Stem Cell Clinic

Stem cell lines grown in lab dish may acquire mutations | Harvard … – Harvard Gazette

Photo by Hannah Robbins/HSCI

In a cross-school collaboration, Harvard researchers Steve McCarroll (left) and Kevin Eggan couple stem cell science with genetics and genomicsto advance the understanding of human brain illnesses. Their latest project identifiedmutations that stem cell lines acquire in culture.

Regenerative medicine using human pluripotent stem cells to grow transplantable tissue outside the body carries the promise to treat a range of intractable disorders, such as diabetes and Parkinsons disease.

However, a research team from the Harvard Stem Cell Institute (HSCI), Harvard Medical School (HMS), and the Stanley Center for Psychiatric Research at the Broad Institute of MIT and Harvard has found that as stem cell lines grow in a lab dish, they often acquire mutations in the TP53 (p53) gene, an important tumor suppressor responsible for controlling cell growth and division.

Their research suggests that genetic sequencing technologies should be used to screen for mutated cells in stem cell cultures, so that cultures with mutated cells can be excluded from scientific experiments and clinical therapies. If such methods are not employed it could lead to an elevated cancer risk in those receiving transplants.

The paper, published online today in the journal Nature, comes at just the right time, the researchers said, as experimental treatments using human pluripotent stem cells are ramping up across the country.

Our results underscore the need for the field of regenerative medicine to proceed with care, said the studys co-corresponding author Kevin Eggan, an HSCI principal faculty member and the director of stem cell biology for the Stanley Center. Eggans lab in Harvard Universitys Department of Stem Cell and Regenerative Biology uses human stem cells to study the mechanisms of brain disorders, including amyotrophic lateral sclerosis, intellectual disability, and schizophrenia.

The research, the team said, should not discourage the pursuit of experimental treatments but instead be heeded as a call to screen rigorously all cell lines for mutations at various stages of development as well as immediately before transplantation.

Our findings indicate that an additional series of quality control checks should be implemented during the production of stem cells and their downstream use in developing therapies, Eggan said. Fortunately, these genetic checks can be readily performed with precise, sensitive, and increasingly inexpensive sequencing methods.

With human stem cells, researchers can re-create human tissue in the lab. This enables them to study the mechanisms by which certain genes can predispose an individual to a particular disease. Eggan has been working with Steve McCarroll, associate professor of genetics at Harvard Medical School and director of genetics at the Stanley Center, to study how genes shape the biology of neurons, which can be derived from these stem cells.

McCarrolls lab recently discovered a common, precancerous condition in which a blood stem cell in the body acquires a pro-growth mutation and then outcompetes a persons normal stem cells, becoming the dominant generator of his or her blood cells. People in whom this condition has appeared are 12 times likelier to develop blood cancer later in life. The studys lead authors, Florian Merkle and Sulagna Ghosh, collaborated with Eggan and McCarroll to test whether laboratory-grown stem cells might be vulnerable to an analogous process.

Cells in the lab, like cells in the body, acquire mutations all the time, said McCarroll, co-corresponding author. Mutations in most genes have little impact on the larger tissue or cell line. But cells with a pro-growth mutation can outcompete other cells, become very numerous, and take over a tissue. We found that this process of clonal selection the basis of cancer formation in the body is also routinely happening in laboratories.

To find acquired mutations, the researchers performed genetic analyses on 140 stem cell lines 26 of which were developed for therapeutic purposes using Good Manufacturing Practices, a quality control standard set by regulatory agencies in multiple countries. The remaining 114 were listed on the National Institutes of Health registry of human pluripotent stem cells.

While we expected to find some mutations in stem cell lines, we were surprised to find that about 5 percent of the stem cell lines we analyzed had acquired mutations in a tumor-suppressing gene called p53, said Merkle.

Nicknamed the guardian of the genome, p53 controls cell growth and cell death. People who inherit p53 mutations develop a rare disorder called Li-Fraumeni Syndrome, which confers a near 100 percent risk of developing cancer in a wide range of tissue types.

