Scientists can now create mice with two fathers

Scientists at Osaka University in Japan have just created baby mice with two dads. That’s right: these mice have two parents, and both parents are males.

How did they do it, and what might this mean for humans?

Well, as reported recently in the journal Nature, it wasn’t easy. The scientists fertilized 630 eggs to get just seven mouse pups, but all seven mouse pups appeared normal and grew into fertile adults.

Let’s dig into the process just a little bit. The research team, led by biologist Katsuhiko Hayashi, first took cells from male mice, and they had to somehow re-program the cells to create egg cells.

One thing about egg cells in mammals: they are always female. Or to be more precise, they have two copies of the X chromosome. Males have one X and one Y chromosome, and the male mouse cells in this experiment started out that way too.

Hayashi’s team first took cells from male mice and turned them into pluripotent stem cells–a special type of cell that can then be turned into many other types of cells, including eggs. Then they grew these cells in Petri dishes until some of them spontaneously lost their Y chromosomes. Now the cells had 1 copy of the X chromosome, but no Y.

That only got the scientists part of the way to where they needed to be. The team then used another genetic trick that induced some of these cells to pick up an extra X chromosome while they were replicating. At that point, they had created mouse cells with two X chromosomes: in other words, the cells were genetically female.

The next step was to convince these XX cells to turn into egg cells. They did that using additional genetic techniques to coax the pluripotent cells to divide and form egg cells, each of which had just one copy of every chromosome (as egg cells do), including the X chromosome.

Those were the hard parts. Once they had the egg cells, the scientists fertilized them with sperm from other males, and then implanted 630 fertilized eggs in female mice. It wasn’t a very efficient process, but it worked: seven of the embryos successfully matured into baby mice, which grew into normal, fertile adults. (Note that mice only take 3-6 months to reach maturity.)

You might be wondering if all mice (or other mammals) with two male parents would have to be males. Well no, not at all. Sperm cells, which come from males, have either an X or a Y chromosome. After fertilizing the eggs, which all have X, the result is either XX (female) or XY (male), depending on which chromosome the sperm carried.

The scientists who did this work emphasized that we’re still a long way from making it work in humans. Among other things, we’d have to be sure that all of the steps involved in turning the male cell into an egg didn’t create harmful mutations elsewhere.

You might also ask if this means that we can also create babies using two female parents. Well, probably yes, but not using the process described here: to create a baby from two females, we’d need to take a female cell (any cell would do) and then turn it into a sperm cell. This is possible too! As it happens, a 2021 paper from Emory University described how scientists have recently created sperm cells from pluripotent cells in rhesus macaques. If viable sperm cells can be created, then they can be used to fertilize eggs, which would give us offspring with two female parents. (In this case, all of the babies would be female.)

But at least in principle, it may soon be possible for two men to have a child where both of them are the child’s genetic father.

Can we re-grow cartilage in damaged knees? A new Stanford study offers hope

Knee pain is one of the most common afflictions among athletes and among older people in general. I’ve written about treatments for knee pain before, specifically about the many so-called alternative therapies that just don’t work.

(Quick review: the supplements glucosamine and chondroitin don’t work. Injections of hyaluronic acid don’t work. Acupuncture really doesn’t work. Simple pain relievers like ibuprofen work, but only for a short time.)

The problem is that cartilage, which provides a cushion between the large bones of the upper and lower leg, doesn’t regenerate itself. When you have cartilage damage, either from an injury or just wear and tear, you lose that cushion and you get pain and inflammation. Because the cartilage doesn’t really heal, if the damage gets severe, you might eventually need a knee replacement.

There is hope, though. For years now, I’ve been following stem cell research to see if it offers the promise to truly regenerate cartilage (or any other tissue, for that matter). Stem cells are special types of cell that can generate all of the different cells in our bodies, from blood cells to heart cells to lung cells to cartilage. Back in 2006, scientists made a major breakthrough when they discovered how to turn normal cells back into stem cells. Ever since, scientists have been exploring how to turn stem cells into just what we want them to be.

