Interested in stem cell developments.
Register for free to join our community of investors and share your ideas. You will also get access to streaming quotes, interactive charts, trades, portfolio, live options flow and more tools.
Register for free to join our community of investors and share your ideas. You will also get access to streaming quotes, interactive charts, trades, portfolio, live options flow and more tools.
Doesn’t the RCA Building (aka the GE Building, the Comcast Building, The Slab, 30 Rock) have a side entrance that goes into an ancillary lobby called the Vacuum Tube Lobby?
Re: "And for that matter, man will be able to visit the outer reaches of the Galaxy by quarter 4 IF milestones are met. lol"
This may be accurate, elysse. Don't forget time is a construct of the human mind. Past, present and future may not necessarily happen in that order and not only does the Past impact on the Future but the Present and Future may also impact on the Past. That may be why Feynman said we should not even try to understand what Einstein called "spooky action at a distance."
7 COME 11
THE IMMORTAL CHALLENGE
By Jeffrey Perkel, Ph.D.
BioTechniques 58:154-160 (April 2015)
Reproducibility in life science is a hot button topic at the moment. Jeffrey Perkel examines the ways in which stem cell researchers are dealing with this issue in their work.
Arguably, there is no hotter area in life science research to- day than induced pluripotent stem (iPS) cells. With applications in basic research, drug discovery, and cell therapeutics, iPS cells—essentially embryonic stem cells without the embryo— have attracted tremendous excitement from academics, fund- ing agencies, and pharmaceutical companies alike. The first clinical trial based on an iPS cell–derived product has launched in Japan, less than a decade removed from Shinya Yamanaka’s discovery of the iPS cell process in 2006.
Yet as iPS cell R&D speeds towards the clinic, a nagging question remains: Just how easy is it to replicate findings be- tween labs?
REAGENT DILEMMA
No one doubts the iPS process itself; thousands of papers have been published on the subject, with lab after lab successfully generating and differentiating iPS cells into everything from cardiomyocytes to neurons.
But the devil, as they say, is in the details. iPS cells are gener- ated by expressing a handful of key gene-regulatory transcrip- tion factors in terminally differentiated cells (such as fibroblasts), causing these cells to revert to an embryonic stem cell–like pluripotent state. Researchers have developed many ways to deliver the transcription factors, including lentiviral or Sendai viral vectors, episomal DNAs, mRNA transfection, and self- replicating RNAs. Even small molecules can now be used to induce iPS cell formation. Ultimately, using these approaches should lead to the emergence of pluripotent iPS cell clones in a few weeks, if all goes well. Yet the definition of “pluripotency” is “pretty crude,” says Emile Nuwaysir, Chief Operations Officer and Vice President at Cellular Dynamics International (CDI), a company specializing in the generation of iPS cells and the ter- minal cells differentiated from them.
Pluripotency basically describes a cell that can divide indefinitely, expresses certain pluripotency factors, and differentiates into all three germ layers—endoderm, ectoderm, and mesoderm. iPS cells do vary substantially in genetic background, as they are created from different individuals. Thus, they are at least as different as, say, different inbred mouse strains, ac- cording to cell researcher Paul Knoepfler, Associate Professor of Cell Biology and Human Anatomy at the University of California, Davis. But even genetically identical lines created from the same individual can differ in transcriptional or epigenomic profiles—a reflection, perhaps, of subtle differences in culture conditions or handling—which is why researchers typically use multiple independent iPS cell clones for internal validation.
Genetics, though, are only one side of the reproducibility coin—cells are exquisitely sensitive to their environment as well. “It’s amazing how incredibly fickle these cells can be,” says Robert Lanza, Chief Scientific Officer of Ocata Therapeutics (formerly Advanced Cell Technology), which is advancing pluripotent stem cell–based therapeutics. Switching lots of serum or growth factor, he says, “can make all the difference in the world.”
Indeed, in a 2010 study by the International Stem Cell Initiative, 5 labs tested 10 embryonic stem cell lines (which are very similar to iPS cells) using 8 culture methods. “Of the 8 culture systems, only the control and those based on 2 commercial media, mTeSR1 and STEMPRO, supported maintenance of most cell lines for 10 passages,” the authors reported. [1]
Unreliable reagents are “a major, major, major, major problem,” says Pamela Robey, Acting Scientific Director of the NIH Stem Cell Unit.
“And I think [it] is also a major contributor to the fact that people have a hard time sometimes reproducing even their own data.” Stem cell re-agents, Robey notes, cost “an arm and a leg,” often have limited shelf lives, and can vary wildly in quality and potency from batch to batch.
“Sometimes a milligram [of growth factor] has a biological potency of 1, and sometimes it’s 0.5,” Nuwaysir says. Robey says she had a situation in her lab where she was using a particular antibody and “getting great, great, great results. And then we bought a new batch, and we could not get that lot to work, come hell or high water.
Lanza recalls one incident at Ocata where two sets of researchers using the same cells experienced very different results—all thanks to the packaging of the six-well culture dishes they used. One of the researchers was using individually wrapped plates, which worked; the other used plates bundled in stacks, which didn’t. Both sets of plates were from the same vendor and even had the same lot number. “To this day we have no idea what it was that made the difference,” Lanza says—perhaps one batch was left out in the sun too long. “Who knows?”
