Genetically modified T cells which attack HIV have been shown to be both effective and safe after more than a decade.

A clinical trial testing a gene therapy for HIV patients is now 11 years old. Recently, the researchers running the study published an examination of the patients after all this time. Of the study’s 43 patients, all were healthy, and 41 of them confirmed that their immune cells which received a genetically-altered boost were still performing as hoped more than a decade after the initial infusions.

Researchers first collected some of the patients’ T cells, the type of white blood cell that fights infections and tumors. They then added a retroviral vector to the cells that inserted its DNA into the cells’ own DNA. The important part of the new DNA would cause the T cells to recognize a protein found on HIV and target the virus for attack. The modified T cells were injected back into the patients between 1998 and 2002.

One of major concerns with gene therapies is the risk that the inserted DNA will cause cell replication errors and turn the cell cancerous. Years ago, in a different study, two out of nine young boys developed leukemia after undergoing gene therapy for X-linked severe combined immunodeficiency (“Bubble Boy disease”). But there is a key difference between that trial and the current one. The earlier trial involved genetic modification of blood stem cells. As none of the participants in the current study have developed cancer after 11 years, the researchers are concluding that the type of cell makes all the difference. “T cells appear to be a safe haven for gene modification,” Carl June, one of the lead researchers of the study said in a press release.

The study was co-led by Bruce Levine, head of the Clinical Cell and Vaccine Production Facility at Pennsylvania University’s Perelman School of Medicine. It was published earlier this month in Science Translational Medicine.

Eleven years of being both effective and safe is a gene therapy breakthrough. But as promising as the study is, there’s still room for improvement. Patient viral loads were not reduced to undetectable levels, something routinely achieved by drugs. This could be due to an inadequate dosage of T cells. But now that T cells have been shown to be gene friendly, a higher dose could be tried in the future. Also, they tested function of the modified T cells in lab dishes. But while there was no direct confirmation that the cells are performing effectively inside the body, the fact that all 43 patients are healthy seems to be pretty rigorous evidence.

The trial was led by University of Pennsylvania researchers Bruce Levine and Carl June.

So how is it possible that the modified T cells are still chugging along after 11 years? Human T cells can live for years, and they divide,  passing their genetic material on to their cellular progeny. In fact, the current level of gene function in the patients indicates that over half of the original modified T cells or their progeny should still be functional for 16 years following infusion.

Even though the modified T cells in the current study haven’t proved more effective than drugs, they may still yet as higher doses are tried. HIV can be effectively controlled with drugs but patients are often required to take multiple pills at specific times of the day for the rest of their lives. And the drugs often have unpleasant side-effects such as nausea, vomiting, or diarrhea. Even if HIV levels aren’t rendered undetectable, as they weren’t in the current study, just decreasing a patient’s dependency on drugs would be a major accomplishment.

The promising results a decade out isn’t just good news for HIV patients and clinicians alone. Gene therapies targeting other diseases could benefit from the protocol. Any malady that can be helped by setting the molecular sights of T cells on a target should be fair game. In fact, Levine and June are already reprogramming T cells to seek out and destroy leukemia tumors. In a paper published last October they reported how cancerous cells in three patients were wiped out in just three weeks. As in the HIV trial the T cells were modified to recognize and attack cells expressing a specific protein. CD19 is a protein found on leukemia cells but not on healthy ones.

It’s about time gene therapies began delivering on the promise that so many have hoped for. Researchers are busy trying to find out why gene therapies turn stem cells into tumors but behave so well in T cells. Answering that question could open the door to gene therapies in other cell types. The current study is the latest in a spurt of good news for gene therapies. Other trials have stopped bleeding in hemophilia patients, successfully treated Parkinson’s symptoms, and helped the blind to see. Let’s hope we’re entering an era in which successful gene therapy trials are becoming the norm rather than the exception.

[image credits: Scientific American and Philly.com]
images: Scientific American and Philly.com

Polymer scaffolds guide stem cells growth into customized sizes and shapes.

It may be hard to remember what it was like to lose a tooth as a child, but many adults get an unpleasant reminder as they age when their teeth begin to fall out (even those who don’t play hockey) and must consider dentures or dental implants. For years, researchers have investigated stem cells in an effort to grow teeth made for a person’s own cells. Toward this end, endodontics professor Dr. Peter Murray and colleagues from the College of Dental Medicine at Nova Southeastern University (NSU) have developed methods to control adult stem cell growth toward generating dental tissue and “real” replacement teeth.

