Be Your Own Fountain of Youth: Using Your Cells for Regenerative Medicine

Chasing the Holy Grail of Cell Therapy

Helen Albert, Labtech.eu

Biotech entrepreneur Darrin Disley, ex-CEO and co-founder of the successful Cambridge gene editing biotech Horizon Discovery, has a new quest — creating the perfect cell therapy. He spoke to me about his position as CEO of new biotech Mogrify and why he thinks now is a good time to get into cell therapy.

Following the meteoric rise of Horizon Discovery from a small startup in 2007 to a company of 500 people and a market cap of more than €445M, Disley decided to step down as CEO of the gene editing company in February 2018. After taking a year off to travel and “get fit and healthy” he is now back in Cambridge and firmly back on the biotech scene to head up a new cell therapy biotech.

Mogrify, which has recently raised a seed round of €3.3M to kick start its technology development, specializes in transforming one type of cell into another. The key difference from other cell transformation methods is that the company can find the chemical recipe needed to flip one adult cell into another adult cell type, without transforming it into a stem cell first.

“If you could take a cell from one part of the body and turn it into any other cell at any other stage of development for another part of the body, you effectively have the Holy Grail of regenerative medicine,” enthused Disley.

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Consumer Genomics Breast Cancer Test FAIL

23andMe DTC Breast and Ovarian Cancer Risk Test Misses Almost 90 Percent of BRCA Mutation Carriers

Julia Karow, GenomeWeb

SEATTLE (GenomeWeb) – A study led by researchers at Invitae has found that 23andMe's direct-to-consumer BRCA test, which tests for three common variants in the BRCA1 and BRCA2 genes and is authorized by the US Food and Drug Administration, misses almost 90 percent of BRCA mutation carriers, both in those with and those without a personal or family history of cancer. 

In addition, it misses almost 20 percent of BRCA mutations in those of self-reported Ashkenazi Jewish descent because it doesn't test for them.

The results of the study, which looked at data from almost 125,000 de-identified individuals who had been referred to Invitae for diagnostic testing with one of the firm's cancer risk tests, was presented yesterday at the American College of Medical Genetics and Genomics annual meeting by Edward Esplin,Dian a clinical geneticist at Invitae.

Esplin told GenomeWeb that the study, which did not mention 23andMe by name, was meant to criticize a screening strategy with an FDA-authorized DTC test that appears to have limited clinical utility rather than to criticize 23andMe for offering the test.

In his presentation, he pointed out that the FDA's authorization for the test last year "sounds more like a warning than an approval." FDA cautioned that the test, which examines three founder mutations in the BRCA genes that are common in the Ashkenazi Jewish population, does not assess more than 1,000 other known BRCA mutations, so a negative result does not rule out someone is a mutation carrier. It also advises that positive test results should not be used to determine any treatments without confirmatory testing and genetic counseling. 

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Cancer evading the Immune System, covered in the New York Times

Cancer’s Trick for Dodging the Immune System

Matt Richtel, The New York Times

Cancer immunotherapy drugs, which spur the body’s own immune system to attack tumors, hold great promise but still fail many patients. New research may help explain why some cancers elude the new class of therapies, and offer some clues to a solution.

The study, published on Thursday in the journal Cell, focuses on colorectal and prostate cancer. These are among the cancers that seem largely impervious to a key mechanism of immunotherapy drugs.

The drugs block a signal that tumors send to stymie the immune system. That signal gets sent via a particular molecule that is found on the surface of some tumor cells.

The trouble is that the molecule, called PD-L1, does not appear on the surface of all tumors, and in those cases, the drugs have trouble interfering with the signal sent by the cancer.

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Looking Everywhere for Cancer Drugs

Nature’s Bounty: Revitalizing the Discovery of New Cancer Drugs from Natural Products

Cancer Currents Blog

Dr. Grkovic has spent the last several years intimately involved in improving processes for analyzing products of nature—from marine creatures to soil-dwelling fungi to plant leaves—to see whether chemical compounds within them might be starting blocks for new cancer drugs. (The Natural Products Support Group is part of the Frederick National Laboratory for Cancer Research, an NCI-sponsored contractor-operated facility.)

