Transgenic stem cells lead to a miraculous cure

Sometimes I read a science paper and I just say "Holy cow, this is amazing." I don't have that reaction very often, but I did last week.

Amidst all the hype, the hope, and the controversy about gene therapy and stem cell research, some very real progress is being made. Scientists can create working versions of human genes, package them into a virus, and then use the virus to deliver the genes to a real person. This approach creates "transgenic" cells that have bits of virus DNA within them, but the virus can be engineered to be harmless.

Last week, scientists reported in the journal Nature how they saved the life of a 7-year-old boy using transgenic stem cells. Twenty years ago, this would have been science fiction. Even today it is nothing short of astonishing.

Here's the story, summarized from the paper by Tobias Hirsch, Michele de Luca, and their colleagues. In June 2015, a 7-year-old boy was admitted to the Burn Unit of Children’s Hospital of Ruhr University, in Bochum, Germany, where Hirsch and his colleagues (Tobias Rothoeft, Norbert Teig, and others) work. The child wasn't suffering from burns: he had a devastating genetic disease, junctional epidermolysis bullosa (JEB), that had caused him to lose 80% of his skin.

Figure 1b from Hirsch et al. Schematic
representation of the clinical picture.
The denuded skin is indicated in red;
blistering areas are indicated in green.
Flesh-colored areas indicate currently
non- blistering skin. Transgenic grafts
were applied on both red and green areas.

Children with JEB suffer from constant blistering, wounds, and scarring. The disease is uncurable and children often die before reaching their teens. The 7-year-old boy was near death when he was admitted to the hospital–his weight had dropped to 17 kilograms (38 pounds) and he had severe skin infections from streptococcus and pseudomonas bacteria.

Dr. Hirsch and his team were struggling to keep the boy alive, and they had no treatments to offer. In desperation, they searched the scientific literature and found a possible treatment using gene therapy, developed by Michele De Luca, of the Center for Regenerative Medicine at the University of Modena and Reggio Emilia in Italy. Dr. De Luca had only tried this treatment twice before, and even then only on tiny patches of skin. He had never tried it on such a severe case.

The boy and his parents had no other options to save his life. They agreed to let Dr. De Luca try.

In September of 2015, De Luca took a small patch of undamaged skin (4 square centimeters) back to his lab in Italy. There, he used a retrovirus containing a functioning copy of the LAMB3 gene–the gene that was mutated in the boy–to infect the skin cells. The retrovirus integrated itself into the genome of many of the skin cells, giving them the ability to function normally. Then De Luca grew the repaired cells into new skin grafts, enough to cover 80% of the child's body.

In a series of surgeries starting in October 2015, Hirsch and his colleagues applied the skin grafts to the young boy. The results were amazing.

As reported in the paper itself:

"Virtually complete epidermal regeneration was observed after 1 month.... Over the following weeks, the regenerated epidermis surrounding the open lesions and the epidermal islands spread and covered most of the denuded areas."

In other words, it worked. The new skin completely replaced the missing or damaged skin on 80% of the boy's body. What's even more remarkable is that two years later, his skin remains normal. The new skin is functioning perfectly and the young boy has returned to school.

The science behind this treatment represents the culmination of decades of research into gene therapy, stem cells, retroviruses, and genomics. To make it all work, we had to know: the identity of the gene that caused the disease (LAMB3); the DNA sequence of a normal LAMB3 gene; how to insert the human gene into a retrovirus; how to create a modified retrovirus that wouldn't harm humans; and much more.

The success of the therapy also revealed new insights into stem cells in human skin: the small patch of undamaged skin from the boy contained many cells, a few of which were stem cells (holoclones) that could replenish the skin indefinitely. It was these stem cells that allowed the skin grafts to take hold and continue to function, hopefully for the rest of the boy's life.

Sometimes science and medicine converge, and miracles happen.

(Note: the paper is "Regeneration of the entire human epidermis using transgenic stem cells" by T. Hirsch et al.)

Stem cell therapy offers hope for “irreversible” heart damage

In December 2011, I reported on one of the first attempts to inject stem cells into damaged hearts. In that study, published in The Lancet, scientists grew stem cells from patients’ own hearts after the patients had suffered serious heart attacks. These were patients who had serious, irreversible heart damage. As the study leader, Dr. Roberto Bolli, said at the time, 

“Once you reach this stage of heart disease, you don’t get better. You can go down slowly, or go down quickly, but you’re going to go down.”

Amazingly, in that study, the patients got better. 14 of the 16 patients had improved heart function after 4 months, and the results were even better after one year. The stems cells grew into new, functioning heart cells.

That was just one study. Now there have been more, and the results continue to be very encouraging. Just last week, the Cochrane Collaboration published a review of 23 trials, all of them attempting stem cell therapy for heart disease. These trials looked at the use of bone marrow stem cells in patients whose hearts were failing. Unlike the 2011 study, which looked at heart attack patients, these studies looked at patients with advanced heart disease who had not suffered a heart attack. The results: overall, stem cell treatments reduced the risk of death and improved heart function, though the benefits were not as dramatic as in the patients with heart attacks. 

What is most exciting in the newest studies is the long-term reduction in the risk of death. Six of the studies reported long-term results (more than one year) on mortality. In these studies, 8 patients died out of 241 who received stem cell therapy (3.3%). In contrast, 30 patients died out of 162 (18.5%) who did not receive stem cells. The numbers are small, but this is a huge benefit: patients were about 5 times less likely to die. The Cochrane review concluded that

“The risk of mortality over long-term follow-up was significantly lower for those who received BMSC [bone marrow stem cell] therapy.”

