Scientists in the US and Australia are freezing samples of coral in hopes that polyp organisms and sperm may allow them to regrow coral in the lab and replace dying species in the ocean.

The Great Barrier Reef is dying. As pollution and other man-made influences threaten the reef, which is not expected to survive past 2050, Australian scientists are taking measures to freeze the corals’ demise – literally. They hope to save the endangered species by freezing eggs and sperm from the coral, then fertilize and regrow the coral in the lab. As they enter the deep freeze, the Great Barrier Reef coral will become the latest in a large number of species stockpiled in cryogenic chambers in an attempt to reverse the advance towards extinction.

The first experiments in the 1950s attempted, with little success, to freeze sperm from the bull, ram, fowl and other mammals. Today there are a number of institutions around the world collecting all sorts of biological material from the animal and plant kingdoms as an insurance measure against endangerment or a world catastrophe of biblical proportions.

In 1972, the San Diego Zoo began freezing skin cells from rare and endangered species in hopes that future technologies could bring species back from the dead, if it came to that. This was long before the science of molecular biology advanced to a point where DNA would be sequenced, duplicated, and manipulated. Today, 8,600 animals of 800 different species are preserved at the zoo. Included among the samples are cells from the northern white rhino. There are only seven northern white rhinos left in the world, two females and five males. The survival of their species lies entirely in the zoo’s vials of liquid nitrogen that keep the cells, as the group has produced no offspring since 2000.

Other groups, like the Reef Recovery Institute, have their own efforts to cryopreserve coral.

The prudence of those 1970s scientists could pay off soon. This past August a group of scientists at Kyoto University in Japan successfully turned embryonic stem cells from mice into sperm. The sperm was then used to impregnate a dam, and led to the birth of a healthy litter. With all the biological alchemy that stem cell researchers are doing with skin cells these days, it’s easy to believe that the experiment’s success will eventually lead to the conversion of skin cells to gametes. Even though the study was done in mice and it remains to be seen if human skin cells can be similarly converted, it certainly was a promising outcome.

A number of other groups are putting the prospect of extinction on ice. The Smithsonian’s Genome Resource Bank, which is helping to preserve the coral, has a repository that already contains more than 1,600 samples of frozen sperm or embryos from 70 different species including endangered species such as the cheetah, black-footed ferret, and Eld’s deer. It also stores over 8,000 blood serum samples from 80 species. The UK’s Frozen Arc is home to 48,000 samples from 5,000 different species.

Plants are being put into a prophylactic deep freeze as well. The Svalbard Global Seed Vault in Norway has over 400,000 different samples totaling some 200 million seeds. Rather than preparing for a global catastrophe the Svalbard Vault serves more as a safety net to the 1,400 crop diversity collections around the world. Many of the collections are located in politically and economically unstable countries. The Svalbard Vault is meant to ensure their sustainability when samples are lost or destroyed.

As for saving the Great Barrier Reefs, gametes will be harvested from the colorful polyps that decorate reef surfaces. Polyps are the builders of coral. The soft-bodied organisms have a protective limestone skeleton at their base. After setting down to spend their lives on a particular rock or the sea floor, the polyps multiply into a cloned colony of thousands that behave as a single organism. Large stretches of fused calicle are what we call coral reefs.

By freezing polyp embryo and sperm cells and storing them in a cryo vault, scientists in Australia and the US hope to create a kind of Noah’s Arc for coral to ride out the angry climate change calamity. Increases in water temperature leads to coral bleaching, the whitening that occurs when algae living inside the coral are expelled. Bleached coral can survive, but mortality does rise due to increased stress. Optimistically, the cryofreezing scientists hope to replace the dead coral with healthy coral once the climate stabilizes.

The Great Barrier Reef, one of Australia’s great national treasures, is the world’s largest reef system. In fact, it is the world’s largest structure built by living organisms. The approximately 20,000 years old reef is comprised of over 2,900 individual reefs and 900 islands that stretch across an area of about 133,000 square miles (344,400 square kilometers). Comprising 60 percent of total coral reef coverage it is the world’s largest.

Elkhorn coral is one of many species of coral facing extinction.

One-quarter of all marine species make coral reefs their home. But reefs are not only important for the underwater ecosystem, coastal people depend on coral for the sea life their habits harbor and to protect them from hurricanes and tsunamis. The Pew Center on Global Climate change estimates that coral reefs generate about $30 billion of the annual global economy. The reefs also represent a rich bed of biopharmaceutical opportunity. Scientists are digging through these “medicine cabinets of the 21st century” in search of cures for cancer, arthritis, and other diseases. Scientists predict that 70 percent of the world’s coral reefs could be lost over the next 50 years. In just the past 30 years, the Caribbean has seen an astonishing 80 percent of their corals destroyed.

Whether it’s to safeguard endangered species, preserve crop diversity, or assist human reproduction by freezing gonads, cryopreservation is a technique that could be nearing its long sought after potential. But while it makes sense in principle to combat the destruction of the Great Barrier Reef by freezing polyp material, can it really make a difference in practice? The 133,000 square miles that the Great Barrier Reef is over 40 percent the area of the continental United States. You wanna play Johnny Appleseed across that stretch of land? How about under water?

I asked Steve Palumbi, a marine biologist at Stanford and author of several books about ocean preservation, if he thought we could actually replace enough of the lost coral to make a difference. He wrote, “I am not familiar with the specific proposal but…on one hand it doesn’t seem like much of a gamble unless there is a huge cost or lots of natural coral reproduction will be thwarted. On the other hand, Noah took females on the Arc too – where would the eggs come from?”

In the absence of stem cell reprogramming into gametes, nowhere. But repopulating an area with northern white rhinos is more feasible and carries more impact than resetting 133,000 square miles of dead coral. Regardless, whether or not the cryo-coral plan works out, cryopreservation is sure to rescue some species on the path to extinction, whether they be some misplaced rice strains or northern white rhinos.

Palumbi’s response to my concerns: “Sure, this particular proposal may have holes. But underlying it is the worry that coral reefs will disappear within the next century, and that suggests more strident actions than normal. If you walked out one day and saw the very last coral in Australia about to die – what would you be willing to do to save it?”

I don’t know and I hope I never find out.

[image credits: Elephant Journal, NOAA, WillGoTo, and Reef Recovery Institute]
image 1: Great Barrier Reef
image 2: elkhorn coral
image 3: Hegedorn
image 4: Coral

Microscopes? That's so 2010. The lenseless ePetri dish just made one graduate student's day a lot easier.

A camera-attached laboratory microscope: $2,500.
An imaging chip, a smartphone, and some Lego blocks: $400.

Scientists at Caltech, out to ruin microscope manufacturers, have built their own device to monitor cells growing in a Petri dish. The device – which they call an ePetri dish – does away with the normal habit of taking the Petri dish out of the incubator and inspecting them under a microscope. Instead it takes images of the entire dish surface over time from inside the incubator. Without ever disturbing the cells they’re trying to grow, researchers can now take these cell growth “movies” and replay them whenever they want.

With the ePetri system, cells are grown on a CMOS image sensor – the kind found in common digital cameras. A smartphone placed above the sensor provides – via a commercially available app – a scanning spot of light that sweeps back and forth across its LED screen. Legos provide an enclosure that the smartphone rests on (no Lego NXT needed here). The contraption sits inside the incubator while a wire connects the sensor to laptop outside. Pictures are taken by the sensor and transferred to the laptop. With the ePetri system, scientists no longer have to remove the cells from the incubator but can simply look at the laptop images. Less manipulation makes for better cell health and reduced risk of contaminating them.

No microscope necessary. The ePetri system was able to track stem cells change over time with sub-micrometer resolution..

It also cuts down on work. Peering through a microscope limits visual range to a very small section of the Petri dish. Because ePetri scans the entire dish at a resolution of about half a micrometer – plenty of mag to see single cells. With the ePetri system scientists have the option of viewing the entire culture at once or zooming in to visualize single cells. And the continuous scanning capability means they get to watch their cells change in realtime.
Michael Elowitz, a professor of biology and bioengineering at Caltech and a co-author of the study, thinks ePetri is a game changer. “It radically reconceives the whole idea of what a light microscope is,” he said in a press release. “Instead of a large, heavy instrument full of delicate lenses, [we] have invented a compact lightweight microscope with no lens at all, yet one that can still produce high-resolution images of living cells.”