The work has been part of an ambitious, Cancer MoonshotSM-funded initiative, called the NCI Program for Natural Products Discovery (NPNPD), to make it easier for other researchers to mine nature for leads on new cancer drugs.

A big part of that story has taken place in the well-worn home of NCI’s Natural Products Branch, on the NCI campus in Frederick, MD.

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"Elite" stem cells help dominate the reprogramming niche

Not all stem cells are created equal

Researchers have discovered a population of cells – dubbed to be “elite” – that play a key role in the process of transforming differentiated cells into stem cells. The finding has important implications for regenerative medicine.

Stem cells have the ability to transform into specialized cells – from lung to brain. Stem cells are common in embryos, but within the last 15 years, a technique called cell reprogramming has enabled scientists to turn mature cells back into so-called pluripotent stem cells, with the power to develop into any cell type.

While reprogramming is well understood, less is known about the intricacies of how individual reprogramming cells behave in a population setting. Researchers found a group of cells that appear to have a competitive advantage in reprogramming. The research is published in Science.

The team used cells extracted from mouse skin, known as mouse embryonic fibroblasts (MEFs). They used DNA-barcoding technologies to give each MEF a unique tag, track individual cells during reprogramming and associate them with their parent population. They also used computational modelling to help understand the complex data generated and to make predictions that were tested in the lab.

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Nanopore pioneers ultrafast tumor analyses

Same-day genomic and epigenomic analysis of brain tumors

via GIPHY

A plethora of technologies are currently required to assess different genomic and epigenomic alterations; however, the associated costs and long turnaround times combined with extensive infrastructure and training requirements have, to date, hindered their implementation1 . To address these challenges, Dr. Philippe Euskirchen and co-workers at the ICM Brain and Spine Institute, France, assessed the potential of nanopore sequencing technology to deliver comprehensive and cost-effective characterisation of genetic alterations in brain cancer samples — including analysis of copy number (CN) alterations, epigenetic base modifications, and single nucleotide variations (SNVs)1,2. Furthermore, all nanopore sequencing workflows were designed to go from sample to result within a single day.

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Selective Serotonin reuptake of by Chromatin

Mood-Altering Messenger Goes Nuclear

Francis Collins, NIH Director's Blog

Serotonin is best known for its role as a chemical messenger in the brain, helping to regulate mood, appetite, sleep, and many other functions. It exerts these influences by binding to its receptor on the surface of neural cells. But startling new work suggests the impact of serotonin does not end there: the molecule also can enter a cell’s nucleus and directly switch on genes.

While much more study is needed, this is a potentially groundbreaking discovery. Not only could it have implications for managing depression and other mood disorders, it may also open new avenues for treating substance abuse and neurodegenerative diseases.

To understand how serotonin contributes to switching genes on and off, a lesson on epigenetics is helpful. Keep in mind that the DNA instruction book of all cells is essentially the same, yet the chapters of the book are read in very different ways by cells in different parts of the body. Epigenetics refers to chemical marks on DNA itself or on the protein “spools” called histones that package DNA. These marks influence the activity of genes in a particular cell without changing the underlying DNA sequence, switching them on and off or acting as “volume knobs” to turn the activity of particular genes up or down.

The marks include various chemical groups—including acetyl, phosphate, or methyl—which are added at precise locations to those spool-like proteins called histones. The addition of such groups alters the accessibility of the DNA for copying into messenger RNA and producing needed proteins.

In the study reported in Nature, researchers led by Ian Maze and postdoctoral researcher Lorna Farrelly, Icahn School of Medicine at Mount Sinai, New York, followed a hunch that serotonin molecules might also get added to histones [1]. There had been hints that it might be possible. For instance, earlier evidence suggested that inside cells, serotonin could enter the nucleus. There also was evidence that serotonin could attach to proteins outside the nucleus in a process called serotonylation.

