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Ethics and Policy
Researcher claims to have made first gene-edited baby. But did it really happen?
November 27, 2018 November 27, 2018 / Kevin McCormack	/ Leave a comment
Claude Vorilhorn, founder of Raelism; Photo: courtesy thoughtco.com
Remember the Raelians? Probably not. But way back in 2002 the group, some described them as a cult, claimed it had created the world's first cloned baby. The news made headlines all around the world raising fears we were stepping into uncharted scientific territory. Several weeks later the scientist brought in by the Raelians to verify their claims called it an "elaborate hoax."
He Jiankui: Photo courtesy MIT Technology Review
Fast forward 16 years and a Chinese scientist named He Jiankui of Shenzhen claims he has created the first genetically modified humans. Again, it is generating headlines around the world and alarming people. In an interview with CNBC, Hank Greely, a bioethicist at Stanford, said if it happened it was "criminally reckless and I unequivocally condemn the experiment."
The question now is did it happen, or is this just another "elaborate hoax"?
The concerns about this story are real. The scientist claims he used CRISPR to modify embryos during fertility treatments, resulting in the birth of twin girls.
CRISPR has been making headlines all of its own in the last few years as a fast, cheap and efficient way of editing genes. CIRM supports research using CRISPR for problems such as sickle cell disease. The difference being that our research works with adults so any changes in their genes are just for them. Those changes are not passed on to future generations.
The work making headlines around the world used CRISPR on embryos, meaning a child born from one of those embryos would pass those changes on to future generations. In effect, creating a new kind of human being.
This approach raises all sorts of serious issues – scientific, ethical and moral – not the least of which is that the technique could create unknown mutations down the road that would be passed on to future generations. That's why in the US the editing of embryos for pregnancy is banned.
But almost as soon as the news was announced there were questions raised about it. The research was not published anywhere. A hospital that the researchers named in their ethical approval documents is denying any involvement.
If it did happen, it could open a new, and potentially frightening chapter in science. In an interview on CNN, Julian Savulescu, director of the Oxford Uehiro Centre for Practical Ethics at the University of Oxford, called the use of CRISPR in this manner as "genetic Russian Roulette."
"If true, this experiment is monstrous. Gene editing itself is experimental and is still associated with off-target mutations, capable of causing genetic problems early and later in life, including the development of cancer."
And in an interview on the BBC, Prof Robert Winston, Professor of Science and Society at Imperial College London, said: "If this is a false report, it is scientific misconduct and deeply irresponsible. If true, it is still scientific misconduct."
Our best hope right now is that this is just a repeat of the Raelians. Our worst fear, is that it's not.
Has Regenerative Medicine Come of Age?
August 29, 2018 August 27, 2018 / Kevin McCormack	/ 1 Comment
For the past few years the Signals blog site – which offers an insiders' perspectives on the world of regenerative medicine and stem cell research – has hosted what it calls a "Blog Carnival". This is an event where bloggers from across the stem cell field are invited to submit a piece based on a common theme. This year's theme is "Has Regenerative Medicine Come of Age?" Here's my take on that question:
Many cultures have different traditions to mark when a child comes of age. A bar mitzvah is a Jewish custom marking a boy reaching his 13th birthday when he is considered accountable for his own actions. Among Latinos in the US a quinceañera is the name given to the coming-of-age celebration on a girl's 15th birthday.
Regenerative Medicine (RM) doesn't have anything quite so simple or obvious, and yet the signs are strong that if RM hasn't quite come of age, it's not far off.
For example, look at our experience at the California Institute for Regenerative Medicine (CIRM). When we were created by the voters of California in 2004 the world of stem cell research was still at a relatively immature phase. In fact, CIRM was created just six years after scientists first discovered a way to derive stem cells from human embryos and develop those cells in the laboratory. No surprise then that in the first few years of our existence we devoted a lot of funding to building world class research facilities and investing in basic research, to gain a deeper understanding of stem cells, what they could do and how we could use them to develop therapies.
Fast forward 14 years and we now have funded 49 projects in clinical trials – everything from stroke and cancer to spinal cord injury and HIV/AIDS – and our early funding also helped another 11 projects get into clinical trials. Clearly the field has advanced dramatically.
In addition the FDA last year approved the first two CAR-T therapies – Kymriah and Yescarta – another indication that progress is being made at many levels.
But there is still a lot of work to do. Many of the trials we are funding at the Stem Cell Agency are either Phase 1 or 2 trials. We have only a few Phase 3 trials on our books, a pattern reflected in the wider RM field. For some projects the results are very encouraging – Dr. Gary Steinberg's work at Stanford treating people recovering from a stroke is tremendously promising. For others, the results are disappointing. We have cancelled some projects because it was clear they were not going to meet their goals. That is to be expected. These clinical trials are experiments that are testing, often for the first time ever in people, a whole new way of treating disease. Failure comes with the territory.
As the number of projects moving out of the lab and into clinical trials increases so too are the other signs of progress in RM. We recently held a workshop bringing together researchers and regulators from all over the world to explore the biggest problems in manufacturing, including how you go from making a small batch of stem cells for a few patients in an early phase clinical trial to mass producing them for thousands, if not millions of patients. We are also working with the National Institutes of Health and other stakeholders in discussing the idea of reimbursement, figuring out who pays for these therapies so they are available to the patients who need them.
And as the field advances so too do the issues we have to deal with. The discovery of the gene-editing tool CRISPR has opened up all sorts of possible new ways of developing treatments for deadly diseases. But it has also opened up a Pandora's box of ethical issues that the field as a whole is working hard to respond to.
These are clear signs of a maturing field. Five years ago, we dreamed of having these kinds of conversations. Now they are a regular feature of any RM conference.
The simple fact that we can pose a question asking if RM has come of age is a sign all by itself that we are on the way.
Like little kids sitting in the back of a car, anxious to get to their destination, we are asking "Are we there yet?" And as every parent in the front seat of their car responds, "Not yet. But soon."
Scientists fix heart disease mutation in human embryos using CRISPR
August 3, 2017 / Karen Ring	/ Leave a comment
Last week the scientific community was buzzing with the news that US scientists had genetically modified human embryos using CRISPR gene editing technology. While the story broke before the research was published, many journalists and news outlets weighed in on the study's findings and the ethical implications they raise. We covered this initial burst of news in last week's stem cell stories that caught our eye.
Shoukhrat Mitalipov (Leah Nash, New York Times)
After a week of suspense, the highly-anticipated study was published yesterday in the journal Nature. The work was led by senior author Dr. Shoukhrat Mitalipov from Oregon Health and Sciences University (and a member of CIRM's Grants Working Group, the panel of experts who review applications to us for funding) in collaboration with scientists from the Salk Institute and Korea's Institute for Basic Science.
In brief, the study revealed that the teams' CRISPR technology could correct a genetic mutation that causes a disease called hypertrophic cardiomyopathy (HCM) in 72% of human embryos without causing off-target effects, which are unwanted genome modifications caused by CRISPR. These findings are a big improvement over previous studies by other groups that had issues with off-target effects and mosaicism, where CRISPR only correctly modifies mutations in some but not all cells in an embryo.
Newly fertilized eggs before gene editing, left, and embryos after gene editing and a few rounds of cell division. (Image from Shoukrat Mitalipov in New York Times)
Mitalipov spoke to STATnews about a particularly interesting discovery that he and the other scientists made in the Nature study,
"The main finding is that the CRISPR'd embryos did not accept the "repair DNA" that the scientists expected them to use as a replacement for the mutated gene deleted by CRISPR, which the embryos inherited from their father. Instead, the embryos used the mother's version of the gene, called the homologue."
Sharon Begley, the author of the STATnews article, argued that this discovery means that "designer babies" aren't just around the corner.
"If embryos resist taking up synthetic DNA after CRISPR has deleted an unwanted gene, then "designer babies," created by inserting a gene for a desirable trait into an embryo, will likely be more difficult than expected."
Ed Yong from the Atlantic also took a similar stance towards Mitalipov's study in his article titled "The Designer Baby Era is Not Upon Us". He wrote,
"The bigger worry is that gene-editing could be used to make people stronger, smarter, or taller, paving the way for a new eugenics, and widening the already substantial gaps between the wealthy and poor. But many geneticists believe that such a future is fundamentally unlikely because complex traits like height and intelligence are the work of hundreds or thousands of genes, each of which have a tiny effect. The prospect of editing them all is implausible. And since genes are so thoroughly interconnected, it may be impossible to edit one particular trait without also affecting many others."
Dr. Juan Carlos Izpisua Belmonte, who's a corresponding author on the paper and a former CIRM grantee from the Salk Institute, commented on the impact that this research could have on human health in a Salk news release.
Co-authors Juan Carlos Izpisua Belmonte and Jun Wu. (Salk Institute)
"Thanks to advances in stem cell technologies and gene editing, we are finally starting to address disease-causing mutations that impact potentially millions of people. Gene editing is still in its infancy so even though this preliminary effort was found to be safe and effective, it is crucial that we continue to proceed with the utmost caution, paying the highest attention to ethical considerations."
Pam Belluck from The New York Times also suggested that this research could have a significant impact on how we prevent disease in newborns.
"This research marks a major milestone and, while a long way from clinical use, it raises the prospect that gene editing may one day protect babies from a variety of hereditary conditions."
So when will the dawn of CRISPR babies arrive? Ed Yong took a stab at answering this million dollar question with help from experts in the field.
"Not for a while. The technique would need to be refined, tested on non-human primates, and shown to be safe. "The safety studies would likely take 10 to 15 years before FDA or other regulators would even consider allowing clinical trials," wrote bioethicist Hank Greely in a piece for Scientific American. "The Mitalipov research could mean that moment is 9 years and 10 months away instead of 10 years, but it is not close." In the meantime, Mitalipov's colleague Sanjiv Kaul says, "We'll get the method to perfection so that when it's possible to use it in a clinical trial, we can."
Stem Cell Stories that Caught our Eye: CRISPRing Human Embryos, brain stem cells slow aging & BrainStorm ALS trial joins CIRM Alpha Clinics
July 28, 2017 July 28, 2017 / Karen Ring	/ 1 Comment
Here are the stem cell stories that caught our eye this week. Enjoy!
Scientists claim first CRISPR editing of human embryos in the US.
Here's the big story this week. Scientists from Portland, Oregon claim they genetically modified human embryos using the CRISPR/Cas9 gene editing technology. While their results have yet to be published in a peer review journal (though the team say they are going to be published in a prominent journal next month), if they prove true, the study will be the first successful attempt to modify human embryos in the US.
A representation of an embryo being fertilized. Scientists can inject CRISPR during fertilization to correct genetic disorders. (Getty Images).
