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.

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.

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.