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Stem Cell-Sheet Transplantation Possible for Heart Failure Renal and Urology News In the new study, researchers used stem cells from the patient's own thigh muscle to create a patch they placed on the heart. That's in contrast to many past studies, where researchers have injected stem cells often from a patient's bone marrow ... PERSONALIZED CELL THERAPY MARKET GLOBAL INDUSTRY INSIGHTS, TRENDS, OUTLOOK, AND ...satPRnews (press release) all 12 news articles »

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Turning skin cells into blood vessel cells while keeping them young Science Daily Other methods reprogram a cell so that it directly assumes a new identity, bypassing the stem-cell state. In the last few years, scientists have begun to explore another method, a middle way, that can turn back the clock on skin cells so that they lose ...

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Stem cell drug screen yields potential alternative to statins Science Daily Next, they generated induced pluripotent stem cells from these skin cells. Stem cells continually double their numbers while in culture. This meant that a sample of converted skin cells from a single patient with FH provided a renewable source of liver ...

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M

ice that walk straight and fluidly dont usually make scientists exult, but these did: The lab rodents all had a mouse version of Parkinsons disease and only weeks before had barely been able to lurch and shuffle around their cages.

Using a trick from stem-cell science, researchers managed to restore the kind of brain cells whose death causes Parkinsons. And the mice walked almost normally.The same technique turned human brain cells, growing in a lab dish, into the dopamine-producing neurons that are AWOL in Parkinsons, scientists at Swedens Karolinska Institute reportedon Monday in Nature Biotechnology.

Success in lab mice and human cells is many difficult steps away from success in patients. The study nevertheless injected new life into a promising approach to Parkinsons that has suffered setback after setback replacing the dopamine neurons that are lost in the disease, crippling movement and eventually impairing mental function.

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This is not going to happen in five years or possibly even 10, but Im excited about the potential of this kind of cell replacement therapy, said James Beck, chief scientific officer of the Parkinsons Foundation, which was not involved in the study. It could really give life back to someone with Parkinsons disease.

There is no cure for Parkinsons, a neurodegenerative disease that affects an estimated 10 million people worldwide, most prominently actor Michael J. Fox. Drugs that enable the brain to make dopamine help only somewhat, often causing movement abnormalities called dyskinesia as well as bizarre side effects such as a compulsion to gamble; they do nothing to stop the neurodegeneration.

As Parkinsons patients wait, Fox Foundation and scientist feud over drug trial

Rather than replacing the missing dopamine, scientists led by Karolinskas Ernest Arenas tried to replace dopamine neurons but not in the way that researchers have been trying since the late 1980s. In that approach, scientists obtained tissue containing dopamine neurons from first-trimester aborted fetuses and implanted it intopatients brains.Although a 2001clinical trialfound that the transplants partly alleviated the rigidity and tremors of Parkinsons, the procedure caused serious dyskinesia in about 20 percent of patients, Beck said. More problematic is that fetal issue raises ethical concerns and is in short supply.

It was clear that usable fragments of brain tissue were extremely difficult to recover, said Dr. Curt Freed, of the University of Colorado, who pioneered that work.

Instead, several labs have therefore used stem cells to produce dopamine neurons in dishes. Transplanted into the brains of lab rats with Parkinsons, the neurons reduced rigidity, tremor, and other symptoms. Human studies are expected to begin in the US and Japan this year or next, Beck said.

In the Karolinska approach, there is no need to search for donor cells and no cell transplantation or [need for] immunosuppression to prevent rejection, Arenas told STAT. Instead, he and his team exploited one of the most startling recent discoveries in cell biology: that certain molecules can cause one kind of specialized cell, such as a skin cell, to pull a Benjamin Button, aging in reverse until they become like the embryonic cells called stem cells. Those can be induced to morph into any kind of cell heart, skin, muscle, and more in the body.

Muhammad Ali and Parkinsons disease: Was boxing to blame?

Arenas and his team filled harmless lentiviruses with a cocktail of four such molecules. Injected into the brains of mice with Parkinsons-like damage, the viruses infected plentifulbrain cells called astrocytes. (The brains support cells, astrocytes perform jobs like controlling blood flow.)The viruses also infected other kinds of cells, but their payload was designed to work only in astrocytes, and apparently caused no harm to the other cells.

The molecules, called transcription factors, reprogrammed some of the astrocytes to become dopamine neurons, which were first detected three weeks later in the mouse brains. The dopamine neurons were abundant 15 weeks later, an indication that after changing into dopamine neurons the astrocytes stayed changed.

Five weeks after receiving the injections, the mice, which used to have Parkinsons-like gait abnormalities, walked as well as healthy mice. That suggests that direct reprogramming [of brain cells] has the potential to become a novel therapeutic approach for Parkinsons, Arenas told STAT.

That could have value for preserving the brain circuitry destroyed by Parkinsons, said Colorados Freed.

A lot of hurdles need to be overcome before this becomes a Parkinsons treatment. The Trojan horse system for delivering the reprogramming molecules inside viruseswould need to turn more astrocytes into dopamine neurons and leave other kinds of cells alone: Although viruses getting into mouse brain cells apparently caused no harm, that might not be so in people. We will need to use virus with selective [attraction] for astrocytes, Arenas said.

The morphed cells would presumably be ravaged by whatever produced Parkinsons in the first place. But in other cell transplants, Arenas said, the disease catches up with transplanted cells in 15 to 20 years, buying patients a good period of time. He thinks it might be possible to give patients a single injection but hold off some of the reprogramming with a drug, turning it on when the brain again runs short of dopamine neurons.

The basic technology to develop such strategies currently exists, he said.

The Karolinska lab is working to make the techniquesafer and more effective, including by using viruses that would deliver reprogramming molecules only to astrocytes. We are open to collaborations aimed at human studies, Arenas said.

Would patients be willing to undergo brain injections? People with Parkinsons disease, Beck said, are willing to go through a lot for any hope of improvement.

Sharon Begley can be reached at sharon.begley@statnews.com Follow Sharon on Twitter @sxbegle

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Suspended from a tree in the wilds of Tennessee, the remains of his hang-glider entangled in the branches above, his lower left leg pulverised and his chest badly bruised from his dramatic fall into the forest canopy, Alan Mackay-Sim felt hyper-alert from the electricity of adrenalin, the clarity of shock. Only the wind was audible, softly rustling the branches around him as he sucked in the forest air, perfumed with poplar and sweet-gum.

Knowing that the adrenalin coursing through his veins would soon give way to an agonising and possibly debilitating pain, the 28-year-old used these precious minutes to assess his predicament, to figure it out coolly like a man of science.

A broken leg, no doubt shattered in multiple places. Possibly hours before his fellow hang-gliding friends would be able to locate him; if they didn't reach him by nightfall, he could be dangling here until the next morning. Unfastening his harness and climbing down to the ground five metres below was not an option, at least, not without incurring further injury. To prevent blood from pooling and to save his leg, he quickly concluded, he'd have to carefully oh-so carefully free the hang-glider's stirrup bar and one of the ropes from his harness, create a splint for his injured left leg, secure it to his right leg and hoist up both limbs while hanging there like a gammy fruit bat.

Mackay-Sim had only arrived in the US a few weeks before, a post-doctoral researcher from the University of Sydney eager to extend his studies into the olfactory system specifically, what the nose tells the brain at the University of Philadelphia. But on that blustery October day back in 1979, when a freak wind gust whooshing around Lookout Mountain near Chattanooga sent a promising young Australian scientist nosediving into the forest, before a rescue team found himhanging in the tree just before sunset, both legs securely elevated, Mackay-Sim was set to gain some useful insights that would become valuable to him in his later life. Insights that would be peculiarly relevant to his work as a pioneering stem cell researcher specialising in the treatment of spinal cord injuries.

So badly broken was his leg that Mackay-Sim spent more than six months in a wheelchair, and many more months afterwards receiving intensive physiotherapy.

"It gave me some insight into what life's like in a wheelchair, and it stayed with me," says Mackay-Sim, settling into a chair in his office at the Institute for Drug Discovery at Griffith University, just down the corridor from the laboratory where he spent years toiling over petri dishes of nasal stem cells, in his life's mission to treat spinal injuries, hereditary spastic paraplegia and diseases like Parkinson's.

A photo of the late actor Christopher Reeve is pinned on a noticeboard behind him. "I met Christopher in 2003 when he came out for a conference; he was interested in our clinical trials," Mackay-Sim says, looking at the photo. "Then in the following year I spent some time at his home in New York, and we talked a lot about spinal cord injury repair, and his own personal story."

As Mackay-Sim explains, the higher up the spinal cord an injury is, the more severe the effects. "As we know, Christopher fell off a horse and became a full paraplegic on a respirator, but in fact he suffered only a small injury; the problem was that the bleed went straight into his spinal cord. It only takes a very small injury to stop transmission; you can have large injuries to the chest and not suffer long-term repercussions but here, in the neck, a small event can change your life."

Back in the late 1980s, after he started at Griffith University, Mackay-Sim became interested in a set of extraordinary busy-bee cells in the human nose called olfactory ensheathing cells nerve cells that regenerate every single day to recreate our sense of smell. If these wonder cells are continually regenerating, he kept asking himself, could they not be transplanted to another part of the body where cells don't regenerate, like the spinal cord?

Years of scientific slog followed until 2002, when Mackay-Sim was the first researcher in the world to remove cells from the nose of a patient paralysed in a car accident, grow them in a cell culture and then, with the help of surgeons at Brisbane's Princess Alexandra Hospital, implant them in the same patient's spinal cord. "By the time Christopher died in 2006, we'd transferred stem cells from the nose into three patients and shown it was safe to do so," he says. "One of the patients recovered some sensation above the injury, which was hopeful, but one person does not make real scientific evidence."

For Mackay-Sim, the importance of scientific breakthroughs in the treatment of life-threatening illnesses is deeply personal. In 2014, he was diagnosed with multiple myeloma, an incurable form of leukaemia. As a result of the illness, which breaks down bones in an advanced form of osteoporosis, and the punishing series of treatments that followed his diagnosis, involving radiation, chemotherapy and stem cell therapy (albeit a very different form from the one the scientist was researching), Mackay-Sim lost nine centimetres in height and shed more than 15 kilograms of body weight. "I became extremely sick from the chemotherapy just prior to the bone marrow transplant," the 65-year-old recalls. "It was the worst experience of my life."

