Cells Weekly – May 15, 2016

by Alexey Bersenev on May 16, 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!

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1. ISSCR Guidance for translation of stem cell research
It was probably the most discussed news this week. The International Society for Stem Cell Research (ISSCR) has released a final version of updated Guidance for Stem Cell Science and Clinical Translation. I’ve written about some sides of it earlier today.
Two issues from this Guidance were mostly covered and discussed by the scientific media and public – ISSCR’s position on gene editing of human embryos and over-hyping the field by researchers. Here I’ve picked some articles about the Guidance:
Global standards for stem-cell research (Nature)
Confronting stem cell hype (Science)
Human-embryo editing now covered by stem-cell guidelines (Nature News)
Stem cell organization to scientists: Enough with the hype! (ArsTechnica)
Science hype is too common. Stem cell researchers say it needs to stop. (Vox)

2. “Secret meeting” on synthetic genomes
As reported by few media sources, Harvard held “by invite only” scientific meeting with focus on synthetic genomes. About 130-150 stakeholders were invited, but it was closed for press and “no tweeting allowed”. The meeting was co-hosted by prominent geneticist George Church. Excerpt from STAT:

Church said that the meeting was originally going to be “an open meeting with lots of journalists engaged.” It was supposed to be accompanied by a peer-reviewed article on the topic. But, he said, the journal (which Church declined to identify) wanted the paper to include more information about the ethical, social, and legal components of synthesizing genomes — things that were discussed at the meeting.

“This is a major journal,” Church said. “So we can’t push them around.”

They chose to respect the embargo.

This is laughable! Science is religion, embargo is a thing to worship!

Such secrecy triggered a wave of criticism from peers. Very prompt critical response was written by Drew Endy and Laurie Zoloth. Excerpt from NYT:

Dr. Endy, though invited, said he deliberately did not attend the meeting at Harvard because it was not being opened to enough people and was not giving enough thought to the ethical implications of the work.

I’d also recommend you to read a blog post by Andy Balmer – Synthetic Biology’s Second World.

3. Complications of cell therapy for eye disease
Two recent reports from US and S. Korea describe unexpected complications of “stem cell therapy” by autologous bone marrow cells for retinitis pigmentosa. The first report published in JAMA Ophthalmology describes central retinal artery occlusion, developed immediately after cell therapy procedure (performed outside of clinical trial settings). The second case describes epiretinal membrane formation in one eye ( of two treated) after cell injection:

New thick epiretinal membrane (ERM) with extensive macular pucker was found on her left eye. She underwent pars plana vitrectomy and membranectomy. After biopsy, many CD34-positive stem cells were detected in ERM specimen.

The authors “suspect neuronal differentiation of bone marrow cells”.

4. In vivo genome editing for mapping of intracellular proteins
New technique for labeling and imaging of intracellular proteins in vivo in the brain was developed by researchers from Max Planck Florida Institute for Neuroscience:

Here, we developed a simple and generalizable technique to image endogenous proteins with high specificity, resolution, and contrast in single cells in mammalian brain tissue. The technique, single-cell labeling of endogenous proteins by clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9-mediated homology-directed repair (SLENDR), uses in vivo genome editing to insert a sequence encoding an epitope tag or a fluorescent protein to a gene of interest by CRISPR-Cas9-mediated homology-directed repair (HDR).

More and more magic becomes reality with CRISPR/Cas9 editing!

5. Interview with Chad Cowan
Eric Topol of MedScape recently interviewed Harvard’s professor, stem cell researcher Chad Cowan. I’d highly recommend you to want this ~20 min video. Cowan said a lot of interesting things about potential of iPS cells in medicine and genomic editing. My favorite excerpt on CRISPR-based gene editing:

Dr Topol: Except for the patents. What are you going to do about that?
Dr Cowan: If I got to decide, I can tell you what I would do. There are two warring patent families. One was out first and the other thinks it had the original art. They are going to battle in the courts for years to try to decide this. As a rational person, I would say, “We both agree that there are important things in both patents. Why don’t we make an agreement about cross-licensing so that we can all move ahead and make the medicines? But I’m not the person making the decision.

