Its the promise of stem cell medicine: Someday soon, clinics will rebuild diseased or broken hearts, kidneys, pancreases or blood by growing and reprogramming human cells, then adding them back to the bodies of the patients they came from.
If only it were that easy.
After two decades of human stem cell research, researchers have learned how to create what appear to be reasonably functional versions of several types of cells, first using genetic tricks to turn cells back to an uncommitted state and then molding them into the type of cell needed say, an insulin-producing cell or a particular kind of nerve cell. And many early clinical trials of stem cell medicine have shown genuinely promising results.
But applying such techniques en masse simply wont be practical, because the lengthy processes for extracting and preparing an individuals own cells wont scale up, some scientists say.
For one thing, everyones cells will behave a little bit differently, says Lonnie Shea, a biomedical engineer at the University of Michigan, Ann Arbor. And then theres the bottom line. It is beyond too expensive, says Douglas Melton, cofounder of the Harvard Stem Cell Institute, a network of more than 1,000 Harvard-affiliated scientists.
Instead, increasingly, labs around the world are seeking to design off-the-shelf cell therapies using universal donor cells that are genetically altered to avoid the many-armed responses of the immune system against foreign tissues. Scientists want to create a suite of such cells tailored for specific tissue repairs: universal muscle cells, universal skin cells or universal insulin-producing pancreatic beta cells.
The big dream is a cell that would be like a pill, which could go into any patient, says Melton, who called for a global push to realize this vision at a stem cell meeting in Los Angeles in June.
This trend in regenerative medicine parallels events in cancer medicine. Personalized treatments that genetically reengineer the T cells of patients with certain blood cancers are often effective, but such therapies cost hundreds of thousands of dollars per patient and it can take years for manufacturing to get up and running. Cancer researchers around the world now are working to create off-the-shelf versions.
Its all part of a broader effort to bring the rapidly advancing power of genetic engineering more deeply into regenerative medicine, says pediatric hematologist Leslie Kean of Harvard Medical School, director of the Stem Cell Transplant Center at Boston Childrens Hospital. This is not just science fiction anymore.
Our bodies normally are quick to reject any cell that isnt our own. While that response often can be overridden by drugs designed to suppress the immune system, these medicines bring significant risks and side effects. So the goal is for universal donor cells to be hypoimmunogenic able to hold off the immune systems many lines of defense without requiring immunosuppression.
In one development, scientists at the University of California, San Francisco and colleagues reported in Nature Biotechnology in February that theyd created hypoimmunogenic mouse and human cells through a several-step process. The starting ingredients were iPS cells (induced pluripotent stem cells). These are adult cells engineered to lose their specific cell identities so they can once again become many different cell types, a condition known as pluripotency. By tinkering with a few genes in these iPS cells, the researchers could produce heart cells, muscle cells and endothelial cells (which line the inside of blood vessels). All showed stealth behavior to the two main branches of the immune system adaptive and innate when transplanted into mice.
To accomplish this, the lab did two things. First, it knocked out several molecules of the human leukocyte antigen (HLA) system components of the adaptive immune system. The proteins of this system normally stud the surface of cells and signal otherness to T cells if they dont match with the bodys.
If you take that away, the T cells cannot recognize a cell as foreign, and you dont see T cell activation anymore, says Sonja Schrepfer, the studys senior author and head of UCSFs Transplant and Stem Cell Immunobiology Lab and a founding scientist for the Seattle-headquartered startup company Sana Biotechnology.
This image shows insulin-producing beta cells that were made from stem cells. Cells like this could one day be transplanted into people with type I diabetes, but they would need to be protected by immune-suppressing drugs or encapsulation. Cost and complexity will remain huge barriers for most therapies based on pluripotent stem cells until scientists can create cells that dont trigger immune responses.
CREDIT: MELTON LAB / HARVARD UNIVERSITY
But removing HLA activity still leaves other, innate aspects of the immune system intact. For example, natural killer cells will normally wipe out cells that no longer make certain HLA proteins. To solve that problem, Schrepfer and colleagues tapped into a long-studied phenomenon of pregnancy known as fetal-maternal tolerance: why the mothers immune system will not reject a fetus even though half the proteins are from the father.
The fetus, it turns out, avoids attack by boosting or tamping down the activity of various genes, including one called CD47. And by increasing activity of CD47 as well as removing some HLA molecules, Schrepfers team got the results they wanted.