There was also the initial shock of the diagnosis, and grief for the loss of his health after a highly active life, from football and rowing in his teens to distance cycling, scuba diving and hang-gliding, which he took up while atuniversity. "Both my parents lived into their 80s and 90s and I'd been cycling up to 200 kilometres a week for decades, so I wasn't anticipating something like this."

Still, as a scientist he couldn't help but observe the trajectory of his illness with stricken fascination. "I had some good conversations with my oncologist," he smiles. "As a biologist examining my own biology, it did demystify lots of things. One minute I was a grieving patient, the next an interested scientist."

Above all, Mackay-Sim refuses to sentimentalise his battle with the illness and asks that I don't embroider it in this story by turning it into some kind of triumph of personal will power over disease. "My survival is determined by the vagaries of the particular cancer I've got," he says matter-of-factly. "Some people have nasty genetic diseases that mean they die earlier. For the moment, I feel very healthy."

Surely his extreme fitness at least helped him to survive the ravages of chemo? "I think being fit and active all my life has given me a higher quality of life after treatment," he acknowledges. "But one doctor put it to me that I probably would have sought out treatment earlier if I wasn't so fit, because I dismissed the symptoms as simple back pain from the cycling. It took two years after the chemo and radiation for the pain to go away. 2016 was a year of normality for me my back became stable enough for me to get on a road bike again."

The diagnosis added poignancy to the evening in Canberra in late January when Mackay-Sim, out of 3000- plus nominations, was crowned Australian of the Year. Sitting alongside him were his American-born wife of nearly 34 years, Lisa Peine, a retired primary school teacher, their 28-year-old daughter Matilda, a trainee psychiatrist, and 25-year-old son Callum, an engineer.

Mackay-Sim with wife Lisa Peine in North Queensland in 1983. Photo: Courtesy of Alan Mackay-Sim

Perhaps no Australian of the Year is better placed to recognise just how precious a year can be, and more determined to seize the moment to put science and innovation at the top of the national conversation. A former Queenslander of the Year, Mackay-Sim sees science as vital to our future national wellbeing, especially after the recent wake-up call in international school education rankings, which placed Australia behind Kazakhstan and Slovenia in maths and science.

Mackay-Sim agrees unequivocally with Michelle Simmons, professor of quantum physics at the University of NSW, who drew headlines recently when she declared that the "feminised" nature of Australia's high school physics curriculum (emphasising the sociology of science with essays and theory instead of rigorous lab experiments and mathematical problem-solving) had been an unmitigated failure. Introduced in the 1980s, the approach had resulted in a long, slow decline in standards.

"Scientific understanding comes from learning the processes; it can be hard work but is absolutely essential," Mackay-Sim insists. "The key to a good science education in schools is to get well-trained teachers." (Mackay-Sim has been deeply encouraged by some of the science teachers he's met since winning the award.)

The choice of Mackay-Sim the first scientist honoured as Australian of the Year since immunologist Ian Frazer in 2006 was met with near-universal applause by Australia's scientific community, who no doubt feel dispirited in this post-truth world of climate-change denial, cuts to the CSIRO and the growing view by government agencies that basic research isn't worth it.

"We need to invest in young scientists," Mackay-Sim declared in his acceptance speech, adding that the discovery of new medical treatments can reduce the strain on health budgets. "More than 10,000 Australians live with a spinal cord injury a new person is added to this tally every day." But politicians need to take a long-term view of the benefits of basic research, he tells me, "a view much longer than the political horizon".

The announcement also gave the image of the Australian of the Year awards a much-needed polish. The 2016 winner, Lieutenant-General David Morrison, drew criticism for charging up to $15,000 a pop forpublic speaking engagements, as well as grandstanding about sexism in the military despite his own handling of the army's "Jedi Council" sex scandal, in which demeaning sex videos of women were distributed among a group of soldiers. (It was revealed that Morrison's office knew of the scandal 11 months prior to the former Chief of Army releasing a now-famous condemnation on YouTube of those involved.)

Will Mackay-Sim accept speakers' fees? "I knew nothing about speakers' fees when I accepted the award," he says crisply. "I'm not pursuing money after all, I've spent my life doing public research."

Although he hasn't received any fees to date, Mackay-Sim insists that if they are offered, the funds will be donated to the Hereditary Spastic Paraplegia Research Foundation, his charity of choice.

Mackay-Sim only had a day or so to bask in the glow of being named Australian of the Year before there was a claim his scientific achievements had beenoverstated in the application. A Polish scientist, Professor Pawel Tabakow, after being approached by an Australian journalist in Europe, declared that Mackay-Sim had nothing to do with the world-first surgery using olfactory stem cells that enabled a Polish paraplegic, Darek Fidyka, to walk again. "It is not our business who should be Australian of the Year," Tabakow told The Weekend Australian. "But it is our business when his work is being linked to the surgery of Fidyka. He has no link whatsoever."

The scientific hullaballoo arose from the submission to the Australia Day Council (ADC), which states that Mackay-Sim's research "helped play a central role in proving the safety of science that was a precursor to Dr Tabokow in Poland undertaking the first successful restoration of mobility in a quadriplegic man".

Although Mackay-Sim didn't write the submission to the ADC, doesn't know who did, and never claimed to be involved in Tabokow's work, an artificial straight line was drawn between the two scientists, especially when the word "precursor" was dropped from condensed versions of the ADC's quote in multiple news stories (we'll examine the fallout from the controversy a little later).

Padding amiably about his large, multi-room laboratory, past refrigerator-sized storage cabinets containing cell cultures, past white-coated scientists peering into microscopes, Mackay-Sim seems to be in his element, with every second person saying "Hi", "Hello", or "How are you?" If stem cells are indeedthe microscopic building blocks of the world, this is the tiny universe the scientist feels most comfortable in. But it's a laboratory that now has to hum along without him Mackay-Sim retired late last year, his duties now limited to popping into the university once a week as an emeritus professor.

Later in the day, Professor George D. Mellick, head of Clinical Neurosciences at Griffith, tells me that Mackay-Sim has always set aside time to mentor younger scientists, and to explain sometimes hideously complicated science to a lay audience, but would be the last person to crow about his own scientific achievements.

"One of the things that isn't highlighted very much about Alan's work is his research into Parkinson's. We've been able to learn a lot about Parkinson's by studying cells from people with the disease, and the information coming out of this research will hopefully lead to better treatments."

Back in his office, Mackay-Sim gives me a quick rundown, 101-style, on the human nose. No, the human sense of smell doesn't necessarily decline with age, unless illness or disease set in, and it is astonishingly adept at distinguishing hundreds of thousands of different odours. Yes, women do have a superior sense of smell to men, but the difference is surprisingly only slight. Yes, the first symptom of Parkinson's, before the typical tremors set in, is a reduced sense of smell, as it is with those sufferers who will go on to develop dementia. And yes paws down dogs do have a vastly more powerful sense of smell than humans, although it's impossible to quantify by exactly how much (Mackay-Sim has been known to hide from his spoodle Henry, to measure how long it takes for the dog to find him).

As he relays all this, Mackay-Sim's eyes twinkle and a smile lights up his face: it's easy to see how he'd be the perfect academic for Griffith to call on to schmooze a government minister or potential philanthropist and secure desperately sought-after funding. I ask him about his trademark moustache, which he's had since the early 1990s, when he shaved off a beard. "My wife wouldn't recognise me without it," he jokes. "She says that a small mammal could roost beneath my mouth."

Mackay-Sim, whose double-barrelled surname comes from his paternal grandfather, grew up in middle-class Roseville, on Sydney's leafy North Shore, the third of four brothers. His mother Lois was a nurse during World War II and later a full-time mum while his father Malcolm ran a hardware importing and distributing business, Macsim Distributors (now Macsim Fasteners, owned by Alan's eldest brother, Fraser). At North Sydney Boys' High he was "the opposite of a shit-stirrer. I was vice captain, head of the cadets, played football, was in the rowing team, had a shot at athletics, sang in the choir I did it all."

With wife, Lisa Peine, in Sulawesi, Indonesia, 2007. Photo: Courtesy of Alan Mackay-Sim

After graduating with honours in science from Macquarie University, Mackay-Sim picked up tutoring work in the department of physiology at the University of Sydney, where he completed a PhD on the brain's visual system. Two academic stints in the US followed, first at the University of Pennsylvania from 1979 until 1981, followed by two years at the University of Wyoming, during which time he met his wife Lisa, then living in northern Colorado.

The pair married in 1984, by which time Mackay-Sim had been offered a research role in the department of physiology at the University of Adelaide. He started at Griffith University in 1987, where his research concentrated on the biology of nasal cells.

At the height of the heated moral debate over the use of embryonic stem cells whether the therapeutic potential of stem cells could justify destroying human embryos to extract them Mackay-Sim met Pope Benedict XVI at a Vatican conference in 2005. The Pope congratulated him on his exclusive use of adult stem cells.

"I wasn't avoiding embryonic stem cells for religious reasons," Mackay-Sim explains. "It just so happenedthat I was working with adult stem cells at the time and the conference was looking at alternatives to using embryonic stem cells. But it was a scientific conference and I was impressed with its calibre; the only difference was that men in purple robes were sitting at the back asking questions."

Later in the same trip, Mackay-Sim was invited, along with a host of others, to the Apostolic Palace at Castel Gandolfo the Vatican summer palace. "You feel the history of the Roman Catholic Church, with the Pope coming in with his cardinals and the Swiss Guards," he says. "I'm not a believer, but it was a very powerful experience."

In 2006, the debate over embryonic stem cells virtually vanished when scientist Shinya Yamanaka from Japan's Kyoto University stunned the world by proving that stem cells needn't come from human embryos adult cells can be reprogrammed to act like stem cells, to be returned to an embryo-like state (Yamanaka's discovery won him the Nobel Prize in 2012). "Yamanaka worked out how to genetically engineer any cells so that they had the properties of embryonic stem cells," says Mackay-Sim, who nonetheless continued to focus on adult stem cells only.

Mackay-Sim accomplished his own world first in 2002 when, with the assistance of doctors at Brisbane's Princess Alexandra Hospital, he transplanted olfactory stem cells into the spinal cord of a man crippled in a car accident. The procedure was repeated with two other paraplegic patients at the same hospital and the study wrapped up in 2007.

