Genetic Engineering & Biotechnology News

JUL 2017

Genetic Engineering & Biotechnology News (GEN) is the world's most widely read biotech publication. It provides the R&D community with critical information on the tools, technologies, and trends that drive the biotech industry.

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Angelo DePalma, Ph.D. Interest in nonnatural peptide drugs has waxed and waned over the past 30 years. The science has been fascinating, but delivery and pharmacokinetic issues remain. During the 1990s, Affymax popularized libraries of short peptides immobilized on inert substrates, but these peptides never led to novel therapeutic molecules or strategies. Now, Bicycle Therapeutics has taken up the "peptide challenge" by rolling out an improved pep- tide expression platform. The company was launched in 2009 to follow up discoveries made by Gregory Win- ter, Ph.D., who was then deputy director of the MRC Centre for Optimizing the Delivery of Peptide- Based Therapeutics At times, biological categorization has gone awry, re- sulting in famous gaffes (Aristotle himself said that spi- ders had six legs and thus qualified as insects)—yet the practice has endured. More recently, biological categorization was taken up by Charles Darwin, who distinguished between splitters and lumpers. Splitters, he said, are "those who make many species," whereas lumpers are "those who make few." Today, categorization is reaching ever deeper into the stuff of life. For example, it is establishing catego- ries based on differences in gene expression that occur from cell to cell. To find these differences, latter-day Aristotles and Darwins are relying on a new technique: RNA sequencing, or RNA-seq. It promises, as did ear- lier exercises in categorization, to reveal new entities and previously unknown relationships among them. For example, it may distinguish cell subtypes that are more or less significant at different stages of develop- ment, or in different states of health and disease. Originally, RNA-seq was more of a lumper. It be- gan with bulk RNA-seq approaches, which measure average gene expression levels across cell populations. Increasingly, however, RNA-seq is becoming more of a splitter. The ultimate in transcriptome-level splitting is single-cell RNA-seq technology. Bulk RNA-seq and single-cell RNA-seq technolo- gies are both capable of providing deep, rapid, and unbiased analyses of the transcriptome, and both are becoming routine in the study of gene expression. Sin- gle-cell RNA-seq, however, surpasses bulk RNA-seq in terms of the kinds of information it can generate. It is single-cell RNA-seq that can identify novel see page 18 Richard A. Stein, M.D., Ph.D. Categorization has preoccupied biologists going back to the days of classical Greece, when no less a figure than Aristotle classified living things by asking successive narrowing questions such as, "Is it animal or vegetable?" and "How many legs does it have?" RNA-Seq: Less Lumping , More Splitting July 2017 GEN ROUNDUP Watch This 3D Cell Culture Space 10 Accelerating Novel Therapeutic Discovery 30 Top Trends in Tissue Engineering 35 see page 24 Dwain Dsouza What do you do when you have a chronic or even crip- pling disease that you happened to get just because you inherited it? As little as three decades ago, you would have been stuck with the disease with no hope for a cure. Today, however, you might look forward to a new cure. The promise of fixing these genetic blunders of nature with one or a few treatments is close to becom- ing a reality. Since it was conceptualized in the 1970s, gene ther- apy has had its ups and downs. In 1990, it was first used to treat Gene Therapy: A New Twist on an Old Helix see page 32 Leading the Way in Life Science Technologies Tocagen is developing Toca 511, an injectable vector that pro- vides a gene for an enzyme that can activate a 5-fluorocytosine (5-FC)-containing prodrug. Toca 511 selectively infects brain tumor cells, where 5-FC, an anticancer agent, is released. In this image, which shows a section of mouse brain, healthy and Toca-511- infected tumor cells appear in white and brown, respectively. At the University of Wisconsin–Madison, single-cell RNA-seq was used to study regulators of human embryonic stem cell differentiation. Specifically, a transcriptomic signature was identified that helped establish a time frame for a cell- fate decision. The inset shows human H1 cells transitioning toward a primitive streak state marked by the expression of transcription factor BRACHYURY (blue). (G1 phase: red; G2/M phase: green.) The main image is a snapshot from the same experiment, but it is stained differently. (BRACHYURY: purple.; G1 phase: red; G2/M phase: green; DNA: blue.) This snapshot reveals various cell-cycle phases and gene-expression states. It also captures variability in nucleus size and cell-cell contact.

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