To mitigate such variability, companies and cell banks develop extensively detailed standard operating procedures (SOPs) to document and verify every conceivable detail. At Ocata, such documents can run to “hundreds and hundreds” of pages, Lanza says, documenting everything from how to thaw cells
and to how to form embryoid bodies, to the source and quality of the reagents used at each step. “It’s basically getting rid of the variability that exists in a normal research setting.”
It doesn’t help that iPS cell culture is so complicated, with dozens of chemical and physical factors in play. One popular culture medium called TeSR, which was invented in the lab of CDI cofounder (and stem cell pioneer) Jamie Thomson, contains 27 distinct chemical components, Nuwaysir says, “none of which have assays for [biological] potency.” A more recent formulation from Thomson’s lab, Essential-8 (E8), cuts the recipe down to a more manageable eight: four chemicals and four biologicals. “You can have GMP [good manufacturing practice], build assays for them, inventory large quantities for them—E8 is a huge improvement, a much more stable plat- form,” notes Nuwaysir.
Even if researchers do everything right, stem cells in culture can change or “drift” over time, with “minor clones” taking over the culture and changing its character. As a result, says Glyn Stacey, Director of the UK Stem Cell Bank, his facility routinely tests cells for genetic stability, gene ex- pression, pathogen contamination, and other parameters.
ENHANCING REPRODUCIBILITY
Of course, reproducibility isn’t just a concern for stem cell researchers. There is an increasing emphasis on reproducibility across all of the life sciences, with some journals adopt- ing tighter guidelines for describing reagents and methods in an effort to make the validation of published findings easier.
This is in part in thanks to a growing recognition that not all data reported in the literature can be replicated. In one high-profile example, C. Glenn Begley and Lee Ellis in 2012 described an at- tempt to “confirm published findings” from 53 “landmark” hematology/oncology studies. “[S]cientific findings were confirmed in only 6 (11%) cases,” they re- ported. “Even knowing the limitations of preclinical research, this was a shocking result.” [2]
Still, precisely what those data mean isn’t exactly clear—Begley and Ellis reported their findings in a Nature commentary, not a peer-reviewed article, providing no data or experimental details. So it is unclear what the failure rate would be forstem cells. Although Nuwaysir says a similar analysis of stem cell research could yield the same failure rate, he also adds, “there is a logical fallacy to say only 6 of the 50 were true.” Rather, he explains, “it means they were unable to reproduce them. The authors [trying to replicate the studies] have variability too.” Knoepfler, who regularly blogs on the subject of stem cell reproducibility, says, “I expect that the same kind of study done in the stem cell field would yield a much higher rate of reproducibility,” in part, because whereas drug-discovery research is high-risk, “to my knowledge, most stem cell research is already reproduced in multiple labs over time.”
To date, no large-scale studies on the extent of stem-cell data reproducibility have been published. But an example of what such an effort might entail is underway in oncology. Backed by $1.3 million from the Laura and John Arnold Foundation, the Reproducibility Project: Cancer Biology—a collaboration between the Center for Open Science and Science Exchange—is seeking to validate the key experimental findings of 50 “high-impact” oncology studies published between 2010 and 2012.
According to Elizabeth Iorns, co- founder of the Science Exchange, few papers document the methods used in sufficient detail. “Our experience is that papers rarely have enough information in the protocols to be able to replicate experiments without going back to the authors for help,” she says. Frequently, information is insufficient to uniquely identify the exact reagents used, and methods sections are usually summaries instead of detailed experimental protocols.
The Reproducibility Project has three primary objectives: to generate a public data set of reproducibility; to create a set of best practices for documenting protocols in the literature; and to highlight the value of research into reproducibility. “People undervalue [such studies] at the moment,” she says.
Iorns notes, for instance, that when the now-discredited STAP (stimulus-trigged acquisition of pluripotency) stem cell studies were published in early 2014, many labs rushed to try to replicate the findings. “But it wasn’t actually a replication,” she says. “Many different labs tried different cells and [different] methods and didn’t see the same thing. What does that tell you? How do you interpret that?” It wasn’t until researchers tried to replicate the STAP cell findings precisely—using the same cells and growth conditions— that they could begin to see that the process didn’t work at all.
Emile Nuwaysir says the definition of pluripotency is “pretty crude.”
The Reproducibility Project: Cancer Biology will use, to the best of its ability, “the exact same protocols as the original study,” Iorns says. “We are trying to use the same mouse mod- els, cell lines, and reagents, to understand if you take an experi- ment from one lab, can you get the same result in another lab?”
WHAT CAN YOU DO?
One way to researchers can address stem cell reproducibility is with better communication. For instance, researchers in the lab of Dennis Clegg, Professor and Co-Director of the Center for Stem Cell Biology and Engineering at the University of California, Santa Barbara have developed protocols to differentiate iPS and embryonic stem cells into retinal pigment epithelial cells. When it came time to scale those protocols for use in a clinical trial for the treatment of age-related macular degeneration, Clegg had to transfer the protocol to researchers at the City of Hope.
“You can’t just send a protocol and say ‘do it’,” Clegg says. Stem cell culture, he explains, is “almost an art form.” Researchers need to work closely with their colleagues to learn the nuances, the little details that don’t make it into a printed protocol. “We even in some cases make movies with iPhones on particular [steps].”