To repair damaged cartilage, what we’d really like is fresh new cartilage grown from our own stem cells. This is what a new study out of Stanford University, just published in the journal Nature Medicine, promises to do.

Here’s how it works. It turns out that the ends of our leg bones do contain stem cells, and if the bones are damaged, those stem cells will create new cells in response. The problem is that the new cells are basically scar tissue, not cartilage. The scar tissue wears out pretty quickly, and doesn’t provide the cushioning that cartilage does.

Stimulating the stem cells to get started is easy, if a bit crude: orthopedic surgeons already do this by drilling very tiny holes in the ends of the bone, a technique called microfracture. This provides some pain relief when the scar tissue appears, but it’s only temporary.

The Stanford team, led by Matthew Murphy, Charles K.F. Chan, and Michael Longaker, decided to use some of the latest findings about stem cells to steer the cells in a different direction after microfracture surgery. They did this by adding two proteins to the ends of the bones. The first one was BMP2 (bone morphogenetic protein 2), which encourages the stem cells to make new bone cells. They also added a second protein, VEGFR1 (vascular endothelial growth factor), which halts the process of bone formation in a way that leaves cartilage instead.

What’s exciting about this therapy is that it actually worked! New cartilage grew from the stem cells, and it appeared to reduce pain. The big caveat here, and this bears emphasis, is that the experiments were done in mice–and many studies that work on mice fail to reproduce in humans. Recognizing this limitation, the Stanford team also conducted experiments using human cells that had been transplanted into mice, showing that the treatment did indeed create human (not mouse) cartilage.

Next up will be studies in humans, to see if this works as well in people as it did in mice. If it does, another big advantage, as Prof. Longaker pointed out, is that both BMP2 and VEGF have already been approved by the FDA for other uses. This should make it easier to get approval for the new treatment as a therapy for aching knees. He suggested that, eventually, doctors might:

“follow a ‘Jiffy Lube’ model of cartilage replenishment. You don’t wait for damage to accumulate — you go in periodically and use this technique to boost your articular cartilage before you have a problem.”

So when can we get this new cartilage-healing treatment? More studies will likely take years.

Well, as Dr. Robert Marx pointed out in the NY Times, there’s nothing to stop orthopedists from trying this treatment out right away, because the drugs required are already on the market. Thus long before we see convincing evidence that it works in humans, doctors might be trying this out. For a patient who has deteriorating cartilage, if given the choice between waiting many years to see how the studies turn out versus trying a promising new treatment right away, the temptation might be too great to resist.

This is where things get tricky. There are already numerous orthopedic practices offering “stem cell therapy for knees” along with “platelet-rich plasma,” which they will inject right into your knees (for a price, of course). It took me less than 30 seconds of Googling to find dozens of practices offering these therapies, with assurances that they “repair the knee naturally ... by stimulating the creation of cartilage.” Note that these clinics are not using the new Stanford technique (not yet, at least), and there’s no good evidence that these injections will re-grow cartilage, despite the testimonials on many websites. So for anyone looking for knee pain treatments, caveat emptor.

Let’s hope this new treatment method works. For those of us (including myself) with aching knees, this new therapy is the most promising one I’ve seen in a very long time.

A new kind of fasting provides significant immune system benefits

I've written about fasting and its effects on health before. Six years ago, a study showed that a 3-day fast can essentially reset the immune system, providing many potential benefits. These benefits include better cardiovascular health, better endurance, lower blood pressure, and reduced inflammation.

Newer data, which I'll get to in a minute, shows that you might not have to fast nearly that long to get these benefits.

In the 2014 study, Valter Longo and colleagues at USC found that fasting lowered white blood cell counts, which in turn triggered the immune system to start producing new white blood cells. White blood cells (or lymphocytes) are a key component of your body’s immune system. Once you start eating again, according to Longo, your stem cells kick back into high gear to replenish the cells that were recycled.