Steve Connor from MIT Technology Review broke the story earlier this week noting that the only reports of human embryo modification were published by Chinese scientists. The China studies revealed troubling findings. CRISPR caused "off-target" effects, a situation where the CRISPR machinery randomly introduces genetic errors in a cell's DNA, in the embryos. It also caused mosaicism, a condition where the desired DNA sequences aren't genetically corrected in all the cells of an embryo producing an individual with cells that have different genomes. Putting aside the ethical conundrum of modifying human embryos, these studies suggested that current gene editing technologies weren't accurate enough to safely modify human embryos.
But a new chapter in human embryo modification is beginning. Shoukhrat Mitalipov (who is a member of CIRM's Grants Working Group, the panel of scientific experts that reviews our funding applications) and his team from the Oregon Health and Science University said that they have developed a method to successfully modify donated human embryos that avoids the problems experienced by the Chinese scientists. The team found that introducing CRISPR at the same time an embryo was being fertilized led to successful correction of disease-causing mutations while avoiding mosaicism and "off-target" effects. They grew these embryos for a few days to confirm that the genetic modifications had worked before destroying them.
The MIT piece quoted a scientist who knows of Mitalipov's work,
"It is proof of principle that it can work. They significantly reduced mosaicism. I don't think it's the start of clinical trials yet, but it does take it further than anyone has before."
Does this discovery, if it's true, open the door further for the creation of designer babies? For discussions about the future scientific and ethical implications of this research, I recommend reading Paul Knoepfler's blog, this piece by Megan Molteni in Wired Magazine and Jessica Berg's article in The Conversation.
Brain stem cells slow aging in mice
The quest for eternal youth might be one step closer thanks to a new study published this week in the journal Nature. Scientists from the Albert Einstein College of Medicine in New York discovered that stem cells found in an area of the brain called the hypothalamus can slow the aging process in mice.
The hypothalamus is located smack in the center of your brain near the brain stem. It's responsible for essential metabolic functions such as making and secreting hormones, managing body temperature and controlling feelings of hunger and thirst. Because the body's metabolic functions decline with age, scientists have suspected that the hypothalamus plays a role in aging.
The mouse hypothalamus. (NIH, Wikimedia).
In the current study, the team found that stem cells in the hypothalamus gradually disappear as mice age. They were curious whether the disappearance of these stem cells could jump start the aging process. When they removed these stem cells, the mice showed more advanced mental and physical signs of aging compared to untreated mice.
They also conducted the opposite experiment where they transplanted hypothalamic stem cells taken from baby mice (the idea being that these stem cells would exhibit more "youthful" qualities) into the brains of middle-aged mice and saw improvements in mental and physical functions and a 10% increase in lifespan.
So what is it about these specific stem cells that slows down aging? Do they replenish the aging brain with new healthy cells or do they secrete factors that keep the brain healthy? Interestingly, the scientists found that these stem cells secreted vesicles that contained microRNAs, which are molecules that regulate gene expression by turning genes on or off.
They injected these microRNAs into the brains of middle-aged mice and found that they reversed symptoms of aging including cognitive decline and muscle degeneration. Furthermore, when they removed hypothalamic stem cells from middle-aged mice and treated them with the microRNAs, they saw the same anti-aging effects.
In an interview with Nature News, senior author on the study, Dongsheng Cai, commented that hypothalamic stem cells could have multiple ways of regulating aging and that microRNAs are just one of their tools. For this research to translate into an anti-aging therapy, "Cai suspects that anti-ageing therapies targeting the hypothalamus would need to be administered in middle age, before a person's muscles and metabolism have degenerated beyond a point that could be reversed."
This study and its "Fountain of Youth" implications has received ample attention from the media. You can read more coverage from The Scientist, GenBio, and the original Albert Einstein press release.
BrainStorm ALS trial joins the CIRM Alpha Clinics
Last month, the CIRM Board approved $15.9 million in funding for BrainStorm Cell Therapeutic's Phase 3 trial that's testing a stem cell therapy to treat patients with a devastating neurodegenerative disease called amyotrophic lateral sclerosis or ALS (also known as Lou Gehrig's disease).
The stem cell therapy, called NurOwn®, is made of mesenchymal stem cells extracted from a patient's bone marrow. The stem cells are genetically modified to secrete neurotrophic factors that keep neurons in the brain healthy and prevent their destruction by diseases like ALS.
BrainStorm has tested NurOwn in early stage clinical trials in Israel and in a Phase 2 study in the US. These trials revealed that the treatment was "safe and well tolerated" and that "NurOwn also achieved multiple secondary efficacy endpoints, showing clear evidence of a clinically meaningful benefit. Notably, response rates were higher for NurOwn-treated subjects compared to placebo at all time points in the study out to 24 weeks."
This week, BrainStorm announced that it will launch its Phase 3 CIRM-funded trial at the UC Irvine (UCI) CIRM Alpha Stem Cell Clinic. The Alpha Clinics are a network of top medical centers in California that specialize in delivering high quality stem cell clinical trials to patients. UCI is one of four medical centers including UCLA, City of Hope, and UCSD, that make up three Alpha Clinics currently supporting 38 stem cell trials in the state.
Along with UCI, BrainStorm's Phase 3 trial will also be conducted at two other sites in the US: Mass General Hospital in Boston and California Pacific Medical Center in San Francisco. Chaim Lebovits, President and CEO, commented,
"We are privileged to have UCI and Dr. Namita Goyal join our pivotal Phase 3 study of NurOwn. Adding UCI as an enrolling center with Dr. Goyal as Principal Investigator will make the treatment more accessible to patients in California, and we welcome the opportunity to work with this prestigious institution."
Before the Phase 3 trial can launch at UCI, it needs to be approved by our federal regulatory agency, the Food and Drug Administration (FDA), and an Institutional Review Board (IRB), which is an independent ethics committee that reviews biomedical research on human subjects. Both these steps are required to ensure that a therapy is safe to test in patients.
With promising data from their Phase 1 and 2 trials, BrainStorm's Phase 3 trial will likely get the green light to move forward. Dr. Goyal, who will lead the trial at the UCI Alpha Clinic, concluded:
"NurOwn is a very promising treatment with compelling Phase 2 data in patients with ALS; we look forward to further advancing it in clinical development and confirming the therapeutic benefit with Brainstorm."
Why Stem Cell Advocates Texans for Cures say "Right to Try" Legislation Should be Fought
July 24, 2017 / Kevin McCormack	/ Leave a comment
This week in Washington DC a delegation from the stem cell advocacy group Texans for Cures is meeting with members of Congress from both parties. The focus of the meetings are three bills promoting "Right to Try" legislation. Supporters of the bills say they will empower patients battling terminal illness. Texans for Cures say, quite the contrary, that these laws will endanger patients. In this guest blog, Texans for Cures explain why they feel these laws are bad.
In 2014, the Goldwater Institute published a policy report titled, "Everyone Deserves the Right to Try: Empowering the Terminally Ill to Take Control of their Treatment."[i] The report calls for states to pass "Right to Try" legislation as a means to reclaim patients' medical autonomy and right to determine their own medical treatment.
This policy recommendation is built on the theory that the Food and Drug Administration (FDA) should not be able to restrict terminal patients' access to potentially life-saving treatments so long as the treatment has been tested for basic safety. While this idea may seem immediately appealing, the policy undermines medical research in several ways that are harmful to the development of new treatments.
Texans for Cures opposes this legislation because it harms the sound development of treatments for future patients on the mere chance that it may provide relief to current patients that have received a terminal diagnosis. In short, Right to Try policies ignore the attendant risks and overemphasize the potential benefits.
"Right to Try" Model Legislation and State Enacted Variants
The Goldwater Institute's policy report included model legislation for interested legislators, which it summed up as follows:
Simply stated, Right to Try allows a patient to access investigational medications that have passed basic safety tests without interference by the government when the following conditions are met:
The patient has been diagnosed with a terminal disease;
The patient has considered all available treatment options;
The patient's doctor has recommended that the investigational drug, device, or biological product represents the patient's best chance at survival;
The patient or the patient's guardian has provided informed consent; and
The sponsoring company chooses to make the investigational drug available to patients outside the clinical trial.
Since the Goldwater Institute published this policy report in 2014, 33 states have enacted Right to Try laws.[ii] These laws contain minor variations from the model legislation, but each operates similarly to limit the FDA's oversight roll.
Right to Try is Loosely Grounded in the Constitution and May Require Federal Action
Due to the fact that these laws may infringe on the FDA's authority over drug development and distribution, the policy report attempts to ground Right to Try in one's constitutional right to liberty. This constitutional underpinning is loose and is not firmly supported by Supreme Court precedent.[iii] With the constitutional basis of Right to Try resting on a weak foundation, it is important for Right to Try proponents to pass a complimentary Right to Try statute on the federal level in Congress.
There are three bills actively working through the Congressional process that would prohibit the FDA or any other federal agency from interfering with a patient's Right to Try: H.R. 878 by Representative Biggs,[iv] H.R. 2368 by Representative Fitzpatrick,[v] and S. 204 by Senator Johnson.[vi] Each of these bills shares three common provisions, while H.R. 2368 has two additional provisions:
Common Provisions:
Prohibition on federal action
No use of outcomes
Provisions Unique to H.R. 2368:
Manufacturers are not required to make treatments available
Permits manufacturers to receive compensation or recover costs
All three of the federal bills would remove the FDA's ability to intervene in state Right to Try programs. They also create a liability shield for any producer, manufacturer, distributor, prescriber, dispenser, possessor, or user participating in the program. And finally, each prohibits the use of outcomes from patients participating in Right to Try as a criteria for FDA review of the treatment. This means that harmed patients would have limited or no legal recourse, and the FDA may need another Act of Congress to grant them the authority to intervene in any programs that prove to be dangerous. However, it may be difficult to know if these programs are harming patients or not, because the bills do not provide any mechanism for tracking outcomes and using that information for oversight.
Each bill is drafted in a way that would remove FDA oversight authority and would allow states to proceed with Right to Try policies and grants states broad discretion to tailor these programs without federal oversight. However, H.R. 2368 contains two additional provisions that would compliment and potentially override state statute. First, the bill gives manufacturers the authority to deny patients access to investigational treatments, which is consistent with the Goldwater Institute's model legislation. Second, the bill allows manufacturers to receive compensation or recover costs involved in making the drug available to patients. This second provision is particularly problematic in that it would allow manufacturers to charge patients for unproven treatments unless they were explicitly prohibited from doing so by state law.
How Right to Try Laws Structurally Harm the Research Process
Right to Try laws create a number of problematic incentives and penalties that would likely harm the long term development of new therapies. First and foremost, under Right to Try, patients will be able to bypass the clinical trial process, request investigational treatments, and pay the cost of the drug, rather than enter into a clinical trial. Given that clinical trials may involve the use of placebos, Texans for Cures is concerned that patients may choose to exercise Right to Try rather than participate in a clinical trial, because under Right to Try the patient avoids the possibility of receiving a placebo.
Additionally, there is no mechanism in the proposed bills for tracking outcomes of patients participating in Right to Try, and there is no mechanism for government intervention if Right to Try proves to be unreasonably risky.