Rohit Kulkarni, Senior Investigator at the Joslin Diabetes Center in Boston, is attempting to turn pluripotent stem cells into insulin-producing beta cells. He has been working to replicate recent findings from the laboratories of Doug Melton at Harvard and Timothy Kieffer at the University of British Columbia that purport to have cracked the beta-cell problem. “We are about three-quarters of the way through the Melton and Kieffer protocols, and it’s working so far,” Kulkarni says. “But that’s because we’ve been sure to get the same reagents from the same companies.” Communication was also key. Kieffer’s team uses a technique called “air-liquid interface” culture at one point in their protocol, and Kulkarni’s team had no experience with it. “We needed details on what exactly that entailed.”
Clegg says his lab has never personally experienced a protocol failing to work as advertised, though he admits he also hasn’t tried too many. But he has experienced first hand the behavioral differences that can exist between seemingly identical cell lines.
One particular embryonic stem cell line, H9, can efficiently differentiate into RPE cells, while another popular line, H1, does not. “What we had heard anecdotally is that H9 tends to be bi- ased towards neural lineages, including RPE, so it sort of made sense,” Clegg says. “But what’s the difference between those two [lines], we don’t know.” Clegg has observed similar plasticity differences between iPS lines—a difference that could pose a problem for clinical applications, especially if they involve patient-specific cells (as opposed to banked and validated HLA- matched iPS cell lines).
One potential solution is to increase the quality and standardization of pluripotent stem cell reagents and methods, and to some extent, that already is happening.
Timothy Kamp, co-director of the Stem Cell and Regenerative Medicine Center at the University of Wisconsin–Madison School of Medicine and Public Health, notes, for instance, that fewer researchers these days culture their pluripotent stem cells on mouse embryonic fibroblast (MEF) feeder cell layers. MEFs, he explains, made embryonic stem cell culture possible—“They were an essential stepping stone.” But they also introduce substantial variability, as each MEF culture is different. As a re- sult, many researchers now use defined substrates, such as laminins and vitronectin, or at least BD Biosciences’ Matrigel, a tumor-derived extracellular matrix extract.
Fetal bovine serum as a culture additive is slowly being phased out in favor of better-defined, xenobiotic-free serum replacements. So, too, are protein growth factors, which in a few cases can be replaced with small molecules. In 2012, Kamp coauthored a study showing that human pluripotent stem cells could be differentiated into cardiomyocytes “solely via small molecule modulation of regulatory elements of Wnt/ beta-catenin signaling.” [3]
Discussions are going on within the stem cell community regarding the development of standard reagents, such as cell lines or nucleic acids, that could be used as stable benchmarks across experiments and between labs. The National Institute of Standards and Technology is also looking into stem cell standards. At the moment though, researchers are mostly on their own.
Validation studies aren’t sexy, all agree, and nobody wants a PhD in reagent quality control. Yet if stem cell research is to ever reach its full potential, the stem cell community may need to accept that protocol tweaking and experimental validation will be a part of their lives for some time to come.
REFERENCES
1. International Stem Cell Initiative Consortium, V. Akopian, P.W. Andrews, S. Beil, N. Benvenisty, J. Brehm, M. Christie, A. Ford, et al. 2010. Comparison of defined culture systems for feeder cell free propagation of human embryonic stem cells. In Vitro Cell Dev Biol Anim. 46:247-258.
2. Begley C.G. and L.M. Ellis. 2012. Drug development: Raise standards for preclinical cancer research. Nature. 483:531-3
3. Lian X., C. Hsiao, G. Wilson, K. Zhu, L.B. Hazeltine, S.M. Azarin, K.K. Raval, J. Zhang, T.J. Kamp, and S.P. Palecek. 2012. Robust cardiomyocyte differentiation from human pluripotent stem cells via temporal modulation of canonical Wnt signaling. Proc Natl Acad Sci U S A. 109:E1848-1857.
Reetala, as indicated:
Regen. Med. (2015) 10(2), 99–102
EDITORIAL: HOPE FOR REGENERATIVE TREATMENTS: TOWARD SAFE TRANSPLANTATION OF HUMAN PLURIPOTENT STEM-CELL-BASED THERAPIES
Erin A Kimbrel Ocata Therapeutics (formerly Advanced Cell Technology), Marlborough, MA 01752, USA
Robert Lanza Author for correspondence: Ocata Therapeutics (formerly Advanced Cell Technology), Marlborough, MA 01752, USA
Regen. Med. (2015) 10(2), 99–102
Keywords: cell-based therapies • clinical trials • embryonic stem cells • induced pluripotent stem cells • regenerative medicine
SAFETY FIRST
Ever since their discovery and isolation in 1998, human embryonic stem cells (hESCs) have been touted as the future of regenerative medicine, with a heavy burden of promise and expectation placed upon them to deliver an unprecedented number of cell-based therapies. In theory, their ability to undergo unlimited self-renewal and to generate any cell type in the body makes pluripotent stem cells (PSCs) such as human embryonic stem cells and induced pluripotent stem cells (iPSCs) an ideal starting material for treat- ing a wide variety of diseases with cell-based therapies. Yet, in reality, potentially seri- ous risks including the propensity to form tumors or trigger an immune response, tech- nical hurdles in directing their in vitro dif- ferentiation and ethical concerns over the destruction of embryos have thwarted efforts to bring PSC-based therapies to the clinic. After decades of work, strict regulations sur- rounding the use of PSC-based therapies have finally culminated in their careful and deliberate application in a handful of new clinical trials, which are helping allay fears over their safe use. Below, we discuss the sta- tus of PSC-based therapies in regenerative medicine, including safety considerations, currently approved clinical trials and a look at what is on the horizon.