An important caveat is that this is still “low quality” evidence, meaning that we need to see more data, on many more patients, before we can have confidence in the results. But it is still very encouraging, especially when no other treatment offers anything remotely this promising for advanced heart disease.

The evidence continues to build that stem cells can repair heart tissue damaged by heart attacks. Just a couple of months ago, Britain launched the largest study yet of stem cell treatments for heart attacks, involving 3,000 patients in Europe. This new review shows that they can help repair some of the damage from other types of heart disease as well.

Heart disease is the leading cause of death in the United States, and we should be pursuing every plausible treatment, though very few exist. Stem cells offer the hope that, for the first time ever, we might be able to reverse heart damage that was previously thought to be irreversible. Stem cell treatments are a true breakthrough, and rather than cutting medical research, as we have been doing for the past five years, we should be pouring resources into this remarkable new medical technology and the therapies that it makes possible.

Embryonic stem cells: can we really restore vision to the blind?

Restoring sight to the blind is, literally, a miracle.  For centuries, men have told stories of miracles in which a blind person suddenly was able to see again.

In modern times, there have been cases of vision restored thanks to corneal transplants and cataract surgery.  These are amazing treatments themselves, and they have become almost routine in the developed world.  But when the cells inside the eye are damaged, there is nothing we can do.

Until now.  In an amazing advance, scientists at Advanced Cell Technology reported this week in The Lancet that they used embryonic stem cells to restore partial vision to 2 patients who were legally blind.  One patient had macular degeneration, a very common but incurable eye disease, and the second had Stargardt disease.  Both diseases are progressive and usually lead to blindness.

Both diseases also affect internal eye cells known as retinal pigment epithelium (RPE) cells.  The research team, led by Robert Lanza, took human embryonic stem cells and coaxed them into becoming RPE cells.  They tested the RPE cells extensively for any signs of contamination by viruses or bacteria, and once they confirmed that the cell cultures were pure, they injected them into the eyes of these first two patients.  (Earlier studies were done in mice and rats before trying the therapy on humans.)

After four months, both patients showed improvements in vision.  This is an amazing result for macular degeneration, which has been, until now, irreversible.  The cells appeared to "take" in both patients, attaching to other cells in the eye and replacing damaged areas.  As Rob Stein and David Brown reported in the Washington Post

"One of them no longer needs a large magnifying glass to read and can reportedly thread a needle. The other has begun to go shopping on her own."

According to the study, neither patient has shown any signs of rejecting the cells.

The Lancet study, which you can read here, was funded entirely by private funds due to U.S. government restrictions on embryonic stem cell research.

This is only an early result from a very small study, but coming on the heels of reports just a few months ago, in which adult stem cells restored heart function to patients with advanced heart failure, the promise of stem cells again got just a bit brighter.

So yes, maybe we really can make the blind see again.

Stem cell hopes for damaged hearts

As the holiday season begins, I decided to discuss some good news about real science.

The promise of stem cell research just got a lot brighter.

There was some very good news from the world of medicine just a couple of weeks ago. For the first time, stem cells were injected into the hearts of humans who had suffered serious heart damage, and patients improved dramatically. It appears that, as everyone hoped, the stem cells grew into new heart cells to replaced the damaged tissue. This is the promise of all stem cell research: to repair or replace damaged organs that otherwise would never recover. In principle, we can someday use the same technique to replace damaged livers, kidneys, spinal cords, cartilege, and virtually all other tissues in the human body.

In the new study, just published in The Lancet, a group of researchers led by Robert Bolli grew stem cells from patients' own hearts, after the patients had suffered serious heart attacks, leaving their hearts permanently damaged. Bolli explained to CNN reporter Caleb Hellerman:

"Once you reach this stage of heart disease, you don't get better. You can go down slowly, or go down quickly, but you're going to go down."

In an effort to repair the patients' hearts, Bolli and colleagues collected a small amount of tissue from each patient's own heart, and purified stem cells from that tissue. By using the patient's own cells, there is no danger of rejection as there would be with cells from an unrelated donor.

They measured the patients' heart function by how much blood was being pumpled through the left ventricle. The patients had an average Left Ventricular Ejection Fraction (LVEF) of 30.3% at the beginning of the study, an indication of very severe heart disease. Four months later, the 16 patients who received the stem cells had an average LVEF of 38.5%, while patients in the control group (who didn't get the stem cells) showed no change. Even more dramatically, after one year the patients LVEF had improved further, to 42.5%.

Thus, remarkably, the cardiac stem cells seem to have "taken" in these patients, growing back into healthy cardiac cells in these severely ill patients. The researchers used MRI to measure the damaged heart tissue in 7 of their patients, and found that it had actually decreased by 30% after one year. In a companion trial at Cedars-Sinai Heart Institute in Los Angeles, Dr. Eduardo Marbán reported similarly positive results. Marbán told CNN that the patients grew approximately 600 million new heart cells after the procedure, comparable to the number of cells that die in a serious heart attack.

One reason these findings are especially dramatic is that they show convincingly that the human heart contains stem cells that can re-grow into new heart cells. It is entirely possible that heart damage that has always been thought to be irreversible can be completely repaired - someday.

The results are very preliminary, and only a few patients have been treated so far, but this is a major triumph for stem cell research. The research in question used adult stem cells, but embryonic stem cells may prove even more effective, and may be easier to obtain because they don't have to come directly from someone's heart.* Heart disease is the leading cause of death in the U.S., and we need to pursue every possibility for new treatments. Those who oppose stem cell research - including embryonic stem cell research - should wake up and take notice: many lives are at stake.

*Disclaimer: Until June 2011, I was a member of the Maryland Stem Cell Research Commission, a state commission established by the legislature and the governor to promote human stem cell research through state-funded grants. The views expressed here, as always, are my own, and do not represent the Commission.