Dr Topol: Do you think the intellectual property–patent issue will hold the field back?
Dr Cowan: I don’t think so. Some very smart business people taught me this: In terms of therapeutics, no patent has ever prevented a therapeutic from getting to a human. It turns out that the way a lot of the people who back companies financially think about it is like a speeding ticket. In the worst case, if you get your technology—and it’s using somebody else’s patent—into the clinic and you say, “I’m about to commercialize it,” then you just have to write the check to pay for the access to the activity. No one holding a patent would prevent you from actually therapeutically curing someone. In fact, there is a way that you can use an injunction in the United States to require that.

6. Report on Harvard’s MSC Colloquium
The report was recently posted on HSCI web-site.

There is a widening gap between academic and commercial enterprises in regards to the clinical trial process, said Arnold Caplan, PhD, from Case Western University, who coined the term mesenchymal stem cell in 1991 and is considered a founder of the field. “The whole value system of running a clinical trial and being judged against standard of care, which is a pharmacological concept, is completely illogical.”

7. Fresh reviews:
From discovery to approval of an advanced therapy medicinal product-containing stem cells, in the EU (Regen Med)
Growing human organs in pigs—A dream or reality? (Theriogenology)

8. New methods and protocols:
Transplantation dose alters the differentiation program of HSC (Cell Rep)
Whole organism lineage tracing by genome editing (BioRxiv)
Generation of stem cell-derived β-cells from patients with type 1 diabetes (Nat Commun)
Rapid induction of cerebral organoids from human iPS cells (Stem Cells TM)
Optimization of liver decellularization (PLoS ONE)

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Not Lost in Translation: ISSCR Guidelines 2016

by Alexey Bersenev on May 15, 2016 · 0 comments

in regulation

One of the biggest news this week was a release of final updated 2016 version of the Guidelines for Stem Cell Science and Clinical Translation (you can download pdf version here). Everyone who involved in stem cell research and/ or clinical translation of stem cell-based interventions should read this document! I think, ISSCR did a great job in getting this information together thorough task force of 25 experts and feedback from 85 external consultants. There was a public commenting period, so, everyone had an opportunity to contribute to the guidelines development. Importantly, new ISSCR Guidelines include a number of controversial issues, which were not previously covered comprehensively, such as gene editing of human embryos, mitochondrial replacement therapy, donor consent for pluripotent stem cell banking, patient sponsored and pay-to-participate trial and other topics.

A few general comments:

  1. There is no clear scope in the Guidelines. So, sometimes it is not very clear to what category of “stem cell stakeholders” does it apply. The Guidelines indicate that “code of conduct applicable to all researchers in the field”. But what about patients and advocates, industry professionals, regulators and policy makers, communicators and physicians? The Guidelines frequently calls for collaboration of all stakeholders, but specifically written for stem cell researchers.
  2. It is not very clear to me if the Guidelines apply to all types of stem cells. When I was reading it I had a feeling that the whole document was written with pluripotent stem cells (iPS/ ES cells) in mind. Some statements and recommendations may not be applicable to adult stem cells in general or to minimally manipulated cells, for example (emphasis mine):

    Recommendation 3.2.2.2: Risks for tumorigenicity must be rigorously assessed for any stem cell-based product, especially if extensively manipulated in culture, genetically modified, or when pluripotent.

    So, if I have subset of CD34+/CD45RA- cells, freshly isolated from apheresis and infused within few hours, why ISSCR wants me to do tumorigenicity studies? FDA will be fine without it.

