Cells Weekly – October 2, 2016

by Alexey Bersenev on October 3, 2016 · 0 comments

in notes

Cells Weekly is a digest of the most interesting news and events in stem cell research, cell therapy and regenerative medicine. Cells Weekly is posted every Sunday night!

1. First live birth using mitochondrial replacement technique
International team of researchers reported this week first live birth of a boy, using mitochondrial replacement technique – spindle nuclear transfer (SNT). His mother is a carrier of mutated mitochondrial DNA, known as Leigh syndrome. SNT procedure took place in Mexican clinic, child was born in New York to a couple from Jordan.
New Scientist broke the news, causing an explosion in mass media:

Zhang has been working on a way to avoid mitochondrial disease using a so-called “three-parent” technique. In theory, there are a few ways of doing this. The method approved in the UK is called pronuclear transfer and involves fertilising both the mother’s egg and a donor egg with the father’s sperm. Before the fertilised eggs start dividing into early-stage embryos, each nucleus is removed. The nucleus from the donor’s fertilised egg is discarded and replaced by that from the mother’s fertilised egg.
But this technique wasn’t appropriate for the couple – as Muslims, they were opposed to the destruction of two embryos. So Zhang took a different approach, called spindle nuclear transfer. He removed the nucleus from one of the mother’s eggs and inserted it into a donor egg that had had its own nucleus removed. The resulting egg – with nuclear DNA from the mother and mitochondrial DNA from a donor – was then fertilised with the father’s sperm.

Many researchers think that the case could change attitude toward mithochondrial replacement therapy and impact regulations. On the other hand, this “first case” caused some criticism for taking advantage of weak regulatory system (or its absence) and for ethical issues.

2. Engineering T cellbots
Wendell Lim’s lab from USCF continue to explore the ways to control CAR T-cells precisely, using “magic of synthetic biology”. Previously, his group described synthetic Notch receptor on CAR T-cells. In the new Cell paper, they made polyfunctional synNotch T-cells, responsive to environment.

We show that synNotch receptors can be used to sculpt custom response programs in primary T cells: they can drive a la carte cytokine secretion profiles, biased T cell differentiation, and local delivery of non-native therapeutic payloads, such as antibodies, in response to antigen. SynNotch T cells can thus be used as a general platform to recognize and remodel local microenvironments associated with diverse diseases.

Importantly, new type of synNotch T-cell can make drugs, such as check point inhibitors. Lim started to use new term “cellbots” in the media.

Read more from NIHilist’s Immunology blog.

3. Results of Phase 2 CAR-T cell trial in lymphoma
US-based company Kite Pharma announced preliminary results of their Phase 2 clinical trial, assessing efficacy of CD19 CAR-T cells in patients with lymphomas. Results of this trial is a big deal, because it is a pivotal trial, data from which will be used for BLA submission to FDA and market approval. The results are positive, but many people expected better outcomes. Combined data from different types of lymphoma demonstrated 44% of overall survival and 39% of complete remission. The caveat is – at 3 months readout. There is some skepticism in the field about durability of responses. Field is suffering right not from relapse rates. It is also unclear whether FDA will be OK about 3-month data or will ask to wait until 6-month readout.
Read nice summary on EP Vantage.

4. Bioprinted hyperelastic material for bone healing
Researchers from Northwestern University created new synthetic biomaterial with osteoregenerative properties. Importantly, the material could be printed rapidly on demand:

We evaluated HB in vivo in a mouse subcutaneous implant model for material biocompatibility (7 and 35 days), in a rat posterolateral spinal fusion model for new bone formation (8 weeks), and in a large, non-human primate calvarial defect case study (4 weeks). HB did not elicit a negative immune response, became vascularized, quickly integrated with surrounding tissues, and rapidly ossified and supported new bone growth without the need for added biological factors.

Read more from Science News.

5. Ups and downs of NgAgo genome editing
Kate Qin Zhao wrote on a Medium great essay about new genome editing technique, called NgAgo. What I like especially about this piece is an emphasis on role of social media in reproducibility efforts:

Through this global replication effort of NgAgo, we can see more clearly that, the way we share information on scientific research has forever changed in the age of social media.
Social media has become a great vehicle to quickly promote a scientific discovery/invention. But, it also could be a double-edged sword. Once the message is out, if there is a problem, hiding it from the public will no longer be easy.

Highly recommended!