A lab member prepares an ePetri dish in the following video. He does his best not to speak, but I’m sure he’s very excited.

Elowitz and his colleagues gave ePetri a test run by using it to monitor the growth of stem cells. With it they were able to track the cells as they differentiated across the entire dish surface – an extremely labor-intensive and time-consuming undertaking with the use of a single microscope. They published the study recently in the Proceedings of the National Academy of Sciences.

Beyond monitoring cell growth, the ePetri scientists envision using the system to monitor other devices such as lab-on-a-chip tools. They also think doctors could use the system to test bacteria samples right there in the office instead of sending them out to a lab for testing. Currently the team is looking to make the ePetri dish a self-contained system by giving it its own small incubator. Of course, if they use anything but ziplock bags and soda cans it simply won’t be as cool.

[image credits: Proceedings of the National Academy of Sciences]
[video credits: caltech via YouTube]
images: ePetri
video: ePetri

"Stem cell tourism" – seeking out unproven and expensive treatments in countries without safety regulations – claims two more victims in China.

Stem cell research has the potential to revolutionize medicine. But while researchers continue to make strides to bring the technology to the clinic, some clinicians are already using stem cell therapies to treat conditions ranging from stroke to diabetes. No, there’s been no long-awaited breakthrough. These clinicians are in countries like Russia, Thailand and China where regulations for cell treatments are lax or nonexistent. Over the past decade thousands of desperate patients who seek out a stem cell miracle as their final option have traveled far, paid large sums of money, and suffered dearly for it. Two recent deaths in China remind us once again about the true price of “stem cell tourism.”

Reuters recently reported the story of Hong Chun who had suffered a minor stroke and the neurological damage made it difficult for him to use chopsticks. He went to the Chinese army’s 455 PLA Hospital in Shanghai hospital where the doctors injected his spinal cord and buttocks with what they claimed were donor stem cells. The next day Hong left the hospital, but he didn’t get far. The 27 year old became so sick on the train ride home he had to be rushed from the train to another hospital. He became brain dead and died within a month. Hong had paid 30,000 yuan ($4,800) to the Shanghai hospital for the stem cell therapy. Hong’s father went to Shanghai to find out why his son had died. Administrators told him that his son did not die in their hospital, paid him 80,000 yuan and discouraged him from pursuing matters further. “I can’t get my son back,” he told Reuters. “But people must know about these stem cell therapies and no one must be deceived.”

According to China’s official website for “medial tourism in China,” the 455 PLA Hospital’s stem cell transplantation center continues to be a source of pride – and cutting edge treatment. “The national stem cell engineering…base can transform the latest stem cell research achievement into clinical application. Now the base has operated stem cell transplantation treatment to type 1 diabetes, to liver disease, to solid tumor. Now stem cell transplantations are making much progress in treating diabetes and its complications.”

Fan Hongkun was a woman in need of treatment for liver disease. She was suffering from a chronic hepatitis B virus infection that had pushed her liver to late-stage cirrhosis. “We saw the therapy advertised online and talked to the doctor over the phone,” Fan’s son told Reuters. “He said the stem cells were like seeds, after being planted on a liver, they grow, divide and spread and finally form a healthy liver.” Like Hong, Fan had sought the help of a major hospital run by the Chinese army, the Beijing Military General Hospital. “My mother said the PLA (Chinese army) doesn’t lie. That’s why she trusted them.”

The Chinese army's 455 PLA Hospital in Shanghai.

Prior to receiving the stem cells doctors took Fan off lamivudine, an antiviral medication that was keeping the hepatitis B virus in her body from multiplying. Stopping the treatment, according to the doctors, was necessary to “prepare her for the stem cell therapy.” Fan never received the treatment. Without her medication the virus proliferated out of control. She went into a coma and died. Fan’s family tried to sue the hospital but a Chinese court dismissed the case.

The fact is the vast majority of stem cell trials fail. The only stem cell therapy that has gained widespread approval is hematopoietic stem cell transplantation (HSCT) to treat leukemia. In 2006 there were 50,417 HSCTs performed at 1,327 clinics in 71 countries. The treatment remains a major medical breakthrough. But HSCT became a viable treatment through a painstaking trial-and-error process that spanned decades. The examples above highlight the willingness of people to shortcut that process and exploit the terminally ill for profit or, even worse, a draconian type of experimental program that uses humans as guinea pigs.

If places like China’s military hospitals are in fact taking such a barbaric approach to science the implications for stem cell research are hard to predict. On the one hand, they might have hit that homerun and miraculously grown Fan back her liver – whole and healthy and functional. The doctors would be famous overnight, China would be at the forefront of the stem cell world, and South Korea’s disgraced Woo-Suk Hwang would grouse at taking the long way. But who knows? It is possible that by skipping clinical trials and testing treatments directly on the desperate China will push past countries that practice incremental, regulation-”hampered” science like the US.

But not if stem cell researchers like Zubin Master and David Resnik have anything to say about it.

Earlier this year the two wrote an commentary in the European Molecular Biology Organization Journal, entitled “Stem cell tourism and scientific responsibility.” They argue that scientists need to take a lesson from the history of cancer treatment abuse. Educating the public and doctors is not going to be enough. The information will not reach patients and doctors. Worse, desperate patients and unethical doctors will too often ignore the information. The onus of regulation, they argue, falls to the stem cell researchers in control of the stem cells themselves and other materials needed for treatment. This approach has great potential as many of the clinics doling out the questionable treatments are small and don’t generate the stem cells themselves. Successfully generating stem cells from embryonic cells or by transforming adult cells is tricky business. It’s a science for which the methodology is still painstakingly being worked out. Because of this, these smaller labs will rely on larger, legitimate labs for the materials.

“…stem cell scientists have a unique and important role to play in addressing the problem of stem cell tourism. Stem cell scientists should carefully examine all requests to provide cell lines and other materials, and share them only with responsible investigators or clinicians. They should require recipients of stem cells to sign material transfer agreements (MTAs) that describe how the cells may be used, and to provide documentation about their scientific or medical qualifications.”

Material transfer agreements are contracts governing the exchange of material between two parties. They will often have explicit guidelines as to how the material can and cannot be used. MTAs are par for the course when labs in the US exchange materials such as rare antibodies or cell lines. One would expect they should be the bare minimum requirement for handing over material that will be injected into patients.

I hadn’t actually heard of “stem cell tourism” until recently. But a quick online search turns up horror story after horror story, like the young boy in Moscow who’d developed tumors in his brain and spinal cord after being injected with stem cells. It turned out that the stem cells were poorly characterized – they not only contained cancerous cells but they were derived from two different donors.

We can only hope that stem cell researchers will take on the extra work of policing the unscrupulous recipients of their materials. A little more work on one end could make for less horror stories on the other.

[image credits: trendhunter and 455 PLA Hospital]
image 1: needle
image 2: PLA Hospital

An early headline of the AIDS epidemic (New York Times, 1981). The condition made patients vulnerable to Kaposi's sarcoma, a rare cancer.

On June 5th, 1981, the Morbidity and Mortality Weekly Report told the world about five rapidly deteriorating men who arrived at clinics in Los Angeles. They exhibited a disturbing array of symptoms – swollen lymph nodes, skin rashes, and failing immune systems. At the time of publication, two patients had already died. The scourge that we now know as AIDS had begun.

Three decades, volumes of research papers, and 30 million deaths later, we’ve learned much about this killer retrovirus, yet an actual cure remains an unrealized dream for the millions currently infected worldwide. In the ongoing conflict of host vs. pathogen, no adversary has proved more tenacious than HIV. Why?

For one, HIV has a high evolutionary potential – rapidly altering its gene sequences to build drug resistance and avoid detection from vaccines. In fact, there are at least 93 common mutations that make HIV drug-resistant. Once you nail down one subtype of HIV, another one invariably pops up. Also, HIV is a retrovirus than can integrate with the host’s genome. The virus is so inextricable because it literally becomes a part of the afflicted. Furthermore, it’s a master of hide-and-seek, evading the effects of drugs by hiding in lymph nodes during clinical latency. Lastly, the virus disarms the immune system so other opportunistic infections can overrun the defenseless body. Amid this diabolical synergy of viral advantages, this malicious microbe has been one-upping the world’s best scientists for thirty long years. And it’s a battle we’re currently losing. According to the latest UN reports, for every two patients who start taking anti-HIV drugs, there are five new infections.