  3. Lack of definitions. One of the most frequently used in Guidelines term “stem cell-based interventions” begs a definition. “Stem cell-based product” is not defined as well. It is missing, even in glossary section. What is “stem cell intervention”? Is administration of bone marrow mononuclear cell fraction in myriad of diseases stem cell-based intervention? Some developers say yes, some – no. It will be good to know ISSCR position on it.
  4. Cell processing and manufacture section mostly describes current regulatory requirements, some of which are not even guidelines, but laws. I think, in this case would be better just refer directly to particular FDA/EMA documents, where cell manufacturing requirements outlined much better.
  5. ISSCR is very very critical of (1) patient-sponsored and pay-to-participate trials and (2) clinical translation via medical innovation, but the ISSCR may be (rarely) OK with it in certain situation with number of conditions. So, the Guidelines are not very permissive, but not totally prohibitive for these controversial things.

Now I’d like to share some quotes and my thoughts about new topics from the document, related to transparency, data reporting and communication. Let’s start from transparency:

Researchers and clinicians pursuing stem cell research should promote timely exchange of accurate scientific information to other interested parties. Researchers should communicate with various public groups, such as patient communities, to respond to their information needs, and should convey the scientific state of the art, including uncertainty about the safety, reliability or efficacy of potential applications. Researchers and sponsors should promote open and prompt sharing of ideas, methods, data, and materials.

That’s exactly what stem cell researchers do not do or do very badly right now. They do not promote exchange of information to another parties, they do not communicate it to anywhere, unless asked by mass media, journalists or institution’s PR office. Will stem cell researchers change with this Guidelines?

Next quote (emphasis mine):

Accompanying the enormous attention paid by the media and the public to cellular therapies is the problematic trend towards initiation of clinical application and trials far in advance of what is warranted by sound, rigorous, and dispassionately assessed preclinical evidence.

So, too much attention from public is problematic for stem cell researchers, because they feel pressure to start trials earlier than evidence of benefit are available. The blame on public pressure, not on researchers themselves. Don’t they want to be the first, have a “scientific glory”, enjoy grants money and attention? And what about regulators safeguard, who gives “green light” to the trials? Next quote from section 3.5.2:

The stem cell research community benefits from providing patients and the general public access to scientific information, opportunities to participate in clinical research, and treatment.

So, public attention could be problematic, but it is beneficial for stem cell researchers. Next, the series on communication-related things that stem cell researchers do not do:

The research community is encouraged to engage interactively with the public through responsive outreach and communications and by providing opportunities for public comment and feedback.

Researchers should make efforts to seek timely corrections of inaccurate or misleading public representations of research projects, achievements, or goals.

For the first time ISSCR provides recommendations on how to not hype your research:

… forward-looking statements on inherently uncertain developments, such as predictions on time required until clinical application, the likelihood of product approval, or speculation on the potential economic impact of currently unrealized technologies, must be accurate,circumspect and restrained.

For potentially sensitive or high-profile cases, it is advisable to seek additional comments from independent experts to ensure objectivity and balance.

Clinical trials designed to evaluate safety and/or efficacy should not be described using language that might suggest the primary intent to be the delivery of care, as this may lead to confusion about the risk/benefit profile of study participation (see also Recommendation 3.3.3.1). Communications about ongoing studies should explain that clinical efficacy is not established, and that the results may reveal the intervention to be ineffective or, in some cases, harmful.

Now, I’d like to bring your attention to transparency and results reporting. Trials registration and adverse events reporting are not only signs of transparency (as per Guidelines), but also regulatory requirements.

Preclinical studies—at least those that are aimed at confirming the core principles and hypotheses underwriting a development program— should be reported in full regardless of whether they confirm, disconfirm, or are inconclusive with respect to the hypothesis they are testing. The guidelines recognize that publication may reveal commercially sensitive information and therefore acknowledge that a reasonable delay is permissible to secure appropriate protections of intellectual property. Nevertheless, preclinical studies supporting a trial should be published before the first report of trials.