While the procedures didn't result in any of the patients regaining useful movement in their legs, the results of Mackay-Sim's clinical trials, published in 2005 and 2008, paved the way for further development of olfactory stem cell transplantation.

One researcher who followed Mackay-Sim's trials closely was Geoffrey Raisman from University College London, who visited the Australian team shortly after the first operation in Brisbane to study their work. Raisman later led the British team who worked with Polish surgeon Tabakow on Darek Fidyka in 2012.

Tabakow deployed 100 separate micro-injections of olfactory sheathing cells above and below Fidyka's spinal injury, with the hope these cells would provide a skeleton for nerve fibres to grow and reconnect. A former volunteer firefighter, Fidyka had become paralysed in 2010 after a severe knife attack by the jealous ex-husband of his girlfriend. The repeated stab wounds to Fidyka's back severed his spinal cord, paralysing from the waistdown. (Fidyka's attacker, a fellow firefighter, committed suicide shortly afterwards.)

There's no doubt Tabakow's work was a major advance on Mackay-Sim's research. Tabakow's strategy was to extract ensheathing cells specifically from the olfactory bulbs in Fidyka's nose, grow them in a culture, while also extracting nerve cells from his ankle in a multi-pronged attempt at spinal cord reconstruction. After a series of operations, Fidyka can walk with the assistance of a frame, has regained some bladder control and sexual function, and can ride a tricycle.

Raisman described their new stem cell procedure as "more impressive than man walking on the moon", but it will have be tested on other paraplegics, including those with more severe injuries than Fidyka's, such as car accident victims who have had more of their spinal cord damaged, before it can be declared a reliable method of restoring mobility. As impressive as Tabakow's achievement is, it has still only worked on one patient.

Nobody, however, disputes Mackay-Sim's immense contribution to stem cell transplantation; his work is unimpeachable. If nothing else, he was at the forefront of the science showing that restoring the ability to walk to paraplegics is no longer science fiction. "What I've always said is that we did the first phase of clinicaltrials with olfactory stem cells, and the aim of those trials was to show they were safe," says Mackay-Sim. "That was the first important step."

Mackay-Sim wrote to Tabakow shortly after the controversy blew up, explaining that he didn't write the submission to the Australia Day Council, and was in no way claiming credit for Fidyka's remarkable recovery. "He wrote back a very nice email," says Mackay-Sim. "I believe I've given credit to other scientists in every interview I've given to journalists. I feel comfortable in my behaviour and ethics."

With Prime Minister Turnbull in January this year. Photo: Elesa Kurtz

Mackay-Sim can remember the day when he felt something was wrong terribly wrong. He'd been suffering back pain for months, but dismissed it as old age, or strain from bending over on his bicycle on long rides, and stocked up his pantry with painkillers. "I was in Colorado with Lisa visiting her family, and the pain became so bad I couldn't walk very far. I found the pain eased when I got on my bicycle. I flew home a week before she did; the plane trip back was absolute hell."

What followed was a swift diagnostic journey from his GP to specialists at Brisbane's Wesley Hospital, resulting in a devastating diagnosis. "They suspected something cancerous quite quickly. I didn't realise how ill I was; by this stage, my kidneys weren't coping at all with the antibodies released from my white blood cells, which were going berserk trying to fight the disease. I was at risk of kidney failure and my bones were becoming very fragile. I started therapy almost immediately, in June 2014. Then began the cycles of chemotherapy and stem cell treatment in December."

Since the beginning of last year, however, Mackay-Sim's health has dramatically improved, and even though he's retired to his beachside home in Currimundi on the Sunshine Coast, he is still active in university affairs. He concedes that his health may prevent him from being as active as Rosie Batty, perhaps our most vigorous Australian of the Year to date. But he's already spoken at functions in Brisbane, Sydney and Perth, and will be attending the national March for Science on April 22, which coincides with Earth Day. He moves with the speed and fluidity of a man 10 or 15 years younger.

"I feel very healthy, very energised at the moment," says Mackay-Sim, who is planning a bicycle ride in Italy's Dolomites in July with a couple of mates. (Last year he and his wife went on the Great Victorian Bike Ride, a seven-day ride averaging 85 kilometres a day.)

"I do need to be selective with the number of invitations around Australian of the Year," he concedes, "but I'll do everything I can. After all, what more exciting time could you have to talk about science?"

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Australian of the Year Alan Mackay-Sim on the advantage of being 'an interested scientist' - The Sydney Morning Herald

Spinal Cord Stem Cells Comments Off on Australian of the Year Alan Mackay-Sim on the advantage of being ‘an interested scientist’ – The Sydney Morning Herald | April 9th, 2017

A team of scientists from the University of California, Los Angeles has been able to synthesize an artificial thymus, a human organ that is important to the bodys immune system. An artificial thymus, they say, could produce necessary cancer-fighting T-cells for the body.

On demand.

T-cells, of course, are white blood cells which naturally fight diseases that develop in or infect the body. These T-cells are artificial, though, so they would have to be engineered to target specific forms of cancer, in order to be effective. Still, if this is manageable, then it could provide scientists and health practitioners with additional natural defensesalbeit, bionicfor attacking disease.

The thymus rests in front of the heart. It uses stem cells from the blood to make immune-boosting T-cells, which literally circulate throughout the body to specifically target things that dont belong. In this case, the thymus would create T-cells that could seek out specific cancerous growths without jeopardizing the health of existing tissue.

For the study, the Japanese researchers looked at 27 patients who had received transplants form stem cells that had been taken from their own thigh muscles. These patients showed no sign of any major complications; most patients also showed significant improvement with their symptoms.

Research team member Gay Crooks comments, We know that the key to creating a consistent and safe supply of cancer-fighting T-cells would be to control the process in a way that deactivates all T-cell receptors in the transplanted cells, except for the cancer-fighting receptors. It is important, of course, to take stem cells from the patient who needs them because the body is likely to reject any foreign stem cells (and their byproducts). Apparently, they have been at this study for more than two decades but, unfortunately, the researchers acknowledge that past attempts only showed modest results. From these results, though, they were able to devise a method for producing sheets of muscle stem cells which could then be attached to the inner layer of the sac (which encloses the heart). These stem cells will stimulate healing through the production of chemicals which encourage cardiac regeneration, though the stem cells, themselves, do not survive in the long term.

The results of this study have been published in the scientific journal Nature Methods.

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Can An Artificial Thymus, Made from Stem Cells, Pump Out Enough T-Cells To Fight Cancer? - Dispatch Tribunal

Cardiac Stem Cells Comments Off on Can An Artificial Thymus, Made from Stem Cells, Pump Out Enough T-Cells To Fight Cancer? – Dispatch Tribunal | April 9th, 2017

By Suzanne Laurentnews@seacoastonline.com

NEWMARKET Karen Olivier is excitedly looking forward to what she calls her stem cell birthday.

Olivier, 40, is traveling April 23 to Monterrey, Mexico, to undergo a procedure that will reset her immune system and stop the inflammation in her body, caused by her relapsing-remitting multiple sclerosis.

Diagnosed with MS at the age of 24, Olivier learned about a treatment called hematopoietic stem cell therapy, or HSCT, from a Facebook page. It gave her hope that if she had this treatment, it would stop the progression of the disease.

She began blogging about her journey leading up to her trip to Mexico.

I want others to know this is an option, she said.

According to the National Multiple Sclerosis Society, HSCT attempts to reboot the immune system, which is responsible for damaging the brain and spinal cord in MS. In HSCT, hematopoietic (blood cell-producing) stem cells are derived from the persons own bone marrow or blood, are collected and stored, and the rest of the individuals immune cells are depleted by chemotherapy.

The stored hematopoietic stem cells are then reintroduced to the body. The new stem cells migrate to the bone marrow and, over time, produce new white blood cells. Eventually they repopulate the body with immune cells, building a new immune system that doesnt know what MS is.

In early clinical trials, 78 percent of participants experienced no new disease activity after the procedure and did not need disease-modifying therapies to control their disease.

Olivier had been taking disease modifying drugs, or DMDs, for 15 years, starting with Avonex, a once weekly intramuscular injection. She then took Rebif, a subcutaneous injection three times a week. After she took a daily injection of Copaxone. In 2009, she started on Tysabri, receiving an infusion every 28 days.

I did well on the Tysabri, but in the past couple of years, my symptoms progressed and my most recent MRI showed new disease activity on my thoracic spine, Olivier said. At the rate my MS was progressing, I would probably be in a wheelchair in two years.

Since 1993, the Federal Drug Administration has approved DMDs to treat relapsing-remitting MS. All are designed to suppress the immune system to one degree or another. These drugs cost about $5,000 per month and they must be taken indefinitely, since relapses will occur if the drugs are stopped.

Oliviers insurance covered the cost of the drugs, but her copays and coinsurance amounts were still very high, she said. One month of a DMD infusion can cost between $7,000 and $9,000.

Olivier researched a clinical trial of HSCT in Chicago, a program begun in 1996 by Dr. Richard Burt, now chief of the division of medicine-immunology and autoimmune diseases at Northwestern Universitys Feinberg School of Medicine.

Trial criteria included relapsing-remitting MS, and failure on at least two DMDs and two flare-ups in the past 12 months, requiring treatment from steroids, she said.

In the United States, HSCT can cost between $150,000 and $200,000.

Insurance may have covered it out-of-network, but my plan has a substantial out-of-pocket maximum, Olivier said. It would have require multiple trips to Chicago for several years, and I could have ended up in the control group.

Olivier began to explore receiving HSCT in other countries and decided to apply for the treatment at Clinica Ruiz in Mexico last October when she was recovering from a flare-up. Clinica Ruiz is based in Pueblo, Mexico, but has expanded to a second clinic in Monterrey.

She and her husband, Jason, agreed spend the $54,500 out-of-pocket cost for the outpatient treatment that also includes transportation to and from a two-bedroom apartment where she will stay for 28 days. Her mother is traveling with her, as the treatment protocol requires the patient to have a caregiver present.

I was accepted based on my MS history and my expanded disability status scale (EDSS) score that basically measures how mobile you are, Olivier said.

Olivier will undergo two days of chemotherapy to wipe out her immune system. She will then have seven days of injections to promote stem cell growth, after which stem cells will be harvested from her blood.

Ill then have two more days of chemotherapy, she said. Im excited. No chemo, no cure.