The red ribbon has come to represent the solidarity of individuals and families living with HIV. Hopefully, in my lifetime, this powerful symbol will become a relic of the past when HIV is snuffed out of existence. Here's to hoping.

Nonetheless, HIV’s days on the winning side could be numbered. Multiple paths toward a cure and eradication are sprouting, and the headlines seem to imply that we’re closing in on a solution. So, what are those paths, and how will they help us get there?

When it comes to vanquishing a disease, there are two ways to skin a cat – treating the illness post-infection or preventing transmission. In the case of HIV, early and aggressive treatment can also be a highly effective prophylactic measure. According to early results from a landmark study led by Myron Cohen at UNC-Chapel Hill, rapid deployment of antiretrovirals (ARVs) – drugs that suppress HIV infection and slow the progression to AIDS – caused a 96% reduction in transmission. It just goes to show that early detection and treatment are key, and  sometimes the best defense is a good offense.

Dr. Myron Cohen of UNC shows we can significantly curb HIV using the tools we already have.

As promising as this approach seems, there are some limitations to consider. To see a real impact of early ART on a global scale and consistently catch HIV in the early stages, testing needs to be cheap, fast, ubiquitous, de-stigmatized, and occur on a regular basis. Sobering impracticality currently makes this exceedingly difficult, and even post-industrial nations have issues getting their people tested. There’s also the financial burden of HIV treatment. While a cost drop followed the introduction of generic drugs, there’s still a dire need for more cost-effective ARV regimens. If people don’t have access to the drugs, early ART is dead in the water.

It won’t be able to eradicate HIV on its own, but perhaps fine-tuning ART regimens will help give HIV a major wallop, provided that costs of testing and drugs are sufficiently mitigated. With greater access to ARVs and the falling cost of bioassays, there’s plenty reason to be hopeful on this front.

Optimized ART and promising new vaccines bring us closer toward AIDS abolition on the population level, but they mean nil to the ones who’ve been HIV positive for years. For these individuals, the outlook is much better than it was in the 1980s, but the quality of life can still be grim. Enter the “Berlin patient,” a man functionally cured of HIV with stem cells from the bone marrow of an immune donor. It was an amazing proof-of-concept, but the operation was not without difficulties. Aside from genetic compatibility snags, harvesting can be painful, discouraging donating and constricting the marrow pool.

Daniel Kraft presenting the Marrow Miner at TED in 2009.

Fortunately, on the side of marrow harvesting, the future is already looking brighter. A few years ago, Daniel Kraft, a Stanford physician-scientist and Singularity University track chair, invented the cleverly-coined Marrow Miner. Not only can it gather up to six times more adult stem cells than traditional methods, it’s far less invasive and can be performed in an outpatient setting. It probably won’t make bone marrow donation as popular as blood drives, but it could make it a hell of a lot easier and donor-friendly than it used to be. With more stem cells to choose from and a greater chance of genetic compatibility, there could be more “Berlin patients” waiting in the wings.

But why even risk compatibility snags when you can use your own genetically enhanced stem cells? Way back in 2009, Singularity Hub reported on one gene therapy trial that boosted CD4+ counts by infusing HIV patients’ blood cells with virus-impeding genes. The results were nothing to sneeze at, but the technique only replaced a fraction of the cells, leaving the remainder vulnerable to a viral rebound. The trick is giving the immune system a complete genetic remodeling – a challenge elegantly reviewed in a recent issue of Human Molecular Genetics.

It’s very easy to be enthralled by stem cell and gene therapies for HIV, but as we’ve seen, there are still many barriers to overcome. To put things into perspective, the FDA has yet to approve a single gene therapy for any disease, HIV or otherwise. Gene therapy and stem cell research appear to be creeping forward phlegmatically,  but the mountaintop is within the sights of scientists. They might  just need a pair of binoculars at this point.

The 30 year struggle against AIDS has been a grueling one. Glimmers of hope from the research community have faded into unfulfilled promises, turning the barrage of “breakthrough!” headlines into some sort of a cruel joke. However, as futurephiles, we at the Hub recognize the paramount role that long-term trends play in the shaping of humanity’s destiny. And so far, the trend has been a good one. HIV was once an imminent death sentence, but can now be held at bay for decades. On the horizon, platform biotechnologies are paving the way to new treatments. Even so, we should not underestimate the existential risk posed by emergent viruses, both man-made and naturally occurring. Futurist Nick Bostrom posed the question in his seminal paper:  ”What if AIDS was as contagious as the common cold?” While this may deviate from the pathogen’s optimal virulence, it is a prospect that sends chills down my spine. If we don’t keep these bugs in check, then these lofty notions of cybernetics, life-extension, and Singularity could become a fool’s dream, and the great achievements of humanity would blow away like dust in the wind. We can’t let that happen. We’ve come too far to let HIV or any other virus stand in our way. Microbes, you’ve been warned.

While the seer speaks of greener pastures on the other side, the microbial menace lurks 'neath the bridge, threatening those who dare to cross.

[Images Credits: 1. The New York Times 2.  Healthplanone.com (modified)3. UNC 4. TED 5. Wikimedia Commons, Microsoft Clip Art (modified) ]

[Sources: Morbidity and Mortality Weekly Report,  AVERT, The Lancet, New Scientist, Human Molecular Genetics, Science Insider]

Marius Wernig and colleagues at Stanford successfully transdifferentiated human skin cells into functional neurons–and they only needed 4 genes to do it.

As if gathering speed toward some uncertain but reachable destination, scientists have checked yet another item off the grand list of things to do before stem therapy is made reality. Marius Wernig’s group at Stanford University became the first to successfully convert mature human skin cells into functional neurons while avoiding the induced pluripotent stem cell stage. The accomplishment gives us reason for optimism, but also warns of the challenges that lie ahead.

The study comes on the heels of an already remarkable milestone recently achieved by the Wernig lab. In January 2010 the group successfully converted mature skin cells they’d gotten from mice to neurons. Incredibly, only three genes were needed for the conversion: Asc11, Brn2, and Mytl1. Affectionately known as “BAM,” these three genes were among a group of candidates they tested known to induce the differentiation of stem cells to neurons. They attached the BAM genes to virus vectors and infected the skin cells, and in a matter of days they had a dish full of neurons. It was the first time skin cells had been converted to neurons in a lab. The reprogramming process followed a protocol that is increasingly being used to convert skin cells to other cell types. Known as transdifferentiation, the procedure skips the heretofore common practice of first inducing the mature cell to stem cell pluripotency and goes straight to differentiation. The reprogramming victory in mice cells set the stage for an attempt with human cells.

Wernig’s group derived skin cells from aborted fetus tissue and the foreskins of newborns. Initially, the BAM combination appeared to have worked. But upon closer inspection, the cells in the dish that looked like neurons were incapable of the electrical communication that is the essence of neuronal function. Back to the drawing board, Wernig’s group pulled another gene off the neuronal differentiation list: another transcription factor called NeuroD. It did the trick. Four to five weeks after infection, they had a dish of neurons that expressed the proper proteins, were electrically active, and formed synapses with other neurons. When plated together the human neurons even formed synapses with mouse neurons. The triumphant conversion of human cells moves the field of regenerative medicine one step closer to patient-specific replacement of lost or dysfunctional neurons. The procedure could also enable scientists to study neurons from patients with neurological disorders such as Parkinson’s disease or Alzheimer’s.

Skipping the iPS stage, as we’ve mentioned before, has multiple advantages. For one, the transcription factors that drive reprogramming can also cause tumors. By deactivating the genes before the–in this case–skin cell is induced to full pluripotency, the risk of tumor generation is decreased. On top of that, the iPS-based procedure is labor-intensive and time consuming. Earlier this year a group at Scripps Research Institute converted mouse skin cells to beating heart cells. Avoiding the iPS stage cut the time from weeks to days. Further darkening the iPS approach, in a recent study mice rejected induced stem cells derived from the skin cells of a genetically identical mouse. It is thought that the rejection was caused by the transcription factors used to induce the iPS cells. Scientists and clinicians were left to wonder if indeed patient-specific iPS cells would one day be a viable treatment.