The idea behind this strategy is that you have to fast for several days to get the benefits: basically, you have to fully deplete your energy reserves (in the form of glycogen), and it takes your body at least 24 hours, and probably 48 hours or more, to do this. That's the not-so-good news. The good news is that you probably only need to fast once or twice a year to gain the benefits that Longo described.

Last week, in a paper just published in the New England Journal of Medicine, Rafael de Cabo and Mark Mattson reviewed multiple strategies for fasting that have been tested in the years since Longo's study. The news continues to be very encouraging: intermittent fasting is good for you. I don't have time or space here to discuss all the results, but I want to focus on one fasting strategy that has surprisingly good benefits.

It turns out that you can get many of the benefits of fasting without doing a 3-day fast, which for most people is really, really difficult to accomplish. Instead, you can try a much easier type of fasting, called "time-restricted" fasting. With this strategy, you fast every day, by eating all of your food in a 6-hour or 8-hour window. Or you can go with the more difficult strategy (but still easier than a 3-day fast) where you fast for 2 entire days per week. Here, then, are two intermittent fasting strategies that have similar health benefits:

• Time-restricted: eat lunch starting at 12 noon, and finish dinner by 8:00pm. Fast until the next day at noon (16 hour fast). Do this every day.
• 5:2 fasting: fast for 2 different days each week, which means eating just 500-700 calories worth of food and drink on those days. Eat normally on the other 5 days.

The first strategy–a daily 16-hour fast–is the easiest, but its benefits might be equal to those of 5:2 fasting and the 3-day fast. (No study has directly compared these 3 fasting regimens.)

The benefits of intermittent fasting are numerous. As de Cabo and Mattson explain, they include

"[improvements in] blood pressure; resting heart rate; levels of HDL and LDL cholesterol, triglycerides, glucose, and insulin resistance.... In addition, intermittent fasting reduces markers of systemic inflammation and oxidative stress that are associated with atherosclerosis."

Fasting also helps with weight loss, for obvious reasons. Cutting out all snacks in the evening, which is the biggest change imposed by time-restricted fasting, means not only a reduction in calories consumed, but also a reduction in the amount of highly processed ("junk") foods in one's diet as well.

Furthermore, because intermittent fasting reduces inflammation, it may also improve symptoms of arthritis and even rheumatoid arthritis.

Why does fasting work? It's all about getting your body to switch over from glucose metabolism to ketone metabolism. Our usual 3-meal-a-day diet provides our body with a constant source of fuel in the form of glucose. Once that glucose is used up, though, our body switches to using fatty acids and ketone bodies. Ketone bodies provide more than fuel: as de Cabo and Mattson explain,

"Ketone bodies regulate the expression and activity of many proteins and molecules that are known to influence health and aging."

Ketone metabolism seems to bring a host of health benefits. The trick is getting our bodies to switch over to it, now and then. If we eat constantly, then our bodies happily subsist on glucose and never make the switch.

Does fasting truly reset your immune system? Six years ago, I concluded that a 3-day fast does the trick, at least partially. The science suggests that, if you can do it, a prolonged fast for 2-3 days will induce your body to clean out some old immune cells and switch on production of new ones. Now we're learning that intermittent fasting, which is easier to do, may work in much the same way, with multiple health benefits.

[Note: one of the authors of the NEJM study, Mark Mattson, is a Professor at Johns Hopkins School of Medicine, making him a colleague of mine. However, we are in different departments and we have never met.]

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.)

ClinicalTrials.gov, a great resource for patients, is being abused to market bad medicine

This wasn't supposed to happen.

Since 1997, the National Institutes of Health has maintained a database of clinical trials, ClinicalTrials.gov, that lists trials under way in the U.S. and throughout the world. It's an invaluable resource, providing a single source for patients trying to find where to get the newest experimental treatments, and for doctors and scientists looking to enroll patients in their trials.