6. Ogawa-Yamanaka Stem Cell Prize 2016
Gladstone Institutes held this week annual ceremony for Ogawa-Yamanaka Stem Cell Prize award. This year awardee was stem cell researcher from Harvard University Douglas Melton.
Here is Melton’s talk:

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Cells Weekly – September 25, 2016

by Alexey Bersenev on September 26, 2016 · 0 comments

in notes

Cells Weekly is a digest of the most interesting news and events in stem cell research, cell therapy and regenerative medicine. Cells Weekly is posted every Sunday night!

Announcement 1
Annual 2016 Ogawa-Yamanaka Stem Cell Prize award ceremony will take place on Wednesday, September 28 at 11am PST at the Gladstone Institutes (San Francisco, California). If you will not be in San Francisco, you can watch live-stream of the event online.
The Ogawa-Yamanaka Stem Cell Prize recognizes individuals whose original translational research has advanced cellular reprogramming technology for regenerative medicine. Recipients receive an unrestricted prize of $150,000 USD

Announcement 2
All “cell reprogramming crowd” gathered for 3 days in Berkley, California for Cell Symposia “10 Years of iPS“. There is a quite good activity on twitter, so you can follow it live via hashtag #csstemcells16.

1. FDA public hearing on regulation of cell therapy
Last week FDA organized first public hearing in the history of cell therapy field. I did not attend, but was watching it via live webcast. Here is my coverage:

The reason for the hearing was unexpectedly high number of controversial comments about 4 guidances that FDA released in 2014-2015. These guidances are aimed to clarify FDA’s current thinking on regulatory classification of Human Cell Tissue Products (HCT/P) and included definitions of “same surgical procedure“, “homologous use“, “minimal manipulation” and “adipose tissue-derived products“. The latest guidance was released almost a year ago, so it was long overdue to have this public hearing. Unusual public participation and controversial comments made FDA to reschedule this event from April to September and split it for 2 days. You can watch recorded webcast here and here.

I’d like to invite you all to discuss it with me!

2. CRISPR gene editing of normal human embryos
NPR released the news this week about the first attempt to use CRIPS gene editing on healthy human embryos in Sweden:

The step by the developmental biologist Fredrik Lanner makes him the first researcher known to attempt to modify the genes of healthy human embryos. That has long been considered taboo because of safety and ethical concerns.

Lanner, however, says he is initially planning only to study the modified embryos for the first seven days of their growth and would never let them develop past 14 days. The potential benefits could be enormous, he argues.
“Having children is one of the major drives for a lot of people,” Lanner says. “For people who do struggle with this, it can tend to become an extremely important part of your life.”

3. Results of 2 cellular immunotherapy trials
I’d like to bring your attention to two recently published clinical studies in cancer cellular immunotherapy field. First, defined composition of CAR T-cell therapy of non-Hodgkin’s lymphoma by Fred Hutchinson Cancer Center. Important conclusion here is that good efficacy and cell persistence was observed after addition of fludarabine in conditioning regimen. Sorting of CD8+ cell subsets (bulk versus central memory) was useless.
Second study is small safety trial, which assessed so-called memory-like NK cells in acute myeloid leukemia (AML). Besides safety endpoints, 4/9 patient went to complete remission – very good preliminary result for NK cell field.

4. The history of the first bone marrow transplant
Jovana Drinjakovic of the Signals blog wrote a wonderful story about the first bone marrow transplant cases in adults:

It was a failed transplant that saved his life. In 1958, Radojko Maksic became the first person to receive a bone marrow graft from a stranger, after he was accidentally exposed to a lethal dose of radiation in Belgrade, in what was then Yugoslavia. He still lives in Belgrade, almost 60 years after the procedure.

Highly recommended to read whole piece!

5. Assessment of young blood plasma in Alzheimer Disease model
Stanford’s neuroscientist Tony Wyss-Coray, who studied effects of “young blood” on brain rejuvenation, has started company (Alkahest) and clinical trial 2 years ago. However, preclinical data for this particular trial were not released. Now, Wyss-Coray’s group published a rationale study for Alzheimer Disease trial:

Aged mutant amyloid precursor protein mice with established disease showed a near complete restoration in levels of synaptic and neuronal proteins after exposure to young blood in parabiosis (synaptophysin P = .02; calbindin P = .02) or following intravenous plasma administration (synaptophysin P < .001; calbindin P = .14).

6. Testing of pancreatic organoids in transplantation model
Organoids field is moving to in vivo models. It is important test for the safety, engraftment and function of organoids. Researchers from Germany created human pancreatic organoids from pluripotent stem cells and tested them in xenomodel:

Upon orthotopic transplantation into immunodeficient mice, these organoids form normal pancreatic ducts and acinar tissue resembling fetal human pancreas without evidence of tumour formation or transformation. Finally, we implemented this unique phenotyping tool as a model to study the pancreatic facets of cystic fibrosis (CF). For the first time, we provide evidence that in vitro, but also in our xenograft transplantation assay, pancreatic commitment occurs generally unhindered in CF.