Not too long ago, this neuron was a skin cell.

There were differences between the two Wernig studies that highlights the higher complexity of human cells to mouse and may portend a challenging road to treatment. As already noted, coaxing the human skin cell into a neuron required an additional fourth gene. Another difference was reprogramming efficiency. Only 2 to 4 percent of the human skin cells became neurons. That’s about 8 percent of the efficiency they’d had while converting mouse cells. More troubling is the fact that almost all of the nascent human neurons communicated with the sole neurotransmitter glutamate. In the brain alone there are over 100 different neurotransmitters that mediate the innumerable subtleties of neuronal function. Scientists will be severely limited in the diseases they are able to study or treat until they find ways to produce neurons that produce the neurotransmitters gone awry in those diseases, such as dopamine in Parkinson’s disease. With these snags in mind, Wernig’s group is currently focusing their efforts on optimizing their protocol to produce more numerous and diverse neurons.

More often than not in science we overestimate progress in the shortterm but under-estimate progress in the longterm. It’s a rule of thumb in the lab that however long you think it will take to finish something–triple that. But stem cell researchers seem to be ignoring the rule and knocking down their objectives as fast as we science writers can describe them. It wasn’t very long ago at all that the first mature cells were successfully induced to pluripotent stem cells. But in the five years since that demonstration was carried out in mice, the iPS field has already been succeeded by the field of transdifferentiation which is now charging forward with a torrent of its own. In just the past year researchers for the first time transdifferentiated skin cells into heart, blood, and liver cells. As my training was in neuroscience, I’m particularly excited about the latest entry to the transdifferentiation club. But the field is and will continue to be exciting to watch regardless, and I can hardly wait to see what they come up with next.

[image credits: Stanford University and Nature]
image 1: Wernig
image 2: Nature

Scientists were finally able to grow sperm in the lab–from mice. It still remains to be shown if the same procedure can be used for humans.

In an amazing technical feat researchers in Japan have accomplished something that has stymied the field for the past half century: they successfully grew sperm in the lab. They then used the sperm to impregnate female mice and produce a healthy litter. The breakthrough holds promise for millions of men worldwide with infertility.

Published recently in Nature, the work was pioneered by Takehiko Ogawa and colleagues at Yokohama City University. The procedure involves taking biopsies of mouse testes, breaking them up into 1 to 3 mm pieces, placing them on agarose that has been partially soaked with a special medium, and letting them be for two months. If all goes according to plan, the chemicals in the medium would induce the gonadal stem cells to differentiate into mature sperm. Getting the ingredients of that medium right has been the major confound since efforts to produce sperm in the lab began in the 1960s.

To make their lives easier they used mice genetically modified with green fluorescence protein (GFP) that would only become activated in cells that had differentiated into viable sperm. The researchers could then just look through the microscope and all of the stem cells that had successfully differentiated to sperm would glow green.

Imagine, after years of frustration, peering into the microscope and seeing a lovely field of glowing green. But Ogawa and his crew didn’t pop the champagne just yet. The ultimate proof was then to see if their homegrown sperm was healthy and functional–could they be used to successfully fertilize an egg and produce normal, healthy offspring. Using two different methods they fertilized 23 and 35 oocytes, respectively. The dams gave birth to 7 and 5 live offspring who survived to adulthood and were able to produce offspring of their own.

Now it’s time to break out the champagne.

Sperm is often stored frozen in sperm banks for future use. To simulate this scenario Ogawa’s team cryopreserved the sperm in liquid nitrogen for 4 to 25 days. When the cells were thawed and cultured, expression of the GFP marker confirmed that they resumed full spermatogenesis in culture. They have yet to demonstrate that the freeze-thaw cycle leaves their cultured sperm intact well enough to produce healthy offspring that are in turn able to produce healthy offspring. It remains possible that freezing and thawing the cells left some as yet undetected structural damage, for example, or caused some epigenetic changes–changes in the molecules bound to genetic material that affects gene expression. Nevertheless, their demonstration is already an amazing accomplishment.

After 50 years of effort researchers have finally discovered a way to grow sperm in the lab. Swapping out a commonly-used culture ingredient may be the key.

Given the increasing number of successfully grown tissues and stem cell acrobatics flipping one type of cell to another, we may be getting the impression that simply growing sperm in a dish isn’t all that groundbreaking. You half expect those rambunctious miniature tadpoles to will themselves alive on their own. But growing sperm–a gamete–is much more complicated than growing somatic—rest of the body–cells. It is a sequential, multistep process involving a complex list of players named primordial germ cell, spermatogonium, primary spermatocyte, secondary spermatocyte, spermatid and mature sperm. Each of these stages requires an equally complex battery of signals provided by the non-germ cells that surround them. The whole process of going from stem to sperm cell takes over 60 days in humans; in mice (and most other mammals) it takes over a month. Successfully commanding a month long differentiation is a daunting challenge. We’d been trying since the 1960s but, until Ogawa’s study, we’d failed every time.

Through much trial and error, the researchers happened upon a key modification to their protocol that seemed to make all the difference. When trying to grow sperm in a dish a researcher would typically use fetal bovine serum (FBS), serum from the blood of newborn calves. FBS is a widely-used supplement in mammalian tissue cultures. Ogawa’s group had had some success with FBS in the past, but they decided to try replacing their FBS with what’s called knockout serum replacement (Ko-SR). This was a strange move, as Ko-SR is essentially FBS with most of the ingredients that promote the differentiation of cells removed. It’s typically used by stem cell researchers who want their stem cells to remain in an undifferentiated state. Surprisingly, and to the delight of Ogawa and colleagues, the Ko-SR had just the opposite effect: it promoted the differentiation of the sperm stem cells into mature sperm. It’s still unclear why the Ko-SR worked, but Ogawa suspects it’s due to one of the differentiation-inducing ingredients that still remains, called parvalbumin. If this turns out to be true, not only would the study give us a new tool to treat infertility, it will teach us something new about the basic biology of sperm maturation.

The team’s 12 newborn mice mark the triumph of a half a century’s effort. When you’re dealing with biological complexity slow and incremental is not only the pace of progress, it’s safer. It would be a tragedy if we were to give a man who had already conquered cancer the hope of having children, only to hand him the devastation of an unhealthy child. Taking genes into our own hands is risky business (let’s not forget that Dolly had progressive lung disease) and it remains to be seen whether or not the strategy can be used to make human sperm and to make human beings. Nevertheless, the team’s 12 newborn mice are a testament to power of relentless tinkering. And as they continue to tinker I don’t expect we will have to wait another sixty years to hear their good news.

[image credit: Rama and pdimages.com/web9 via wikicommons]

image 1: wikicommons_mouse

image 2: wikicommons_sperm

Race horse medicine affects people, changing an invasive surgery to a simple injection.

In a very unusual breakthrough, a stem cell treatment for racehorses is ready to be tried… on you. British scientists pioneered a technique in horses where an individuals’ own stem cells are grown outside the body, then injected into the damaged tendon.  There will be a clinical trial in the UK in which 24 human patients will undergo this radical new stem cell treatment for similar tendon injuries. We’ll tell you about the proven benefits in racehorses so you’ll understand the possible benefits in people. The test subjects who join the clinical trial will be in the unique position of enjoying a medical procedure that is years behind the veterinary equivalent.  If human beings have the same barely believable 80% recovery rate, this will be a leap forward for sports medicine.The transition from ponies to people began  in 2005.  After successful early treatments on horses, veterinarian Roger Smith published “Harnessing the stem cell for the treatment of tendon injuries: heralding a new dawn?” in the Journal of British Sports Medicine, which is a human medical journal.  Roger Smith, a professor at the British Royal Veterinary College, works with VetCell Bioscience Ltd., a British company that specializes in equine tendon injuries.  Smith explained in his paper, “it is hoped that our experience with horses will pave the way for this technology to be used successfully in human tendon and ligament injuries.” After years of extensive tests (on horses) they’re ready to move their treatment on people.  You can visit the VetCell website and sign up to be one of the 24 patients in the clinical trial that’s happening this year through their sister company, MedCell.