Less is more in modifying iPS cells, Schrepfer says. Editing of each molecule has risks, so you want to find the minimum combination you need to achieve hypoimmunity.
Another example of preliminary success with hypoimmunogenic human cells came from a team within the Harvard Stem Cell Institute network, led by stem cell researcher Chad Cowan, now with Sana Biotechnology.
Like the UCSF group, the scientists lowered the activity of certain HLA genes and boosted activity of the CD47 gene in pluripotent cells. But they also increased the production of a different class of HLA molecules: ones that help the fetus dodge the mothers immune system.
And they added another step, taking lessons learned from cancer cells that evade the immune system. Through genetic tinkering, the team boosted the production of a protein called PD-L1 that these tumor cells use to turn away T cells.
The complex set of genetic modifications, reported in the journal PNAS in April, significantly dialed down immune reaction when the cells were infused in mice. T cell responses were blunted, and attacks by natural killer cells and macrophages (another class of immune cell) were minimal.
As research on universal donor cell therapies moves forward, one of the biggest concerns is that these cells which are made pluripotent again, then turned into the required adult tissues, using imperfect gene editing tools may generate tumors. To garner FDA approval, cell lines will have to be extensively vetted for any signs of danger, but there are worries that no process can provide complete protection.
There are always theoretical concerns about cells retaining some measure of pluripotency, which would mean that they wouldnt have a signal to stop growing, says Kean of Boston Childrens Hospital. Still, she says, theres been a ton of research to suggest that really wont be an issue with the iPS-derived cells that are being produced now; a lot of those potential risks have been engineered out.
Labs also can add an insurance policy in the form of suicide genes, a technique long studied in clinical trials for cancer, in which cells are engineered to kill themselves if exposed to a certain chemical compound. If the cell starts to do anything thats troublesome, youll take a pill like doxycycline, and itll kill those cells and only those cells, Melton says.
Teratomas tumors comprising a variety of tissue types such as hair, bone and teeth are a particular worry in the use of pluripotent stem cells in therapies, including for regulatory agencies, says stem cell researcher Juan Domnguez-Bendala of the Diabetes Research Institute in the University of Miami Miller School of Medicine. Nobody can be certain of what may happen when you start transplanting thousands of patients. One single case of a teratoma may set the field back for years.
And so Domnguez-Bendala, who is developing insulin-producing pancreatic beta cells to treat type I diabetes, has generated human pluripotent stem cells with two kinds of suicide genes. One of them is designed to spring to life in any implanted cell that transforms into something other than a beta cell. The other can be activated in cells that show molecular signs of forming a tumor.
The immune system is there 24/7, always knocking at the door.
Reporting in the journal Stem Cell Reports in March, Domnguez-Bendala and colleagues found that they could largely prevent tumor formation when the cells were transplanted in mice, and any that slipped through the net could be destroyed. Our strategy allows us to selectively preserve the cells of interest while killing off everything else, he says, and it can be easily adapted to any specific cell.
Tumors are not the only risk, though. The excitement about universal donor cells is tempered with caution because the immune system has such a full bag of tricks, says Shea, who coauthored an overview of the technology in the Annual Review of Biomedical Engineering. The immune system is there 24/7, always knocking at the door. If you can do something to protect the cells, thats a great start, but it has to be on, 24/7 it cant weaken.
Its unclear, he says, how the immune system as a whole will react if certain cells in the body are chronically making immune-suppressing molecules. Perhaps the universal donor cells initially will engraft and function well, but problems may crop up over time. Maybe the grafted cells will eventually be destroyed. Or what if those cells are infected with a virus will the immune system be able to eliminate it?
Given such concerns, many immunologists believe that it may be necessary to retrain the immune system rather than just find ways for cells to dodge its bullets.
Keans lab, for example, is looking for a combination of drugs that can be administered for a limited time to reset the immune system so that the transplant is tolerated without interrupting normal protective immunity.
Different types of cells may require different degrees of immune stealthiness, Kean points out. Insulin-producing beta cells ideally will last a lifetime, while heart muscle cells may not need to persist for long if their job is just to offer temporary support while the heart repairs itself.
Generating universal donor cells is not the only approach to off-the-shelf regenerative medicine, and this concept may be combined with other therapeutic techniques.