In recent years, companies offering questionable stem cell therapies got the bright idea that they could describe their treatments as clinical trials, register them on ClinicalTrials.gov, and thereby get some free advertising. Most stem cell treatments are not FDA-approved, and many have little or no data supporting their effectiveness, but clinics can still register their "trials" on the NIH site, making it appear that they are supported and endorsed by the government. A new study by Leigh Turner, published this week in Regenerative Medicine, reveals the growing extent of this problem.

What's especially worrisome is that some stem-cell treatment clinics charge patients very high fees to participate in their "trials." Some patients (perhaps most) don't know that legitimate clinical trials virtually never charge fees.

Consider this example, reported last July by Emily Bazar at Kaiser Health News: California resident Linda Smith has knee osteoarthritis, and was looking for treatments that could restore her knees to health without surgery. She found a stem cell trial at ClinicalTrials.gov that was run by StemGenex, a clinic in La Jolla. The clinic promised it could inject stem cells into her knees to replace lost cartilage. When she inquired about signing onto the trial, Smith was shocked to learn that StemGenex wanted a $14,000 fee for her to participate.

StemGenex claimed that “The actual treatment is not part of the study protocol”: you pay for the treatment, they explained, and the study is merely a followup to see how you did afterwards.

What nonsense. I checked the StemGenex site today (a year after the quotes above), and they proudly boast that they are registered on ClinicalTrials.gov, and that

"Stem cell therapy for Osteoarthritis is being studied for efficacy in improving the complications in patients through the use of their own stem cells."

Hmm. This sure sounds like the study is about the treatment. StemGenex's site strongly suggests that their therapy works wonders:

"The goal of each stem cell treatment is to inject the stem cells into the joint to create cartilage (chondryte cells)."

Sounds good, right? If only it were true.

I've got bad knees myself, so I've been following the research on stem cell treatments for cartilage replacement for years. I would love to be able to get a simple injection that could repair my damaged cartilage. Alas, though, no one has yet developed an effective stem cell treatment for bad knees, although it is plausible, and legitimate trials are under way right now (here's one).

Unfortunately, the lack of evidence hasn't stopped clinics from offering stem cell injections right now, accompanied by all sorts of promises that are not backed by science. It's not just knee injections, either: this past March, Sharon Begley at STAT reported on three women who were blinded by stem cell therapy injected into their eyes.

Most patients think, mistakenly, that if a clinic offers stem cell therapy, it must have been approved by the FDA. That's not true–clinics offering these therapies don't have FDA approval, and they argue that they don't need it (which might be correct, but that's a topic for another day).

Patients also assume that trials listed on ClincialTrials.gov must have been approved by some government agency, but that's not true either. The site is a clearinghouse that uses the honor system, nothing more, to ensure that trials listed there are legitimate. If you read their Disclaimer (but who does?), you find that studies listed on the site are not necessarily funded by NIH or approved by the FDA.

Turner's study found 7 trials that openly state they charge patients to participate. At least they're honest about it. Turner found many more (including several run by StemGenex) that appear to charge patients despite not explaining their policy on ClinicalTrials.gov. For example, a stem cell trial by Cell Surgical Network plans to enroll 3000 patients and will charge each of them $6000 or more to participate. As Turner writes

"Cell Surgical Network uses its registered ClinicalTrials.gov study as a powerful marketing device. Press releases and the websites of the clinics that are part of this network emphasize that the study is registered on ClinicalTrials.gov."

NIH needs to start policing this site before the situation gets worse. Coincidentally, I know just where they can find the resources to do it. NIH just announced that it's about to start regulating all sorts of basic science studies as clinical trials, a move that will cause a "massive amount of dysfunction and paperwork," according to one MIT scientist. Rather than over-regulating basic science, NIH should devote those same resources to cleaning up and then continuously monitoring the ClinicalTrials.gov database.