The specific mutations that the researchers observed are dominant-negative mutations, meaning that when they are present on even one copy of p53, they are able to compromise the function of the normal protein, whose components are made from both gene copies. The exact same dominant-negative mutations are among the most commonly observed mutations in human cancers.

These precise mutations are very familiar to cancer scientists. They are among the worst p53 mutations to have, said Ghosh, a co-lead author of the study.

The researchers performed a sophisticated set of DNA analyses to rule out the possibility that these mutations had been inherited rather than acquired as the cells grew in the lab. In subsequent experiments, the Harvard scientists found that p53 mutant cells outperformed and outcompeted non-mutant cells in the lab dish. In other words, a culture with a million healthy cells and one p53 mutant cell, said Eggan, could quickly become a culture of only mutant cells.

The spectrum of tissues at risk for transformation when harboring a p53 mutation includes many of those that we would like to target for repair with regenerative medicine using human pluripotent stem cells, said Eggan. Those organs include the pancreas, brain, blood, bone, skin, liver, and lungs.

However, Eggan and McCarroll emphasized that now that this phenomenon has been found, inexpensive gene-sequencing tests will allow researchers to identify and remove from the production line cell cultures with worrisome mutations that might prove dangerous after transplantation.

The researchers point out in their paper that screening approaches to identify these p53 mutations and others that confer cancer risk already exist and are used in cancer diagnostics. In fact, in an ongoing clinical trial that is transplanting cells derived from induced pluripotent stem cells, gene sequencing is used to ensure the transplanted cell products are free of dangerous mutations.

This work was supported by the Harvard Stem Cell Institute, the Stanley Center for Psychiatric Research, the Rosetrees Trust, the Azrieli Foundation, Howard Hughes Medical Institute, the Wellcome Trust, the Medical Research Council, the Academy of Medical Sciences, and by grants from the NIH.

By Al Powell, Harvard Staff Writer | April 26, 2017

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Stem cell lines grown in lab dish may acquire mutations | Harvard ... - Harvard Gazette

Neurological Regenerative Medicine Unlocking the Potential of … – SelectScience

Source: http://www.123rf.com

Dr. Murdoch is a stem cell biologist with an interest in development and regenerative medicine. After completing post-doctoral training at Yale University, she took the role of Assistant Professor at Eastern Connecticut State University, where her time is split between teaching and researching nervous system development.

As our understanding of stem cells has increased, the possibility of using stem cell therapies to treat disease is on the horizon. Barbara Murdoch, Ph.D., Assistant Professor at Eastern Connecticut State University, is studying stem cells found in the olfactory epithelium (OE) with the aim of finding therapies for neurodegeneration.

Exclusive neurogenic niche: The olfactory epithelium

The OE is one of the few tissues in the body which is known to regenerate neurons, preserving our sense of smell throughout our lives.

Have you ever had the experience where you smell something and the scent evokes a memory from years back in time? asked Dr. Murdoch. This is because not only can the stem cells in the OE divide and differentiate to replace the lost neurons, but they can also recreate the exact same connection in the brain as the neuron they are replacing.

Dr. Murdoch explained how by studying these stem cells, she hoped to elucidate the environment and signaling molecules which restrict them to certain cell fates. The aim of her research is to direct neural stem/progenitor cells to create neurons in vitro. We can transplant neuronal precursor cells which are on their way to make neurons into patients, for example to help them recover after a stroke, said Dr. Murdoch.

Development of the olfactory epithelium approaches

One approach to understanding what dictates cell fate is to investigate the regions enriched for progenitors and determine their local microenvironment. The communication signals forming the microenvironment can be used to drive the production of new neurons from neuronal precursors in vitro. To investigate olfactory development, Dr. Murdoch carries out confocal microscopy using antibodies against numerous cell markers such as nestin, 3-tubulin and GFAP.

