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.

Gain-of-function research on viruses justifies itself with a scientific error

We still don’t know where Covid-19 started, although we’re pretty sure it started in or near the city of Wuhan, China. The leading theories are that it started either in the Huanan Wholesale Seafood Market (in Wuhan), a live animal food market, or in the Wuhan Institute of Virology (WIV), a large virus research center in another part of the city.

We might never know, because we’d need access to all of the viruses being studied at WIV in late 2019, and those viruses might not even exist any longer.

I’ve been on the fence about this question since the pandemic started (as I wrote here and here and here), in part because we just don’t have enough data. However, I’m now starting to lean more strongly towards the hypothesis that the Covid-19 virus started in the Wuhan Institute of Virology. I just listened to the interview that Sam Harris did with science journalist Matt Ridley and biologist Alina Chan, who together wrote an entire book on the origins of Covid-19, and the evidence they compiled is compelling.

Let’s look at a few key points.

First, the virus itself, SARS-CoV-2, almost certainly originated in bats, and those bats almost certainly came from caves in southern China, over 1000 kilometers away from Wuhan. The bats didn’t get to Wuhan on their own.

So either someone transported bats to the Huanan Seafood Market, or they transported viruses from the bats to WIV. These are our choices.

Second, WIV was doing research on coronaviruses for years. Their scientists traveled regularly to caves in southern China to find novel viruses, and they’ve acknowledged that WIV’s labs had bat viruses, including viruses related to SARS-CoV-2, before the pandemic began.

Third–and this point is under some dispute–many scientists have argued that the virus was a naturally-occurring one. However, this doesn’t make it more likely that the virus originated in the seafood market. It’s just as likely that a scientist or technician working at WIV was accidentally infected, and then went home (maybe stopping by the seafood market on the way) and started a worldwide pandemic.

Fourth, it’s hard to believe that it’s merely a coincidence that one of the top virology labs in China just happened to be located in the city where the pandemic began. WIV was not only the foremost lab in China doing work on SARS-like viruses, but they also claimed previously that they intended to do gain-of-function work to make these viruses more pathogenic.

This startling fact emerged when a 2018 grant proposal by EcoHealth Alliance, a US-based nonprofit that was working with WIV, was leaked to the press in 2021. Even though that proposal was never funded, the text describes how EcoHealth would genetically engineer new viruses, taking the spike protein from one bat coronavirus and inserting it into a different one, and then infecting mice to see what happens.

But wait, some will say: we now have peer-reviewed studies pointing to the seafood market as the epicenter of the pandemic. (I wrote about those studies back in March 2022.) However, as Alina Chan and Matt Ridley explained to Sam Harris (and in their book), the Chinese authorities in early 2020 focused all their attention on the seafood market, to the exclusion of anywhere else. They collected loads of samples from people who had been in or near the market, and very little from anywhere else. Thus we seem to have a classic case of confirmation bias: when you only look at the place where you’re convinced the virus originated, and you find some evidence, then you stop looking. We simply don’t know if the virus was anywhere else.

Now, to the main topic for today: the scientific error used to justify gain-of-function research on dangerous viruses, the error that might have led to the Covid-19 pandemic. Let me explain.

Why, one might ask, were scientists from the Wuhan Institute of Virology going out into the wild, to places where humans would not otherwise go, and bringing back deadly viruses?

This doesn’t just happen in China. The US is funding a large effort to do exactly the same thing: through a program called DEEP VZN (”deep vision,” get it?), USAID is funding scientists in the US and in Africa, Asia, and Latin America to venture into unpopulated areas of the jungle, and to find animals carrying viruses that might infect humans. They’re hoping (!) to discover 8,000 to 12,000 new viruses, and they’re particularly interested in viruses that could cause the next pandemic.

Why does anyone do this? Virus hunters believe that through these efforts, they can predict which of these viruses are destined to become the next pandemic. Furthermore, the argument goes, through gain-of-function research, virologists will be able to determine just what the new pandemic strains will look like. Then, armed with this knowledge, they can convince governments and private companies to design, manufacture, and stockpile vaccines against these viruses. This way (the argument goes) when the pandemic emerges, we’ll be ready.