Right to Try seeks to shield all participants from liability, meaning that patients who are harmed will have limited or no legal recourse, even if manufacturers or physicians are negligent. Furthermore, Right to Try laws typically allow manufacturers to recover the cost of manufacturing the treatment for participating patients, but cost is not defined. Does cost include the cost of research and development or is it exclusively the cost of creating that specific treatment? The ambiguity surrounding this term is a cause for concern, because companies may be tempted to use this ambiguity to cover a broader sets of costs than the authors intended.
Texans for Cures opposes this legislative effort because the program could potentially harm patients and, if it does, the law does not provide adequate safeguards or remedies. Additionally, the law does not require any monitoring of outcomes and is therefore unscientific in its approach to treatments that are currently undergoing clinical research.
The FDA is already working to ease the burdens associated with Expanded Access programs, which achieve the end that Right to Try desires: providing access to research drugs for terminal patients. The difference is that Expanded Access has additional safeguards and a mechanism for FDA intervention if treatment is found to be dangerous or harmful to the clinical trial process.
Finding scientifically sound treatments for patients in need is the primary concern of Texans for Cures. Texans for Cures sympathizes with, and its members have similarly experienced, the pain of losing loved ones. The hope and emotion involved in Right to Try laws is not to be taken lightly, but it is precisely because strong emotions can cloud our judgment that we, as a society, must approach the clinical trial process with a clear mental state. Texans for Cures believes that Right to Try will harm the long term development of new treatments and therefore asks for your help in fighting this legislative effort.
[1] Christina Corieri, "Everyone Deserves the Right to Try: Empowering the Terminally Ill to Take Control of their Treatment," Goldwater Institute (2014), https://goldwater-media.s3.amazonaws.com/cms_page_media/2015/1/28/Right%20To%20Try.pdf
2 KHN Morning Briefing, "'Right to Try' Advocates Help Pass Laws In 33 States As Movement Gains National Foothold," Kaiser Health News (2017), http://khn.org/morning-breakout/right-to-try-advocates-help-pass-laws-in-33-states-as-movement-gains-national-foothold/
3 The Goldwater Institute's sole source for constitutional grounding for this law comes from a concurrence by Justice Douglas in Doe v. Bolton, 410 U.S. 179, 218 (1973), where he noted that individuals have a "right to care for one's health and person." The Goldwater Institute appears to recognize the precarious footing of their model legislation, stating in their policy report, "Although the right of terminal patients to access investigational medications has not yet been recognized by the Supreme Court, it is consistent with and can be supported by existing precedent."
[1] H.R. 878 by Representative Biggs, https://www.congress.gov/bill/115th-congress/house-bill/878/text?q=%7B%22search%22%3A%5B%22right+to+try%22%5D%7D&r=2
[1] H.R. 2368 by Representative Fitzpatrick, https://www.congress.gov/bill/115th-congress/house-bill/2368/text?q=%7B%22search%22%3A%5B%22right+to+try%22%5D%7D&r=1
[1] S. 204 by Senator Johnson, https://www.congress.gov/bill/115th-congress/senate-bill/204/text?q=%7B%22search%22%3A%5B%22right+to+try%22%5D%7D&r=3
'Pay-to-Participate' stem cell clinical studies, the ugly stepchild of ClinicalTrials.gov
July 19, 2017 July 19, 2017 / Karen Ring	/ 10 Comments
When patients are looking for clinical trials testing new drugs or treatments for their disease, one of the main websites they visit is ClinicalTrials.gov. It's a registry provided by the National Institutes of Health (NIH) of approximately 250,000 clinical trials spanning over 200 countries around the world.
ClinicalTrials.gov website
If you visit the website, you'll find CIRM's 28 active clinical trials testing stem cell-based therapies for indications like spinal cord injury, type 1 diabetes, heart failure, ALS, cancer and more. These are Food and Drug Administration (FDA)-approved trials, meaning that researchers did the proper preclinical studies to prove that a therapy was safe and effective in animal models and received approval from the US FDA to test the treatment in human clinical trials.
As the largest clinical registry in the world, ClinicalTrials.gov is a very valuable resource for patients and the public. But there are studies on the website that have recently surfaced and taken on the role of 'ugly stepchild'. These are unapproved stem cell therapies from companies and stem cell clinics that are registering their "pay-to-participate treatments". And they are doing so in clever ways that don't make it obvious to patients that the trials aren't legitimate. The reason this is so troubling is that unproven therapies can be dangerous or even life-threatening to patients.
Leigh Turner
Leigh Turner, an associate professor of bioethics at the University of Minnesota, has written extensively about the serious problem of stem cell clinics marketing unproven stem cell therapies to desperate patients. Turner, in collaboration with UC Davis professor Dr. Paul Knoepfler, published a study in Cell Stem Cell last year that identified over 550 clinics in the US that promote unproven treatments for almost any condition, including diseases like Alzheimer's where research has shown that cures are a long way off.
Today, Turner published an article in Regenerative Medicine that shines a light on how companies and clinics are taking advantage of ClinicalTrials.gov to promote their "pay-to-participate" unproven stem cell studies. The article is available for free if you register with RegMedNet, but you can find news coverage about Turner's piece through EurekAlert, Wired Magazine and the San Diego Union Tribune.
In an interview with RegMedNet, Turner explained that his research into how businesses promote unproven stem cell therapies led to the discovery that these studies were being listed as "pay-to-participate" on ClinicalTrials.gov.
"Many of these businesses use websites, social media, YouTube videos, webinars and other tools to engage in direct-to-consumer marketing of supposed stem cell therapies. To my surprise, at one point I noticed that some of these companies had successfully listed "pay-to-participate" studies on ClinicalTrials.gov. Many of these "studies" look to me like little more than marketing exercises, though of course the businesses listing them would presumably argue that they are genuine clinical studies."
While FDA-approved trials can charge study participants, most don't. If they do, it's motivated by recovering costs rather than making a profit. Turner also explained that organizations with FDA-approved studies "need to prepare a detailed rationale and a budget, and obtain approval from the FDA."
Companies with unproven stem cell therapies are ignoring these regulatory requirements and listing their studies as "patient-funded" or "patient-sponsored". Turner found seven such "pay-to-participate" studies sponsored by US companies on ClinicalTrials.gov. He also identified 11 studies where companies don't indicate that patients have to pay, but do charge patients to participate in the studies.
Turner is concerned that these companies are using ClinicalTrials.gov to take advantage of innocent patients who don't realize that these unproven treatments aren't backed by solid scientific research.
"Patients have already been lured to stem cell clinics that use ClinicalTrials.gov to market unproven stem cell interventions. Furthermore, some patients have been injured after undergoing stem cell procedures at such businesses. Many individuals use ClinicalTrials.gov to find legitimate, well-designed, and carefully conducted clinical trials. They are at risk of being misled by study listings that lend an air of legitimacy and credibility to clinics promoting unproven and unlicensed stem cell interventions."
Having identified the problem, Turner is now advocating for a solution.
"ClinicalTrials.gov needs to raise the bar and perform a proper review of studies before they are registered. Better screening is needed before more patients and research subjects are harmed. It's astonishing that officials at the NIH and US FDA haven't already done something to address this obvious matter of patient safety. Putting a disclaimer on the website isn't sufficient."
The disclaimer that Turner is referring to is a statement on the ClinicalTrials.gov website that says, "Listing of a study on this site does not reflect endorsement by the National Institutes of Health (NIH)."
Turner argues that this disclaimer "simply isn't sufficient."
"Patients and their loved ones, physicians, researchers, journalists, and many other individuals all use ClinicalTrials.gov because they regard the registry and database as a source of meaningful, credible information about clinical studies. I suspect most individuals would be shocked at how easy it is to register on ClinicalTrials.gov studies that have obvious methodological problems, do not appear to comply with applicable federal regulations or have glaring ethical shortcomings."
While Turner acknowledges that the NIH database of clinical trials is a "terrific public resource" that he himself has used, he regards it "as a collective good that needs to be protected from parties willing to misuse and abuse it." His hope is that his article will give journalists the starting material to conduct further investigators into these pay-to-participate studies and the companies behind them. He also hopes that "such coverage will help convince NIH officials that they have a crucial role to play in making ClinicalTrials.gov a resource people can turn to for information about credible clinical trials rather than allowing it to become a database corrupted and devalued by highly problematic studies."
Convincing is one thing, but implementing change is another. Turner said in his interview that he knows that "careful screening by NIH officials will require more resources, and I am making this argument at a time when much of the political discourse in the U.S. is about cutting funding for the CDC, FDA, NIH and other federal agencies."
He remains hopeful however and concluded that "perhaps there are ways to jolt into action people who are in positions of power and who can act to help prevent the spread of misinformation, bad science, and marketing packaged as clinical research."
Texas tries to go it alone in offering unproven stem cell therapies to patients
May 22, 2017 May 22, 2017 / Kevin McCormack	/ 5 Comments
Texas Capitol. (Shutterstock)
One of the most hotly debated topics in stem cell research is whether patients should be able to have easier access to unproven therapies using their own stem cells, at their own risk, and their own cost. It's a debate that is dividing patients and physicians, researchers and lawmakers.
In California, a bill working its way through the state legislature wants to have warning signs posted in clinics offering unproven stem cell therapies, letting patients know they are potentially putting themselves at risk.
Texas is taking a very different approach. A series of bills under consideration would make it easier for clinics to offer unproven treatments; make it easier for patients with chronic illnesses to use the "right to try" law to take part in early-stage clinical trials (in the past, it was only patients with a terminal illness who could do that); and allow these clinics to charge patients for these unproven stem cell therapies.
Not surprisingly, the Texas bills are attracting some widely divergent views. Many stem cell researchers and some patient advocates are opposed to them, saying they prey on the needs of vulnerable people, offering them treatments – often costing thousands, even tens of thousands of dollars – that have little or no chance of success.
In an article on STATnews, Sean Morrison, a stem cell researcher at the University of Texas Southwestern Medical Center, in Dallas, said the Texas bills would be bad for patients:
"When patients get desperate, they have a capacity to suspend disbelief. When offered the opportunity of a therapy they believe in, even without data and if the chances of benefit are low, they'll fight for access to that therapy. The problem is there are fraudulent stem cell clinics that have sprung up to exploit that."
Patients like Jennifer Ziegler disagree with that completely. Ziegler has multiple sclerosis and has undergone three separate stem cell treatments – two in the US and one in Panama – to help treat her condition. She is also a founding member of Patients For Stem Cells (PFSC):
Jennifer Ziegler
"PFSC does not believe our cells are drugs. We consider the lack of access to adult stem cells an overreach by the federal government into our medical freedoms. My cells are not mass produced, and they do not cross state lines. An adult stem cell treatment is a medical procedure, between me, a fully educated patient, and my fully competent doctor."
The issue is further complicated because the US Food and Drug Administration (FDA) – which has regulatory authority over stem cell treatments – considers the kinds of therapies these clinics offer to be a technical violation of the law. So even if Texas passes these three bills, they could still be in violation of federal law. However, a recent study in Cell Stem Cell showed that there are some 570 clinics around the US offering these unproven therapies, and to date the FDA has shown little inclination to enforce the law and shut those clinics down.