Recommendation 3.3.7.3: Researchers should promptly publish aggregate results regardless of whether they are positive, negative or inconclusive. Studies should be published in full and according to international reporting guidelines.

Journal editors should accommodate publication of inconclusive and disconfirmatory findings.

Not really happening now… We see publications of negative or inconclusive results very rarely.

My favorite statement on transparency:

Researchers and sponsors should promote open and prompt sharing of ideas, methods, data, and materials.

There is no “open and prompt sharing”! Closed access/ paywalls to publication is prohibiting it. Patents/ IP are prohibiting it. Publishing culture and “fear to be scooped” is prohibiting it.

ISSCR, as did many other organizations in the past, calls for cooperation and collaboration on development of (1) all kind of standards, (2) clinical safety/ outcome registries and (3) public repositories/ banks of stem cell lines:

Recommendation 5.1: Researchers, industry and regulators should work towards developing and implementing standards on design, conduct, interpretation, and reporting of research in stem cell science and medicine.

I’d like to conclude on mechanisms of the Guidelines enforcement:

These ISSCR guidelines should be upheld and enforced through standards of academic, professional, and institutional self-regulation.

I was trying to read new ISSCR 2016 Guidelines very critically and thoroughly. It captures almost all broad and controversial aspects of translational stem cell research in very concise way. Overall, it is a great document – must have on your desk.

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Cells Weekly – May 8, 2016

by Alexey Bersenev on May 9, 2016 · 0 comments

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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!

BRTI

1. Advances in growing human embryos in vitro and 14-days rule debate
This week researchers from Rockefeller University and U of Cambridge reported improved in vitro system for culture of early human embryos. By letting embryos to self-organize in culture, researchers able to maintain them up to 13 days. This is the longest culture maintenance of normal human embryos, ever reported before. Since many countries have a ban on in vitro manipulations with human embryos after 14 days of age, these studies triggered a new wave of debate on so-called “14-days rule”. You can read great coverage of this discussion by Nature (here and here), STAT and Science magazine.

Revisiting the 14-day rule might tempt people to try to rationalize or attack the philosophical coherence of the limit as an ethical tenet grounded in biological facts. This misconstrues the restriction. The 14-day rule was never intended to be a bright line denoting the onset of moral status in human embryos. Rather, it is a public-policy tool designed to carve out a space for scientific inquiry and simultaneously show respect for the diverse views on human-embryo research.

2. Gene therapy of rare brain disease – conference report
Science magazine reported about presentation of preliminary results from gene therapy of rare brain disease on American Society of Gene and Cell Therapy annual meeting:

… all but one of 17 boys with adrenoleukodystrophy (ALD) remained relatively healthy for up to 2 years after having an engineered virus deliver into their cells a gene to replenish a missing protein needed by the brain. The results, which expand on an earlier pilot study, bring this ALD therapy one step closer to the clinic.

94% efficacy is very impressive! The study is sponsored by US-based cell-gene therapy company Bluebird Bio. There was no press release by company.

3. The first approved gene therapy drug in Europe stuck in clinical adoption
Antonio Regalado of MIT Tech Review wrote a provocative piece on Glybera – the world’s most expensive drug. Gene therapy Glybera was approved in Europe in 2012 and since that was only used once. The reason – a price tag of ~$1M Euro. He interviewed physician from Germany, who prescribed Glybera for the first time:

But when the Berlin physician Elisabeth Steinhagen-Thiessen wanted to give a patient Glybera last fall, it wasn’t so easy. She says she had to prepare a submission as thick as “a thesis” for German regulators and then personally call the CEO of DAK, one of Germany’s large sickness funds, or insurers, to ask him to pay the $1 million price tag.

Last September, she gave 40 injections to the muscles of a 43-year-old woman with an ultra-rare disease called lipoprotein lipase deficiency. Such patients don’t process fat correctly. “You draw blood and you are astonished, there is no red blood, it’s cream,” Steinhagen-Thiessen says. One symptom is debilitating abdominal pain. Her patient had been hospitalized more than 40 times.