The NSU researchers’ approach is to extract stem cells from oral tissue, such as inside a tooth itself, or from bone marrow. After being harvested, the cells are mounted to a polymer scaffold in the shape of the desired tooth. The polymer is the same material used in bioreabsorable sutures, so the scaffold eventually dissolves away. Teeth can be grown separately then inserted into a patient’s mouth or the stem cells can be grown within the mouth reaching a full-sized tooth within a few months.

So far, teeth have been regenerated in mice and monkeys, and clinical trials with humans are underway, but whether the technology can generate teeth that are nourished by the blood and have full sensations remains to be seen. Teeth present a unique challenge for researchers because the stem cells must be stimulated to grow the right balance of hard tissue, dentin and enamel, while producing the correct size and shape.

As Dr. Murray explains it, humans already have two sets of teeth, baby and adult sets, over the course of their lifetimes, so “All we are trying to do is copy nature and give the person the third option to re-grow their teeth.” Not only could this be important for replacing lost teeth, but it could become a standard treatment when extreme orthodontics is necessitated. And if the tooth is malformed or fails, it can be extracted and a new one put into place.

To date, the NSU researchers have received about $1.7 million in grants for their dental stem cell research.

Dr. Murray believes that if they can demonstrate control over tooth re-growth and prove that the technology is safe, these teeth will be the first to see widespread adoption in the US. He also reports that interest has been high from the public and even fellow dentists, as evidenced by the recent selling out of his “Regenerative Endodontic Procedures” presentation at the American Dental Association conference in Las Vegas.

You can check out a news piece about NSU’s research here.

Just as developments in embryonic stem cell research launched umbilical cord banks, the promise that dental stem cell therapy holds has led to the rise of tooth banks, such as BioEden, StemSave, and Store-A-Tooth (StemSave, for instance, charges $2,430 to store a child’s tooth for 20 years.) Stem cell therapies are being actively used to repair bone damage, facial bones, and even organs like a heart, but skeptics continue to scoff at the potential of stem cells, oft citing nightmare scenarios or runaway tissue growth. Furthermore, research progress is often clouded by the politics surrounding embryonic stem cell research.

But the one therapy that could silence the naysayers is tooth regeneration.

The statistics on tooth loss are a bit staggering: 7 out of 10 adults age 35 to 44 have lost at least one tooth and a quarter of those aged 65 or older (or about 20 million people) have lost all their permanent teeth. Additionally, side effects from medications can effect oral health, such as changing properties of the saliva that helps fight bacterial growth. And increased tooth loss leads to poor dietary habits even among dentists, according to a recent study, which leads to secondary health effects. Add to this high sugar diets contributing to the obesity epidemic and increasing cases of periodontal disease due to neglect and you can see that the market for tooth replacement is enormous and expected to grow.

Having a full set of functional teeth is increasingly important as an aging population seeks to maintain an active lifestyle. And the growth of social media has led to people’s faces being plastered all over Facebook, Twitter, and YouTube. So how your teeth look is more important than ever, especially with more people carrying high quality cameras built into their mobile devices.

Dentists are at the front line of the increased demand for perfect teeth. A 2009 nationwide survey by NSU revealed that 96% of the dentists polled expected stem cell regeneration to dominate the future of dentistry. Additionally, more than half predicted that the technology would be available within the next decade.

In mice, stem cells grew into a tooth (in green) that had similar properties to natural teeth.

Research into using stem cells to regrow new teeth has been around for at least 10 years. In 2002, Professor Paul Sharpe at the Dental Institute of King’s College in London received a $500,000 Wellcome Trust grant to translate tooth regrowth with stem cells in mice into regenerative dentistry for humans. A company was formed, Odontis, and in 2010 seemed ready to launch its BioTooth technology, but has since fallen off the radar and had its website shut down possibly suffering the same fate that led to Geron Corporation abandoning stem cell research last year. Researchers from Tokyo University in 2009 reported success with implantation of stem cell tooth germs in mice which grew into fully functional teeth within a few months. Scaffolds were also successfully used to regrow anatomically correct teeth in nine weeks by researchers at Colombia University Medical Center.