UC Davis stem cell researcher – and CIRM grantee – Paul Knoepfler is one of the co-authors of the study detailing how many clinics there are in the US. On his blog – The Niche – he recently expressed grave concerns about the Texas bills:
Paul Knoepfler
"The Texas Legislature is considering three risky bills that would give free rein to stem cell clinics to profit big time off of patients by selling unproven and unapproved "stem cell treatments" that have little if any science behind them. I call one of these bills "Right to Profit" for clinics, which if these became law could get millions from vulnerable patients and potentially block patient rights."
Ziegler counters that patients have the right to try and save their own lives, saying if the Texas bills pass: "chronically ill, no option patients in the US, will have the opportunity to seek treatment without having to leave the country."
It's a debate we are all too familiar with at CIRM. Every day we get emails and phone calls from people asking for help in finding a treatment, for them or a loved one, suffering from a life-threatening or life-altering disease or disorder. It's incredibly difficult having to tell them there is nothing that would help them currently being tested in a clinical trial.
Inevitably they ask about treatments they have seen online, offered by clinics using the patient's own stem cells to treat them. At that point, it is no longer an academic debate about proven or unproven therapies, it has become personal; one person asking another for help, to find something, anything, to save their life.
Barring a dramatic change of policy at the FDA. these clinics are not going to go away. Nor will the need of patients who have run out of options and are willing to try anything to ease their pain or delay death. We need to find another way, one that brings these clinics into the fold and makes the treatments they offer part of the clinical trial process.
There are no easy answers, no simple solutions. But standing on either side of the divide, saying those on the other side are either "heartless" or "foolish" serves no one, helps no one. We need to figure out another way.
'Right To Try' laws called 'Right To Beg' by Stem Cell Advocates
December 19, 2016 December 19, 2016 / Kevin McCormack	/ 1 Comment
In recent years, 'Right to Try' laws have spread rapidly across the US, getting approved in 32 states, with at least three more states trying to pass their own versions.
The organization behind the laws says they serve a simple purpose:
'Right To Try' allows terminally ill Americans to try medicines that have passed Phase 1 of the FDA approval process and remain in clinical trials but are not yet on pharmacy shelves. 'Right To Try' expands access to potentially life-saving treatments years before patients would normally be able to access them."
That certainly sounds like a worthy goal; one most people could get behind. And that's what is happening. Most 'Right To Try' laws are passed with almost unanimous bi-partisan support at the state level.
Beth Roxland
But that's not the view of Beth Roxland, an attorney and health policy advisor with an extensive history in both regenerative medicine and bioethics. At the recent World Stem Cell Summit Roxland said 'Right To Try' laws are deceptive:
"These are not patient friendly but are actually patient unfriendly and could do harm to patients. The problem is that they are pretending to do something that isn't being done. It gives patients a sense that they can get access to a treatment, but they don't have the rights they think they do. This is a right to ask, not a right to get."
Roxland says the bills in all 32 states are almost all identical, and use the same cookie-cutter language from the Goldwater Institute – the libertarian organization that is promoting these laws. And she says these laws have one major flaw:
"There is no actual right provided in the bill. The only right is the right to try and save your life, "by requesting" from a manufacturer a chance to try the therapy. The manufacturer doesn't have to do anything; they aren't obliged to comply. The bills don't help; they give people false hopes."
Roxland says there isn't one substantiated case where a pharmaceutical company has provided access to a therapy solely because of a 'Right To Try' law.
However, Starlee Coleman, the Vice President for Communications at the Goldwater Institute, says that's not true. She says Dr. Ebrahim Delpassand, a cancer specialist in Texas, has testified before Congress that he has treated dozens of patients under his state's 'Right To Try' law. You can see a video of Dr. Delpassand here.
Coleman says ;
"We think the promise of 'Right To Try' is self-evident. If one doctor alone can treat 80 patients in one fell swoop, but the FDA can only manage to get 1200 people through its expanded access program each year, we think the potential to help patients is significant."
Other speakers at the panel presentation at the World Stem Cell Summit said these laws can at the very least play an important role in at least raising the issue of the need for people battling terminal illnesses to have access to experimental therapies. Roxland agreed it was important to have that conversation but she pointed out that what often gets lost in the conversation is that these laws can have hidden costs.
13 states may withdraw hospice eligibility to people who gain access to an early or experimental intervention
4 states may withdraw home care
6 states say patients taking part in these therapies may lose their insurance
Several states allow insurers to deny coverage for conditions that may arise from patients getting access to these therapies
30 states say the companies can charge the patients for access to these therapies
Roxland says the motives behind the 'Right To Try' laws may be worthy but the effect is misleading, and diverts attention from efforts to create the kind of reforms that would have real benefits for patients.
Here is a blog we wrote on the same topic last year.
Eggciting News: Scientists developed fertilized eggs from mouse stem cells
October 19, 2016 / Karen Ring	/ Leave a comment
A really eggciting science story came out early this week that's received a lot of attention. Scientists in Japan reported in the journal Nature that they've generated egg cells from mouse stem cells, and these eggs could be fertilized and developed into living, breathing mice.
This is the first time that scientists have reported the successful development of egg cells in the lab outside of an animal. Many implications emerge from this research like gaining a better understanding of human development, generating egg cells from other types of mammals and even helping infertile women become pregnant.
Making eggs from pluripotent stem cells
The egg cells, also known as oocytes, were generated from mouse embryonic stem cells and induced pluripotent stem cells derived from mouse skin cells in a culture dish. Both stem cell types are pluripotent, meaning that they can generate almost any cell type in the human body.
After generating the egg cells, the scientists fertilized the eggs through in vitro fertilization (IVF) using sperm from a healthy male mouse. They allowed the fertilized eggs to grow into two cell embryos which they then transplanted into female mice. 11 out of 316 embryos (or 3.5%) produced offspring, which were then able to reproduce after they matured into adults.
These mice were born from artificial eggs that were made from stem cells in a dish. (K. Hayashi, Kyushu University)
Not perfect science
While impressive, this study did identify major issues with its egg-making technique. First, less than 5% of the embryos made from the stem-cell derived eggs developed into viable mice. Second, the scientists discovered that some of their lab-grown eggs (~18%) had abnormal numbers of chromosomes – an event that can prevent an embryo from developing or can cause genetic disorders in offspring.
Lastly, to generate mature egg cells, the scientists had to add cells taken from mouse embryos in pregnant mice to the culture dish. These outside cells acted as a support environment that helped the egg cells mature and were essential for their development. The scientists are working around this issue by developing artificial reagents that could hopefully replace the need for these cells.
Egg cells made from embryonic stem cells in a dish. (K. Hayashi, Kyushu University)
Will human eggs be next?
A big discovery such as this one immediately raises ethical questions and concerns about whether scientists will attempt to generate artificial human egg cells in a dish. Such technology would be extremely valuable to women who do not have eggs or have problems getting pregnant. However, in the wrong hands, a lot could go wrong with this technology including the creation of genetically abnormal embryos.
In a Nature news release, Azim Surani who is well known in this area of research, said that these ethical issues should be discussed now and include the general public. "This is the right time to involve the wider public in these discussions, long before and in case the procedure becomes feasible in humans."
In an interview with Phys.org , James Adjaye, another expert from Heinrich Heine University in Germany, raised the point that even if we did generate artificial human eggs, "the final and ultimate test for fully functional human 'eggs in a dish' would be the fertilization using IVF, which is also ethically not allowed."
Looking forward, senior author on the Nature study, Katsuhiko Hayashi, predicted that in a decade, lab-grown "oocyte-like" human eggs will be available but probably not at a scale for fertility treatments. Because of the technical issues his study revealed, he commented, "It is too preliminary to use artificial oocytes in the clinic."
Trash talking and creating a stem cell community
October 17, 2016 October 17, 2016 / Kevin McCormack	/ Leave a comment
Imilce Rodriguez-Fernandez likes to talk trash. No, really, she does. In her case it's cellular trash, the kind that builds up in our cells and has to be removed to ensure the cells don't become sick.
Imilce was one of several stem cell researchers who took part in a couple of public events over the weekend, on either side of San Francisco Bay, that served to span both a geographical and generational divide and create a common sense of community.
The first event was at the Buck Institute for Research on Aging in Marin County, near San Francisco. It was titled "Stem Cell Celebration" and that's pretty much what it was. It featured some extraordinary young scientists from the Buck talking about the work they are doing in uncovering some of the connections between aging and chronic diseases, and coming up with solutions to stop or even reverse some of those changes.
One of those scientists was Imilce. She explained that just as it is important for people to get rid of their trash so they can have a clean, healthy home, so it is important for our cells to do the same. Cells that fail to get rid of their protein trash become sick, unhealthy and ultimately stop working.
Imilce is exploring the cellular janitorial services our bodies have developed to deal with trash, and trying to find ways to enhance them so they are more effective, particularly as we age and those janitorial services aren't as efficient as they were in our youth.
Unlocking the secrets of premature aging
Chris Wiley, another postdoctoral researcher at the Buck, showed that some medications that are used to treat HIV may be life-saving on one level, preventing the onset of full-blown AIDS, but that those benefits come with a cost, namely premature aging. Chris said the impact of aging doesn't just affect one cell or one part of the body, but ripples out affecting other cells and other parts of the body. By studying the impact those medications have on our bodies he's hoping to find ways to maintain the benefits of those drugs, but get rid of the downside.
Creating a Community
Across the Bay, the U.C. Berkeley Student Society for Stem Cell Research held it's 4th annual conference and the theme was "Culturing a Stem Cell Community."
The list of speakers was a Who's Who of CIRM-funded scientists from U.C. Davis' Jan Nolta and Paul Knoepfler, to U.C. Irvine's Henry Klassen and U.C. Berkeley's David Schaffer. The talks ranged from progress in fighting blindness, to how advances in stem cell gene editing are cause for celebration, and concern.
What struck me most about both meetings was the age divide. At the Buck those presenting were young scientists, millennials; the audience was considerably older, baby boomers. At UC Berkeley it was the reverse; the presenters were experienced scientists of the baby boom generation, and the audience were keen young students representing the next generation of scientists.
But regardless of the age differences there was a shared sense of involvement, a feeling that regardless of which side of the audience we are on we all have something in common, we are all part of the stem cell community.
All communities have a story, something that helps bind them together and gives them a sense of common purpose. For the stem cell community there is not one single story, there are many. But while those stories all start from a different place, they end up with a common theme; inspiration, determination and hope.