Given the scarcity of data on the effects of PSC based therapies in humans, safety is paramount during the development of any such new product. Preclinical animal stud- ies should examine not only efficacy but also biodistribution, toxicity and tumorigenicity, preferably using the route of administration and dosing equivalent to those intended in humans. In the USA, PSC-derived cellular therapies are controlled under the US FDA’s Code of Federal Regulations Title 21, part 1271 (21 CFR 1271) which is in place ‘to prevent the introduction, transmission and spread of communicable diseases by [human cells, tissues and cellular and tissue-based products] HCT/Ps’. Several related guidance documents regarding cell source, preclinical animal studies and manufacturing recom- mendations have been issued by the FDA [1,2] yet, there are no absolute set of require- ments to dictate what is necessary to gain approval for a PSC-based investigational new drug (IND). Each new application is consid- ered by the FDA on a case by case basis to determine if it is reasonably safe for testing in humans. For the immediate future, PSC- based products that can be locally contained, removed or otherwise have a low risk of immunogenicity are less risky and thus will likely have an easier time gaining approval than those involving systemic injection.
’EYE’ WILL BE THE FIRST TO BENEFIT
There are now 11 approved trials involving PSC-based therapies on the clinical trials website, [3], nine for ocular indications (eight from hESCs, one from iPSCs), one for dia- betes, one for severe heart failure. This is not surprising since, compared with other organs and tissues, the eye is particularly well suited for first-in-man cellular therapies. It is a relatively immunoprivileged site, allowing non-HLA matched cells to be injected into patients with reduced risk of immune rejection and providing an isolated environment for containment of injected cells, thus limiting the potential area in which cells may travel or form tumors. Ocata Therapeutics (formerly Advanced Cell Technology, Marlborough, MA, USA) and collaborators began the first PSC eye- based trials in 2011, to test safety and tolerability of hESC-derived retinal pigmented epithelium (RPE) for dry age-related macular degeneration (AMD) and the related juvenile Stargardt’s disease. Preliminary short-term data for the first two patients treated in the US RPE trial suggested that subretinal injections of hESC-RPE cells are well-tolerated and safe [4]. Medium to long-term safety data for 18 patients, nine with Stargardt’s and nine with dry AMD (with an average follow-up period of 22 months) confirmed that the implanted hESC-RPE persist as a graft and do not pose any serious adverse ocular or systemic effects [5]. Despite being only a Phase I/II trial with end points of safety and tolerability, data suggested that the hESC- based therapy may be helping restore visual acuity and improve vision-associated quality-of-life indices.
“...the human embryonic stem-cell-based therapy may be helping restore visual acuity and improve vision-associated quality-of-life indices.”
Similar hESC-RPE clinical trials are also being carried out in Europe (UK) for Stargardt’s disease, and in Asia (South Korea) through an Ocata licensing part- nership with CHA Bio & Diostech for both dry AMD and Stargardt’s. hESC-RPE therapy has also recently been cleared for a new US-based clinical trial for myo- pic macular degeneration. Not to be outdone by a small biotechnology company such as Ocata, London-based pharmaceutical giant, Pfizer has carved out a niche for itself in the emerging regenerative medicine eye disease market by developing a membrane-immobilized hESC-RPE monolayer as a therapeutic treatment for the wet or exudative form of AMD. Their trial will be conducted in the United Kingdom although it is not yet open for enrollment. Lastly, Cell Cure Neuro- sciences (Jerusalem) was also granted approval in late 2014 to begin a hESC-RPE clinical trial; they will test their cell suspension product, Opregen for dry AMD.
AN ‘I’ FOR AN ‘EYE’
?The advent and optimization of iPSC technology has provided an ethically sound alternative to hESCs as a starting cell source. Adding a new twist to PSC- based RPE therapies, researchers at the RIKEN institute in Japan became the first to test an iPSC-based therapy in humans when they initiated wet AMD clinical trials involving iPSC-derived RPE sheets in September 2014 [6]. iPSC technology, initially developed in Japan by Yamanaka et al., has come a long way since its 2006 inception [7]. Improvements in the safety and efficiency of reprogramming methods used to generate iPSCs have transformed them into a strong competitor of hESCs. However unlike hESCs, an abundance of starting material is available for their derivation, they are ethically noncontroversial and can easily be used to generate banks of HLA- matched or even personalized cellular therapeutics, thus reducing concerns over potential immunogenic- ity. These factors make them desirable as a source of PSCs for regenerative medicine endeavors. For now, however, the world will continue to watch the progress of both the hESC- and iPSC-RPE clinical trials very closely to see the long-term safety and efficacy of these therapies.