May 7 will be what Olivier calls her stem cell birthday when she receives her stem cells back to reboot her immune system. She will then be in isolation in the apartment for about a week. Her mother will have to wear special precaution gear during that time.

Some people see improvements in the first three months, with full recovery in two years, Olivier said. Some might say Im not sick enough for this treatment, but the earlier someone gets it, the better, before the MS causes major damage.

She added that some people believe this is a risky procedure and it has not been FDA-approved yet in the United States.

But many people have died on Tysabri and the drug approved by the FDA last week, Ocrevus, has an increased risk of cancer after two to three years. I am hoping the HSCT will stop the progression of my MS, and hope that I never have to go on another DMD in my life.

To read Oliviers blog, visit knockoutmsblog.wordpress.com.

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Local woman heads to Mexico - News - seacoastonline.com ... - Seacoastonline.com

Bone Marrow Stem Cells Comments Off on Local woman heads to Mexico – News – seacoastonline.com … – Seacoastonline.com | April 9th, 2017

KEWANEE -- Miss You Can Do It believes she can do it again.

Abbey Curran, diagnosed with cerebral palsy at birth, founded the annual Miss You Can Do It pageant in 2004 for girls and young women with special needs.

She now facesa different type of challenge; searching for a bone-marrow match for her dad, Mike Curran, of Kewanee. Mr. Currant was diagnosed with leukemia and is receiving inpatient chemotherapy at the OSF St. Francis Medical Center in Peoria.

Ms. Currant is working with the Be the Match Registry seeking a bone-marrow match for her father. She also is planning two "drives" to find a match -- the first, 4-8 p.m. April 9 at Raelyns Pub & Eatery, 217 N. State St., Geneseo, and a secondm 2-7 p.m. April 15 at Cernos Bar & Grill, 213 W. 3rd St., Kewanee. Both will offer free refreshments.

Ms. Curran said the "Be the Match Registry is run by the National Marrow Donor Program to help facilitate bone marrow and blood stem cell transplants. The group coordinates national and international medical facilities in marrow transplantation.

Joining me in this effort -- by coming to the drive, helping to save lives -- is easy to do, Ms. Curran said. It will not cost participants a single penny. But all participants will get free food, cake and beer. All that is required for this first step in the process involves a cheek swab and filling out a bit of paperwork.

Participants must be 18 to 60 years old, in good health and willing to donate to any person, Ms. Curran said.The actual marrow donation usually happens through an automated process; in some cases it involves minor surgery under anesthesia at no cost to the donor.

Out of six siblings and myself, my father hasnt found a bone-marrow match, she said. I look at this as another challenge -- another impossible that I need to make possible.

When Ms. Curran learned neither she nor any of her fathers relatives were a bone marrow transplant match, she decided to not only help her father but others desperate to find bone-marrow matches. Determination is a natural trait for Ms. Curran.

My life has been full of challenges and I have taken pride in making the impossible possible, the unrealistic realistic, and I plan to do the same in finding a bone-marrow match for my Dad, she said. "I will find a match and I hope I get hundreds of people to attend these upcoming 'Be the Match events. I am preparing for them.

"I grew up the 'hog farmers daughter from Henry County, she said. I was also born with cerebral palsy. I have always had big dreams and set out to make the impossible possible.

"When I was told I couldnt and shouldnt be the Henry County Fair Queen, I made history by being the first and only woman with a disability to ever make it to Miss USA, as I won Miss Iowa USA in 2008.

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Daughter seeks bone marrow match for her dad - Quad-Cities Online

Bone Marrow Stem Cells Comments Off on Daughter seeks bone marrow match for her dad – Quad-Cities Online | April 9th, 2017

MARQUETTE, Mich. (WLUC) - UP Health System Marquette will host a bone marrow registry drive on April 12th, 2017 on the 3rd floor of the North Entrance to the hospital.

Every four minutes, someone is diagnosed with a blood cancer in the US. For thousands of patients with leukemia or other blood diseases like sickle cell anemia, a marrow transplant is their only hope.

Joining the bone marrow registry takes roughly 10 minutes of paperwork and a cheek swab. Only 1 in 430 registry members go on to donate. If you match with a patient in need, you will receive a phone call asking to donate. Donation is always voluntary. Surgery is not always required for bone marrow donation; almost 80% of donors donate their blood stem cells in a non-surgical procedure that is very similar to donating plasma.

Please note that UP Health System - Marquette is not affiliated with the National Marrow Donor Program or the Be The Match organization. Our presence here will be to help facilitate and educate those interested in joining the Be The Match registry.

Be The Match is operated by the National Marrow Donor Program (NMDP) which manages the largest and most diverse marrow registry in the world, working to save lives through transplant.

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Bone Marrow Registration Drive to be held at UP Health System Marquette - UpperMichigansSource.com

Bone Marrow Stem Cells Comments Off on Bone Marrow Registration Drive to be held at UP Health System Marquette – UpperMichigansSource.com | April 9th, 2017

April 6, 2017 A mouse heart section showing human progenitor cells that formed functional human blood vessels. Purple color signifies human blood vessels, red staining signifies the blood vessels of the mouse that received the human cell implants. Credit: Jalees Rehman.

Researchers from the University of Illinois at Chicago have identified a molecular switch that converts skin cells into cells that make up blood vessels, which could ultimately be used to repair damaged vessels in patients with heart disease or to engineer new vasculature in the lab. The technique, which boosts levels of an enzyme that keeps cells young, may also circumvent the usual aging that cells undergo during the culturing process. Their findings are reported in the journal Circulation.

Scientists have many ways to convert one type of cell into another. One technique involves turning a mature cell into a "pluripotent" stem cellone that has the ability to become any type of celland then using chemical cocktails to coax it into maturing into the desired cell type. Other methods reprogram a cell so that it directly assumes a new identity, bypassing the stem-cell state.

In the last few years, scientists have begun to explore another method, a middle way, that can turn back the clock on skin cells so that they lose some of their mature cell identity and become more stem-like.

"They don't revert all the way back to a pluripotent stem cell, but instead turn into intermediate progenitor cells," says Dr. Jalees Rehman, associate professor of medicine and pharmacology at UIC, who led the team of researchers. Progenitor cells can be grown in large quantities sufficient for regenerative therapies. And unlike pluripotent stem cells, progenitor cells can only differentiate into a few different cell types. Rehman calls this method to produce new cells "partial de-differentiation."

Other groups have used this technique to produce progenitor cells that become blood vessel cells. But until now, researchers had not fully understood how the method worked, Rehman said.

"Without understanding the molecular processes, it is difficult for us to control or enhance the process in order to efficiently build new blood vessels," he said.

His group discovered that the progenitors could be converted into blood vessel cells or into red blood cells, depending on the level of a gene transcription factor called SOX17.

The researchers measured the levels of several genes important for blood vessel formation. They saw that as progenitor cells were differentiating into blood vessel cells, levels of the transcription factor SOX17 became elevated.

When they increased levels of SOX17 even more in the progenitor cells, they saw that differentiation into blood vessel cells was enhanced about five-fold. When they suppressed SOX17, the progenitor cells produced fewer endothelial cells and instead generated red blood cells.

"It makes a lot of sense that SOX17 is involved because it is abundant in developing embryos when blood vessels are forming," Rehman said.

When the researchers embedded the human progenitor cells into a gel and implanted the gels in mice, the cells organized into functional human blood vessels. Skin cells that had not undergone a conversion did not form blood vessels when similarly implanted.

When they implanted the progenitor cells into mice that had sustained heart damage from a heart attack, the implanted cells formed functional human blood vessels in the mouse heartsand even connected with existing mouse blood vessels to significantly improve heart function.

The human adult skin cells used by Rehman's team can easily be obtained by a simple skin biopsy.

"This means that one could generate patient-specific blood vessels or red blood cells for any individual person," Rehman said. Using such personalized cells reduces the risk of rejection, he said, because the implanted blood vessels would have the same genetic makeup as the recipient.

Rehman and his colleagues noticed something else about the progenitor cells - they had elevated levels of telomerase - the "anti-aging" enzyme that adds a cap, or telomere, to the ends of chromosomes. As the caps wear away a little bit each time a cell divides, they are believed to contribute to aging in cells, whether in the body or growing in culture in the laboratory.

"The increase in telomerase we see in the progenitor cells could be an added benefit of using this partial de-differentiation technique for the production of new blood vessels for patients with cardiac disease, especially for older patients," Rehman said. "Their cells may already have shortened telomeres due to their advanced age. The process of converting and expanding these cells in the lab could make them age even further and impair their long-term function. But if the cells have elevated levels of telomerase, the cells are at lower risk of premature aging."

While telomerase has benefits, the enzyme is also found in extremely high levels in cancer cells, where it keeps cell division in overdrive.

"We were concerned about the risk of tumor formation," Rehman said, but the researchers didn't observe any in these experiments. "But to truly determine the efficacy and safety of these cells for humans, one needs to study them over even longer time periods in larger animals."

Explore further: Adult stem cells help build human blood vessels in engineered tissues

More information: Lianghui Zhang et al, SOX17 Regulates Conversion of Human Fibroblasts into Endothelial Cells and Erythroblasts via De-Differentiation into CD34Progenitor Cells, Circulation (2017). DOI: 10.1161/CIRCULATIONAHA.116.025722

Researchers from the University of Illinois at Chicago have identified a molecular switch that converts skin cells into cells that make up blood vessels, which could ultimately be used to repair damaged vessels in patients ...

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Turning skin cells into blood vessel cells while keeping them young - Medical Xpress

Skin Stem Cells Comments Off on Turning skin cells into blood vessel cells while keeping them young – Medical Xpress | April 9th, 2017

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Spinal Cord Injury (SCI) Stem Cell Treatment

Spinal Cord Stem Cells Comments Off on Spinal Cord Injury (SCI) Stem Cell Treatment | April 8th, 2017

Yesterday we highlighted the GTCbio Stem Cell Summit in Boston. Another company we've been closely following is also represented at the conference, Asterias Biotherapeutics (NYSE: AST). Asterias is developing therapies based on pluripotent stem cells to address significant unmet medical needs in neurology and oncology. According to Boston Children's Hospital, pluripotent stem cells are the body's master cells, potentially able to produce any cell or tissue the body needs to repair itself. Like all stem cells, pluripotent stem cells are also able to self-renew, meaning they can perpetually create more copies of themselves.