Shea, for instance, works with immunologist Haval Shirwan of the University of Louisville School of Medicine on a method that transplants insulin-producing cells on a microporous scaffold that is coated with molecules designed to blunt T cell attacks. If a short regimen of an immunosuppressant drug is given at the same time, these transplanted cells survive well in lab mice.
Other labs take an even more radical approach they want to develop drugs that trigger cells in the patients own body to reprogram themselves and repair their own tissues. Sana and the biotech startup Oxstem in Oxford, England, are both pursuing this approach.
Overall, researchers say its an exciting time in off-the-shelf regenerative medicine though with plenty of work still to do.
So far, Melton notes, only a handful of functionally mature cells have been created from stem cells, including beta cells, heart muscle cells and certain kinds of skin, retinal and nerve cells. And its still years before universal donor cells will be tested in humans.
But he also stresses the potential of the quest. The promise of this kind of regenerative medicine is not to just find new treatments, he says, but to literally find cures for diseases.
Continue reading here:
Now in development: off-the-shelf stem cells - Knowable Magazine
- Asia Pacific Cell Therapy Instruments Market Forecast to 2027 - Covid-19 Impact and Regional Analysis - By Product ; Cell Type ; Process ; End User,... - November 27th, 2020
- Global Animal Stem Cell Therapy Market Research Report by Size, Data, Developments, Global Demand, In-Depth Analysis and Forecast 2020 to 2025 |... - November 27th, 2020
- Europe Cell Therapy Instruments Market Forecast to 2027 - Covid-19 Impact and Regional Analysis - By Product ; Cell Type ; Process ; End User, and... - November 27th, 2020
- Scaffold Technology Market Research Report by Product, by Application, by End-User - Global Forecast to 2025 - Cumulative Impact of COVID-19 -... - November 27th, 2020
- The Thorough Analysis Of The Global Stem Cell Media market Research During COVID-19 Health Crisis - The Courier - November 27th, 2020
- Autism genes affect development of neurons and glia - Spectrum - November 27th, 2020
- Global Live Cell Imaging Market Report 2020-2025: Market Size is Projected to Reach USD 2.8 Billion by 2025 from USD 1.8 Billion in 2020 - PRNewswire - November 27th, 2020
- North America Cell Therapy Instruments Market Forecast to 2027 - COVID-19 Impact and Regional Analysis By Product ; Cell Type ; Process ; End User,... - November 27th, 2020
- Post-doctoral Fellow in Computational Stem Cell Biology job with THE UNIVERSITY OF HONG KONG | 234737 - Times Higher Education (THE) - November 27th, 2020
- Circulating Tumor Cells and Cancer Stem Cells Market Research Report 2020 with Manufacturing Process Analysis and Market Concentration Rate till 2026... - November 27th, 2020
- Analyzing Impacts of Covid-19 on Global Cell Culture Media Market Effects, Aftermath and Forecast To 2025 - The Courier - November 27th, 2020
- Accretion: Current and Future Business Analysis in Cell Expansion Market - PharmiWeb.com - November 27th, 2020
- Adipose Tissue-Derived Stem Cells (ADSCS) Market Expected to Witness High Growth over the Forecast 2027 - Cheshire Media - November 27th, 2020
- Stem Cell Market to Witness a Pronounce Growth During (2020-2026) Cheshire Media - Cheshire Media - November 27th, 2020
- Demand with COVID-19 impact analysis on Cell Expansion Market - The Courier - November 27th, 2020
- Approval of Phase I/II Clinical Trial of ATG-016 (Eltanexor), a Second Generation Selective Inhibitor of Nuclear Export (SINE), in Mainland China for... - November 27th, 2020
- Researchers grow first plant-based gel to help organoid development for biomedical applications - Microbioz India - November 27th, 2020
- California's stem cell research agency looks to the future - Bond Buyer - November 25th, 2020
- Unexpected discovery about stem cell immortality study - News - The University of Sydney - November 25th, 2020
- Breakthroughs in Stem Cell Based Treatment of Heart Disease - The Connecticut College Voice - November 25th, 2020