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Cells Weekly – September 5, 2016

by Alexey Bersenev on September 5, 2016 · 0 comments

in notes

Cells Weekly is a digest of the most interesting news and events in stem cell research, cell therapy and regenerative medicine. Cells Weekly is posted every Sunday night!

1. Amniotic Therapies versus FDA
US-based manufacturer of amniotic tissue-derived products for regenerative medicine Amniotic Therapies has received warning letter from FDA. This letter is warning company for many reasons, but two major are the following: (1) misbranding and marketing their product as 361 HCT/P, which they are drugs and must be regulated as 351 drugs and (2) contamination of one lot with mycoplasma and 4 adverse events as a consequence. The letter was issued on August 17 and it gives only 15 days for response. Apparently, company response was not satisfactory and FDA may order to cease operation (I was not able to find documented proof of it). The company responded by lawsuit against FDA (“to block FDA’s order”) – you can read details here. Few hours after filing lawsuit, Texas federal judge barred FDA from “shuttering” of company “over perceived sanitary problems”. The company said that contamination was doctor’s fault, who administered the product to patient without reading package insert.

2. Update on Macchiarini’s investigation
Karolinska University Hospital, which investigated ethical research misconduct by tissue engineering pioneer Paolo Macchiarini, has released report this week. Hospital, basically admitted that Macchiarini’s hire should not even happen in the first place:

“Much went wrong in connection with Macchiarini’s transplants of synthetic trachea,” said Asplund in a statement when he presented the results of the inquiry on Wednesday.
“Macchiarini should not even have been employed at the hospital. There were shortcomings in how the decisions about the transplants were made and how they acted on existing laws. The hospital has a big task ahead to ensure patient safety and trust.”

Some leadership positions were suspended. Read more details on For Better Science blog:

The Asplund report found gross violations of medical ethics, patient right, even recruitment processes when analysing the history of the scandal around the Italian surgeon. Unlike repeatedly declared by both KI and KS, Macchiarini’s trachea transplants were not medical emergencies and not compassionate care cases…

Also read some details from Nature News:

The affair has damaged trust in clinical research in Sweden, says the report, but the hospital is already taking steps to improve things. For example, it has prepared internal guidelines for experimental clinical methods and for how to deal with whistle-blowers.
Acting KI vice-chancellor Karin Dahlman-Wright said in a statement that “it would be extremely regrettable if the Karolinska Institutet had exerted any kind of pressure” in hiring Macchiarini. The KI will publish its own report on the case on 5 September. Macchiarini and his lawyer declined to comment on the latest report.

3. Credit for discovery of medical optogenetics
Anna Vlasists by STAT News wrote a great piece about development of medical optogenetics field and its pioneers. The major theme of her article is who should be credited for key discoveries and pioneering the field. We all know that Karl Deisseroth and Ed Boyden are widely credited as pioneers, but another researcher – Zhuo-Hua Pan, conducted key experiments first. Pan just got “less lucky” with his publication (it stuck in reviews for 2 years), so, Deisseroth and Boyden published first:

So Pan and Dizhoor wrote a paper about their work and submitted it to Nature on November 25, 2004, according to the submission letter Pan shared with STAT. The editors at Nature suggested they send it on to a more specialized journal called Nature Neuroscience, which rejected it. Early the next year, Pan sent the paper to the Journal of Neuroscience, where it was reviewed but then again rejected.

Why didn’t Pan’s paper get published first? He may never know the answer. After Boyden’s paper came out, Pan wrote to the editor at Nature Neuroscience asking how they could have rejected his paper but published Boyden’s.
In her response, the editor replied that while the papers were similar, Boyden et al. presented theirs as a new technology rather than as a scientific finding. Pan’s paper, it seemed, was too narrow, only focusing on using channelrhodopsin to restore vision, while Boyden’s paper took the broad view of thinking of channelrhodopsin as a tool for neuroscience in general.

Anna Vlasists discusses the problem with delaying of publications and crediting scientists for discoveries. We can draws parallels with CRISPR patents/ crediting war, since both technologies have a “Nobel Prize potential”.