text:
Eduardo Saul Schwartz (born 1940) is a professor of finance at SFU's Beedie School of Business, where he holds the Ryan Beedie Chair in Finance. He is also a Distinguished Research Professor at the University of California, Los Angeles. He is known for pioneering research in several areas of finance, particularly derivatives. His major contributions include: the real options method of pricing investments under uncertainty; the Longstaff–Schwartz model -  a multi-factor short-rate model; the Longstaff-Schwartz method for valuing American options by Monte Carlo Simulation;  the use of Finite difference methods for option pricing.

He has been faculty at the University of British Columbia and UCLA, and visiting at the London Business School, the University of California, Berkeley and the Universidad Carlos III in Madrid.  His wide-ranging research has focused on different dimensions in asset and securities pricing.  Topics in recent years include interest rate models, asset allocation issues, evaluating natural resource investments, pricing Internet companies, the stochastic behaviour of commodity prices, valuing patent-protected R&D projects and optimal carbon abatement strategies.

He has published more than 100 articles in finance and economics journals and with Lenos Trigeorgis is an author of Real Options and Investment Under Uncertainty. He is the winner of a number of awards for both teaching excellence and for the quality of his published work. He has served as associate editor for over 20 journals, including Journal of Finance, Journal of Financial Economics and Journal of Financial and Quantitative Analysis. He is a past president of the Western Finance Association and the American Finance Association. He is a fellow of the American Finance Association and the Financial Management Association International. He is a research associate of the National Bureau of Economic Research.