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CliffNotes genome another Synthetic Lifeform

First computer-generated genome could lead to custom synthetic lifeforms

Scientists at ETH Zurich have created the first fully computer-generated genome of a living organism. The brand new genome, named Caulobacter ethensis-2.0, was built by essentially cleaning up and simplifying the natural code of a bacterium called Caulobacter crescentus. For now it exists as one large DNA molecule and not a living organism itself, but the team says this is a huge step towards creating completely synthetic life and medicinal DNA molecules.

Over a decade ago, a team led by geneticist Craig Venter created the first "synthetic" bacterium, which was basically a digital copy of the Mycoplasma mycoides genome. That was then implanted into recipient cells and found to be a viable version of the real creature, even being able to self-replicate.

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Single-Nucleus RNA Sequencing and its variants

Single-Nucleus RNA Sequencing (sNuc-seq) Applications

By P Surat, Ph.D. Reviewed by Michael Greenwood, M.Sc.

In earlier studies investigating RNA or DNA, all the cells of a population were pooled together to collect information. However, the diversity and complexity of various cell types are becoming increasingly clear. Single nucleus RNA sequencing techniques have been developed to sequence the RNA present in single cells.

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Consumer sequencing startup hope to rival 23andMe

A Silicon Valley startup just launched a DNA-based health test that could be a big competitor to 23andMe

• On Tuesday, DNA testing startup Helix launched a new test that looks at your risk of diseases like breast cancer, colon cancer, and high cholesterol.

• You can buy the test online for $260, but it must be approved by a physician.

• Helix partnered with clinical diagnostics company PerkinElmer to create the test, which includes genetics counseling.

• The test also uses a type of sequencing that some experts say all DNA-based health tests should use.

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Blood tests versus biopsies

Could a simple blood test replace the invasive tissue biopsy?

Answer: It’s complicated …

Jake Siegel / Fred Hutch News Service

For years, the idea seemed as far-fetched as a fairy tale.

Once upon a time, there was a tumor cell that died. It’s innards spilled out into the bloodstream of the body where it had lived. The owner of that body went to a doctor and got a blood draw for a test, which identified the cell’s floating DNA fragments as cancer. The doctor then drew up a personalized treatment plan based on those bits of DNA, and the patient lived happily ever after …

The appeal of a simple blood test to detect and analyze cancer is obvious. It could replace the necessary evil of tissue biopsies — invasive, often risky and painful procedures to collect tumor cells with a needle or through surgery. A vial of blood sounds like a better trade than a chunk of tissue.

Recently, the idea of these so-called “liquid biopsies” seems less like a fantasy. 

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Cleveland Clinic Commentary for Cancer Screening

Personalizing guideline-driven cancer screening

Gautam Mankaney, MD Carol A. Burke, MD, FACG, FACP, FASGE

Cleveland Clinic Journal of Medicine (Commentary)

Reports of cancer date back thousands of years to Egyptian texts. Its existence baffled scientists until the 1950s, when Watson, Crick, and Franklin discovered the structure of DNA, laying the groundwork for identifying the genetic pathways leading to cancer. Currently, cancer is a leading global cause of death and the second leading cause of death in the United States.

In an effort to curtail cancer and its related morbidity and mortality, population-based screening programs have been implemented with tests that identify precancerous lesions and, preferably, early-stage rather than late-stage cancer.

Screening for cancer can lead to early diagnosis and prevent death from cancer, but the topic continues to provoke controversy.

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Gene-Edited Anolis Lizards

UGA scientists create world’s first gene-edited lizards

A group of University of Georgia researchers led by geneticist Douglas Menke has become the first in the world to successfully produce a genetically modified reptile—specifically, four albino lizards—using the CRISPR-Cas9 gene-editing tool. The team’s results, which appeared online March 31, have been submitted for peer review.

“Reptiles are very understudied in terms of their reproductive biology and embryonic development,” said Menke, associate professor in the department of genetics. “There are no good methods to manipulate embryos like we can easily do with mammals, fish or amphibians. To our knowledge, no other lab in the world has produced a genetically altered reptile.”