I was at a meeting when, just by chance, I came across a representative from Covance (now BioLegend) who had an anti-nestin antibody and was kind enough to give me a sample. When I tried it, it was brilliant in the olfactory epithelium and the brain, said Dr. Murdoch.

Dr. Murdoch published her findings in the 2008 Journal of Neuroscience paper, demonstrating that there were stem cell-like cells in the embryonic OE which are very similar to neural cells in the brain known as radial glia cells. Radial glia are responsible for the production of most if not all neurons in the brain. Previously, it was thought that radial glia cells were restricted to the central nervous system, but Dr. Murdochs research shows that they are also present in the OE, which is part of the peripheral nervous system.

The reason I think this was missed by so many other researchers was that the antibody that was typically used as a marker of neural stem cells, the anti-nestin antibody, worked well in the brain but not very well in the OE, Dr. Murdoch explained. However, the new antibody from BioLegend was targeting a different epitope, allowing it to identify and bind well to nestin expressed in the OE.

Dr. Murdoch described finding effective primary antibodies as a somewhat hit or miss process. Often when Im searching for antibodies, I try to get a sample and test it with the organism and tissue type Im using. When you find antibodies that work, you stick with them. Thats the reason why I stick with the antibodies from BioLegend, as they are so specific time and time again, Dr. Murdoch added.

The image shows differentiation into neurons (green) and glia (red). Blue indicates cell nuclei. Provided by Dr. Murdoch.

Future research and application in regenerative medicine approaches

Now an Assistant Professor at Eastern Connecticut State University, Dr. Murdoch is furthering her research by using chick embryos as a model to study how the OE develops.

Were trying to find pockets of progenitor cells and learn what the environmental influences surrounding those cells are in vivo, Dr. Murdoch explained.

This research has implications for regenerative medicine, where the same signals found in vivo can be recreated in vitro to make new neurons from neural precursors, derived either from human embryonic or induced pluripotent stem cells. Future work will aim to construct 3D scaffolds combined with signaling molecules and matrices to affect cell fate, Dr. Murdoch said.

Research such as Dr. Murdochs is contributing to an improved understanding of the signaling cascades found in neurogenic niches. Understanding the factors which decide cell fate and coordinate the generation of complex tissue is an important step in developing stem cell therapies to treat neurodegenerative states, such as Parkinsons disease, traumatic brain injury and stroke.

Dr. Murdochs work is funded by the CSU-AAUP.

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Henrietta Lacks And Modern Medicine’s Greatest Unpaid Debt – Huffington Post

On Saturday evening I, along with millions of other people, watched the premiere of Auntie Oprahs film, The Immortal Life of Henrietta Lacks, on HBO. At the beginning of the film, I was nestled in my bed, eating a bowl of popcorn. I knew the premise of the movie and seriously, who doesnt love a good Oprah Winfrey performance (and let me just say, as usual, she delivered). But by the middle of the film, I was no longer lying comfortably, instead I was sitting upright, slightly teary-eyed...and by the end, there was popcorn on the floor and I was standing in front my television, gripping my remote tightly and shaking my head in disbelief. I immediately scrolled through Facebook to see if I was alone, and just as I imagined, I wasnt.

Several people with skin like mine who watched the film felt just like I did. Dont get me wrong, the movie was well done and the acting was superb, but it did something that I wasnt expecting. It evoked emotions that are still somewhat difficult for me to articulate. Simply put, I hurt for Henrietta Lacks and her family.

As I watched the movie, I thought to myself, why didnt I learn more about Henny (Henny because shes now my auntie in my head) in school? From grades 7-12, I attended a health sciences magnet school. In college, I was a biology major. To say I know a little something about HeLa is an understatement, but I honestly dont recall hearing much about the owner of those magical cells. Yes, magical. Black girl magic isnt just a hashtag, you know. But I digress. Like many Black women, Henrietta Lacks was an unknown hero who, thanks to the book and subsequent film about her life, is no longer an obscure entity. However, unlike the three heroines in one of my favorite movies, Hidden Figures, Henriettas story did not have such a happy ending.