A dose of Glybera contains trillions of viruses harboring correct copies of the lipoprotein lipase gene. And Steinhagen-Thiessen says the treatment, at Charite Hospital in Berlin, was a success. The woman hasn’t been back to the emergency room since the treatment and is now “living like you and me.”

Very interesting piece, highly recommended!

Also read Antonio’s piece on soon-to-be approved another gene therapy in Europe.

4. Fetal tissue transplantation in Parkinson’s brain – a quarter of a century outcome
Researchers from Sweden, who performed the first fetal neural tissue transplantations in Parkinson’s disease about 25 years ago, reported very interesting pathology case. They described histopathological findings on autopsy material, obtained from unique patient, who underwent procedure 24 years ago:

The patient enjoyed major clinical benefits for at least a decade after transplantation. After a quarter of a century, complete graft-derived dopaminergic reinnervation was still evident in the transplanted putamen. α-Synuclein–positive inclusions, some with the appearance of typical Lewy bodies, were present in 11–12% of the grafted dopaminergic neurons, reflecting spread of pathology from the host brain to the transplant. The clinical improvements were gradually lost from 14 y posttransplantation, indicating that even extensive graft-derived dopaminergic reinnervation loses its efficacy in a severely degenerating brain.

5. The future of senolytic therapy
Senolytic therapy is elimination or altering of senescent cells to achieve tissue regeneration and/or anti-aging effect. Nick Dragojlovic wrote a nice brief overview of senolytic therapy on the Signals blog:

The race is on, and at least two biotechnology companies have been founded to tackle the problem: Oisin Biotechnologies, which is pursuing an innovative gene therapy approach; and, UNITY Biotechnology, a company backed by the Mayo Clinic and ARCH Venture Partners that has leading senescent cell researchers like Judith Campisi as advisors. Other companies are sure to follow in short order now that senescent cells have been demonstrated in an animal model to be a promising target for regenerative medicine. It may take a number of years for senolytic drugs to make their way from animal models to the clinic, but when they do become available, they have the potential to be transformative.

6. Changes in gene expression profile of mesenchymal stromal cells after freeze
SamplingScience blog covered recent study, published in Stem Cells and Development:

Turns out that the profiles between fresh and cryopreserved MSCs did not differ much. In fact, the profiles of fresh and cryopreserved MSCs from the same donor were more similar to each other than those of fresh MSCs that were obtained from different donors. Less than 300 genes were differently expressed, up to only 10fold. Compare that to the over 2,000 genes that were up to 720fold differently expressed between fresh mesenchymal stem cells and those located in murine lung tissue!

7. Mesenchymal stromal cells enhance tumor growth via tumor-derived exosomes
One of potential mechanisms of tumor growth promotion by mesenchymal stromal cells was recently described by researchers from China. Exosomes, released by tumor endow MSCs with ability to enhance tumor growth:

We report here a critical role of tumour cell-derived exosomes in endowing bone marrow-derived MSCs (BM-MSCs) with a tumour-favourable phenotype. Tumour cell-derived exosomes affected neither the growth factor production nor the immunosuppressive property of MSCs; rather, they endowed MSCs with a strong ability to promote macrophage infiltration into B16-F0 melanoma or EL-4 lymphoma.

8. New methods and protocols:
Review: Modeling pancreatic cancer with organoids (Trends in Cancer)
mTORC1 inhibition enhances human pluripotent stem cells differentiation toward blood progenitors (Stem Cell Rep)
Propagation of nephron progenitors derived from embryos and pluripotent stem cells (Cell Rep)
Optimization of iPS cell generation from urine-derived cells (Stem Cell Rep)
Single factor hepatic reprogramming facilitated by small molecules (Cell Rep)

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Results of very interesting survey were published in the latest issue of Cell Stem Cell. It was the first big social media survey about attitudes to human genome editing technologies, performed by researchers. Here is methodology of the study:

We developed an online survey about attitudes to the application of genome engineering in different contexts (see Supplemental Information), translated it into a range of international languages, and recruited study respondents via social media (Facebook, Twitter, Google, and WeChat). We designed the survey to capture pertinent demographic details and gauge agreement for specific applications of gene editing using a five-point Likert scale. Specifically, we investigated whether there was greater support for gene editing in life-threatening diseases when compared to debilitating diseases; whether the acceptance of this technology varied between its use on human embryos or on terminally differentiated somatic cells; and whether it should be applied to non-health-related traits such as intelligence, strength, or physical appearance.

The authors surveyed ~12.5k people from 185 countries. About 80% of people provided demographic data. The median age of participants was 24 years old! Here is on piece of results:

(click to view full and enlarged figure)

As you can see from the picture, survey participants (since median age was 24, I’d call them “youth”) are very very supportive of using gene editing technologies for treatment of diseases. No matter life threatening or debilitating diseases. No matter editing of cells from adults, children or embryos!

I think, for the youth – social media generation, the results somewhat expected. One of the most interesting parts of the survey was using of gene editing for altering of “non-disease characteristics”, in other words – for enhancement and selection of desired traits. Even though 43% of participants disagreed with this, the other half was not sure or agreed:

There was substantially less support among our respondents for the use of gene editing technology for non-health-related purposes (Figure 2), with 43.3% (3,884/8,961) of people stating they disagreed with this application. Participants who agreed with it (2,402/8,961, 26.8%) were questioned about the specific non-health-related traits they would modify with gene editing. Intelligence had the highest acceptance at 68.0%, followed by strength or sporting ability (58.4%) and appearance (51.3%).

Some other interesting demographic-related findings from the study:

  • “males were more likely to agree with all gene editing applications” than females
  • older age group was more likely to disagree
  • people from countries with high GDP were more supportive applications for diseases and less supportive for non-health related use
  • level of education was highly correlative to support of gene editing for health-related applications

Among many surveys on public perception of gene editing, I’d highly recommend to pay attention to this one, because it represents opinions of youth – a generation, which will implement these technologies in practice.

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Cells Weekly – May 1, 2016

by Alexey Bersenev May 2, 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. Vitamin increases mice lifespan via stem cells modulation mechanism International group of researchers have published very interesting study this week, where demonstrated that nicotinamide adenine dinucleotide […]

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Crude versus defined CAR T-cell therapy product

by Alexey Bersenev May 1, 2016 cell product

In the race for the most potent CAR T-cell therapy, there is a big interest to the issue of purity and composition of the final cell product. In this post, I’ll try to summarize the current knowledge about defined CAR T-cell products, based on two clinical studies, published this week. What is defined product and […]

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Cells Weekly – April 24, 2016

by Alexey Bersenev April 24, 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. Islets transplantation in diabetes is on a way to standard of care Human pancreatic islets transplantation in type 1 diabetes has been experimental procedure in the […]

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Clinical Cell Processing News – part 2, 2016

by Alexey Bersenev April 22, 2016 adipose

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: Review: Toward a scalable and consistent manufacturing process for the production of human MSCs (Cell Gene Ther Insights) […]

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Cells Weekly – April 17, 2016

by Alexey Bersenev April 18, 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. Therapeutic use of iPS cells from older people could be problematic Research team led by Shoukhrat Mitalipov, have published a study this week, where showed that […]

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Toward clinical translation of whole organ bioengineering

by Alexey Bersenev April 16, 2016 tissue engineering

The graph below illustrates the problem of donor organ shortage for transplantation in USA: In the last two decades, scientists offered a few potential solutions to this problem: (1) whole organ bioengineering (WOBE) via decellularization – recellularization (decell-recell), (2) xenotransplantation and (3) generation of exogenic human organs in animal chimeras. Since introduction of CRISPR-based genome […]

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