Gene manipulation using CRISPR typically involves injecting gene-editing solutions into an animal’s newly fertilized egg or single-cell embryo, causing a mutation in the DNA that is reproduced in all subsequent cells. However female reptiles can store sperm in their oviducts for long periods, making it difficult to pinpoint the exact moment of fertilization. Also, the physiology of their fertilized eggs, which have pliable shells with no air space inside, presents challenges for manipulating embryos without damaging them.

Working with the species Anolis sagrei, commonly called the brown anole, Menke’s team overcame these challenges by microinjecting CRISPR proteins into multiple immature eggs, or oocytes, still located in the lizards’ ovaries. Targeting the tyrosinase gene, they successfully injected 146 oocytes from 21 lizards, then waited for the oocytes to be fertilized naturally. Within a few weeks, they realized their goal: four offspring displaying the telltale trait of albinism, which results when tyrosinase is inactivated.

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OncoCell Presents Noninvasive Blood-Based Assay for Prostate Cancer

OncoCell Announces Late-Breaking Poster Presentation at AACR 2019 on a Noninvasive Blood-Based Assay for Prostate Cancer Prognosis

ATLANTA--(BUSINESS WIRE)--Apr 1, 2019--OncoCell MDx, a company developing novel noninvasive diagnostic and prognostic tests, will present results from a feasibility study of a new prostate cancer prognostic assay in a late-breaking poster session at the American Association of Cancer Research (AACR) Annual Meeting tomorrow. The study demonstrates that the blood-based immunogenomics RNA expression assay provides a prognostic summary comparable to that of prostate biopsy.

OncoCell’s Subtraction-Normalized Expression of Phagocytes (SNEP) based platform, invented by Professor Amin Kassis, while at Harvard Medical School, uses a proprietary algorithm to interrogate changes in gene expression of two immune cell types consequent to prostate cancer including phagocytic (CD14) and non-phagocytic (CD2) cells, filters out intrinsic genomic variation not related to the disease, and identifies and validates prostate cancer-specific signatures. A study of blood samples from 713 prostate cancer patients showed the platform provides a prognostic summary including tumor Gleason grade distribution, size/volume and heterogeneity that is comparable to prostate biopsy information, and that it stratifies patients with aggressive disease that need life-saving treatment from those with indolent disease.

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New Genome Assembler Makes Progress on Fundamental Problem

Assembly of long, error-prone reads using repeat graphs

Mikhail Kolmogorov, Jeffrey Yuan, Yu Lin & Pavel A. Pevzner

Nature Biotechnology (Research Article)

Abstract—Accurate genome assembly is hampered by repetitive regions. Although long single molecule sequencing reads are better able to resolve genomic repeats than short-read data, most long-read assembly algorithms do not provide the repeat characterization necessary for producing optimal assemblies. Here, we present Flye, a long-read assembly algorithm that generates arbitrary paths in an unknown repeat graph, called disjointigs, and constructs an accurate repeat graph from these error-riddled disjointigs. We benchmark Flye against five state-of-the-art assemblers and show that it generates better or comparable assemblies, while being an order of magnitude faster. Flye nearly doubled the contiguity of the human genome assembly (as measured by the NGA50 assembly quality metric) compared with existing assemblers

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AI for variant classification and clinical reporting

Fabric Genomics Announces AI-based ACMG Classification Solution for Genetic Testing with Hereditary Panels

SEATTLE--(BUSINESS WIRE)--Apr 1, 2019--Fabric Genomics will launch a new solution this week for variant interpretation and clinical reporting, allowing clinical laboratories to dramatically accelerate turnaround times. This new software solution, called Fabric Hereditary Panels with ACE (AI Classification Engine), will debut at the American College of Medical Genetics and Genomics (ACMG) annual meeting in Seattle, Washington. It incorporates an extensively validated, automated ACMG classification engine, enabling laboratories to speed up accurate variant classification and clinical reporting.