Henrietta was diagnosed with cervical cancer and died from the disease at the age of 31. As a result, she left a special legacy and five children whose lives would never be the same. But it wasnt her untimely death that shocked me as that was quite common back in the day. No, it was the blatant disregard for her basic human rights that I found so appalling. To which human right am I referring? Henrietta was not given the right to consent, and even though it was not required at that time, ethically, she should have been asked for the use of her cells.

Picture this. Youre a young woman, lying in a hospital bed, gravely ill and undergoing treatment for a disease you dont fully understand. There are doctors and nurses coming in and out of your room. They are talking to you, smiling at you, and poking you with needles. They spread your legs to take a piece of your cervix so they can figure out how to fix you. Its ok because you trust them. But not one time do they ask you if they can use the cells from your body to learn more about your disease. No one takes the time to explain to you how the use of your cells could possibly benefit others for years to come. And after you pass away, no one consults your grieving family members to obtain permission to continue the use of your cells.

Mrs. Lacks, we need your permission for something. Can we use the cells from your biopsy for research? Theres a possibility that you could help us understand this disease better. You could also be helping others.

I imagine a conversation like that with Henrietta would have sufficed, but that didnt happen. So lets not sugarcoat it. Henriettas cells were stolen. Her cells were taken and used to advance research and medical practices and she went virtually unknown for years. And to make matters worse, her family still has not been properly compensated. Unbelievable, I know. Now, some may wonder whats so great about Henriettas cells anyway. Why does her family deserve anything after all of this time? Well, let me explain.

Henrietta cells, i.e., HeLa, were unique. You may say she was an ordinary woman with extraordinary cells. HeLa cells are an immortalized cell line, meaning the cells can be reproduced infinitely in a lab. Her cells have aided in the advancement of science and modern medicine tremendously. For example, the cells were used to develop the polio vaccine. In addition, they have been instrumental in HIV and cancer research. Oh, but it doesnt stop there. These cells even paved the way for in vitro fertilization, and the list goes on and on. And while I am thankful for the progress Henriettas cells have afforded medical research, the treatment of Blacks as guinea pigs in the past has left a very bitter taste in my mouth.

Real talk. What occurred to Henrietta wasnt an isolated incident. We all know about the Tuskegee Experiment the time scientists used Black men as lab animals to study the effects of Syphilis but I wonder just how many stories like Henriettas and the Tuskegee Experiment are still untold? And why have the contributions of so many Blacks been undervalued or erased from the history books? And lastly, why is health equity still so difficult to attain in 2017. What do I mean by that last question? Well, for example, Black women are still dying from breast and cervical cancers at higher rates than other ethnic/racial groups. The same goes for Black men and prostate cancer. I could go on but you get the point. The fact is, I dont know the answers to these questions, and as a public health professional, I am working everyday to identify solutions. But what I do know is this, modern medicine has a huge unpaid debt. The creditors are the descendants of Mrs. Henrietta Lacks, and I, for one, think its time to pay up.

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Henrietta Lacks And Modern Medicine's Greatest Unpaid Debt - Huffington Post

Lonza US cell therapy plant slapped with FDA warning letter – FiercePharma

Swiss CDMO leader Lonza has had its cell therapy facility in the U.S. slapped with a warning letter after halting some production there two months ago because of sterility problems with a product it was producing for a client.

The company acknowledged the FDA action in its first-quarter earnings report Tuesday, saying that the warning letter was issued Monday for its facility in Walkersville, Maryland. The FDA had concerns about issues including validation and aseptic process simulations, the drugmaker said.

Lonza takes this issue seriously, and has already started to address all issues raised by the FDA, the company said.

Lonza first learned about the issue in December after product end-user notified the FDA of the issue, Lonza spokeswoman Constance Ward said in an email Tuesday. Lonza opened an investigation after confirming the sterility issue. She said the plant halted production of the product in the affected manufacturing area in early February, while also quarantining the inventory it had on hand.