The clinical trial will treat achilles tendinitis (they’re British, they spell it with an “i”) without surgery. For treatment, bone marrow stem cells are collected from the horse, er, person, then coaxed into becoming tendon cells.  The lab grown tendon cells are injected into the site of injury.  Injecting a cure without major surgery is a big freakin’ deal because, in humans, surgery produces “Moderate to severe pain … in 20% to 30% of patients … In addition, a wound infection can occur and the infection is very difficult to treat in this location,” according to the American Academy of Orthopaedic Surgeons.  (You can also see the above surgery image in full gore mode.) VetCell states that in the “athletic horse” tendon stem cell therapy leads to about 80% recover rates, compared to about 40% using conventional surgery, as well as having very low re-injury rates after treatment.

The process of tendon repair in the horse, from VetStem's website

VetCell’s transition into human medicine shows that innovation can come from unexpected sources. “The move from clinical veterinary to human medicine is inspiring and unusual; we normally see the translation happening the other way around.” Said sports medicine professor Nicola Maffulli, of The London Independent Hospital. (His quote’s gone a bit viral, showing up in 347 websites.) In the past,  SingularityHub has published the sad fact that animals are often getting access to innovative medical treatments before humans.  Perhaps VetCell’s bold move could pave the way for other animal bio-tech treatments to smoothly transition to humans.

The reason animals can get commercial drugs and treatments faster than people in the US and other Western countries is simple: there is enormous oversight in human medical research.  Veterinary research is comparably simple. According to the FDA, bringing a new drug to market for humans requires pre-clinical laboratory tests, animal tests, and human clinical trials.  Each one of those steps costs money, lots and lots of it. Approval for veterinary drugs is simpler, requiring a single study that proves the drug is safe and effective. Because of regulatory difference, progress on animal medical research can move very quickly compared to human research.

A gap between availability of human and animal bio-tech isn’t necessarily bad.  A growing company can find important revenue through veterinary products while developing human medicine. The Intralytix company in Maryland, USA, has two animal products that are already completed and licensed out and three human products are still under development.  Intralytix is researching phage therapy, which delivers bacteria-slaughtering viruses to infections.  While they work on human medicine, they’re making food and food animals safer for humans.

The most interesting aspect of this stem cell treatment is that it has been thoroughly investigated on animals that live as practicing athletes, putting incredible strain on their bodies.  This is probably an improvement on lab animal only testing.  In the meantime, if you’ve got a banged up achilles tendon, you can go sign up for VetCell’s clinical trial.  When you go in for your injection, be comforted knowing the treatment was developed for horses worth more than your house.

[Image credit: Ruptured tendon surgery www.podiatrytoday.com; race horse, Jeff Kubina on Flickr; hypodermic needle, Armin Kübelbeck, wikimedia commons.  Info graphic from vetcell.com]
[sources: Smith and Webbon B.J.Sports Medicine, 2005, VetCell, MedCell]

Newborn Umut Talha was selected from 12 embryos to serve as a stem cell donor for his siblings.

Umut Talha’s name means “our hope” in Turkish, and his birth brought some much needed good fortune into the lives of his siblings. The infant, born January 26th of this year, is France’s first reported case of a child being conceived with in vitro fertilization and genetic screening to ensure it could serve as a viable stem cell donor. Umut’s older two siblings suffer from beta-thalassemia, an inheritable blood disorder that requires its victims to undergo regular blood transfusions. Using preimplantation genetic diagnosis, doctors at Antoine Beclere Hospital were able to select Umut from one of twelve fertilized embryos such that he would not have beta-thalassemia and so his umbilical cord blood might treat one or more of his siblings. His sister, aged two, is set to receive cells from his cord blood in the next few months. You can meet Umut and his family in the video below. While his birth is undoubtedly good news for he and his siblings, his arrival has raised more questions about the ethics of genetic selection among embryos. Is Umut simply a well planned addition to a needy family, or is he a sign of more nefarious designer babies to come?

Doctors at Antoine Beclere have named Umut a ‘double-hope’ baby because his conception was designed to grant both him, and another child a healthy life. In the French press, ‘medical baby’ is the term most used, with ‘savior sibling’ popular in English. The concept of genetically screening embryos to guarantee donor status isn’t new – it first found success in the US at the turn of this century. Yet Umut Talha arrives at a time when France is reopening debate on bioethical questions like the ones raised by his birth. After all, if you can screen your embryos to select the one that is the best donor for your other children, why shouldn’t you be allowed to screen for other genetic traits?

Watch from 0:52 to 3:07 in the following video to see clips of Umut Talha with his family, and the press conferences surrounding his birth. The discussion that follows it probably isn’t worth your time.

News of Umut’s conception has engendered the expected reactions from various parts of the political spectrum. Catholic bishops in France have condemned the action, for instance. However, bioethics surrounding this use of preimplantation genetic diagnosis and in vitro fertilization are hardly clear cut. After all, IVF is a (relatively) common conception technique used by thousands of couples every year, and PGD is primarily aimed at lowering instances of deadly or painful genetic disorders. Are we concerned that Umut was screened to ensure that he would have a life free of suffering from beta-thalassemia, that he was selected to help save someone’s life, or both?

In the end, it may not matter which concerns us most. Cases like Umut are just one example of how genetic testing could affect reproduction at all stages of pregnancy. We’ve seen how prenatal parental genetic screening can be used to reduce instances of recessive genetic disorders. Some pioneering couples are even getting their childrens’ entire genome sequenced many years after birth. There are benefits to these applications of genetic testing that can be as useful (in some cases) as PGD and IVF.

Where there are benefits humans are sure to explore. The only question is whether or not the innovators of embryonic genetic screening will have to do it clandestinely. If cases like Umut encourage France and other nations to permit some measured forms of genetic intervention to help save lives, then we’ll likely see these small seeds of the technology slowly blossom into more complete forms of genetic screening in the years ahead. If, instead, ethical concerns lead us to outlaw such practices then parents will pursue them in other countries. The medical tourism industry is always looking for more patients.

The bottomline is that parents will do almost anything to help their children. If that means having another child, or undergoing ethically complex procedures, they’ll do it. If it means breaking the law, or traveling to somewhere that has a different law, they’ll do that too. Umut Talha is certainly a ‘double hope’ for his family, but he’s also a promise to the world. Just like the other ‘savior siblings’ that have come before him, he heralds a day when parents everywhere will have the power to shape their children from their genetics up.

[screen capture and video credits: France24]
[source: Antoine Beclere Hospital, Frane24, AFP]

Dr. Sheng Ding pioneered a method by which skin cells are converted to heart cells without going through an induced pluripotent stem cell state.

It’s faster, more powerful, and user-friendly. No, I’m not talking about the latest generation tablet, I’m talking about the latest upgrade in stem cell research. The transformation of adult cells from one type to another is common enough. We’ve reported on researchers successfully transforming skin cells into heart, blood, and intestinal cells. This process typically involves converting the adult cell to a pluripotent, stem cell state, from which it can differentiate into one of the specialized forms. As if the cell one day realized that it never really wanted to grow up to be a skin cell, scientists could help revert it back to its infant—or, embryonic—state so it could have another go at life. A recent study by scientists at the Scripps Research Institute in La Jolla, California showcases a different method that bypasses this initial transformation to the stem cell state. Apparently you can teach an old dog new tricks.

Over the last decade scientists have had increasing success in converting skin cells and other types of cells into something different, including heart and blood cells. Efforts are underway across the world to improve the techniques and clinical viability of these cell conversions. The work by Dr. Sheng Ding and his colleagues at Scripps qualifies as a major improvement. The road ahead still requires much work, but it’s clear that each day mankind moves closer to producing cells of every type, custom made for your body.

Faster

The novelty of the new research coming out of Scripps is not going from skin cells to heart cells beating in a dish—that stuff’s becoming old hat—but that they accomplished it in just 11 days. It is normally a two step process that requires four to five weeks. It also requires a lot more work, owing to the step where the skin cells are converted to induced pluripotent stem cells (iPS). This is done by introducing four genes recently discovered to reprogram differentiated adult cells to embryonic stem cell-like pluripotency. The four genes encode transcription factors, proteins in the cell nucleus that regulate the expression of other genes. Typically the four genes are active for two to four weeks before the differentiated cell is converted to an iPS cell. Ding’s group modified this protocol by allowing the genes to work for as little as four days before deactivating them. The result are skin cells “pushed” in the direction of the induced stem cell state without actually becoming iPS cells. Turns out that’s enough, which, aside from saving time, reveals something new about stem cell biology. The current work was performed using skin cells from mice and it remains to be seen if the shortcut can be applied to human skin cells. Nevertheless, to render the iPS cell stage unnecessary is a major paradigm change for the field and it will be interesting to see if the new paradigm bolsters progress in the near future.