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Clinical application of tumor evolution analysis

Translating insights into tumor evolution to clinical practice: promises and challenges

Matthew W. Fittall and Peter Van Loo

Genome Medicine (Review Article)

Abstract—Accelerating technological advances have allowed the widespread genomic profiling of tumors. As yet, however, the vast catalogues of mutations that have been identified have made only a modest impact on clinical medicine. Massively parallel sequencing has informed our understanding of the genetic evolution and heterogeneity of cancers, allowing us to place these mutational catalogues into a meaningful context. Here, we review the methods used to measure tumor evolution and heterogeneity, and the potential and challenges for translating the insights gained to achieve clinical impact for cancer therapy, monitoring, early detection, risk stratification, and prevention. We discuss how tumor evolution can guide cancer therapy by targeting clonal and subclonal mutations both individually and in combination…

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Next Generation Sequencing Assay for Blood Cancers

Researchers Develop Targeted Next Generation Sequencing Assay for Myeloid Neoplasms

via GIPHY

Researchers from South Korea said they have developed a next-generation sequencing (NGS) assay to detect somatic mutations, translocations, and germline mutations in a single assay for the purpose of supplementing or replacing conventional tests in patients with myeloid neoplasms.

Writing in a recent issue of PLoS One, the researchers said were able to discover a high frequency of germline mutations in cancer predisposition genes. Patients with these mutations exhibited different clinical characteristics, suggesting that germline predisposition has significant clinical implications.

Lowering the barrier to stem cell therapies

Team develops iPS cells with less chance of being rejected

Researchers developed a way to produce induced pluripotent stem (iPS) cells with a lower risk of rejection, overcoming a major obstacle to the clinical application of regenerative medicine.

A team headed by Akitsu Hotta, a junior associate professor at Kyoto University’s Center for iPS Cell Research and Application (CiRA), used genome editing technology to change the structure of genes to create safer iPS cells. The findings were published in the U.S. scientific journal Cell Stem Cell on March 8.

Although using donor blood of third-party individuals results in cheaper and faster iPS cell production, the procedure poses a higher risk of immune rejection after transplantation.

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Deep sequencing of Adult Gliomas has promising results

Prospective Clinical Sequencing of Adult Glioma

Siyuan Zheng, Kristin Alfaro-Munoz, Wei Wei, Xiaojing Wang, Fang Wang, Agda Karina Eterovic, Kenna R Mills Shaw, Funda Meric-Bernstam, Gregory N Fuller, Ken Chen, Roel G. Verhaak, Gordon B. Mills, W.K. Alfred Yung, Shiao-Pei Weathers and John F. de Groot

Molecular Cancer Therapeutics (Research Article)

Abstract—Malignant gliomas are a group of intracranial cancers associated with disproportionately high mortality and morbidity. Here we report ultradeep targeted sequencing of a prospective cohort of 237 tumors from 234 patients consisting of both glioblastoma (GBM) and lower-grade glioma (LGG) using our customized gene panels. We identified 2485 somatic mutations including single nucleotide substitutions and small indels using a validated in-house protocol. Sixty one percent of the mutations were contributed by 12 hypermutators. The hypermutators were enriched for recurrent tumors, had comparable outcome, and most were associated with temozolomide exposure. TP53 was the most frequently mutated gene in our cohort, followed by IDH1 and EGFR. We detected at least one EGFR mutation in 23% of LGGs, which was significantly higher than 6% seen in TCGA, a pattern that can be partially explained by the different patient composition and sequencing depth. IDH hotspot mutations were found with higher frequencies in LGG (83%) and secondary GBM (77%) than primary GBM (9%). Multivariate analyses controlling for age, histology, and tumor grade confirm the prognostic value of IDH mutation. We predicted 1p/19q status using the panel sequencing data, and received only modest performance by benchmarking the prediction to Fluorescent In Situ Hybridization (FISH) results of 50 tumors. Targeted therapy based on the sequencing data resulted in three responders out of 14 participants. In conclusion, our study suggests ultradeep targeted sequencing can recapitulate previous findings and can be a useful approach in the clinical setting.

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