MAKING PROGRESS IN BIG INDICATIONS: DIABETES & MORE
Potentially powerful (and lucrative) uses for hESCs and iPSCs, including the treatment of widespread indications such as diabetes and heart disease, have been in development for many years. Excitingly, the first clinical trial for each of these uses has recently begun and is actively recruiting. In both instances, the PSC-based product is being tethered to or embedded in a solid support, which assists with the cell- based product’s function but is also an important safety feature for these first-in-man trials. Viacyte, Inc. (San Diego, CA, USA) [8]) is testing a subcuta- neously implanted device called VC-01 for Type 1 diabetes. It consists of their hESC-derived pancreatic endoderm cells (termed PEC-01) encapsulated in a biologically-compatible medical device. Encapsula- tion prevents direct exposure of the PEC-01 cells to cells of the immune system, thus preventing the prov- ocation of an immune response. Moreover, the fact that the device is implanted under the skin means that it can easily be removed if serious adverse events are noted. Previous work shows that PEC-01 cells can differentiate into, among other cell types, glucose- sensing, insulin-producing cells similar to pancreatic ß cells [9] and can regulate blood glucose levels after transplantation into mice [10,11]. In addition to this trial, a new study by Doug Melton’s group at Harvard Medical School shows that functional insulin- producing cells, with all the characteristics of adult human pancreatic ß cells, can now be produced from hESCs in a manner amenable to large scale manufacturing [12]. Similar to Viacyte’s device, Melton et al. are now trying to develop a way to encapsulate their cells so that they can persist in a diabetic patient without immune rejection [13].
TARGETING THE BIGGEST KILLER OF ALL
Heart disease is the leading cause of death around the world [14] and people afflicted with it may soon start benefiting from PSC-based therapies. Philippe Menasche’s group at the University of Paris is testing their CD15+ Isl-1+ hESC-derived cardiac progenitors in a clinical trial for patients with severe heart fail- ure. The hESC-derived progenitors are embedded in a fibrin gel patch which is then engrafted onto infarcted epicardium in attempts to improve cardiac function [3]. These progenitors have been extensively studied in both rodent and nonhuman primate models of myo- cardial infarction where they improved left ventricular end systolic volume [15,16]. Interestingly, while cardiac function improved, the engrafted cells disappeared by 4 months post surgery, suggesting that the mechanism for their therapeutic effect is induction of endogenous repair mechanisms or growth and differentiation of endogenous progenitors [16]. Other scientists are tak- ing an alternative approach and testing mature cardio- myocytes differentiated from hESCs for therapeutic effects in myocardial infarction. A recent study in a nonhuman primate model showed that engraftment of 1 billion hESC-derived cardiomyocytes resulted in large areas of healthy cardiac muscle that could con- duct electromechanical signals within the infarcted area [17]. The study also noted the appearance of non- fatal arrhythmias though, suggesting more work needs to be done to improve the safety of the therapy before it can be tested in human clinical trials.
PSC-BASED THERAPIES FOR NEUROLOGICAL DISEASES: PARKINSON’S LEADS THE WAY
?Other substantial indications being targeted by PSC- based therapies include neurological conditions such as Parkinson’s disease (PD), where degeneration of midbrain dopaminergic (DA) neurons are one of the causative agents leading to progressive motor impair- ment. A recent article by Malin Parmar’s group shows that hESC-derived DA neurons transplanted into a rat model of PD can survive long-term and innervate appropriate regions of the mid to forebrain. The data suggests their functional engraftment rivals that of fetal tissue-derived neurons, which have been safely used in humans, albeit with variable success [18]. Another 2014 study led by Jun Takahashi, demonstrated that in vitro-purified iPSC-DA progenitors differentiated into mature DA neurons and rescued motor function upon injection into a rat model of PD [19]. Takahashi’s group has performed safety studies in nonhuman pri- mates, using autologous iPSC-derived therapies, and has asserted they plan to test an autologous iPSC- based PD therapy in human clinical trials within the next 1–2 years [20]. The precedent for clinical use of iPSC-derived products has been established in Japan and investment in technology may also help bring an iPSC-based therapy for spinal cord injuries to clinical trials within the next few years as Shinya Yamanaka is working with Keio University’s Hideo Okano toward this goal [21].
With various clinical trials underway and new trials on the horizon, pluripotent stem cell based therapies are beginning to flourish – even under the strict regu- lations imposed to ensure their safe application – and may just live up to the tremendous expectations placed upon them decades ago.
FINANCIAL & COMPETING INTERESTS DISCLOSURE
EA Kimbrel and R Lanza are both employees of Ocata Thera- peutics, formerly known as Advanced Cell Technology, a bio- technology company focused on stem-cell-based therapeu- tics and regenerative ophthalmology. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
References
1 Carpenter MK, Frey-Vasconcells J, Rao M S. Developing safe therapies from human pluripotent stem cells. Nat. Biotechnol. 27, 606–613 (2009). ?
2 Frey-Vasconcells J, Whittlesey KJ, Baum E, Feigal EG. Translation of stem cell research: points to consider in designing preclinical animal studies. Stem Cells Transl. Med. 1, 353–358 (2012). ?
3 Clinical Trials. www.clinicaltrials.gov ?
4 Schwartz SD, Hubschman JP, Heilwell, . Embryonic stem cell trials for macular degeneration: a preliminary report. Lancet 379, 713–720 (2012).
5 Schwartz SD, Regillo CD, Lam BL et al. Human embryonic stem cell-derived retinal pigment epithelium in patients with age-related macular degeneration and Stargardt’s macular dystrophy: follow-up of two open-label Phase 1/2 studies. Lancet doi:10.1016/S0140-6736(1014)61376-61373 (2014) (Epub ahead of print).