- Mount Sinai Cardiologist Awarded $2.9 Million NIH Grant to Advance Work with Stem Cells and Heart Repair after Heart Attack - Cath Lab Digest - November 25th, 2020
- Stem Cell Therapy Global Market Report 2020-30: Covid 19 Growth and Change - Yahoo Finance UK - November 25th, 2020
- Global Cell Harvesting Market to Reach US$381,4 Million by the Year 2027 - PRNewswire - November 25th, 2020
- Middle East & Africa Cell Therapy Instruments Market Forecast to 2027 - COVID-19 Impact and Regional Analysis By Product ; Cell Type ; Process ;... - November 25th, 2020
- Global Stem Cell Banking Market to Get Expansion admist COVID 19, Scope With Advanced Technologies Top Key Players and Forecast 2020-2027 - The... - November 25th, 2020
- New study on CRISPR: the stake of unintended consequences in embryos - BioNews - November 25th, 2020
- The Stem Cell Characterization and Analysis Tools Market to grow incomparably in the next decade - The Market Feed - November 25th, 2020
- New solution to kill coronavirus on common surfaces in seconds - University of California - November 25th, 2020
- Agricultural Equipment Market to Witness Robust Expansion Throughout the Forecast Period 2027 - re:Jerusalem - November 20th, 2020
- Animal Stem Cell Therapy Market Projected to Witness Vigorous Expansion by 2027 - re:Jerusalem - November 12th, 2020
- The Canine Stem Cell Therapy Market To Move Away From Insipidness, Reach US$ 218.2 Mn - PRnews Leader - November 12th, 2020
- Rheumatoid Arthritis Stem Cell Therapy Market to Ride on Increased Prevalence of Rheumatoid Arthritis - TMR Research Blog - November 12th, 2020
- Stem Cell Therapy Market Growth Analysis 2020 By Industry Top Manufacturers, Business Opportunities, Industry Growth, Size, Gross Margin, Regional... - November 12th, 2020
- Stem Cell Media Market 2020 Industry Analysis and Trends Forecast to 2026 Thermo Fisher, CellGenix, Lonza, STEMCELL Technologies, Corning - The Think... - November 12th, 2020
- Autologous Stem Cell and Non-Stem Cell Based Therapies Market is Projected to Grow Massively in Near Future - The Daily Philadelphian - November 12th, 2020
- Global Live Cell Imaging Markets, 2020-2025 - Growing Adoption of High-Content Screening Techniques in Drug Discovery - Yahoo Finance UK - November 12th, 2020
- GLOBAL STEM CELL MARKET FORECAST 2021-2028 - GlobeNewswire - November 12th, 2020
- Flow Cytometry Market Is Expected to Generate Revenue of US$ 11.3 billion by 2030, Globally - GlobeNewswire - November 12th, 2020
- Stem Cell Therapy Market 2020 to 2025: Business Development Strategies and Top Manufacturers Analysis : Anterogen Co., Ltd. (South Korea), MEDIPOST... - November 12th, 2020
- ADC Therapeutics Reports Third Quarter 2020 Financial Results and Provides Recent Business Highlights - BioSpace - November 12th, 2020
- Stem Cell Characterization and Analysis Tool Market Size Analysis: Growth Factors, Share by Regional Production, Revenue and Regional Trends with Key... - November 12th, 2020
- Forma Therapeutics Reports Third Quarter 2020 Financial Results and Provides Business Update - Galveston County Daily News - November 12th, 2020
- Adipose Tissue-Derived Stem Cells (ADSCS) Market Expected to Witness High Growth over the Forecast 2027 - BCFocus - November 12th, 2020
- Marker Therapeutics Reports Third Quarter 2020 Operating and Financial Results - PRNewswire - November 12th, 2020
- CODA Biotherapeutics Receives Grant from the National Institute of Neurological Disorders and Stroke (NINDS) of the National Institutes of Health... - November 12th, 2020
- Brain Development and Disorder Research Receives $1.5 Million NSF Boost - USC Viterbi School of Engineering - November 7th, 2020
- Many Initiatives Still Too Close to Call in California - Courthouse News Service - November 7th, 2020
- Election 2020: Californias ballot initiative system isnt working. - Vox.com - November 7th, 2020
- Stem Cell Therapy Market is estimated to be worth USD 8.5 Billion by 2030 - PRnews Leader - November 5th, 2020
- Cancer Stem Cell Therapeutics Market Outlooks 2020: Size, Cost Structures, Growth rate and Industry Analysis to 2027 - Eurowire - November 5th, 2020