The company draws its name from the common starfish, Asterias rubens, which has the ability to regenerate lost limbs even in adulthood. The company's lead product candidate, AST-OPC1, is currently in a Phase 1/2a dose ranging trial for spinal cord injury. As Patrick Cox discussed two months ago, Asterias' clinical trial has been generating significant interest.

In the company's earnings call last week, CEO Steve Cartt highlighted the ongoing clinical and corporate progress:

Source: Asterias Biotherapeutics Corporate Presentation, Jan. 24, 2017

We note that the company's cash position is much better than it was a year ago. As shown in the chart above, Asterias' spinal cord trial is funded by a grant from the California Institute of Regenerative Medicine (CIRM), which has certainly eased the burden. As of the end of February 2017, the company's cash and cash equivalents totaled $19.9 million and combined with its available-for-sale securities (mostly BioTime stock - see below*) totaled $33.5 million. Ryan Chavez, CFO, said, "We believe we currently have sufficient capital to fund operations through at least the first quarter of 2018."

* Readers may recall that Asterias was spun out of BioTime (NYSE: BTX) in 2014. BioTime remains the dominant shareholder, controlling 47% of the outstanding common and three out of the nine board seats (with a fourth board seat occupied by Broadwood Capital, BioTime's largest shareholder). Also, as mentioned above, Asterias holds about $13 million worth of BioTime stock. While the kids all seem to be playing well in the sandbox, this close relationship merits watching.

Jane Lebkowski, Asterias' President of Research and Development, was part of an immunotherapy roundtable at the Stem Cell Summit yesterday, discussing the company's research in therapeutics for lung cancer. Today, April 6th, at 10:40am ET, Dr. Michael West, CEO of BioTime, will deliver the conference keynote address entitled "The Promise of Pluripotency in the Manufacture of Advanced Cell-Based Therapeutics" - which sounds like a direct advertorial for a key BioTime asset - Asterias Biotherapeutics.

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Asterias (AST): Blazing the Stem Cell Trail for Spinal Cord Injury - Equities.com

Spinal Cord Stem Cells Comments Off on Asterias (AST): Blazing the Stem Cell Trail for Spinal Cord Injury – Equities.com | April 8th, 2017

Suspended from a tree in the wilds of Tennessee, the remains of his hang-glider entangled in the branches above, his lower left leg pulverised and his chest badly bruised from his dramatic fall into the forest canopy, Alan Mackay-Sim felt hyper-alert from the electricity of adrenalin, the clarity of shock. Only the wind was audible, softly rustling the branches around him as he sucked in the forest air, perfumed with poplar and sweet-gum.

Knowing that the adrenalin coursing through his veins would soon give way to an agonising and possibly debilitating pain, the 28-year-old used these precious minutes to assess his predicament, to figure it out coolly like a man of science.

A broken leg, no doubt shattered in multiple places. Possibly hours before his fellow hang-gliding friends would be able to locate him; if they didn't reach him by nightfall, he could be dangling here until the next morning. Unfastening his harness and climbing down to the ground five metres below was not an option, at least, not without incurring further injury. To prevent blood from pooling and to save his leg, he quickly concluded, he'd have to carefully oh-so carefully free the hang-glider's stirrup bar and one of the ropes from his harness, create a splint for his injured left leg, secure it to his right leg and hoist up both limbs while hanging there like a gammy fruit bat.

Mackay-Sim had only arrived in the US a few weeks before, a post-doctoral researcher from the University of Sydney eager to extend his studies into the olfactory system specifically, what the nose tells the brain at the University of Philadelphia. But on that blustery October day back in 1979, when a freak wind gust whooshing around Lookout Mountain near Chattanooga sent a promising young Australian scientist nosediving into the forest, before a rescue team found himhanging in the tree just before sunset, both legs securely elevated, Mackay-Sim was set to gain some useful insights that would become valuable to him in his later life. Insights that would be peculiarly relevant to his work as a pioneering stem cell researcher specialising in the treatment of spinal cord injuries.

So badly broken was his leg that Mackay-Sim spent more than six months in a wheelchair, and many more months afterwards receiving intensive physiotherapy.

"It gave me some insight into what life's like in a wheelchair, and it stayed with me," says Mackay-Sim, settling into a chair in his office at the Institute for Drug Discovery at Griffith University, just down the corridor from the laboratory where he spent years toiling over petri dishes of nasal stem cells, in his life's mission to treat spinal injuries, hereditary spastic paraplegia and diseases like Parkinson's.

A photo of the late actor Christopher Reeve is pinned on a noticeboard behind him. "I met Christopher in 2003 when he came out for a conference; he was interested in our clinical trials," Mackay-Sim says, looking at the photo. "Then in the following year I spent some time at his home in New York, and we talked a lot about spinal cord injury repair, and his own personal story."

As Mackay-Sim explains, the higher up the spinal cord an injury is, the more severe the effects. "As we know, Christopher fell off a horse and became a full paraplegic on a respirator, but in fact he suffered only a small injury; the problem was that the bleed went straight into his spinal cord. It only takes a very small injury to stop transmission; you can have large injuries to the chest and not suffer long-term repercussions but here, in the neck, a small event can change your life."

Back in the late 1980s, after he started at Griffith University, Mackay-Sim became interested in a set of extraordinary busy-bee cells in the human nose called olfactory ensheathing cells nerve cells that regenerate every single day to recreate our sense of smell. If these wonder cells are continually regenerating, he kept asking himself, could they not be transplanted to another part of the body where cells don't regenerate, like the spinal cord?

Years of scientific slog followed until 2002, when Mackay-Sim was the first researcher in the world to remove cells from the nose of a patient paralysed in a car accident, grow them in a cell culture and then, with the help of surgeons at Brisbane's Princess Alexandra Hospital, implant them in the same patient's spinal cord. "By the time Christopher died in 2006, we'd transferred stem cells from the nose into three patients and shown it was safe to do so," he says. "One of the patients recovered some sensation above the injury, which was hopeful, but one person does not make real scientific evidence."

For Mackay-Sim, the importance of scientific breakthroughs in the treatment of life-threatening illnesses is deeply personal. In 2014, he was diagnosed with multiple myeloma, an incurable form of leukaemia. As a result of the illness, which breaks down bones in an advanced form of osteoporosis, and the punishing series of treatments that followed his diagnosis, involving radiation, chemotherapy and stem cell therapy (albeit a very different form from the one the scientist was researching), Mackay-Sim lost nine centimetres in height and shed more than 15 kilograms of body weight. "I became extremely sick from the chemotherapy just prior to the bone marrow transplant," the 65-year-old recalls. "It was the worst experience of my life."

There was also the initial shock of the diagnosis, and grief for the loss of his health after a highly active life, from football and rowing in his teens to distance cycling, scuba diving and hang-gliding, which he took up while atuniversity. "Both my parents lived into their 80s and 90s and I'd been cycling up to 200 kilometres a week for decades, so I wasn't anticipating something like this."

Still, as a scientist he couldn't help but observe the trajectory of his illness with stricken fascination. "I had some good conversations with my oncologist," he smiles. "As a biologist examining my own biology, it did demystify lots of things. One minute I was a grieving patient, the next an interested scientist."

Above all, Mackay-Sim refuses to sentimentalise his battle with the illness and asks that I don't embroider it in this story by turning it into some kind of triumph of personal will power over disease. "My survival is determined by the vagaries of the particular cancer I've got," he says matter-of-factly. "Some people have nasty genetic diseases that mean they die earlier. For the moment, I feel very healthy."

Surely his extreme fitness at least helped him to survive the ravages of chemo? "I think being fit and active all my life has given me a higher quality of life after treatment," he acknowledges. "But one doctor put it to me that I probably would have sought out treatment earlier if I wasn't so fit, because I dismissed the symptoms as simple back pain from the cycling. It took two years after the chemo and radiation for the pain to go away. 2016 was a year of normality for me my back became stable enough for me to get on a road bike again."

The diagnosis added poignancy to the evening in Canberra in late January when Mackay-Sim, out of 3000- plus nominations, was crowned Australian of the Year. Sitting alongside him were his American-born wife of nearly 34 years, Lisa Peine, a retired primary school teacher, their 28-year-old daughter Matilda, a trainee psychiatrist, and 25-year-old son Callum, an engineer.

Mackay-Sim with wife Lisa Peine in North Queensland in 1983. Photo: Courtesy of Alan Mackay-Sim

Perhaps no Australian of the Year is better placed to recognise just how precious a year can be, and more determined to seize the moment to put science and innovation at the top of the national conversation. A former Queenslander of the Year, Mackay-Sim sees science as vital to our future national wellbeing, especially after the recent wake-up call in international school education rankings, which placed Australia behind Kazakhstan and Slovenia in maths and science.

Mackay-Sim agrees unequivocally with Michelle Simmons, professor of quantum physics at the University of NSW, who drew headlines recently when she declared that the "feminised" nature of Australia's high school physics curriculum (emphasising the sociology of science with essays and theory instead of rigorous lab experiments and mathematical problem-solving) had been an unmitigated failure. Introduced in the 1980s, the approach had resulted in a long, slow decline in standards.

"Scientific understanding comes from learning the processes; it can be hard work but is absolutely essential," Mackay-Sim insists. "The key to a good science education in schools is to get well-trained teachers." (Mackay-Sim has been deeply encouraged by some of the science teachers he's met since winning the award.)

The choice of Mackay-Sim the first scientist honoured as Australian of the Year since immunologist Ian Frazer in 2006 was met with near-universal applause by Australia's scientific community, who no doubt feel dispirited in this post-truth world of climate-change denial, cuts to the CSIRO and the growing view by government agencies that basic research isn't worth it.

"We need to invest in young scientists," Mackay-Sim declared in his acceptance speech, adding that the discovery of new medical treatments can reduce the strain on health budgets. "More than 10,000 Australians live with a spinal cord injury a new person is added to this tally every day." But politicians need to take a long-term view of the benefits of basic research, he tells me, "a view much longer than the political horizon".

The announcement also gave the image of the Australian of the Year awards a much-needed polish. The 2016 winner, Lieutenant-General David Morrison, drew criticism for charging up to $15,000 a pop forpublic speaking engagements, as well as grandstanding about sexism in the military despite his own handling of the army's "Jedi Council" sex scandal, in which demeaning sex videos of women were distributed among a group of soldiers. (It was revealed that Morrison's office knew of the scandal 11 months prior to the former Chief of Army releasing a now-famous condemnation on YouTube of those involved.)