You can see the beating cells in a video below from newsy.com’s coverage of the study:

More Powerful

In addition to being faster, Ding’s protocol boosts efficiency. The old protocol yields an estimated maximum of approximately 0.2 heart cells for every skin cell plated. Skipping the iPS cell stage yields a whopping 1.2 heart cells per skin cell. In the paper the team speculates that the increased efficiency is due to the generation of mitotically active cells which are able to divide and multiply. Resembling heart precursor cells, they speculate further that “these intermediate cells, if successfully isolated and stabilized in culture, could become an expandable and renewable source for not just cardiomyocytes, but many other terminally differentiated cardiovascular cells as well.” In the paper they extend this thought, suggesting that the principle of a versatile intermediate might be important, not only for creating the numerous types of cells that go into making a heart, but for stem cell applications in all tissues.

Scientists at the Scripps Research Institute needed just eleven days to convert skin cells in beating heart cells.

User Friendly

The four genes that researchers use to produce the iPS cells is risky because these same genes can turn cells into tumors. Inactivating them after only a few days instead of a couple weeks reduces this risk. And, like any self-respecting technology, an upgrade is in the making. Because they can turn cells cancerous, stem cell researchers have been searching for a way to reprogram differentiated cells into iPS cells without using the four genes altogether. Demonstrating that the genes are only needed for a few days instead of weeks simplifies the problem and makes the genes easier to replace.

To be sure, stem cell research has a lot of ground to cover before it becomes an effective treatment for disease. For example, the current study was done in mice and it remains to be seen whether or not the shortened protocol produces the same results in human cells. I find it impressive, however, that the four genes widely used by researchers to convert fully-differentiated, adult cells into embryonic-like, pluripotent stem cells were discovered less than five years ago. Since then iPS cells have been gotten by converting other cells besides skin, including cells from the stomach and liver. The current study was the first that we are aware of to bypass the iPS cell stage for differentiation to heart cells, but this shortcut has already been taken for differentiation into blood cells. It is exciting to note that human cells were used in that study.

But in case you hadn’t heard, stem cells have already been used in tissue replacement therapies. We’ve previously reported on tracheal transplants of two women. This involved a donor trachea (from a cadaver) that was coated with a layer of the patients’ stem cells which fostered regrowth of the trachea. Because the new layer of cells originated from the patient the risk of an immune response against the new trachea was minimized.

From my vantage point, it seems that stem cell therapies are inevitable. I also believe that the day is long in coming. Unfortunately it seems that many people have been set up to hope for miracles after the hyperbolic political battles over stem cell research in the past. But therapies rarely come from sudden miracles. Instead it is the incremental advances and shifts in paradigm, such as that achieved by Ding and his colleagues, that will bring us the stem cell therapies we are hoping for.

[image credit: The Scripps Research Institute]

[video credits: newsy.com]

Stem cells injected into the brain could be the key to healing stroke victims.

There are few medical calamities that terrify as many people as a stroke. Of those that survive the sudden blocks or ruptures in their brain, nearly half suffer permanent damage that will never be repaired. Researchers in Scotland could be changing that. The University of Glasgow’s Institute of Neuroscience and Psychology recently injected fetal stem cells into the brain of a stroke survivor 18 months after his near fatal injury. The man, who is in his 60s, is the first patient in a clinical trial to test the safety and feasibility of using stem cells to repair ischaemic stroke damage (which accounts for 80% of all strokes). According to the University of Glasgow, his injection is pioneering the use of stem cells for this condition, and the purveyor of these cells, ReNeuron, says it is the first UK company to get approval for a human stem cell clinical trial in the country. While it will be months before we are likely to know if the treatment has helped heal the damage in this man’s brain, the possibility of success is yet another sign that stem cells are the most promising technology of the early 21st Century.

Look through the hospital beds in the UK and you’ll find that nearly one in four of the people in long-term care are there because they suffered a stroke. There are 150,000 stroke victims in the UK and 700,000 in the US each year. Because strokes often leave patients alive but critically impaired they are responsible for billions in healthcare costs. That price tag is only going to increase as the global population continues to age. Finding the right therapy will be critically important in the years ahead.

Stem cells, then, provide a unique opportunity to improve the lives of millions while saving billions, which is the reason this Pilot Investigation of Stem Cells in Stroke (PISCES) was begun. ReNeuron’s therapy, ReN001, is derived from the cells of a 12 week old fetus collected in the US (the cells are sometimes designated as CTX). At that phase of development the cells are already differentiating into nerve lineages. It’s hoped that the stem cells, injected into the putamen, will release chemicals that stimulate the growth of new neurons and blood vessels. Animal models have already shown how similar injections can reduce inflammation and heal scar tissue associated with ischaemic stroke, as well as promote the growth of new vascular tissue.

There is a lot riding on this first unnamed male patient. While the University of Glasgow and ReNeuron plan on having 11 more clinical trial participants (all between 60 and 85, and all 6 to 24 months after stroke), they have yet to be completely approved. Safety monitoring agencies in the UK will need to review the first patient’s condition in December, and only after that will the others be enrolled and given injections. Varying amounts of CTX will be used. The first patient received around 2 million cells, while subsequent injections in other subjects will increase to 5M, 10M, and 20M. Patients will be monitored for 2 years after injection, with follow up examinations continuing into the long term. Because the fetal stem cells are already differentiated into nerve lineages their risk for producing tumors and cancer is deemed to be less.

This study (which has a registered clinical trial number in the US) is really only aimed at determining safety and feasibility. As such, doctors in Glasgow and representatives at ReNeuron aren’t overselling the fetal stem cell therapy at this point. Still, there’s a reasonable expectation that patients could heal some level of brain damage, and possibly regain some lost motor skills and functions. The real dream would be for stem cell therapies to completely reverse the changes caused by the stroke. That level of healing is far from expected in this clinical trial, if it is even possible at all.

Like other fetal and embryonic stem cell projects, ReN001 has the potential to heal many people using the same line of cells. The stem cell injections are almost like drug doses. Unlike many other projects that use the patient’s own stem cells (autologous transplants), here ReNeuron provides the cells for each patient. We’ve seen similar work in the US with Geron’s spinal cord injury trials, but in general US stem cell research (outside of California) seems to be lagging behind in this field. China, meanwhile, has been going on a trial and error rampage for the last few years, injecting stem cells into every part of the body. Chances are that they’ve treated a stroke victim at some point with some kind of stem cells, but without the rigorous methodology of this UK study. Hopefully PISCES, which has such an enormous potential to heal patients, will not only lead to success in these UK trials, but encourage similar work to accelerate in the rest of the world. There are a lot of grandchildren out there who’d like to be able to play with their grandparents. Strokes can rob us of those experiences, but stem cells could bring them back.

[image credit:Guardian]
[sources: Guardian, ReNeuron Press Release, University of Glaskow Press Release]

Gene therapy has treated a man's genetic blood disease. Others, like sickle cell anemia shown here, could be next.

Gene therapy is making a difference in the lives of patients. A phase I/II clinical study run by researchers at Harvard Medical School and the University of Paris has added a new gene into a man’s cells and freed him from a lifetime of blood transfusions. The patient has beta-thalassaemia, a kind of genetically inherited blood disease that keeps his body from producing the right hemoglobin chains for his red blood cells. Like many with beta-thalassaemia, the man has been dependent on blood transfusions since childhood. After his experimental gene therapy he has not needed a transfusion for 21 months! The new genetic material was added to his body’s own bone marrow stem cells in an autologous transfusion via bluebird bio‘s experimental new LentiGlobin therapy. The study was recently published in the journal Nature. Though these results are very preliminary they speak to a wide range of new treatments that will be made possible through gene therapy.