6 Reardon S, Cyranoski D. Japan stem-cell trial stirs envy. Nature 513, 287–288 (2014).
7 Takahashi K, Yamanaka S. Induction of pluripotent stem 15 cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126, 663–676 (2006).
8 Viacyte.?http://viacyte.com 16 ?
9 D’Amour KA, Bang AG, Eliazer S et al. Production ofpancreatic hormone-expressing endocrine cells from human embryonic stem cells. Nat. Biotechnol. 24, 1392–1401?(2006).
10 Kelly OG, Chan MY, Martinson LA et al. Cell-surface?markers for the isolation of pancreatic cell types derived from?human embryonic stem cells. Nat. Biotechnol. 29, 750–756 18?(2011). derived dopamine neurons show similar preclinical efficacy
11 Schulz TC, Young HY, Agulnick AD et al. A scalable system?for production of functional pancreatic progenitors from?human embryonic stem cells. PLoS ONE 7, e37004 (2012). 1?
12 Pagliuca FW, Millman J R, Gurtler M et al. Generation of functional human pancreatic beta cells in vitro. Cell 159, 428–439 (2014). ?
13 Lauerman J. Harvard breakthrough grows insulin-control cells in bulk. ?www.bloomberg.com/news/articles/2014-10-09/harvard- breakthrough-grows-insulin-control-cells-in-bulk ?
14 World Health Organization. The top ten causes of death- fact sheet No. 310. ?www.who.int/mediacentre/factsheets/fs310/en/
15 Menasche P, Vanneaux V, Fabreguettes J R et al. Towards a clinical use of human embryonic stem cell-derived cardiac progenitors: a translational experience. Eur. Heart J. doi: 10.1093/eurheartj/ehu192 (2014) (Epub ahead of print).
16 Bellamy V, Valérie Vanneaux, Alain Bel et al. Long term functional benefits of human embryonic stem cell-derived cardiac progenitors embedded into a fibrin scaffold. J. Heart Lung Transpl. (2014) (In Press).
17 Chong JJ, Yang X, Don CW et al. Human embryonic-stem- cell-derived cardiomyocytes regenerate non-human primate hearts. Nature 510, 273–277 (2014). 18 Grealish S.E. Diguet A, Kirkeby B et al. Human ESC-?and potency to fetal neurons when grafted in a rat model of Parkinson’s disease. Cell Stem Cell 15, 653–665 (2014).
19 Doi D, Samata B, Katsukawa M et al. Isolation of human induced pluripotent stem cell-derived dopaminergic progenitors by cell sorting for successful transplantation. Stem Cell Rep. 2, 337–350 (2014).
20 GForce-PD. GForce- a new global initiative around stem cell based therapies for Parkinson’s disease www.gforce-pd.com/gforce-a-new-global-iniatitive-around- stem-cell-based-therapies-for-parkinsons-disease/ ?
21 Fox C. Japan starts world-first stem cell trial, plans more. In: Drug Discovery and Development. Advantage Business Media Rockaway, NJ, USA (2014).
Re: "Doesn't "no news" mean fake rise? Hope its something different."
Buy on rumor, sell on news.
I do think we will have another run up through the rest of the afternoon and finish the day close to the HOD established in the afternoon.
MEET THE GOOGLE EXECUTIVE WHO PLANS TO CHEAT DEATH: RAY KURZWEIL TAKES 150 VITAMINS A DAY SO HE CAN ‘HOLD OUT LONG ENOUGH FOR INVENTION OF ROBOTS THAT WILL KEEP HUMANS ALIVE’
skg | 24/7 | Oct 20, 2013
Google engineering director and futurist Ray Kurzweil believes we are close to realizing everlasting life and is dead-set on getting us there.
The inventor and noted author believes the key to such a scientific breakthrough is a system of ‘bridges’ that enable the body to move from strength to strength over time.
The youthful 65-year-old currently takes 150 supplements a day, which he argues if the first bridge.
The idea is to build enough bridges to ensure the body holds out long enough for life-lengthening technology to come into its own.
He has likened the biology of the body to computer software and believes we are all ‘out of date’.
Key to the fountain of youth: Ray Kurzweil, futurist and Google engineering director, says the biology of the body is much like computer software and that we are in need of of an upgrade. The hope is to go along enough ‘bridges’, or stages, to reach the point where life-lengthening technology is at its greatest
Bridge number one: Staying as healthy as possible. Ray Kurzweil currently takes 150 supplements a day to keep his body at its peak
In an interview with Canadian magazine Maclean’s, Kurzweil says he hopes the supplements will keep him healthy enough to reach the ‘nanotech revolution’.
‘I can never say, “I’ve done it, I’ve lived forever,” because it’s never forever,’ he said.
‘We’re really talking about being on a path that will get us to the next point.
‘Bridge one: Stay as healthy as possible with diet and exercise and current medicine.
‘The goal is to get to bridge two.
‘Bridge two (is) the biotechnology revolution, where we can reprogram biology away from disease.
‘And that is not the end-all either.
‘Bridge three is to go beyond biology, to the nanotechnology revolution.
‘At that point we can have little robots, sometimes called nanobots, that augment your immune system.