Although the promise of stem cell therapies remains to be realized, there’s little doubt that researchers at NSU and around the world will continue in their efforts to use stem cells for regenerative medicine.

Dr. Murray remains optimistic: “When dental stem cell therapies become routine it will be historic, and the most fantastic time to practice as a dentist.”

[Media: Sun Sentinel]

[Sources: ABC, BBC, DentalAegis, Ivanhoe, PopSci, Sun Sentinel]

A microchip with 1,500 light sensors sits beneath the retina and stimulates neurons which project to the brain's visual cortex.

The blind really are beginning to see again. After receiving retinal implants in a trial, two people in the UK and one in China – all blind – regained part of their vision. And more good news could be on the way as results from other participants comes to light. But the chip is a bright ray of hope for the estimated 1.5 million worldwide that have retinitis pigmentosa, if not for the 285 million visually impaired.

All of the trial participants were made blind by retinitis pigmentosa in which the light-sensitive rods and cones of the retina deteriorate. British participants Robin Millar and Chris James, whose retinas had not responded to light in over a decade, were able to see immediately after the chip was turned on. Seeing the first flashes of light, James told the BBC, was a “magic moment.” Before receiving the implant neither participant was capable of detecting any light at all. The chip now allows James to distinguish between curves and straight lines. And Millar’s magic moment came when he began detecting light coming in through the windows. Professor Robert MacLaren, of Oxford Eye Hospital who co-led the study with Tim Jackson of King’s College Hospital, said the regained vision was a first for a completely blind Brit.

China scores its own first with Tsang Wu Suet Yun. Like James and Millar, Mrs. Tsang had lost her sight to retinitis pigmetnosa. She had been legally blind for 15 years, barely able to detect light. After receiving the same implant as James and Millar, she was able to read letters projected onto a screen.

The following is 2010 footage of a Finnish man who had regained partial vision after receiving an implant from Retina.

The implants act as a replacement for the lost retinal cells by detecting light and then stimulating neurons which send the signal to the brain. Developed by the world leader in retinal implants, Retina Implant Ag, the devices are tiny microchips 5 mm on each side and a tenth of a mm thick, which are implanted just below the retina. The chip’s surface is covered by a microphotodiode array containing 1,500 light-sensitive units. The light intensity of each point is translated into electrical impulses used to stimulate the underlying neurons. The chip is powered by a wireless power unit connected via a cable that runs over the ear and then under the skin to reach the eye. Settings on the power unit can be adjusted to modify the light sensitivity of the array and maximize its effectiveness for individual patients.

The brain needs a period of time to learn how to interpret the "unnatural" signals sent from the chip.

The implant has been involved in retinal trials for six years now, and the current encouraging results could be just the beginning. Results from the first two trials were published in 2010 and prompted the expansion of the trial to sites outside of Germany, including the UK and China.

Being able to distinguish between straight and curved lines or detecting light through a window may not sound like much but, as Prof. MacLaren points out, just being able to enter a room and know where the doors and tables would be is incredibly useful to a blind person. The vibrant colors of the world, however, will remain hidden for the moment. As the implants only convey light contrast they only see in black-and-white. But one unexpected development that’s as much a benefit to Millar as it is a neuroscience curiosity, he’s dreaming in color for the first time in 25 years.

It’s hard to tell without a direct comparison, but Retina’s chip has the potential to out-see the Argus II implant that is already commercially available and helping the blind to see. The Argus II chip doesn’t receive light directly, but relays signals from a glasses-mounted camera. And the chip only has about 60 electrodes with which to stimulate optic nerves and transmit the signal to the brain. Retina’s 1,500 adjustable, light sensing/nerve stimulating units could potentially work so much better.

To reiterate, the current results are part of a clinical trial and the chip is not yet available as a treatment. Replacing dead or non-functional cells with new ones through stem cell therapies would be the ideal treatment. While these therapies have shown great promise recently, there’s no telling just when they’ll deliver on restoring full vision to the blind, if ever. But the results from the current trial are just getting underway. Hopefully it will be more of the same.

[image credits: Retina Implant Ag and Proceedings of The Royal Society]
[video credit: Channel 4 News via YouTube]
images: Retina Implant Ag, Royal Society
video: Retinal Implant Ag

By recovering well-preserved mammoth tissue, like 40,000 year old baby mammoth Lubya, scientists hope to clone the extinct beast and then birth one via an elephant.