Will Mackay-Sim accept speakers' fees? "I knew nothing about speakers' fees when I accepted the award," he says crisply. "I'm not pursuing money after all, I've spent my life doing public research."

Although he hasn't received any fees to date, Mackay-Sim insists that if they are offered, the funds will be donated to the Hereditary Spastic Paraplegia Research Foundation, his charity of choice.

Mackay-Sim only had a day or so to bask in the glow of being named Australian of the Year before there was a claim his scientific achievements had beenoverstated in the application. A Polish scientist, Professor Pawel Tabakow, after being approached by an Australian journalist in Europe, declared that Mackay-Sim had nothing to do with the world-first surgery using olfactory stem cells that enabled a Polish paraplegic, Darek Fidyka, to walk again. "It is not our business who should be Australian of the Year," Tabakow told The Weekend Australian. "But it is our business when his work is being linked to the surgery of Fidyka. He has no link whatsoever."

The scientific hullaballoo arose from the submission to the Australia Day Council (ADC), which states that Mackay-Sim's research "helped play a central role in proving the safety of science that was a precursor to Dr Tabokow in Poland undertaking the first successful restoration of mobility in a quadriplegic man".

Although Mackay-Sim didn't write the submission to the ADC, doesn't know who did, and never claimed to be involved in Tabokow's work, an artificial straight line was drawn between the two scientists, especially when the word "precursor" was dropped from condensed versions of the ADC's quote in multiple news stories (we'll examine the fallout from the controversy a little later).

Padding amiably about his large, multi-room laboratory, past refrigerator-sized storage cabinets containing cell cultures, past white-coated scientists peering into microscopes, Mackay-Sim seems to be in his element, with every second person saying "Hi", "Hello", or "How are you?" If stem cells are indeedthe microscopic building blocks of the world, this is the tiny universe the scientist feels most comfortable in. But it's a laboratory that now has to hum along without him Mackay-Sim retired late last year, his duties now limited to popping into the university once a week as an emeritus professor.

Later in the day, Professor George D. Mellick, head of Clinical Neurosciences at Griffith, tells me that Mackay-Sim has always set aside time to mentor younger scientists, and to explain sometimes hideously complicated science to a lay audience, but would be the last person to crow about his own scientific achievements.

"One of the things that isn't highlighted very much about Alan's work is his research into Parkinson's. We've been able to learn a lot about Parkinson's by studying cells from people with the disease, and the information coming out of this research will hopefully lead to better treatments."

Back in his office, Mackay-Sim gives me a quick rundown, 101-style, on the human nose. No, the human sense of smell doesn't necessarily decline with age, unless illness or disease set in, and it is astonishingly adept at distinguishing hundreds of thousands of different odours. Yes, women do have a superior sense of smell to men, but the difference is surprisingly only slight. Yes, the first symptom of Parkinson's, before the typical tremors set in, is a reduced sense of smell, as it is with those sufferers who will go on to develop dementia. And yes paws down dogs do have a vastly more powerful sense of smell than humans, although it's impossible to quantify by exactly how much (Mackay-Sim has been known to hide from his spoodle Henry, to measure how long it takes for the dog to find him).

As he relays all this, Mackay-Sim's eyes twinkle and a smile lights up his face: it's easy to see how he'd be the perfect academic for Griffith to call on to schmooze a government minister or potential philanthropist and secure desperately sought-after funding. I ask him about his trademark moustache, which he's had since the early 1990s, when he shaved off a beard. "My wife wouldn't recognise me without it," he jokes. "She says that a small mammal could roost beneath my mouth."

Mackay-Sim, whose double-barrelled surname comes from his paternal grandfather, grew up in middle-class Roseville, on Sydney's leafy North Shore, the third of four brothers. His mother Lois was a nurse during World War II and later a full-time mum while his father Malcolm ran a hardware importing and distributing business, Macsim Distributors (now Macsim Fasteners, owned by Alan's eldest brother, Fraser). At North Sydney Boys' High he was "the opposite of a shit-stirrer. I was vice captain, head of the cadets, played football, was in the rowing team, had a shot at athletics, sang in the choir I did it all."

With wife, Lisa Peine, in Sulawesi, Indonesia, 2007. Photo: Courtesy of Alan Mackay-Sim

After graduating with honours in science from Macquarie University, Mackay-Sim picked up tutoring work in the department of physiology at the University of Sydney, where he completed a PhD on the brain's visual system. Two academic stints in the US followed, first at the University of Pennsylvania from 1979 until 1981, followed by two years at the University of Wyoming, during which time he met his wife Lisa, then living in northern Colorado.

The pair married in 1984, by which time Mackay-Sim had been offered a research role in the department of physiology at the University of Adelaide. He started at Griffith University in 1987, where his research concentrated on the biology of nasal cells.

At the height of the heated moral debate over the use of embryonic stem cells whether the therapeutic potential of stem cells could justify destroying human embryos to extract them Mackay-Sim met Pope Benedict XVI at a Vatican conference in 2005. The Pope congratulated him on his exclusive use of adult stem cells.

"I wasn't avoiding embryonic stem cells for religious reasons," Mackay-Sim explains. "It just so happenedthat I was working with adult stem cells at the time and the conference was looking at alternatives to using embryonic stem cells. But it was a scientific conference and I was impressed with its calibre; the only difference was that men in purple robes were sitting at the back asking questions."

Later in the same trip, Mackay-Sim was invited, along with a host of others, to the Apostolic Palace at Castel Gandolfo the Vatican summer palace. "You feel the history of the Roman Catholic Church, with the Pope coming in with his cardinals and the Swiss Guards," he says. "I'm not a believer, but it was a very powerful experience."

In 2006, the debate over embryonic stem cells virtually vanished when scientist Shinya Yamanaka from Japan's Kyoto University stunned the world by proving that stem cells needn't come from human embryos adult cells can be reprogrammed to act like stem cells, to be returned to an embryo-like state (Yamanaka's discovery won him the Nobel Prize in 2012). "Yamanaka worked out how to genetically engineer any cells so that they had the properties of embryonic stem cells," says Mackay-Sim, who nonetheless continued to focus on adult stem cells only.

Mackay-Sim accomplished his own world first in 2002 when, with the assistance of doctors at Brisbane's Princess Alexandra Hospital, he transplanted olfactory stem cells into the spinal cord of a man crippled in a car accident. The procedure was repeated with two other paraplegic patients at the same hospital and the study wrapped up in 2007.

While the procedures didn't result in any of the patients regaining useful movement in their legs, the results of Mackay-Sim's clinical trials, published in 2005 and 2008, paved the way for further development of olfactory stem cell transplantation.

One researcher who followed Mackay-Sim's trials closely was Geoffrey Raisman from University College London, who visited the Australian team shortly after the first operation in Brisbane to study their work. Raisman later led the British team who worked with Polish surgeon Tabakow on Darek Fidyka in 2012.

Tabakow deployed 100 separate micro-injections of olfactory sheathing cells above and below Fidyka's spinal injury, with the hope these cells would provide a skeleton for nerve fibres to grow and reconnect. A former volunteer firefighter, Fidyka had become paralysed in 2010 after a severe knife attack by the jealous ex-husband of his girlfriend. The repeated stab wounds to Fidyka's back severed his spinal cord, paralysing from the waistdown. (Fidyka's attacker, a fellow firefighter, committed suicide shortly afterwards.)

There's no doubt Tabakow's work was a major advance on Mackay-Sim's research. Tabakow's strategy was to extract ensheathing cells specifically from the olfactory bulbs in Fidyka's nose, grow them in a culture, while also extracting nerve cells from his ankle in a multi-pronged attempt at spinal cord reconstruction. After a series of operations, Fidyka can walk with the assistance of a frame, has regained some bladder control and sexual function, and can ride a tricycle.

Raisman described their new stem cell procedure as "more impressive than man walking on the moon", but it will have be tested on other paraplegics, including those with more severe injuries than Fidyka's, such as car accident victims who have had more of their spinal cord damaged, before it can be declared a reliable method of restoring mobility. As impressive as Tabakow's achievement is, it has still only worked on one patient.

Nobody, however, disputes Mackay-Sim's immense contribution to stem cell transplantation; his work is unimpeachable. If nothing else, he was at the forefront of the science showing that restoring the ability to walk to paraplegics is no longer science fiction. "What I've always said is that we did the first phase of clinicaltrials with olfactory stem cells, and the aim of those trials was to show they were safe," says Mackay-Sim. "That was the first important step."

Mackay-Sim wrote to Tabakow shortly after the controversy blew up, explaining that he didn't write the submission to the Australia Day Council, and was in no way claiming credit for Fidyka's remarkable recovery. "He wrote back a very nice email," says Mackay-Sim. "I believe I've given credit to other scientists in every interview I've given to journalists. I feel comfortable in my behaviour and ethics."

With Prime Minister Turnbull in January this year. Photo: Elesa Kurtz

Mackay-Sim can remember the day when he felt something was wrong terribly wrong. He'd been suffering back pain for months, but dismissed it as old age, or strain from bending over on his bicycle on long rides, and stocked up his pantry with painkillers. "I was in Colorado with Lisa visiting her family, and the pain became so bad I couldn't walk very far. I found the pain eased when I got on my bicycle. I flew home a week before she did; the plane trip back was absolute hell."

What followed was a swift diagnostic journey from his GP to specialists at Brisbane's Wesley Hospital, resulting in a devastating diagnosis. "They suspected something cancerous quite quickly. I didn't realise how ill I was; by this stage, my kidneys weren't coping at all with the antibodies released from my white blood cells, which were going berserk trying to fight the disease. I was at risk of kidney failure and my bones were becoming very fragile. I started therapy almost immediately, in June 2014. Then began the cycles of chemotherapy and stem cell treatment in December."

Since the beginning of last year, however, Mackay-Sim's health has dramatically improved, and even though he's retired to his beachside home in Currimundi on the Sunshine Coast, he is still active in university affairs. He concedes that his health may prevent him from being as active as Rosie Batty, perhaps our most vigorous Australian of the Year to date. But he's already spoken at functions in Brisbane, Sydney and Perth, and will be attending the national March for Science on April 22, which coincides with Earth Day. He moves with the speed and fluidity of a man 10 or 15 years younger.