At the center of this scientific strategy is an obvious error about evolution.

I’ll have to get a bit technical to explain here, so bear with me: the genome of the SARS-CoV-2 virus contains about 30,000 bases of RNA. The key protein that lets it infect human cells is called the Spike protein, which is about 1300 amino acids long and is encoded by about 3900 RNA bases. RNA has an alphabet of 4 letters (A, C, G, and U), which means that each of those positions can mutate into one of the other 3 letters. So we have almost 12,000 possible mutations that affect just one base in the Spike protein.

But 2 or more mutations can happen at once, quite easily, and this too could make the virus more infectious. How many combinations of 2 positions and 3 mutations are possible? Well, about 650,000,000.

And these aren’t the only mutations that might create a pandemic virus. So we’re supposed to believe that:

  1. gain-of-function experiments in the lab will create precisely the same mutations that would happen in the wild, and
  2. virologists can then predict, based on their experiments, that a virus is likely to cause a pandemic, and
  3. this evidence is so convincing that governments will manufacture and stockpile vaccines based on these experiments, and
  4. that this in turn will allow us to prevent the next pandemic.

Yeah, right. The evolutionary mistake is in the first point above, by the way.

Something happened in Wuhan. You might think that virologists, upon hearing about the gain-of-function research at WIV, would pause and think, oh no, we hope our colleagues’ research didn’t cause the pandemic! But instead, they closed ranks and doubled down.

In case you think I’m exaggerating, consider this: just a month ago, 156 virologists co-authored an article in the Journal of Virology that declared:

“gain-of-function research-of-concern can very clearly advance pandemic preparedness and the development of vaccines and antivirals. These tangible benefits often far outweigh the theoretical risks posed by modified viruses.”

In case that wasn’t clear enough, they assert twice more in the article that gain-of-function research will help us prepare for pandemics.

Virologists have been making this argument for years, and yet their experiments had no benefit at all–none, zero, zip–when we were finally faced with a true pandemic. Why should we believe this claim now?

Instead, it’s possible that gain-of-function research, along with the search for novel viruses in the wild, might have accidentally caused the pandemic.

Let me conclude by emphasizing that the vast majority of research on viruses and infectious diseases is incredibly important. Vaccines, antibiotics, antivirals, and other treatments have saved millions of lives, and the scientists doing this work should be applauded. Shutting down dangerous gain-of-function research–by which I mean research designed to take a virus or bacterium and make it more deadly in humans or in other animals–would only affect a tiny percentage of virologists worldwide. Let’s tell them to stop. If they can’t find something better to do, other scientists can.

Panel recommends new controls on deadly gain-of-function research. Will the government listen?

Illustration by Erik English

This past week, a government-appointed panel of scientists released a new report recommending 13 actions the U.S. government should take to control “gain-of-function” research that has the potential to create deadly new pathogens.

This has been a long time coming, but the first thing I want to point out is that this is just an advisory panel. The government hasn’t done anything yet. Let’s unpack what happened, shall we?

First, the panel is called the NSABB: the National Science Advisory Board for Biosecurity. The new report, which was at least 3 years in the making, was created in response to a decade’s worth of concerns, raised by many scientists (including me - see my previous articles here and here and here, among others), about the dangers of a specific kind of research known as gain-of-function.

What is gain-of-function (GoF) research? Well, it can include many scientific experiments, including some that are perfectly reasonable. But the term has been used most often to refer to experiments that are designed to take a virus such as influenza or SARS-CoV-2 and alter it intentionally to make it more deadly.

This seems crazy, right? Yet it’s been going on in the influenza virus research world for at least a decade, which is why many scientists have raised alarms.

The Covid-19 pandemic gave this issue much greater urgency, after suspicions arose that the Covid-19 virus, SARS-CoV-2, might have emerged (accidentally) from gain-of-function experiments at a major virology lab in Wuhan, China. (It probably didn’t, but we still don’t know for sure, as I’ve explained in previous columns.)

So back to the topic at hand: the new NSABB report. What do they recommend, and will it matter? I don’t want to go through all 13 recommendations, but overall it’s a very good start, if (and only if) the U.S. government takes them seriously and implements them all.