According to bluebird bio, 60,000 children are diagnosed each year with beta-thalassaemia. About half of those kids end up needing a lifetime of blood transfusions. Bone marrow transplants can help treat the disease but about 75% of patients won’t be able to find a compatible donor. This is just one of several types of haemoglobinopathies that can have troubling effects on those who inherit the wrong genes – sickle cell anemia is a better known example. It’s estimated that around 7% of the world’s population are carriers for these types of illnesses. Gene therapy provides a promising solution. Take the patient’s own bone marrow, isolate stem cells, change the genes in those cells using a lentivirus, and reinsert them into the patient. The altered stem cells will be accepted by the patient and propagate, giving the patient a correct way to produce the hemoglobin he or she needs. It’s a technologically brilliant solution.

In the case of beta-thalassaemia, there’s still a lot of work to be done. This preliminary phase I/II study showed that the procedure was safe and had some positive effects. 33 months after receiving the transfusion, the male patient mentioned above had gone 21 months without need of transfusion. (Clearly there was a warm up time during which the altered cells had to propagate before being effective).

Yet there was another patient (a woman) in the study who received the same therapy and did not benefit. The authors of the study explain that her transplant cells were compromised during the process. Back up procedures were unable to produce a steady population of genetically modified cells in her body. She had no adverse results, but her condition obviously did not improve.

It’s also unclear if the man who did see positive benefits is an ideal example of success. Roughly one third of his blood has the hemoglobin chains produced by the genetically modified cells. That seems to be enough to relieve him of needing transfusions, but this is probably not the optimal level of transformed globin production. Furthermore, there was some concern about the over-expression of a HMGA2 gene that could have been responsible for the some of the LentiGlobin therapy’s success. That’s a concern because elevated HMGA2 levels have been associated with cancers. bluebird bio’s press release, however, says that these HMGA2 levels have been declining in the patient and continue to do so.

At this stage, there’s no guarantee that LentiGlobin itself will be a viable solution for beta-thalassaemia. The study was very small, and I don’t really know if we should call it 50% successful or 100% successful if performed correctly… we’re going to need a lot more tests before we know if this is a successful gene therapy.

Yet the promise of gene therapy continues to grow. We’ve seen other trials ramping up recently, and bluebird bio itself has plans for therapies for Sickle Cell (perhaps through the LentiGlobin platform) and for a neurological disorder. There are a host of genetically inheritable diseases which could be treated with the right forms of autologous transplants and gene modifications. Of course, there are many conditions which one wouldn’t normally consider to be a disease that might also be ‘cured’ through the applications of gene therapies. We may be able to extend life expectancy, grant increased muscle mass, or even raise intelligence through these sorts of manipulations. While gene therapies begin with aiding with tragic illnesses, their ultimate potential could lie in reshaping the human body to match our desires.

[image credit: adultstemcellawareness]
[source: bluebird bio Press Release (PDF), Cavazzana-Calvo et al 2010 Nature]

A recent court ruling could end public funding for embryonic stem cell research in the US.

Stem cell research in the United States was dealt a recent blow when a US district judge ruled that public funding for embryonic stem cell research violated federal law. Judge Royce Lamberth found that congressional statutes, which prohibited federal funding going to any research where embryos were destroyed, applied to research on embryo-derived stem cell lines. This is a surprise, as President Obama’s executive order on stem cells was thought to be a definitive opening of the field in the US. Now, stem cell scientists must scramble to determine which, if any, of their research must not use public funds in order to comply with the new ruling. Embryonic stem cells may be key to finding new treatments for painful and life threatening diseases and this decision may slow such research in the United States for years to come.

A single embryo’s stem cells can be replicated many times over, allowing each stem cell to generate a ‘line’ of cells that many different scientists can use in their research. For a time it was believed that research on pre-existing embryonic stem cell lines did not violate federal prohibitions on research that destroys embryos. As such, George W. Bush signed an executive order limiting public funding for exploration of embryonic stem cells to just 21 lines. Obama expanded that to 75 lines and opened up the possibility of new lines being created through parental consent. Both of these decisions are now in question.

The court case in question is a lawsuit filed by several parties against the federal government to stop public funding of embryonic stem cells. Those parties were led by the Alliance Defense Fund (a conservative Christian legal group) but included an adoption agency, embryos (on their behalf), and two scientists. Earlier court rulings required plaintiffs to have a clear material affect by the executive order, so all but the two scientists were stripped from the case. These two researchers, Dr. James Sherley of Boston Biomedical Research Institute and Dr. Theresa Deisher of AVM Biotechnology, argued that the expansion of public funding for embryonic stem cells would increase competition and limit the funding for their adult stem cell research. Judge Lamberth agreed that there was a clear material consequence for public funding of embryonic stem cells on the two scientists, and further decided that the embryonic stem cell lines were still research that was based on the destruction of embryos. As such, he has blocked all further public funding of embryonic stem cells.

Why is this a problem? Embryonic stem cell research may hold the promise to all sorts of amazing treatments. They could repair spinal injury, grow new retinas, or treat diseases like Parkinson’s and Alzheimer’s. Many felt that the restrictions put in place by George Bush in 2001 horribly damaged the state of US research in the field. Now, public funding could be even more limited in scope.

Yes, private funding for embryonic stem cells will still be there, but we still need public funding. Greater diversity of financing creates greater diversity in research. Public funds would also help research in to diseases whose cures would not be profitable.

You could also argue that research into adult stem cells has had proven successes and that we don’t need embryonic stem cell lines. It is unlikely, however, that adult stem cells will ever be able to replace embryonic stem cells in all forms of research. Just as we need a diversity in funding, we need a diversity in approaches. We need to explore both embryonic and adult stem cells to have the best chances of finding new treatments.

Judge Lamberth’s ruling may be detrimental to US scientific development, but it may also be a correct interpretation of federal law. Those interested in public funding for embryonic stem cell research may eventually need to champion new legislation to explicitly permit such experiments (legislatures may be working on such a bill now). Until that occurs we may be mired in executive orders, court battles, and public debates long after other nations have developed the science more fully. China, for example, has been advancing undisturbed in the field for years. Until the US makes up its mind about embryonic stem cells we are likely to continue falling further behind the global scientific community.

[image credit: Wikicommons (modified)]
[source: AP, NY Times]

Can plant stem cells make you look years younger? I doubt it.

The claims surrounding stem cell treatments are starting to get downright ridiculous. Case in point: so called stem cell technologies used in beauty products and herbal remedies. Various cosmetics lines have begun to market their goods as containing the benefit from plant stem cells. Many claim that these plant based stem cells will stimulate human stem cell growth and promote healthier younger looking skin. I don’t know about you, but my bullsh*t detector just exploded. Plant stem cells as age-defying makeup creams? Seriously? Have we reached the point where we’re so enraptured with the possibility of human stem cell technologies that we’ll buy anything with ‘stem cells’ in the product name? Look below for some pics, video, and plenty discussion about the outrageous hype surrounding these ‘miracle products.’

Click to see a typical claim about the 'scientific' basis for plant stem cell cosmetics.

Human stem cell treatments already have socio-political turmoil surrounding them, we don’t really need more. Along with the original debate surrounding the use of embryonic stem cells, there’s controversy surrounding access to experimental new stem cell therapies. Every day there’s a publication containing promising new information on stem cell treatments for illnesses and injuries. Unsurprisingly the promise surrounding the blossoming science has fueled demand for such treatments to be available as soon as possible. Some can’t wait for regulatory agencies (like the FDA) to approve these technologies so they pursue them in unregulated locations around the globe via medical tourism. That is a trend that many in the field of stem cell research oppose. It’s a mess.

And now we have to add cosmetics into the fray. Companies like Eclos claim that using plant stem cell extracts will stimulate the growth of human skin stem cells, leading to a reduction in wrinkle depth, and healthier appearance. In short, they are selling you stem cells (plant stem cells, mind you!) as a cure for aging. Eclos is far from alone, there are many more doing much the same: Lancome/Nordstrom, Lather, Dr. Brandt Skincare,Emerge StemCell Skincare…the list goes on and on.