What these stem cell clinics are doing is not a clinical trial, and advertising their services through ClinicalTrials.gov is reprehensible. For now, if a doctor or clinic tries to charge you to participate in a clinical trial, your best course may be to find another trial–and another doctor.

Did a biotech CEO successfully reverse her own aging process? Maybe not.

Elizabeth Parrish, CEO of BioViva.

Humans have been searching for the fountain of youth for millenia, dating back to ancient times. No one has found it yet, so I was very skeptical when I saw the recent announcement from BioViva, a biotech company, of what they called the first successful gene therapy against human aging:

"Elizabeth Parrish, CEO of Bioviva USA Inc., has become the first human being to be successfully rejuvenated by gene therapy, after her own company's experimental therapies reversed 20 years of normal telomere shortening."

That's quite a dramatic claim. If true, this would be a historic breakthrough: no one has ever reversed aging before. While human life expectancy has doubled over the past 150 years, virtually all of this progress has been from preventing early deaths, thanks to the developments of antibiotics, vaccines, and public health advances such as clean water.

Human life expectancy has doubled since the 1840's.
Figure source: Natl Institute on Aging.

Most claims about anti-aging therapies are easily dismissed as pseudoscience, nonsense, or scams. Not this one, though. BioViva has two experimental therapies, both based on legitimate science, and both with at least a chance of working. Neither has yet been proven to work in humans, but both are plausible.

According to BioViva and to interviews with its CEO, Elizabeth Parrish, Parrish received two therapies last year, one to protect against the loss of muscle mass, and one to lengthen her telomeres. The recent announcement claims that the telomere-lengthening therapy is already working, so I looked a bit deeper to understand what might be going on.

First a bit of background: telomeres are special DNA sequences that act as "caps" on both ends of every chromosome, providing a kind of protection for your genes. Each time a cell divides, its telomeres get a little bit shorter, and eventually they get too short and the cell dies. Telomeres therefore act as a kind of molecular clock that tells a cell how old it is. Our cells also have a special enzyme called telomerase that rebuilds telomeres. Cells with lots of telomerase can live much longer, and those without it die more quickly. Discovering how this all worked was a tremendous scientific achievement, for which Elizabeth Blackburn, Carol Greider, and Jack Szostak received the 2009 Nobel Prize.

Scientists have been speculating for years that telomerase might somehow hold the key to aging. BioViva's gene therapy delivers telomerase to the blood with the help of weakened viruses called adeno-associated viruses (AAVs), which they modified to carry the telomerase gene. The virus infects human cells and releases its payload into them, where the "transgene" produces extra telomerase.

This may sound very nice, but it's really, really complicated in practice. Gene therapy can have unexpected negative effects, and no human trials have yet shown that anyone can deliver telomerase effectively to human cells. However, studies in mice have shown some remarkable results: in 2012, a group of scientists at the Spanish National Cancer Centre used AAV to deliver telomerase to mice, and found that it "had remarkable beneficial effects on health and fitness" and that

"telomerase-treated mice, both at 1-year and 2-years of age, had an increase in median lifespan of 24 and 13%, respectively."

This exciting scientific result, and a few others like it, are what led BioViva and Elizabeth Parrish to try the same therapy in humans.

But did it work? Well, this is where things get a bit fuzzy. BioViva claims it did, based on their measurements of the length of telomeres in Parrish's white blood cells in September 2015, before therapy started, and again in March 2016. They claim that her telomeres got longer, from 6.71 kilobases (a kilobase is 1000 DNA letters) to 7.33 kilobases. This increase corresponds to about 20 years of aging: in other words, Parrish's white blood cells "have become biologically younger," as the company reported.

Setting aside the problem that we cannot really conclude anything from an experiment involving only one person, we can still ask: did Parrish's telomeres really get longer? As much as I want to believe BioViva's claim, there are several rather serious problems here. First, the company itself reported that Parrish's telomeres were unusually short for her age before the experiment began. Does this mean that the measurements were simply a bit off, and the second measurements were closer to the true number? Second, as UCLA's Prof. Rita Effros explained in an interview at geneticexperts.org,

"The overarching problem is that peripheral blood contains a mixture of many different cell types with disparate telomere lengths.... Thus, a simple change in the proportion of different cell types within the peripheral blood could easily explain the data."