South Korean and Russian scientists have agreed on a project right out of “Jurassic Park.” Maybe not as cool as resurrecting T. Rex, but bringing back a woolly mammoth is sure to attract paying customers. On March 13th, South Korean and Russian scientists agreed on a joint venture to do exactly that.

According to the agreement, the Russian team will collect biological samples and send them to the Korean team for processing. The Koreans hope to create healthy cell cultures from the tissue as a source for high-quality DNA. The mammoth genome was sequenced in 2008 so they have a quality check for the new samples. Once they have quality DNA, they’ll use somatic cell nuclear transfer – the same technique used to clone Dolly – to swap out the nucleus of an Indian elephant egg with a mammoth cell nucleus. The egg will then be implanted into an Indian elephant for a 22-month pregnancy.

Pretty straightforward, right? Of course not. But if all goes well we could find ourselves studying the extinct animal and learning more about it than we ever thought possible. Not to mention, if they allow it, people will come in droves to see the mythical creature with their own eyes. It would be an historical moment for genomics and recombinant DNA technologies, biology, and science as a whole, capturing the imagination of billions around the world.

The biggest challenge right now is to find tissue and isolate cells that have healthy DNA, undamaged from freezing or radiation produced from the ground. Siberia is an ideal place to search for mammoth tissue. They first emerged in the area 400,000 years ago and flourished up until very recently when they died out at the end of the last ice age about 10,000 years ago. The extent of their reign means that the Siberian tundra is stocked with mammoth remains that are relatively well preserved and thus offer hope that healthy tissue may yet be recovered. One source estimates upwards of 150 million mammoths may be frozen beneath the Siberian tundra. Rising global temperatures are said to be thawing Siberia’s permafrost and making it easier to get to the mammoths. And even though the mammoths were mostly dead by about 10,000 years ago due to a rapidly changing climate and human hunters, a small group still persisted on Wrangel Island in northeastern Siberia as recently as 4,700 years ago. Recovering tissue so recently preserved would increase the researchers’ chances for success.

Disgraced Korean scientist Hwang Woo-suk successfully cloned eight coyotes by implanting their DNA into the egg of a domestic dog

But cloning still remains a crapshoot even under ideal conditions. Of the 227 eggs that underwent somatic cell nuclear transfer in Dolly’s cloning, only 29 viable embryos were created. And that procedure involved swapping nuclei from cells of the same species. Interspecies nuclear transfer, what cloning the mammoth requires, is even trickier. As the mammoth’s closest living relative, an Indian elephant egg and female are the best choices to receive the mammoth DNA and then carry the pregnancy to term. But whether or not it will work is anybody’s guess.

It may come as a surprise to some to learn that the Korean team at the Sooam Biotech Research Foundation in Seoul is headed by none other than disgraced stem cell researcher Hwang Woo-suk. Hwang became famous overnight when, in 2005, he claimed to have created human stem cells from a cloned embryo. He was later found to have forced the women in his lab to donate their own eggs, and then later was found to have falsified much of the data anyway. But it was Hwang’s ability to perform interspecies nuclear transfer that caught the attention of Prof. Vasily Vasilyev, the First Vice-Rector of the North-Eastern Federal University in Russia. As described in a press release, Vasilyev became convinced that Hwang’s lab was the right one for the job after seeing a news report. The work has been verified by other scientists.

The Russian lab was already working with a team of Japanese researchers on the mammoth restoration project but failure to reach an official agreement with the Japanese scientists have led to the Russians shifting partners. Along with Hwang’s lab, China’s Beijing Genomics Institute is also involved in the project.

Sooam said they hope to have restored viable cells by the end of 2012. If that happens and they are then able to implant the clone egg into an elephant, it becomes a 22-month wait to see if the pregnancy works. Given the overwhelmingly bad odds for a cloned and implanted egg succeeding to birth, it seems like a really big gamble to put all your ‘eggs’ in one elephant. But no one ever accused Hwang of thinking small. There’s no telling what he’ll do next if he’s successful in raising the mammoth.

[image credits: Britannica, telecomtally.com and Wall Street Journal]
image 1: mammoth
image 2: Lubya
image 3: hwang

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]