He was awarded a Doctor Honoris Causa by the University of Alicante in Spain and by the Copenhagen Business School in Denmark, and a Catedra de Excelencia by the Universidad Carlos III in Madrid. He has also been a consultant to governmental agencies, banks, investment banks and industrial corporations.

Professor Schwartz received a B.Eng. (1963) in Industrial Engineering from the University of Chile, and an M.Sc. (1973) and Ph.D. (1975; supervisor: Michael Brennan) both in business administration from the University of British Columbia.

References

External links
 SFU's Beedie School of Business
 SFU Beedie faculty profile
 Home page at UCLA.
 Curriculum Vitae
 SSRN Author Page
 "Real Options and Investment under Uncertainty"

Living people
Financial economists
20th-century Chilean economists
UCLA Anderson School of Management faculty
UBC Sauder School of Business alumni
University of Chile alumni
Real options
Monte Carlo methodologists
1940 births
National Bureau of Economic Research
Chilean expatriates in Canada
Chilean expatriates in the United States
Presidents of the American Finance Association
21st-century Chilean economists

redpajama_set_name: RedPajamaWikipedia


Kohler Village, with a population of just under 2,000 encompasses a 4.5 square mile area. It is govererned by a board of trustees, and has an excellent school system (pre-kindergarten through grade 12) , three churches, diverse cultural, and recreational amenities.
It is located in Sheboygan County, Wisconsin.
The Village of Kohler, incorporated in 1912, was developed as a garden/industrial community by Walter J. Kohler, son of Kohler Company founder John Michael Kohler. Using the talents of Frederick Law Olmsted, the noted landscape architect who's designs include New York's Central Park and the Biltmore Estate's grounds, Walter Kohler developed one of the nation's first and finest planned communities.
Today the concepts introduced by Walter Kohler are being protected and enhanced through the joint cooperation of Kohler Company and the Kohler Village. Artful planning is reflected throughout the Village, in its emphasis on natural and historic preservation and its carefully considered design for residential and commercial growth.


text:
Els Dos Dies de Trial de Man (oficialment, en anglès, Manx 2 Day Trial), coneguts també com als Dos Dies de Man, són una competició de trial que es disputa anualment a l'Illa de Man. La prova, organitzada per l'Isle of Man Centre ACU, es disputa des de 1955 i és una de les competicions de trial de mitjana durada més antigues i prestigioses de les vigents en l'actualitat. Té categoria de National (la més alta al Regne Unit) i puntua habitualment per al campionat britànic de trial. L'esdeveniment ha estat considerat sovint el millor trial de les Illes Britàniques.

Al llarg de la seva història, els Dos Dies de Man han comptat amb la participació dels pilots britànics més emblemàtics d'aquest esport, entre ells Sammy Miller, Malcolm Rathmell i Martin i Doug Lampkin. El pilot local que més hi ha destacat és Steve Colley, qui n'ostenta el rècord de victòries amb un total d'onze en catorze anys.