As for the invention itself, some scientists say Pan may not have had the big, award-worthy vision that Deisseroth and Boyden had. Stefan Herlitze, one of the others who was scooped for the first publication about channelrhodopsin in neurons, said, “Of course I have to say, Deisseroth and Boyden, they really developed the field further.”
Boyden echoed this. “Karl and I were very interested in the general question of how to control cell types in the brain,” he said. “In recent years, we worked to push these molecules to their logical limits.”
So maybe it doesn’t matter who invented optogenetics, just who has stretched science’s boundaries the furthest.
Asked whether he deserves the recognition that Boyden and Deisseroth have enjoyed, Pan declined to answer. He later told STAT that Deisseroth “also did a very excellent job, no doubt. But he’s also very lucky because if our paper was ahead of him, the story would be different. We would have gotten more credit.”

Highly recommended to read!

4. Role of hematopoietic stem cells in steady state hematopoiesis
It is remain not very clear if all blood cell types are developed from one hematopoietic stem cell (HSC) in normal hematopoiesis, because of limitations of conventional transplantation models. In these models, host bone marrow severely damaged by lethal irradiation and donor cells can skew hematopoietic repopulation in toxic marrow environment. Recent studies, challenged significant contribution of HSCs in immune reconstitution. Results of very recent study, which used more appropriate model of steady state hematopoiesis, were published in Immunity.

Inducible genetic labeling showed that transgene-expressing HSCs gave rise to other phenotypic HSCs, confirming their top position in the differentiation hierarchy. The labeled HSCs rapidly contributed to committed progenitors of all lineages and to mature myeloid cells and lymphocytes, but not to B-1a cells or tissue macrophages.

5. Accelerated aging of immune system after hematopoietic stem cell transplantation
Researchers demonstrated that hematopoietic stem cell transplantation in patients with hematological malignancies significantly accelerates aging of immune system. They measured aging marker p16 on blood cells before and after of chemotherapy with hematopoietic stem cell transplantation. Turns out that expression of this aging marker on T-cells was significantly higher after transplant. Effect was especially profound in autologous transplant and in patient with more cycles of chemotherapy. The senior author said:

“Many oncologists would not be surprised by the finding that stem cell transplant accelerates aspects of aging,” said the study’s senior author Norman Sharpless, MD, director of UNC Lineberger and the Wellcome Distinguished Professor in Cancer Research. “We know that years after a curative transplant, stem cell transplant survivors are at increased risk for blood problems that can occur with aging, such as reduced immunity, increased risk for bone marrow failure, and increased risk of blood cancers. What is important about this work, however, is that it allows us to quantify the effect of stem cell transplant on molecular age.”

6. Cancer stem cell database
Overview of new public database for identification of characterization of cancer stem cell is described this week in Stem Cells TM.

Herein, we describe the Cancer Stem Cells Therapeutic Target Database (CSCTT), the first online database to provide a rich bioinformatics resource for the display, search, and analysis of structure, function, and related annotation for therapeutic targets of cancer stem cells. CSCTT contains 135 proteins that are potential targets of CSCs, with validated experimental evidence manually curated from existing literatures.

Link to database.

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bonus:

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Clinical Cell Processing News – part 4, 2016

by Alexey Bersenev on August 31, 2016 · 0 comments

in clinical lab

Clinical Cell Processing News is a series about new protocols, products and techniques for clinical-grade cell processing and manufacturing. Cell processing devices, cultureware, bioreactors, GMP-grade reagents, cell separation techniques. This series is posted every 2 months.

FEATURED:
Identification and validation of multiple cell surface markers of adipose-derived MSCs for GMP manufacturing (Stem Cell Res Ther) FREE

Our study establishes that clinical-grade AMSCs expanded in hPL represent a homogeneous cell culture population according to classical markers,. Additionally, we validated new biomarkers for further AMSC characterization that may provide novel information guiding the development of new release criteria.

1. A rapid sonication based method for preparation of stromal vascular fraction (Bioimpacts) FREE

The current protocol based on the sonication-mediated cavitation is a rapid, safe and cost-effective method, which is proposed for isolation of SVF and of course ADSCs cultures in a large scale for the clinical trials or therapeutic purposes.

2. Validation of Quantum Cell Expansion system for clinical-scale production of human periosteum derived stem cells (Cytotherapy):

The data show that the hollow fiber bioreactor is capable of robustly expanding autologous hPDCs on a clinical scale (yield between 316 million and 444 million cells starting from 20 million after ± 8 days of culture) while maintaining their in vitro quality attributes compared with the standard flask-based culture.

3. Protocol for GMP manufacturing of ADV-specific T-cells using G-Rex flasks (Cytotherapy):

Thirty-eight of 40 products (95%) met all release criteria. Median purity of the cell product was 88.3% CD3+ cells with a median yield of 2.9 × 107 CD3+ cells. Potency analyses showed a median ADV-specific interferon (IFN)γ response of 5.9% of CD3+ and 2345 IFNγ spot-forming cells/million.