"After inspecting both the customer of the product and the Walkerville operations, the FDA issued Lonza a warning letter that identified issues involving validation, aseptic process simulations, corrective and preventive actions, and environmental monitoring, Ward explained.

She said the company expects to have the problems resolved and FFM media manufacturing back online by mid-2017. The company had already begun a $7.6 million manufacturing upgrade at the facility, which Ward said is slated to be finished in 2018.

While the drugmaker said it expects the latest FDA action to have minimal impact on revenues of its Pharma & Biotech segment, it reported sales in the segment were softer in the first quarter because of the action. Without providing specific numbers, the contract manufacturer Tuesday reported that growth in that segment was driven by demand in mammalian manufacturing, as well as in clinical development and licensing.

This is not the first time that Lonza has faced FDA concerns about its biologics operations in the U.S. An API plant it had in Hopkinton, Massachusetts, was cited in 2011 over a plethora of problems, creating supply problems for a drug it manufactured there at the time for French drugmaker Ipsen. After struggling to get issues resolved, Lonza simply closed the plant and concentrated its biologics work at its extensive site in Visp, Switzerland.

Lonza is preparing to expand its Visp biologics capability further. It will break ground in the second half of the year on a new large-scale biologics production facility that it is building in partnership with Frances Sanofi. The companies announced in February that they would share the cost, and capacity, of a 270 million ($286.3 million) plant at Lonzas site in Visp.

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Lonza US cell therapy plant slapped with FDA warning letter - FiercePharma

Cellectis to Present at the American Society of Gene & Cell Therapy … – Yahoo Finance

NEW YORK--(BUSINESS WIRE)--

Regulatory News:

Cellectis (ALCLS.PA) (CLLS) (Alternext: ALCLS; Nasdaq: CLLS), a biopharmaceutical company focused on developing immunotherapies based on gene edited CAR T-cells, today announced that data on its gene-edited allogeneic off-the-shelf CAR T-cell immunotherapies (UCART) will be presented at the ASGCT 20th Annual Meeting. The meeting will be held from May 10th to 13th, 2017 in Washington, D.C., USA.

Oral presentation:

Development of Gene Edited Allogeneic CAR T-Cell Therapy Philippe Duchateau, PhD. Chief Executive Officer, Cellectis

Session: 300 - Clinical Advancement of Gene Editing-Moving New Science to the Clinic - Organized by the Clinical Trials and Regulatory Affairs Committee

Friday, May 12, 2017 from 8:35 AM to 9:10 AM EST Lincoln 2, 3, 4

Poster presentations:

176 - Genome-Wide Analysis of TALEN Activity in Primary Cells Brian Busser, Sonal Temburni, Aymeric Duclert, Philippe Duchateau and Laurent Poirot

Session: Gene Targeting and Gene Correction I Wednesday May 10, 2017 at 5:30 PM EST Exhibit Hall A & B South

114 - UCART22: An Allogeneic Adoptive Immunotherapy for Leukemia Targeting CD22 with CAR T-cells Anne-Sophie Gautron, Ccile Schiffer-Mannioui, Alan Marechal, Severine Thomas, Agnes Gouble, Laurent Poirot, Julianne Smith

Session: Cancer-Immunotherapy, Cancer Vaccines I Wednesday May 10, 2017 from 5:30 PM to 7:30pm EST Exhibit Hall A & B South

372 - Manufacturing of Gene-Modified Mouse CAR T-Cells Laurent Poirot, Brian Busser, Sonal Temburni, Philippe Duchateau

Session: Gene Targeting and Gene Correction II Thursday May 11, 2017 from 5:15 PM to 7:15 PM EST Exhibit Hall A & B South

About Cellectis

Cellectis is a biopharmaceutical company focused on developing immunotherapies based on gene-edited CAR T-cells (UCART). The companys mission is to develop a new generation of cancer therapies based on engineered T-cells. Cellectis capitalizes on its 17 years of expertise in genome engineering - based on its flagship TALEN products and meganucleases as well as its pioneering electroporation PulseAgile technology - to create a new generation of immunotherapies. CAR technologies are designed to target surface antigens expressed on cells. Using its life-science-focused, pioneering genome-engineering technologies, Cellectis goal is to create innovative products in multiple fields and with various target markets.