‘We can create an immune system that recognizes all disease, and if a new disease emerged, it could be reprogrammed to deal with new pathogens.’
Such robots, according to Kurzweil, will help fight diseases, improve health and allow people to remain active for longer.
‘Biology is a software process,’ Kurzweil told Maclean’s.
‘Our bodies are made up of trillions of cells, each governed by this process.
‘You and I are walking around with outdated software running in our bodies, which evolved in a very different era.
‘We each have a fat insulin receptor gene that says, “Hold on to every calorie”.
‘That was a very good idea 10,000 years ago, when you worked all day to get a few calories; there were no refrigerators, so you stored them in your fat cells.
‘I would like to tell my fat insulin receptor gene, “You don’t need to do that anymore,”.’
Kurzweil referenced a lab mice experiment at the Joslin Diabetes Center, which managed to turn off the mice’s fat insulin receptor gene.
The mice continued to eat, remained slim, did not get diabetes or heart disease and lived 20 per cent longer.
Google is hoping to help expand the human lifespan with its new company Calico, which aims to make improvements in human health and well-being.
Kurzweil has previously predicted that by the late 2020s humans will be able to eat as much junk food as they want because everyone will have a nanobot injected into their bodies that will provide all the necessary nutrients while simultaneously eliminating fat.
Kurzweil is current work towards building smarter computers is being seen as the first step towards developing such technology.
His goal is to improve the natural language processing skills in computers that will allow robots to read, consume and understand human communication.
Kurzweil believes creating intelligent robots is key to human evolution.
elysse, you certainly have not been paying attention to Ray Kurzweil who has been trying to tell you that we all may well live to be active and healthy to age 150 or much longer because of the ongoing progress, and not just with respect to AMD, in Regenerative Medicine.
But, elysse, why wouldn't you then just go ahead with your pick 105 times out of 100?
I do say that many posts made here intended to have the appearance of great seriousness should, in fact, not be taken too seriously. I am not, however, saying that specifically about your posts.
True, mind1, and especially an investment discussion board should not be taken too seriously.
Re: ".. I would rate the chances of a $105 price prediction in the foreseeable future at close to zero or none."
Good enough, elysse. In other words, about the same as your prediction of $1.05.
Re: "... I doubt she is working in 5 companies at the time?"
Why not, they do it on K Street all the time. :)
But, mind1, the point, as per my own impression, is she moved on to the other jobs without quitting any of the previous jobs. :)
But, mind1, the point, as per my own impression, is she moved on to the other jobs without quitting any of the previous jobs. :)
Right Captain Kirk and there is a lot of evidence that OCAT does not at all want a buyout and is primarily interested in developing high value partnerships.
Right Gastro, as long as this rancher's name is not Cliven Bundy.
I understand they give an award for the top innovator in each of several categories within the Pharmaceutical Industry. This year the cherished award will be known as the Riga Tony.
But, Captain Kirk, what will happen to GoDaddy if Danica Patrick gets AMD?
Even if Lanza clearly demonstrates he deserves a Nobel Prize it will most likely take several more years to be awarded.
Frankly, in general I will be more likely to sell covered puts but ready to modify, of course, depending on the ongoing trading pattern.
Yes, elysse, selling covered options are something worth considering.
I did both Trader Joey and think you are quite right here.
Actually, Trader Joey, it is not all that dependent even on the entry point. My first purchase was 10000 shares at $0.90 in 2007 with some additional purchases on the way down from that price. My first purchase is now after the reverse split equivalent to 100 shares at $90.00 but I bought a ton of shares at 0.011 on the day in 2008 ACTC almost went down the drain (or currently for $1.10 per share) and though I currently still have something of a loss I expect in the next 1-4 years to make quite a bit of money on this investment.
Re: ".. Well, tell um to wait about FIVE YEARS or so until at least yr 2020 .."
Once again, Captain Kirk, no one, not even Lanza, has said "until at least yr 2020." What has been said is it might not be until 2020 which (again) also means it might be before 2020.
OK, OK, Captain Kirk........my bad, a tongue in cheek comment and tone often doesn't translate on an MB........mea culpa
REFUTE THIS CAPTAIN KIRK
+++++++++++++++++++++++++++++++++++++++
NEW STUDY: STEM CELL FIELD IS INFECTED WITH HYPE
Michael Hiltzik / LOS ANGELES TIMES / 3-31-2015
Study finds that reporters, fed by scientists, overestimate potential for stem cell cures
Here's how scientific hype begets more hype, and why that could cost you
When billions of dollars are at stake in scientific research, researchers quickly learn that optimism sells.
A new study published in Science Translational Medicine offers a window into how hype arises in the interaction between the media and scientific researchers, and how resistant the hype machine is to hard, cold reality. The report's focus is on overly optimistic reporting on potential stem cell therapies. Its findings are discouraging.
The study by Timothy Caulfield and Kalina Kamenova of the University of Alberta law school (Caulfield is also on the faculty at the school of public health) found that stem cell researchers often ply journalists with "unrealistic timelines" for the development of stem cell therapies, and journalists often swallow these claims uncritically.
The authors mostly blame the scientists, who need to be more aware of "the importance of conveying realistic ... timelines to the popular press." We wouldn't give journalists this much of a pass; writers on scientific topics should understand that the development of drugs and therapies can take years and involve myriad dry holes and dead ends. They should be vigilant against gaudy promises.