What’s the scientific basis for these claims? Well, I think this reference on the Lather website is representative. Small ‘clinical trials’ are used to study the appearance of middle aged women after a few weeks of using the plant stem cell product. The results are always absurdly successful. 100% positive results for Lather. Hallelujah, it’s a miracle! Check out the following video ad from Eclos if you want some more of the same:

I tried, I really did, to find some reputable scientific publications that either proved or alluded to the positive effects of plant stem cells on human skin. I found one possibility, published in the Journal SOFW, which claims that stem cells from the Uttwiler Spautlauber apple (the same breed used in many of the products linked to above) caused an increase in human cell proliferation by 80%. I believe this is the same paper (based on images, etc) that is obliquely referenced by several companies listed above. There are many problems with this article. First, the authors seem to be from a company that promotes and sells various cosmetic products that use the cells under review. Second, I can’t find any indication that SOFW is a reputable peer-reviewed scientific journal (though I will fully retract this concern if someone can provide evidence to the contrary). Lastly, the paper makes claims that these apple stem cells protect and preserve human cells by avoiding senescence (death) and promoting replication. Even if they could do these things, rapid replication and avoidance of cell death reads like a recipe for cancer. Not exactly something we want from our skincare products. Overall, I remain far from convinced of this paper’s scientific accuracy or general veracity…and this was the most professional looking evidence the plant stem cell industry seems ready to offer. In fact, I think it might be the entire ‘scientific basis’ for the whole apple stem cell craze!

Look, stem cells are a real and viable technology. There’s also interesting work being done with plant stem cells that might, one day, have some impact on human stem cell research. But these “stem cell” cosmetics…I can’t make an outright claim that they are fraudulent (egads, considering the legal issues, I don’t know if I would if I could) but I think even a little application of common sense paints them as suspect. It seems clear to me that the cosmetics industry is cashing in on the general hope and hype surrounding the medical use of human stem cells. I’m sure history is full of examples of this happening with every emerging technology – for instance, did you know they used x rays to treat acne?

The problem is that in this case the emerging technology has enough problems on its own. Medical professionals and scientific researchers are  struggling with keeping the public informed about the dangers and limitations of human stem cell technologies already on the market. Do I want to deny the possibility that stem cells might one day be used for cosmetic treatments? Not at all. But I sincerely doubt that any of the hype surrounding these plant stem cell cosmetic lines will pan out. Spend your money as you like, but I think these marketing ploys are part of the problem, not the solution.

[image credits: Eclos, Lather]
[video credit: Eclos]
[sources: SOFW, websites as linked in text]

Sickle cell anemia is a congenital blood disorder that affects all races, but is most common to persons with African ancestry, affecting about 72,000 in the US and millions worldwide. Red blood cells normally take the shape of a doughnut without its hole; in the blood of sickle cell patients, the cells assume an abnormal sickle shape. Sickle cells block small blood vessels and inhibit blood flow, which causes debilitating pain, damages organs and increases the risk of stroke. Many of the risks of sickle cell can be mediated through early diagnosis, dietary supplements, and drug treatment.  But even with modern treatment, life expectancy for sickle cell patients is 42 in males, 48 in females. Some severe cases are resistant to existent therapies and can cut life even shorter.

Because red blood cells are produced in bone marrow, some high-risk children qualify for marrow transplants from a suitable sibling donor. Like all organ transplants, the procedure carries the danger of immune rejection, and so requires immunosuppressant drugs in addition to radiation therapy to kill diseased marrow. Transplants have been traditionally restricted to children, whose organs are comparably stronger than adults who suffer from the disease. Transplants are rare – there have been about 200 in the past few decades – and are attempted only in children whose disorders are life-threatening.

But a new procedure developed by the National Institute of Health (NIH) and Johns Hopkins University has successfully transplanted marrow to adults, reversing the disorder in 9 out of 10 patients. The new treatment uses significantly less radiation (about one fourth) to kill the patient’s existent marrow, combined with the immunosuppressant drug Sirolimus to reduce the likelihood of transplant rejection. By allowing more of the patient’s own marrow to remain, recovery from the transplant is faster and healthier (patients could previously spend months in germ-free isolation while their immune systems recovered). Thirty months after the transplant, the nine patients with successful transplants are healthy and show no side effects.

Many adults with sickle cell anemia take the drug hydroxyurea to treat the disorder. Hydroxyurea works by stimulating the body to produce a form of hemoglobin normally only found during development in the womb. The production of this hemoglobin type helps to balance the proportion of healthy vs. sickle cells in the blood, and reduces the damage done to lungs, kidneys, and liver (not to mention the risk of stroke). But hydroxyurea doesn’t work for all adult patients, making the prospect of adult marrow transplant a much-needed form of alternative therapy.

Kelly Halloway, the first half-match donation recipient at the National Institute of Health

So far, most adult patients who have received marrow transplants have had “full match” donors – siblings with a fully compatible genetic makeup. The chances of a sibling being fully matched are only 25%. But new procedures are expanding the pool of potential donors to “half match” donors, which includes parents and improves the likelihood of a compatible sibling to 75%. That means more sources of transplant marrow, and a better shot at a successful reversal of the disease.

Future research will aim to expand marrow transplants beyond sickle cell patients. Several other congenital blood diseases could conceivably be treated with marrow transplants, including such debilitating disorders as beta-thalassemia. Researchers are currently exploring the emerging possibilities of adult marrow transplants, and will doubtless yield more amazing treatments in coming years.

[image credit: Salisbury Post]

Little Shaheer is alive thanks to cord blood from two donors.

Shaheer Imran from Islamabad was treated for a rare blood disease thanks to the cord blood donations of two strangers in India. The toddler had Familial HLH, a typically fatal disorder that is usually treated by stem cells from close family members. There were no acceptable donors in Shaheer’s family, however, so doctors at Sir Ganga Ram Hospital in New Delhi sought two donors from Reliance Cord Blood Bank in Mumbai. This was probably the first time that a double cord blood stem cell transplant has been made in India. Shaheer is now recovering well, and his case demonstrates the growing potential of banking an infant’s cord blood.

As we mentioned when discussing cord blood banking last year, umbilical stem cells have amazing healing potential. Not only that, but they are a guaranteed match to a child who may be otherwise unable to provide stem cells for autologous treatments in the near future. Shaheer’s case, however, demonstrates another benefit to cord blood banking – anonymous donations to other infants in need. Because Shaheer’s HLH had a genetic basis, he was unable to provide his own stem cells, and his family was not a match. The two separate donors from the Reliance Cord Blood Bank gave him an otherwise unobtainable chance at life. That’s a powerful gift. And due to the particulars of this situation (Shaheer is Pakistani and the donors were presumably Indian), there were even possible political benefits as discussed in the video from IBN Live below:

Stem cell treatments are still in their infancy, but Sir Ganga Ram Hospital had performed dozens of these therapies for HLH conditions similar to Shaheer’s. Typically, however, donations come from a close family member’s stem cells. Shaheer is an only child, however, and had no familial matches. According to Doctor India News, Shaheer is only one of ten or so children in India to receive an anonymous cord blood transplant. Not only did Ganga Ram doctors use an unrelated cord blood donor, they used two – another rarity.

Because HLH destroys the body’s own cells, doctors had to first put Shaheer through chemotherapy before the transplant which was performed on March 15th. According to India Today, it took three weeks for the new cord blood stem cells to start producing new white blood cells, and an additional week for platelets. This seems to be right on schedule as doctors are optimistic about Shaheer’s long term success. Typically 72% of those treated for HLH with stem cells live past early childhood (Ganga Ram officials via India Today).

Parents who save a child’s cord blood are really taking a shot in the dark. The chances that their child will actually need an autologous stem cell transplant are slim. The number of diseases treated in this way are relatively few, though new therapies (such as the one we discussed for Cerebral Palsy) are arriving every day. Shaheer, however, demonstrates that banking cord blood isn’t necessary just an insurance policy for the donor child – it can be a powerful tool to help save someone else’s life as well. While it’s still not clear if cord blood banking will make financial sense for many family’s, the medical potential is growing. News like this may fuel an increase in the number of parents who elect to bank cord blood. In the meantime, best of wishes to young Shaheer and his family, and kudos to the donors in Mumbai who made saving his life possible.

[image credit: Doctor India News]
[video credit: IBN Live]
[source: Doctor India News, India Today, The Hindu, Sir Ganga Ram Hospital]