Característiques

Els Dos Dies de Man es disputen actualment a mitjan juliol, el cap de setmana següent a la setmana de curses de velocitat de la Southern 100 que se celebra al circuit de Billown. Tradicionalment, fins al 2017, s'havien disputat a finals d'agost o a mitjan setembre. La prova admet dos tipus de participants, per a cadascun dels quals es marca un recorregut i unes zones diferents: "solo" (per a pilots amb motocicleta individual) i "sidecars" (per a parelles amb un conjunt de sidecar trial).

L'esdeveniment atrau anualment més de 200 participants, la majoria d'ells britànics i irlandesos, però també d'altres països. La sortida i centre neuràlgic del trial se situa a les instal·lacions del Douglas Rugby Club (Douglas R.U.F.C.), a Douglas, la capital de l'illa. La sortida del primer participant s'efectua a les 8 del matí cada dia i l'arribada acostuma a ser pels volts de les quatre de la tarda. La longitud total del traçat que han de recórrer en dos dies els participants, tant individuals com sidecars, és d'uns 130 km (80 milles), amb un total de zones de penalització que oscil·la entre les 70 i 80.

El cap de setmana següent als Dos Dies de Man té lloc el Classic Weekend, una altra prova de trial de dos dies però reservada a motocicletes clàssiques, on hi competeixen tota mena de motocicletes de trial pre-65 o bé anteriors a la introducció del mono-amortidor posterior.

Recorregut
El recorregut que han de completar els participants consta d'una gran varietat de terrenys i paisatges, a través de turons ondulats, boscos, plantacions i camp obert, amb zones que es marquen  al voltant de penya-segats, rierols i trams costaners rocosos de gran bellesa. Un recorregut típic és el següent:

 Dissabte:
 Els pilots individuals (solos) es dirigeixen cap a l'oest i el sud. Els primers grups de zones es troben a Glen Lough, Old Stoney Mountain Quarry, South Barrule Quarry i Glen Rushen Gulley. A continuació, els competidors encaren la costa sud amb grups de zones a Pooil Vaaish, prop de Gansey, i Scarlett Point. La prova s'acaba amb una zona del tipus indoor a Castletown Square.
 Els sidecars van cap al nord i troben les primeres zones a Larkhill, Ballacarooin i Axenfell Plantation. A la tarda tenen els grups de zones de Dhoon Quarry, Bims Field i, finalment, al mateix Douglas Rugby Club.

 Diumenge:
 Els solos tiren cap al nord en direcció a Ballacreetch, Brandywell Gulley i Axenfell Plantation. Més tard, arriben a Snubbies Glen i fan una parada per dinar al Ramsey Rugby Club. Tot seguit, es dirigeixen a Tholt y Will Plantation, Injebreck Gulley i tornen cap a Douglas a través del West Baldwin Bridge. El darrer grup de zones és a Knock Froy, on també acaben els sidecars.
 Els sidecars es dirigeixen cap al sud i passen per Glen Lough, Cornelly Mines, South Barrule Quarry i Carnagrie abans del dinar. Tot seguit van cap a Peel, on hi ha el grup de zones de Peel Hill i Corletts Sand Quarry, després de les quals tornen cap a Douglas a través de Bernie's Glen fins a les seccions finals de Knock Froy.

Llista de guanyadors
Font:

Vegeu també
 TT de l'Illa de Man
 Dos Dies de Trial Illa d'Eivissa

Referències

Enllaços externs

Competicions de trial al Regne Unit
Illa de Man


No, this is my first fursuit, but I've briefly worn suit heads from friends before.
Yes, I had issues after the first convention the suit was worn at and everything has been fixed in a timely manner but one (that the maker probably forgot about, and I did not reminded them of it, because it could be easily fixed).
Vexare partial in a realistic style as a commission.
This was my first fursuit, and it is surprisingly easy to wear. A fan is installed in the muzzle for optimal ventilation. It does not get hot inside, I've never got sweaty wearing it. The vision is excellent, I only have a minor blind spot, and it's better than any fursuit head I've worn from friends. Because of this, I can walk around just fine without any help.
The base used has been 3D printed from another maker. It's very easy to clean.
The head was a bit too tight at first, and this has been fixed after a convention we attended together. It can be worn with glasses, which was absolutely essential for me.
The inside has not been lined up.
The fursuit head had had some issues after wearing it at a convention (some of the jaw bolts came apart and one ear broke) and it was fixed in a timely manner. My request of the mane in the back being sewn (to the back) wasn't addressed, probably forgotten. I've decided not to bother the maker further about it and fix it myself.
The appearance is perfect, she has been following the concept art very well. The tongue had been forgotten at first but has been added later on.
The fur feels soft and the hair and mane has been very nicely realized.
The maker has mentioned the eyes would be follow-me eyes and they weren't, but it doesn't bother me.
The only minor default is that the markings on the nose are not symmetrical.
Very satisfied with the hand paws overall. They're easy to use even with 4 fingers. They allow for optimal movement, they do not slide off and they're easy to put on.
I really like the appearance of them, they're semi-puffy which is what I was looking for. The markings are symmetrical. I was a bit surprised that the claws are made of fabric and not out of plastic like most realistic suits, but they've grown on me.
The paw pads are made out of silicone and are pleasant to look at.
Nothing special to add about the tail, it is easy to put on and wear.
It was bigger than I imagined but it does not drag on the floor, which is a big plus. It has a nice curve to it that makes it pleasant to look at instead of just "hanging" behind me.
The concept art had been commissioned by me years before knowing about the maker. She did not ask for anything else.
She followed the concept art perfectly (minus the symmetry on the muzzle) and I'm very pleased with it.
The whole partial is very nice and every part of it match up. The colors are consistent. The costume is consistent with the maker's realistic style.
I found out about the maker in a local furry meeting. I then contacted her on Facebook and we agreed on the project the very day I contacted her.
The maker got back to me immediately.
The maker tends to treat you more like a friend than a potential customer.
The deadline was a convention we were both attending and it has been respected. The suit was delivered there in person.
This means the reviewer would recommend Le coin d'Irinae.
Overall, minus the markings symmetry that could have been realized better on the muzzle and the claim that the suit would come with follow-me eyes and did not, I'm very satisfied of the partial.
I think the best thing about it is how great the vision is inside.
The suit went through light changes after me getting it (I asked for a different hair placement and more hair overall). The suit also came without a tongue (forgotten by the maker) but she added it afterwards. The changes were free and were realized quickly.
Several issues showed up after a convention (a bolt in the jaw fell off, and one ear broke), and were fixed by the maker in a timely manner.
I would work with this maker again.