Cellectis is listed on the Nasdaq market (CLLS) and on the NYSE Alternext market (ALCLS.PA). To find out more about us, visit our website: http://www.cellectis.com

Talking about gene editing? We do it. TALEN is a registered trademark owned by the Cellectis Group

Disclaimer

This press release and the information contained herein do not constitute an offer to sell or subscribe, or a solicitation of an offer to buy or subscribe, for shares in Cellectis in any country. This press release contains forward-looking statements that relate to the Companys objectives based on the current expectations and assumptions of the Companys management only and involve risk and uncertainties that could cause the Company to fail to achieve the objectives expressed by the forward-looking statements above.

View source version on businesswire.com: http://www.businesswire.com/news/home/20170425006830/en/

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Cellectis to Present at the American Society of Gene & Cell Therapy ... - Yahoo Finance

First-Of-Its-Kind Cancer Treatment Developed By Santa Monica Company Helps Save Lives – CBS Los Angeles

First-Of-Its-Kind Cancer Treatment Developed By Santa Monica Company Helps Save Lives CBS Los Angeles But then the Laguna Beach mother read about a study at UCLA involving a unique immunotherapy called CAR-T cell therapy. She became the first patient to be involved in the clinical trial. Your body is a miraculous thing. It's supposed to heal itself. and more »

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First-Of-Its-Kind Cancer Treatment Developed By Santa Monica Company Helps Save Lives - CBS Los Angeles

Global Stem Cell Therapy Market – Analysis, Technologies and Forecasts to 2021 – Increasing Demand to Develop … – PR Newswire (press release)

The global stem cell therapy market to grow at a CAGR of 36.52% during the period 2017-2021.

The report, Global Stem Cell Therapy Market 2017-2021, has been prepared based on an in-depth market analysis with inputs from industry experts. The report covers the market landscape and its growth prospects over the coming years. The report also includes a discussion of the key vendors operating in this market.

The latest trend gaining momentum in the market is evolution of new destinations in the development of stem cell therapies. Traditionally, the US and European countries are the key destinations for clinical trials for stem cell therapy products. However, the transformation of regulatory landscape in countries such as Japan and South Korea has made these regions as attractive destinations for the development of stem cell therapy products.

According to the report, one of the major drivers for this market is increase in federal funding in stem cell therapy. Research and clinical trials of stem cell therapy require huge investment, which many research institutes and small companies cannot afford. Therefore, many federal organizations provide funding to these institutes and small companies to help their innovative ideas in the development of stem cell therapies. Worldwide, many government organizations have noticed the importance of regenerative medicine, and thus they have allocated funds and grants in that area. For instance, in the US, the NIH and CIRM provide most of the funds.

Key vendors

Key Topics Covered:

Part 01: Executive summary

Part 02: Scope of the report

Part 03: Research Methodology

Part 04: Introduction

Part 05: Understanding of stem cell therapy

Part 06: Ethical issues and regulatory landscape

Part 07: Key clinical trials

Part 08: Market landscape

Part 09: Market segmentation by therapy

Part 10: Market segmentation by applications

Part 11: Geographical segmentation

Part 12: Market drivers

Part 13: Impact of drivers

Part 14: Market challenges

Part 15: Impact of drivers and challenges

Part 16: Market trends

Part 17: Vendor landscape

Part 18: Key vendor analysis

For more information about this report visit http://www.researchandmarkets.com/research/gdv8s6/global_stem_cell

Media Contact:

Laura Wood, Senior Manager press@researchandmarkets.com

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Global Stem Cell Therapy Market - Analysis, Technologies and Forecasts to 2021 - Increasing Demand to Develop ... - PR Newswire (press release)