4. Development of potency assay for immunomodulatory function of MSC (Immunol Lett):

The aims of this study were to develop an optimised rapid turnaround, flow cytometry-based whole-blood assay to monitor MSC potency and to validate its application to MSC immunomodulation. A protocol for short-term LPS stimulation of anti-coagulated whole blood samples followed by combined surface CD45/CD14 and intracellular TNF-α staining was initially developed for analysis on a 4 colour desktop cytometer.

5. A novel method for adipose-derived cell isolation with increased cell yield (Plast Reconstr Surg):

We have developed a protocol that maximizes the yield of ASCs derived from lipoaspirate. We demonstrate that NM-ASCs have increased osteogenic and adipogenic potential in vitro and are non-inferior to CM-ASCs in terms of their ability to generate bone and fat in vivo.

6. Feasibility of manufactturing CAR-CD171 cells for cell therapy of neuroblastoma (Clin Cancer Res)

Manufacturing of lentivirally transduced CD4+ and CD8+ CE7-CAR T cell products under GMP was successful in 4 out of 5 consecutively enrolled neuroblastoma patients in a phase I study. All four CE7-CAR T cell products demonstrated in vitro and in vivo anti-tumor activity. Conclusion: Our preclinical assessment of the CE7 epitope on CD171 supports its utility and safety as a CAR T cell target for neuroblastoma immunotherapy.

7. Clinical-scale production of T-regs from ALS patients (Cytotherapy)

In vitro expansion of Tregs for 4 weeks in the presence of GMP-grade anti-CD3/CD28 beads, interleukin (IL)-2 and rapamcyin resulted in a 25- to 200-fold increase in their number and restored their immunoregulatory activity. Collectively, our data facilitate and support the implementation of clinical trials of adoptive therapy with ex vivo expanded and highly suppressive Tregs in patients with ALS.

8. Validation of MyStem EVO kit for cell purification of the fluid portion of lipospirates (Plast Reconstr Surg):

The alternative procedures enabled comparable yields; the kit rapidly isolated lipoaspirate fluid comprising a homogenous cell population with adipose stem cell immunophenotype, bilineage potential, and efficient osteoinductive and angioinductive features.

9. Review: Scalable microcarrier-based manufacturing of mesenchymal stem/stromal cells (J Biotechnol)

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Cells Weekly – August 28, 2016

by Alexey Bersenev August 29, 2016 notes

Cells Weekly is a digest of the most interesting news and events in stem cell research, cell therapy and regenerative medicine. Cells Weekly is posted every Sunday night! 1. Stem cell blog carnival Canadian the Signals blog hosted for the first time hosted stem cell blog carnival: Think of a blog carnival as a single […]

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Cells Weekly – August 21, 2016

by Alexey Bersenev August 22, 2016 notes

Cells Weekly is a digest of the most interesting news and events in stem cell research, cell therapy and regenerative medicine. Cells Weekly is posted every Sunday night! 1. “Money back guarantee” for cell-gene therapy drug High prices for marketed cell/ gene therapy products is a hot and controversial topic. For example, approved gene therapy […]

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Cells Weekly – August 7, 2016

by Alexey Bersenev August 8, 2016 notes

Cells Weekly is a digest of the most interesting news and events in stem cell research, cell therapy and regenerative medicine. Cells Weekly is posted every Sunday night! 1. Anti-aging trial uses young blood New clinical trial (sanctioned by FDA!), launched by company Ambrosia has captured a lot of attention this week. It uses “young […]

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Will Prodigy change everything?

by Alexey Bersenev August 6, 2016 cell product

In the last decade advanced cell therapies are becoming highly commercialized. Industry developers, in general, favor so-called centralized model of cell product manufacturing/ delivery. In centralized model, one big manufacturing plant produces and delivers many many (thousands) products within a country or internationally. In the last few years, Biotech and cell therapy companies (Novartis, Kite […]

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Cells Weekly – July 31, 2016

by Alexey Bersenev July 31, 2016 notes

Cells Weekly is a digest of the most interesting news and events in stem cell research, cell therapy and regenerative medicine. Cells Weekly is posted every Sunday night! 1. Dispelling the myth of premature aging of cloned animals Very important study, proving that cloned animals don’t have serious health problems with age, was published this […]

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Cells Weekly – July 24, 2016

by Alexey Bersenev July 25, 2016 notes

Cells Weekly is a digest of the most interesting news and events in stem cell research, cell therapy and regenerative medicine. Cells Weekly is posted every Sunday night! 1. CRISPR clinical trial in China Nature reported this week about the world’s first clinical trial, involved CRISPR gene edited cells. The trial is planning to start […]

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