"I feel very healthy, very energised at the moment," says Mackay-Sim, who is planning a bicycle ride in Italy's Dolomites in July with a couple of mates. (Last year he and his wife went on the Great Victorian Bike Ride, a seven-day ride averaging 85 kilometres a day.)

"I do need to be selective with the number of invitations around Australian of the Year," he concedes, "but I'll do everything I can. After all, what more exciting time could you have to talk about science?"

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A stem cell treatment for heart failure patients is safe and shows early signs of effectiveness, according to a study published Wednesday.

The study was conducted by Japanese researchers in 27 patients, who received transplants of stem cells taken from their own thigh muscles. There were no major complications, and most patients showed considerable improvement in their symptoms.

The study was published in the open-access Journal of the American Heart Association. Dr Yoshiki Sawa of Osaka University Graduate School of Medicine was the senior author. It can be found at j.mp/stemheart.

However, two San Diego cardiologists who do stem cell research on heart disease cautioned that similar clinical trials have shown promise over the years, only to fail at the end for various reasons. There is no approved stem cell therapy for heart failure.

So while the trial itself appears to be well-conducted, the researchers are very far from actually proving their treatment is effective, said Dr. Richard Schatz of Scripps Health and Dr. Eric Adler of UC San Diego School of Medicine.

For one thing, the trial was small, they said, and larger trials are where the most rigorous scientific evaluations are made.

These early trials have looked beneficial in the past, Adler said. When we do the larger trials, the results are more equivocal.

Adler said the signs of efficacy in this trial are modest. For example, the change in ejection fraction, a measurement of efficiency in pumping blood, rose from 27 percent to 30 percent in 15 of the 27 patients. Their heart failure was associated with a lack of blood flow, or ischemia. The remaining non-ischemic patients actually had a slight decline.

The entire field of stem cell and regenerative therapy for heart disease has been a disappointment to date, Schatz said.

Weve been at it for 20 years now, and we dont have a product or a positive (late-stage) trial, so that tells you pretty much everything you need to know, he said. Its not for lack of trying or billions of dollars invested. Its just very, very difficult.

The cardiac field has had more success with other technologies, such as cardiac stents. Schatz is the co-inventor of the first stent.

In the study, the researchers acknowledge that previous attempts had only been modestly effective. They devised a method of producing sheets of muscle stem cells and attaching them to the inner layer of the sac that encloses the heart, a layer that rests directly on the heart surface.

The stem cell sheets stimulate healing by producing chemicals that stimulate cardiac regeneration, the study said. The cells themselves dont survive in the long term, but by the time they die they have served their purpose.

Loss of function

Heart failure is a progressive disease in which the heart gradually loses its ability to pump blood. This can be triggered by a heart attack or any other cause that damages the heart muscle.

When damaged heart muscle is replaced with scar tissue, as often happens, the heart loses pumping capacity. It becomes overstressed, and its output of blood declines. This limits the patients ability to engage in intensive physical activity. In advanced cases, patients may become bedridden.

Existing treatments include drugs and LVAD units, which take over some of the hearts function to relieve stress. Some drugs may help the heart work more efficiently, but none have been shown to improve heart failure by actually regenerating lost heart muscle.

Stem cell therapy is tested in patients who havent responded well to other treatments. Trials have been and are being conducted in San Diego area hospitals.

Scripps Health has been testing a cardiac stem cell therapy from Los Angeles-based Capricor. The cells, taken from donor hearts, are injected into the coronary artery, where they are expected to settle in the heart and encourage regrowth.

UC San Diego is testing a heart failure therapy from Teva Pharmaceutical Industries. It consists of bone marrow derived mesenchymal precursor cells. These can give rise to several different cell types, including muscle cells.

And many other trials are going on throughout the country and internationally.

Adler and Schatz said theres reason for optimism in the long run, as technologies improve.

Just because the other trials have been negative doesnt mean this technique wont be beneficial, Adler said. Its just too early to tell.

That said, Schatz emphasized that the nature of the three-phase clinical trial process means that the show-stoppers for a treatment typically appear late.

Tighter standards needed

Clean trials trials where we all agree that this is the patient population we want to look at, are needed, he said.

For example, heart failure comes in two types, he said. Ischemic heart failure is caused by heart attacks and blocked arteries, which impede blood flow. Non-ischemic heart failure can be caused by damage from diseases, such as a virus.

Non-ischemics can be younger people, in their 20s and 30s, while the ischemic patients are older. Mixing those patient groups in a single trial is a mistake, he said.

Theyre different animals, Schatz said.

Another pitfall is failing to screen carefully enough to enroll only patients likely to benefit, Schatz said.

You can have a patient who has chest pain, and coronary disease just incidentally, he said.

His shoulder or chest pain is from a virus. So he goes into the trial and gets a placebo injection in his arm of cortisone, and his arm pain goes away. And because hes in that placebo group, hes counted as a success the pain went away. It has nothing to do with his heart. Thats an extreme example, but we actually saw that happen.

In a failed gene therapy trial for heart disease, some patients apparently had received the injection in the wrong location, missing the heart muscle, Schatz said.

You assume they got the gene, but they didnt, Schatz said. The study was negative, and thats why I think it was negative.

Such errors dont show up in Phase 1 trials, Adler and Schatz said, because theyre focused on evaluating safety. And these early trials dont have many patients, there arent enough to comfortably determine the therapy is really effective.

By the last stage of the trial, these sources of error have often been identified and trial standards have tightened up. And thats when the faulty assumptions made early appear as the trial ends in failure.

Despite those forbidding hurdles, Adler said research should continue.

This disease is killing a lot of people. Theres not going to be enough hearts to go around for transplant. Theres six million Americans with heart failure, and theres 2,000 heart transplants a year. So coming up with novel regenerative cell-based therapy is something were still excited about.

bradley.fikes@sduniontribune.com

(619) 293-1020

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Science Daily

How cells react to injury from open-heart surgery: Research ... Science Daily Investigators have learned how cardiac muscle cells react to a certain type of injury that can be caused by open-heart surgery. The findings point to a new ... and more »

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How cells react to injury from open-heart surgery: Research ... - Science Daily

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TiGenix reports 2016 full year results | P&T Community P&T Community PRESS RELEASERegulated informationinsider information TiGenix reports 2016 full year results (Conference call and webcast today at 13:00 CEST) and more »

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BROOKLINE Fighting for her life, a retired Brookline teacher who has been struggling with cancer for more than four years is hoping to find a donor for a stem cell transplant.

This week, Kathi Bond of Temple has undergone 96 hours of around-the-clock chemotherapy, but next week provides a new and unique opportunity for the 66-year-old woman battling a bone marrow cancer known as multiple myeloma.

A marrow donor registry drive will take place on Tuesday in an effort to find a match for Bond, who has undergone numerous, unsuccessful therapies throughout the past several years.

She is not the type that wants to be lying in a bed staring at a blank wall she would rather be climbing mountains, said Bonds husband, David Bond. She is a very vibrant woman, but on paper she is very ill.

Kathi Bond, who retired in 2013 from her environmental science teaching position in the Brookline School District because of the cancer, has already undergone an autologous stem cell transplant where her own cells were used for the procedure.

While this effort placed her in remission for more than a year, her body eventually began to reject the treatment and she fell ill again in the fall of 2016, and is now at stage 3 multiple myeloma.

I think emotionally, for any cancer patient, it is a roller coaster, said David Bond. You have good days and bad days glimmers of light and then news that things arent working.

Multiple myeloma is a plasma cell disorder that attacks cells in a persons bone marrow. Since traditional treatments are not working for Kathi Bond, doctors are now looking for radical ways to preserve her life, and a donor transplant is the next alternative.

Unfortunately, at this point, they have not found a match for Kathi, said her husband. But we have always felt that optimism is stronger than adversity. There will be a match out there somewhere.

A marrow donor registry drive will take place from 3:30 p.m. to 7 p.m. Tuesday at the Richard Maghakian Memorial School, 22 Milford St. in Brookline. Participants must be ages 18 to 44, and will have their cheek swabbed to determine compatibility.

Kathi Bond, who is currently hospitalized, is attempting to reduce the number of myeloma cancer cells in an effort to make the future transplant more successful. She is working with an oncologist in Nashua, and the Dana-Farber Cancer Institute to determine the best course of action for an incurable illness.

She is fairly strong right now, but a transplant is desperately needed, said David Bond.

Cancer is no longer a private struggle, he said, adding it affects so many families. In 1984, Kathi Bond lost her older sister to lymphoma.

At the time, he said there were no donor drives, walks for cancer or fundraisers to research cancer treatments.

Today, we save lives because we share our story, and compassionate people step forward and join the fight, he said.

The Bonds are hopeful to find a match from next weeks marrow donor registry drive, but said even if they dont, the data may be useful in helping to find a match for someone else in desperate need.

Kathleen Milewski, a second-grade teacher at RMMS in Brookline, along with the Bonds two daughters, have been instrumental in helping to organize Tuesdays drive, according to David Bond.

Joining the registry is as simple as a cheek swab, and the donation process, should you be a match, is similar to giving blood in over 70 percent of the cases, said Milewski. Kathi needs a match in order to continue to live with multiple myeloma.

David Bond said a donor transplant is his wifes greatest hope for a life of near-normalcy. A donors stem cells will result in a total reboot of the patients marrow, and as new donor stem cells develop and mature, they will over-populate the bad cells.

khoughton@newstote.com

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The only practical way to scale-up volumes of mesenchymal stem cells (MSCs) is by using microcarriers in single-use bioreactors, say scientists from A*STAR and Instituto Superior Tcnico.

MSCs are multipotent stromal cells that can differentiate into a variety of cell types which are being investigated for tissue engineering and cellular therapies.

Such cells come from bone marrow, adipose tissue and umbilical cord blood but are very rare, according to Ana Fernandes-Platzgummer, a research scientist for the Stem Cell Engineering Research Group at the Instituto Superior Tcnico in Lisbon, Portugal.

Totipotent cells can form all the cell types in a body, plus the extraembryonic, or placental, cells. The only totipotent cells are embryonic cells within the first couple of cell divisions after fertilisation.

Pluripotent cells can give rise to all of the cell types that make up the body. While embryonic stem cells are considered pluripotent, this class includes induced pluripotent stem cells (iPSC) derived from skin or blood cells that have been reprogrammed back into an embryonic-like pluripotent state.