In other words, it's possible that Parrish's telomeres did not get any longer. Despite the apparently precise numbers, BioViva has not provided any details showing that these measurements are accurate and reproducible (and they didn't respond to my request for these details). Their claim might be much more convincing if they made multiple measurements, both before and after treatment, and if these measurements showed that Parrish's telomere lengths really did increase.

There are a number of red flags about BioViva itself. Parrish herself is not a scientist, though she is an eloquent spokesperson for her company's therapies. More concerning is their Chief Medical Officer, Jason Williams, who previously ran "a dubious stem cell clinic," Precision StemCell (now located in Mexico) that offers stem cell therapies to patients with ALS (Lou Gehrig's disease), for which there is no evidence that they work. Personally, I would not trust Dr. Williams with my medical care.

The bottom line is that we simply don't know if BioViva's treatment worked on Elizabeth Parrish. They need to produce more data, on more patients, to construct even a mildly convincing scientific argument. Getting more patients may be very difficult, though: Parrish bypassed FDA regulations by traveling outside the U.S. (to Colombia) to conduct this experiment on herself.

Telomerase treatment to reverse aging is very promising, and it might really work, someday. I sincerely hope it will.  For now, though, BioViva's announcement leaves me very skeptical.

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.

Can you patent a fraudulent stem cell method? Yes!

Woo-Suk Hwang talks to reporters after
fraud is revealed. Photo: Reuters.

At first I thought the Patent Office was having a little fun. Was it an April Fools Day joke?  No, it's only February - and the U.S. Patent Office never kids around.

What did they do? They issued a patent to Korean scientist Woo-Suk Hwang for a method to create human embryonic stem cells by cloning.  The problem is, Hwang's "invention" was one of the most famous frauds of the past decade. His publications in 2004 and in 2005, in the journal Science, are labelled in bright red letters as retracted, and Science wrote its own separate notice explaining

"the authors of two papers published in Science (2, 3) have engaged in research misconduct and that the papers contain fabricated data."

Hwang's apparent triumph, becoming the first scientist to create human embryonic stem cells in the lab, made him a national hero in South Korea, for a short time.  He was soon appointed the director of a new stem cell research center. But things quickly unraveled beginning in November 2005, when Hwang's co-author Gerald Schatten, a stem cell researcher at the University of Pittsburgh, announced that he was ending his collaboration with Hwang over ethical concerns. By January, Hwang admitted to publishing fake data, but blamed his junior colleagues. Hwang was fired from Seoul National University (SNU) in 2007 and later convicted of bioethical violations and embezzlement. The official investigation by SNU found that Hwang's laboratory

"does not possess patient-specific stem cell lines or any scientific basis for claiming to have created one."

So you wouldn't think this would be approved for a patent, no?  Is the patent office paying any attention at all?  As reported by Andrew Pollack at the New York Times, the patent office does indeed know Hwang's history, and the patent is 

"definitely not an assertion by the U.S. government that everything he is claiming is accurate."

Well, I must say I'm relieved to hear that. Hwang himself admitted the data were fake! As I've written previously, the USPTO simply can't keep up with biotechnology, and the courts don't do any better. In this case, it's hard to imagine a more obvious example of a patent that should be denied: the papers were retracted, and the lead scientist lost his job after his own university concluded that the data was fabricated. And yet the patent office is standing by their decision. What are they thinking?

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.

The Skeptical Optimist

Some readers of this blog may be surprised to learn that I'm very optimistic about the future of science and medicine.  Over the past few years, I've criticized many different frauds, fakes, bad scientists, bogus claims, quack medical practices, and scam artists.  I will continue to do so.