That's especially true in stem cell research, which is slathered with so much money that immoderate predictions of success are common. The best illustration of that comes from California's stem cell program -- CIRM, or the California Institute for Regenerative Medicine -- a $6-billion public investment that was born in hype.
The promoters of Proposition 71, the 2004 ballot initiative that created CIRM, filled the airwaves with ads implying that the only thing standing between Michael J. Fox being cured of Parkinson's or Christopher Reeve walking again was Prop. 71's money. They commissioned a study asserting that California might reap a windfall in taxes, royalties and healthcare savings up to seven times the size of its $6-billion investment. One wouldn't build a storage shed on foundations this soft, much less a $6-billion mansion.
As we've observed before, "big science" programs create incentives to exaggerate results to meet the public's inflated expectations. The phenomenon was recognized as long ago as the 1960s, when the distinguished physicist Alvin Weinberg warned that big science "thrives on publicity," resulting in "the injection of a journalistic flavor into Big Science which is fundamentally in conflict with the scientific method.... The spectacular rather than the perceptive becomes the scientific standard."
Interestingly, the event used by the Alberta researchers as the fulcrum of their study has a strong connection to CIRM. It's the abrupt 2011 decision by Geron Corp. to terminate its pioneering stem cell development program. This was a big blow to the stem cell research community and to CIRM, which had endowed Geron with a $25-million loan for its stem cell-based spinal cord therapy development. Then-CIRM Chairman Robert Klein II had called the loan a "landmark step."
There had been evidence, however, that CIRM, eager to show progress toward bringing stem cell therapies to market, had downplayed legitimate questions about the state of Geron's science and the design of the clinical trial. And Geron had been criticized in the past for over-promising results.
In their study, Caulfield and Kamenova examined more than 300 articles appearing in 14 general-interest newspapers in the United States, Canada and Britain from 2010 to 2013. They scrutinized the articles' reporting of timelines for the "realization of the clinical promise of stem cell research" and their perspective on the future of the field generally. The U.S. newspapers were the New York Times, the Wall Street Journal, the Washington Post and USA Today.
They also examined whether the media's level of optimism changed after the Geron bombshell. They found "no substantial changes in expectations." (The study didn't make any reference to CIRM.)
On the whole, news coverage was strongly optimistic. Of all news reports indicating timelines for effective stem cell therapies, 69% predicted that these would be available "within 5 to 10 years or sooner, just around the corner or in the near future." This, they observed, is "not an accurate reflection of the realities" in making stem cell therapies available.
The danger, Caulfield and Kamenova wrote, is that "this high optimism in media coverage might be adding to the fostering of unrealistic expectations regarding the speed of clinical translation," and also raises questions about "the dynamic of hope that underpins a global market for unproven [stem cell] therapies."
In other words, hype begets hype, and money gets wasted.
One especially telling discovery by Caulfield and Kamenova is that reporting on the ethical, legal and social issues of stem cell research -- once-dominant subjects -- has fallen off. This may reflect the maturing of the field, they acknowledge. But it may also lead to more focus on forecasts and predictions, which don't seem to be getting any more accurate or judicious.
Scientific researchers, especially those working in the biotech industry, already face the same pressure as stock market analysts to predict sunny skies ahead. Yet as we know from the performance of the stock market in the last decade, unreasoned optimism can be very costly.
Gastro, Lanza probably had decided we didn't need the wool yet. But after this current New England winter he might change his mind.
Re: "Ask a couple of research scientists or ceo of a biotech, if possible."
fairviewhill, I don't have to ask anyone about Lancet and NEJM. A CEO should know but might not. Frankly, in any case, anyone referring to "the far lesser Lancet" with respect to "THE NEJM" doesn't know what they are talking about. They are both in the very top tier of journals. What interest do you have in trying to portray Lancet as "lesser?"
Re: "Same could be said for TLD never making THE NEJM, but the far lesser Lancet.
Says an awful lot to me."
and, fairviewhill, by what criteria do you refer to "the far lesser Lancet?" Not at all accurate as far as I know.
Once again, Captain Kirk, the statement in the Worcester Telegram is "Any treatment might not be ready for FDA approval until 2020, Dr. Lanza said."
A correct reading of "might not" also includes that it "might" be ready for FDA approval by 2020 or even "might" be ready before 2020.
Re: "TEVA? Sure. Right on. So now every time some company w/ any ties remotely to drugs or pharma or bio-tech acquires another company- one is supposed to play imagination that it almost could have been OCAT ..."
Great point, Captain Kirk, but, IMO, the last thing OCAT wants is a buyout and will totally resist any such effort. OCAT has been very clear they are only seeking partnerships.
Right, Captain Kirk, even you see a tremendous amount of change (through your own particular colored glasses) since January 2012.
We should note that the Nature article is from January 2012.
OK, elysse, then I will continue to read in what I think is necessary.
Re: "I didn't realize corporations (inanimate legal constructs) can express emotions like "fear" and "courage"?"
Captain Kirk, corporations are people too, aren't they?
Deepak Tweet
Deepak ChopraVerified account
?@DeepakChopra
Stem cell therapy success in treatment of sight loss from macular degeneration http://gu.com/p/42e92/stw
Personally, if they are doing everything they can to move the company ahead I don't care about any PRs not related to major developments.