Multipotent cells are more limited than pluripotent cells but can develop into more than one cell type. This class includes mesenchymal stem cells (MSCs) derived from bone marrow, adipose tissue and umbilical cord blood, and hematopoietic stem cells (HSCs) derived from mesoderm and located in the red bone marrow.

There are only about 100,000 stem cells in an umbilical cord, she told delegates at the 1st Stem Cell Community day in Germany this week. For cellular therapies we need doses of more than one million cells per kg [ideal (IBW) or actual (ABW) body weight] so we need to expand these cells.

Scale-up challenges

Stem cells can be successfully cultivated using flasks and labscale-volume bioreactors but there are many problems in monitoring and controlling growth, and issues with productivity and cell harvest. Therefore scale-up is a problem, hindered further due to a lack of technologies and processes available to cell therapy makers.

The event in Hamburg organised by bioprocessing tech firm Eppendorf looked to address these challenges in stem cell cultivation and scale-up by bringing together industry and academia.

And Fernandes-Platzgummer said that research by the Instituto Superior Tcnico together with Thermo Fisher-owned Life Technologies showed positive results in the expansion of human MSCs from different sources using a fully-controlled stirred-tank bioreactor combined with microcarrier technology.

The advantage of this is its easy scalability, the high surface area [of the microcarrier], the ability to monitor and control cultivation, and the reduced labour costs and risks of contamination, she said.

After five days cultivation the team produced clinically-relevant cell numbers, she added, using an 800ml spinner flask bioreactor, Thermo Fishers serum-free medium StemPro and reagent TrypLE Select CTS, and plastic microcarriers coated with the xeno-free substrate CELLstart (also made by Thermo Fisher).

'10,000 doses per year, each of a billion cells'

In a separate presentation, Steve Oh principal scientist and associate director at the Bioprocessing Technology Institute (BTI), part of Singapores Agency for Science, Technology and Research (A*STAR) said a similar set-up had shown promise in moving MSC cultivation into scalable technologies and his team is trying to move to a 15L scale.

However, the goal for MSC-based therapies would be producing commercial volumes of 10,000 doses per year, each of a billion cells from the onset, he added.

We looked at all the approaches and really the only practical experience I have of a technology that will succeed is microcarrier technology using single-use bioreactors, he said.

Oh added microcarriers produce higher cell densities with the same amount of media while allowing greater control of the process by providing another metric to configure.

Furthermore, having only thin layers of cells between each carrier offers benefits in the harvesting of stem cells which he said is as problematic as cultivation due to the large aggregates of cell clusters formed which are difficult to break up.

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No two stem cells are identical, even if they are genetic clones. This stunning diversity is revealed today in an enormous publicly available online catalogue of 3D stem cell images. The visuals were produced using deep learning analyses and cell lines altered with the gene-editing tool CRISPR. And soon the portal will allow researchers to predict variations in cell layouts that may foreshadow cancer and other diseases.

The Allen Cell Explorer, produced by the Allen Institute for Cell Science in Seattle, Washington, includes a growing library of more than 6,000 pictures of induced pluripotent stem cells (iPS) key components of which glow thanks to fluorescent markers that highlight specific genes.

The Cell Explorer complements ongoing projects by several groups that chart the uniqueness of single cells at the level of DNA, RNA and proteins. Rick Horwitz, director of the Allen Institute for Cell Science, says that the institutes images may hasten progress in stem cell research, cancer research and drug development by revealing unexpected aspects of cellular structure. You cant predict the outcome of a football game if you know stats on all the players but have never watched a game.

The project began about a year ago with adult skin cells that had been reprogrammed into an embryonic-like, undifferentiated state. Horwitz and his team then used CRISPRCas9 to insert tags in genes to make structures within the cells glow. The genes included those that code for proteins that highlight actin filaments, which help cells to move and maintain their shape. It quickly became clear that the cells, which were all genetic clones from the same parent cell, varied in the placement, shape and number of their components, such as mitochondria and actin fibres.

Computer scientists analysed thousands of the images using deep learning programs and found relationships between the locations of cellular structures. They then used that information to predict where the structures might be when the program was given just a couple of clues, such as the position of the nucleus. The program learned by comparing its predictions to actual cells.

The deep learning algorithms are similar to those that companies use to predict peoples preferences, Horwitz says. If you buy a chainsaw at Amazon, it might then show you chain oil and plaid shirts.

The 3D interactive tool based on this deep learning capability should go live later this year. At the moment, the site shows a preview of how it will work using side-by-side comparisons of predicted and actual images.

Benjamin Freedman, a cell biologist at the University of Washington in Seattle, looks forward to playing with the Cell Explorers predictive function once the Allen Institute team has taught their algorithm to recognize more iPS cells that have been changed genetically or chemically. For example, Freedman says he could delete a gene related to kidney disease in one of the fluorescently tagged stem cells from the Allen Institute and see how the mutation affects the glowing structure. Then he could use the sites modelling tool to determine how other cellular components might be altered. Ultimately, Freedman says, we want to understand processes at the cellular level that cause disease in the kidney as a whole.

In the coming months, Allen Institute researchers will update the site with images of stem cells at different stages of cell division, and as they transform into distinct cell types, such as heart and kidney cells. Catching cells at different time points can be crucial to identifying fundamental processes, says Horwitz.

Allen Institute for Cell Science

Structural differences in the DNA (purple) and cellular membrane (blue) of genetically identical stem cells.

The Allen Institutes visual emphasis on stem cells dovetails with a number of efforts to catalogue other aspects of cells. For example, the London-based charity Cancer Research UK is creating interactive virtual-reality models of breast cancer cells in tumours. And an international effort called the Human Cell Atlas seeks to define all human cell types in terms of their molecular profiles, including DNA sequences, RNA transcripts and proteins.

Aviv Regev, a computational biologist at the Broad Institute in Cambridge, Massachusetts, who is working on the Human Cell Atlas, says that the Allen Cell Explorer complements her project by focusing on the look of cellular features as opposed to how genes, RNA and proteins interact within the cell. The community is accepting that there are a lot of differences between cells that we thought were the same until recently, she says, so now were taking an unbiased approach to learn about pieces in the puzzle we didnt know existed before.

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Scientists at the Medical University of South Carolina (MUSC) have found that a class of heart failure drugs might decrease low-density lipoprotein (LDL) cholesterol levels in patients who do not respond to statins. In a study appearing in the April 6, 2017 issue ofCell Stem Cell, cardiac glycosides reduced levels of a precursor of LDL in liver-like cells, and patients taking cardiac glycosides for heart failure had low LDL.

Not everyone with high LDL cholesterol responds to statins. Statins increase levels of a cell surface receptor that removes LDL cholesterol from the bloodstream. However, statins do not work in patients with familial hypercholesterolemia (FH), who have a rare mutation in that receptor. FH patients have very high cholesterol and die of cardiovascular disease by their forties. The existing drugs for FH can cause fatty liver disease, and the best treatment is a liver transplant.

Stephen A. Duncan, D. Phil., SmartStateTMChair of Regenerative Medicine at MUSC, and his colleagues, including Max A. Cayo, Ph.D., an MSTP student at the Medical College of Wisconsin, developed a drug screen to identify an alternative to statins. They focused on apolipoprotein B (ApoB), a molecule that liver cells use to make LDL and which is normal in patients with FH. Drugs that decrease ApoB could potentially lower cholesterol independently of the LDL receptor in FH patients and also in patients with other forms of high cholesterol.

FH was a perfect model for testing alternatives to statins. Yet the rarity of FH meant these liver cells were scarce. Duncan's group obtained skin cells from a patient with the rare disorder from the Next Generation Genetic Association Studies consortium of the National Heart, Lung, and Blood Institute, which studies genetic mutations linked to cardiovascular diseases. Next, they generated induced pluripotent stem cells from these skin cells. Stem cells continually double their numbers while in culture. This meant that a sample of converted skin cells from a single patient with FH provided a renewable source of liver-like cells that retained the mutation.

The team treated their liver-like cells with the SPECTRUM drug library, a collection of 2300 pharmaceuticals, many of which have reached clinical trials. In a surprising finding, all nine cardiac glycosides in the library, some once widely prescribed for heart failure, reduced ApoB levels in liver-like cells from the patient with FH, ranging from 29 percent (ouabain) to 38 percent (digoxin) to 73 percent (gitoxin). In further tests, they also lowered ApoB levels in human hepatocytes and reduced them by 30 percent in mice engineered to grow normal human livers without the FH mutation at doses eight times below their toxicity thresholds. Molecular tests revealed that glycosides shorten the lifetime of the ApoB molecule, in part by increasing how quickly it is degraded.

As everyone needs ApoB to make LDL cholesterol, this was proof that cardiac glycosides could potentially also work in patients with other forms of high cholesterol. To find out, the team combed through more than five thousand records of patients prescribed cardiac glycosides for heart failure who also had LDL cholesterol records. On average, LDL cholesterol levels were lower in those taking a cardiac glycoside (reduction of 9 mg/dL) or a statin (reduction of 14 mg/dL) than in those not taking any drug. No difference in LDL cholesterol levels was noted between those taking an angiotensin-converting enzyme inhibitor, another heart failure drug with no known role in cholesterol production, and those not taking any drug. Duncan's team also found patients who had LDL measurements recorded both before and after being prescribed a cardiac glycoside. LDL cholesterol dropped in 16 out of 21 patients and by an average of nearly 26 points, which was similar to the 32-point drop seen in a matching group of patients prescribed statins.

This study contains the first evidence to date that cardiac glycosides could potentially reduce LDL cholesterol independently of the LDL receptor, where statins act, by promoting ApoB degradation.

It is not clear from this study whether cardiac glycosides decrease LDL cholesterol in patients who do not have heart failure or at what dose they should be used. The cardiac glycosides have narrow ranges of efficacy for the treatment of heart failure, above which they can be toxic. However, they could offer inexpensive, life-saving options for patients with FH. Digoxin, the cardiac glycoside most commonly prescribed for heart failure, costs less than one dollar per day. Additionally, a cardiac glycoside in a low dose could conceivably provide an added benefit to patients already taking a statin. Finally, using stem cell-based screens of drugs that are already on the market is an innovative way to investigate treatments for rare liver diseases.

"There are so few livers available for transplant," says Duncan. "Having the stem cell model where we make liver cells in the culture dish opens up a possibility of using this not only to investigate a disease, but also as a way to discover drugs that could fix a disease."

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