most of the effort these days, especially in industry, is on bispecific antibodies, and the chapter by Danica Stanimirovic et al. is particularly informative about the protein engineering that goes into making these babies, and the relative merits of bsAbs vs other approaches. If you read only one book on the BBB, this should be it. It's halfway between a book and a journal volume, and many academic libraries will have an electronic version.
That said, none of these books will bring you to the state of the art. Most of the research on the BBB is done by big biotech companies, and little of it ever gets published. Suffice it to say that they're way ahead of what's printed in any of these books.
nov 7, 2018. updated nov 23, 2018