- Biologics Safety Testing Market Research Report by Test Type, by Application - Global Forecast to 2025 - Cumulative Impact of COVID-19 - Yahoo Finance... - November 5th, 2020
- Global Regenerative Medicine Market (2020 to 2025) - Industry Trends, Share, Size, Growth, Opportunity and Forecast - ResearchAndMarkets.com -... - November 5th, 2020
- Stem Cell Media Market Projected to Witness Vigorous Expansion by 2027 - The Think Curiouser - November 5th, 2020
- Cell Isolation Market Research and Analysis by Expert: import/export details, Cost Structures and statistics till 2027 - KYT24 - November 5th, 2020
- MorphoSys to Present Data on Tafasitamab at the ASH Virtual Annual Meeting and Exposition - PharmiWeb.com - November 5th, 2020
- The Many Model Systems of COVID-19 - The Scientist - November 5th, 2020
- Soybean Trypsin Inhibitor Market Brief Analysis and Application, Growth by 2026 | Biological Industries, Thermo Fisher Scientific, Sigma-Aldrich... - November 5th, 2020
- Cell and Tissue Culture Supplies Market Analysis with Market Size, Industry Share, trends and Forecast to 2026 - The Think Curiouser - November 5th, 2020
- Voters asked to approve $5.5 billion for stem cell research - Madison.com - November 3rd, 2020
- A Review of Stem Cell-Based Therapies for Parkinson Disease - AJMC.com Managed Markets Network - November 3rd, 2020
- 10 health and science-focused races to watch on election night - STAT - November 3rd, 2020
- Animal Stem Cell Therapy Market 2020, Global Research Analysis Report Growth at CAGR Value, Industry Share, Key Company Profiles, Type, Applications,... - November 3rd, 2020
- Stem Cell Therapy Market To Exceed Revenues Worth US$ By The End Of 2020 2027 - Eurowire - November 3rd, 2020
- Stem Cell Banking Market Research Report 2020 By Segmentations, Key Company Profiles and Demand Forecasts to 2026 - Aerospace Journal - November 3rd, 2020
- Stem Cell Media Market Analysis And Demand With Forecast Overview To 2027 - Aerospace Journal - November 3rd, 2020
- Stem Cell Characterization and Analysis Tool Market : By Component, by Application, by Component Mode, and By Region Global Forecast up to 2026 -... - November 3rd, 2020
- Impact of COVID-19 on Plant Stem Cell For Cosmetics Market Overview with Detailed Analysis, Competitive Landscape & Forecast To 2026 - Eurowire - November 3rd, 2020
- 2020 Election Tracker: All The State Ballot Healthcare Initiatives - Forbes - November 3rd, 2020
- California Proposition 14 is about pikuach nefesh heres why - Forward - November 3rd, 2020
- Retinal Disorders Treatment Market: Advancements in Gene-therapy and Stem-cell Therapy to Bolster Market Growth - BioSpace - November 3rd, 2020
- Stem Cell Alopecia Treatment Market Insights and Development Trends from 2020-2027 - Aerospace Journal - November 3rd, 2020
- Global Stem Cell Therapy Market 2020 Research on Import-Export Details, Business Standards and Forecast to 2025 - PRnews Leader - November 3rd, 2020
- Canine Stem Cell Therapy Market Shows Expected Trend to Guide from 2020-2026 with Growth Analysis by Manufacturers, Regions, Type and Application -... - November 3rd, 2020
- Survival Benefit of GVHD in MDS Is Limited to Specific Patient Subgroup - Cancer Therapy Advisor - November 3rd, 2020
- Orchard Therapeutics Reviews Recent Portfolio Progress and Reports Third Quarter 2020 Financial Results - GlobeNewswire - November 3rd, 2020
- Meat-Tech 3D Ltd. Announces Successful $7 Million Funding Round led by Psagot Provident Funds and other leading institutional investors - PRNewswire - November 3rd, 2020
- Hematopoietic Stem Cells Transplantation (HSCT) Market Size 2020 Global Industry Trends, Future Growth, Regional Overview, Market Share, Revenue, and... - November 3rd, 2020
- Stem Cell Assay 2020 GLOBAL OUTLOOK, RESEARCH, TRENDS AND FORECAST TO 2025 - The Think Curiouser - November 3rd, 2020
- Cell Isolation Market report delivering growth analysis with key trends top companies and forecast 2027 - KYT24 - November 3rd, 2020
- Cancer Stem Cells Market 2020 By Business Opportunity, Innovations, Applications, Upcoming-Trends, Growth-Analysis, Demand-Insight, Segmentation,... - November 3rd, 2020