text:
News story from Rossall School
Rossall School students achieve over 2/3s A*/A grades at A level
Rossall School celebrated another year of fantastic A-Level results with over 2/3s of all grades awarded either A*/A.
Photo: Rossall School
Harriet Clough, Charlotte Combrinck, Abigail Singleton, Alice Hoggarth and Ellie Preston
11th August 2021 — Rossall School's reputation as a centre of academic excellence received yet another boost with the publication of A Level results and the Rossall Diploma results this week.
This outstanding set of results follows swiftly on the heels of a record-breaking year for students pursuing the International Baccalaureate Diploma Programme.
Indeed, the results achieved by all Upper Sixth students at Rossall this year confirm its place as a regional leader within the North West.
All entries from almost a third of all academic departments achieved nothing less than an A grade including English Literature, Geography, German, Spanish, Chinese, Music and Theatre Studies.
A huge number of students achieved a clean sweep of 'A*'s and 'A's this summer and whilst there is much to celebrate as a School, it is the individual success stories that mean so much to staff, parents and pupils.
Worthy of particular mention are three of our sets of twins. Jess and Max Watson, Ed and Will Robinson and Joey and Lily Warwick amassed between them a staggering 12A*s and 9As.
Lily said, "Rossall became my second home. I am so grateful for my ten years here. I would like to thank all the staff at Rossall - especially my PE teachers, as I could not have done it without them."
Will said, "We are both delighted with our results and cannot wait to start our respective universities, and want to say a huge thank you to all our subject teachers for helping us achieve these grades."
Reflecting upon this year's results, Headmaster Jeremy Quartermain remarked, "I am incredibly proud of our Upper Sixth Form students. The outstanding results they have achieved are indicative of the resilience that they have demonstrated throughout the most challenging of times. These results are very well deserved and we are thrilled that so many of our students are progressing to academically rigorous courses at elite universities within the UK and overseas. I would like to pay tribute to our brilliant teachers who successfully inspired our students to learn right throughout the national lockdowns."
For the second year running, the School exercised its independence by running its own Diploma Programme to ensure that all students had the opportunity to sit rigorous examinations before progressing to university in the Autumn.
Senior Deputy Head, Dina Porovic commented, "The Rossall Diploma exams were written to reflect and replicate the rigorous nature of A-Level examinations and, as such, performance in these is comparable to what our students would most likely have achieved had they been permitted to sit their exams."
The School anticipates that over 60% per cent of Sixth Form students will be attending Russell Group or Top 20 universities, whilst a number have been awarded full sports scholarships to top institutions in the USA.
Students are progressing to Imperial College London, King's College London, University of Bristol, University of Warwick, University of Leeds, University of Manchester and Durham University; pursuing subjects as diverse as Medicine, Economics, Politics, Computer Science, English, Architecture and Chemistry.
No fewer than four students will be taking up places to study Medicine. Erin Bradbury, Will Jackson and Sam Currie will be taking up places at Queen's University, Belfast, the University of Leicester and the University of East Anglia respectively, whilst Nino Abesadze has been awarded a 100% scholarship to read Medicine at the prestigious Charles University, Prague.
Taking up full scholarships in the United States are golfers Kieran Hogarth and Lydia Cryer. Kieran will be heading to Chicago State University whilst Lydia has been awarded a highly competitive scholarship to study at Indiana University, Bloomington.
Kieran said, "Rossall has given me opportunities and an experience which I would not have had anywhere else. It has provided me with friends from all different backgrounds and cultures across the globe. Furthermore Rossall has opened doors and possibilities like no other which has put me in the position I am in now to continue my journey. I would just like to say a massive thank you to all the staff across the school for their commitment, dedication and persistent hard work they have given to each pupil in Year 13 over the past two years."
Whilst the vast majority of students who leave Rossall will take up places at top universities, students are increasingly exploring alternative options and Georgia Bowling will be taking up a place on Mercedes Benz's highly competitive Financial Services Chartered Manager Degree Apprenticeship Scheme.
Georgia said, "The prospect of earning whilst learning and gaining vital experience is the reason I chose an apprenticeship. I hope this will lead me to become a manager or accountant at a reputable firm."
Stephan and Thierry Bilby, our fourth set of twins are excitedly looking forward to beginning their RAF careers.
The Headmaster, Jeremy Quartermain concluded: "We will miss this utterly brilliant year group and we wish them all the best for the future."
Georgia Bowling
Twins Will and Ed Robinson
Twins: Jess and Max Watson, Thierry and Stephan Bilby, and Joey and Lily Warwick
Twins Joey and Lily Warwick
Rossall School is a day and boarding school in Lancashire.
Withington Girls' School
D Girls 7-18, Greater Manchester
St Swithun's School
D B Girls 2-18, Hampshire
Scotland's Boarding Schools
scotlandsboardingschools.org.uk
Another year of excellent GCSE results for Rossall pupils
Rossall School opens new Pre-Prep and Nursery provision
Students celebrate stunning results at Rossall School
Da Vinci Academy
Rossall Nursery - An Exciting Development!
England Lioness Millie Bright opens Rossall School's new sports centre
Bolton School Boys' Division
D Boys 7-18, Greater Manchester
Bolton School Girls' Division
D Boys 3m -7, Girls 3m -18, Greater Manchester
DB Coed 6m -18, Cumbria
Stockport Grammar School
D Coed 3-18, Cheshire
Ravenscourt Park Preparatory School
D Coed 4-11, West London

redpajama_set_name: RedPajamaCommonCrawl


to Start a Food Truck!
If you've ever wondered how to start a food truck business, you've come to the right place!
At FoodTruckr, our goal is to help every food truck owner—from the seasoned veterans to the aspiring dreamers like you—take his or her business to the next level. We do that by providing the #1 resource of food truck business know-how. That's why we're so stoked to bring you an unprecedented level of in-depth information in the "How to Start a Food Truck" series—a comprehensive, chronological, and crazy-awesome guide to starting your very own food truck business.
In this series, we're going to take you all the way from the very first seeds of your dream to opening day. The topics are broken up into categories below so that you can start at the place that best corresponds to your own entrepreneurial journey.
So—are you ready to learn how to start a food truck and make your dream a reality? Then sit down, relax, and get ready to dig in!
You dream about opening a food truck, but you haven't spent a lot of time thinking about the logistics yet. What should you sell? Is it better to have a food truck or a restaurant? How big should your menu be?
This unit will guide you through the process of getting started and help you figure out whether or not a food truck is right for you.
Lesson 01: Should You Go Mobile or Brick and Mortar?
You've spent some time thinking about your food truck and you know this is what you want. Congratulations! Now, it's time to get into the nitty-gritty work of figuring out what it will take to get a truck on the road.
In this unit, we'll cover the four key factors that determine how viable a truck is in your city: local laws and licensing requirements, parking opportunities, commissaries, and health code standards.
Now that you've figured out whether or not a food truck is a viable option in your city, you're ready to start making some real decisions about the business side of your food truck.
In the third unit of "How to Start a Food Truck," we'll explain how to write a business plan, discuss goal-setting strategies and common food truck goals, calculate the necessary profit margins for your truck, and prepare an emergency fund to protect you when unexpected expenses arise.
With a business plan in place, financing options chosen, and goals set, you've done some awesome work—and you're well on your way to opening a food truck.
In the fourth unit of "How to Start a Food Truck," we're going to start taking action on all the research and planning you've done. You'll build an emergency fund, get financing for your truck, learn about insurance, and—finally—buy your very first food truck.
You've prepared, researched, and planned the logistics behind your food truck business—and now you've locked down financing and bought your very first food truck. Though it's been a lot of hard work, we know you must be thrilled that it's all finally starting to pay off with some real, tangible results.
In Unit 5, we'll focus on maintaining the momentum you've achieved over the past several weeks and move on to some of the nitty-gritty work that will allow you to make your business official. We'll cover food truck insurance, truck maintenance, business establishment, and licenses.
You've done a lot of heavy lifting to make your food truck business official and to secure all the documents you need before you can head out on the road. Now that you've got the legal stuff out of the way, you're ready to move on to lessons that will help you establish the personal side of your food truck.
In Unit 6, we'll cover the aspects of your food truck business that will make a first impression on your future customers: your brand, logo and truck design, website, and social media presence.
You're getting so close to opening day! By this point, you've already gotten all of the legal and financial stuff out of the way so that you could already be out on the road. However, there's still a lot of polish you can put on your truck in order to make your opening day event a huge success.
Unit 7 takes you through the final touches we recommend completing before officially launching your business. We'll cover ways to get involved with people in the industry, supplies for your truck, payment system options, and hiring food truck employees.
You've registered your business, hired employees, and your truck is stocked and ready to go. What's left to do before you can finally hit the streets for the very first time?
In Unit 8, we'll take you through everything you need to get ready for the big day. We'll show you some super effective pre-launch advertising strategies, help you plan a killer opening day promotion, and give you essential tips to make your first day on the road go as smoothly as possible.
Lesson 30: Open for Business!
Never fear, FoodTruckrs…we've got lots more where that came from on the way! You can enjoy more tasty business advice by subscribing to the FoodTruckr School podcast, reading the "How to Run a Food Truck" blog series, and by connecting with us online. We'd love to hear from you on Facebook, Twitter, or through email. Tell us what you're up to and what questions you have about starting a food truck!


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