But deep down, I'm an optimist.  Science has transformed our lives over the past century, thanks to a list of discoveries far too long to write down, including cures and vaccines for many childhood diseases, better ways to heat and light our homes, and faster ways to travel and communicate. I'm confident science will continue to make progress on all sorts of problems affecting our species. One reason I focus my criticism on pseudoscience is that every minute spent on bad science is a minute that could have been spent on real science, moving us closer to genuine treatments or real scientific discoveries.

I also write on occasion about true breakthroughs, such as the recent success using stem cells to treat damaged hearts, or last year's development of a vaccine against the Ebola virus.  It's good to remind ourselves that good stuff is happening despite all the nonsense being pushed by quacks out there.

But I'm a skeptical optimist.  All real scientists must be skeptics: we know that initially exciting results often turn out to be statistical flukes, experimental errors, or just plain randomness.  We have to check and double-check our results before publishing, and even then we sometimes make mistakes.  Our training makes us skeptical whenever we hear about some amazing new breakthrough, even when we are hopeful that the results are true.

But we can't let pseudoscience take precious resources away from real work.  So it's back to the front lines in the ongoing battle against the anti-science forces: watch this space tomorrow for my choice for the worst quackery of 2011.

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.

Stem cell heroes and villains

Stem cell research in the U.S. has been on a roller coaster ride the past few weeks. First, federal judge Royce Lamberth surprised everyone on August 23 by calling a halt to all federally-funded work on embryonic stem cells (ESCs). Hundreds of NIH-funded scientists learned overnight that their funding was about to be cut off, halting work on cures for a wide range of incurable diseases and conditions, including Parkinson’s disease, spinal cord damage, Lou Gehrig’s disease, heart disease, diabetes, arthritis, and others.

Then, this past Thursday, a federal appeals court announced a temporary stay on Judge Lamberth’s ruling, which allows the funding to continue. However, the court gave both sides only until September 20th to make new arguments, and the research could again be called to a halt before the month is out. Many scientists, including this one, hope the appeals court will throw out the case and let the research proceed.*

Stem cell research is one of the most promising opportunities for truly revolutionary breakthroughs in human health that we’ve seen in decades. Unfortunately, its progress has been slowed dramatically in the U.S. due to objections from the religious right, which mistakenly confuses stem cell research with abortion. Many of these opponents don’t seem to know that thousands of fertilized human eggs are discarded every year, perfectly legally, by fertility clinics, and their opposition to embryonic stem cell research only serves to hamper progress on life-saving cures.

So who is the villain in this latest battle? Much of the media attention has focused on Judge Lamberth, whose interpretation of the Dickey-Wicker amendment has been disputed by many legal and medical experts (for example, here and here). I don’t want to re-hash those arguments here. Instead, let’s take a look at the so-called scientists who filed the case, and examine their claims.

Science, medicine, and politics mix in new mammography and stem cell guidelines

Today's news included two stories that both illustrate how politicians almost always get science wrong. It never seems to be a good thing when politicians sink their teeth into a scientific or medical question: they are only too happy to distort the facts to achieve their political goals.

First, the new mammography guidelines. This was all over the news two weeks ago: an official federal advisory panel, the U.S. Preventive Services Task Force, recommended that women between 40 and 50, who had no risk factors for breast cancer, not have annual mammograms. This caused a firestorm of criticism from many quarters, because the previous guidelines recommended annual screening. The panel determined, after looking at data from the past decade and more, that the risks of excessive screening (many more false positives, and the resulting biopsies and even surgeries) were not justified by the small number of additional cancers detected.

This is a complex issue, and many other bloggers wrote about it, so I'm not going to discuss it in detail. My overall impression was that the panel weighed the evidence and made their recommendations based on the best available science, and I think their decisions were good ones. I'd also note something that the media seems to have missed: about ten years ago, when another panel was debating similar recommendations, there was tremendous political pressure to make annual screening the official policy.