And the virology community is already pushing back - but first let me go into just three of the recommendations.

First, the panel recommends that the government require that all GoF research undergo federal-level review if the work is

“reasonably anticipated to enhance the transmissibility and/or virulence of any pathogen.”

Believe it or not, GoF research that does this kind of thing is going on right now, and there’s no rule saying it must be reviewed first.

Second, the panel recommends that the government only allow such research if there’s simply no better, lower-risk way to gain the same scientific insights. As they put it, scientists who want to do GoF work would have to prove that

“there are no feasible alternative methods ... that poses less risk ... and the risks are justified by the potential benefits.”

That’s a high bar to clear, but it seems eminently reasonable to insist upon it before allowing dangerous GoF research to proceed.

The panel also recommends that the new restrictions on gain-of-function research apply to all research in the U.S., regardless of whether it’s funded by the government. This is an important addition, as illustrated recently when Boston University, after being called out for dangerous gain-of-function experiments on the Covid-19 virus, claimed that they didn’t use NIH funds for this, so (they argued) they didn’t break any rules. Technically, they were correct. This recommendation will close that giant loophole.

There’s much more in the NSABB report, and my primary reaction is that (1) it’s a good start and (2) it’s not nearly enough. I’d like to see the government make a blanket statement that research that will make deadly viruses even more deadly is simply forbidden, at least for now. If someone wants an exception, they could make the case, but I’ve yet to see a good argument for these experiments.

What about that pushback from the virologists that I mentioned above? Well, in a lengthy commentary just published in the Journal of Virology, 156 virologists argue that gain-of-function research is wonderful! And it’s brought so many benefits! Just let us handle this, and don’t worry, they seem to be saying.

To make the benefits explicit, the 156 virologists include a table listing dozens of “useful examples” of gain-of-function research. Let’s look at just two of them.

Example 1: the virologists assert that experiments on a virus called M13 led to faster computers, citing a 2018 article. First, this is nonsense: no one has been a faster computer using a modified M13 virus. Second, the M13 virus is harmless to humans (it only infects bacteria), so it wouldn’t be subject to any regulations on GoF research in human pathogens.

Example 2: this one is even more outrageous. The table lists as a “benefit” an experiment that “established that H5N1 has capacity for mammalian transmissibility.” They then cite a notorious experiment from 2012 in which scientists intentionally modified a deadly bird flu virus (H5N1) in order to make it possible for the virus to be transmitted directly between mammals. This was one of the key experiments that led to the widespread alarm about GoF research in the first places. (I wrote about it back in 2013.)

So no, creating a more-deadly virus and then saying “see? look how dangerous this virus is?” is not what I’d call useful.

Clearly, the virologists who wrote this commentary do not want to see any restrictions at all on the kind of research they do. They just don’t see the need for it. Obviously, I disagree, as do many others, including many virologists who support the NSABB recommendations.

As I wrote at the beginning of this piece, the NSABB report is just a set of recommendations, and the government might not do anything. I hope that the government will implement all of them, and then go even further, and put a stop to the dangerous, sometimes reckless experiments that a very small minority of scientists are engaging in.

We need to study viruses, and we need to control infectious diseases, but we can do this without making pathogens more deadly.

Are there two sides in the vaccine debate?

from December 2020.

I keep getting into debates with people about the safety and efficacy of vaccines. I’m not talking about anti-vaxxers (though I’ve encountered plenty of them), but level-headed, rational people who genuinely have doubts.

Usually their doubts about vaccines come from dubious sources, but there’s so much misinformation out there, often coming from people with the letters M.D. or Ph.D. after their names, that I can understand why it’s confusing.

So let me engage in what is sometimes called “both-sides-ism” (a disparaging term, of course) and consider, briefly, the pluses and minuses of vaccines. While I’m at it, I’ll include some points specific to the Covid-19 vaccines.

Let’s start with the pluses, shall we?

  1. Vaccines are the single greatest public health innovation in the history of medicine. They’ve saved millions of lives.
  2. Vaccines completely eliminated smallpox from the planet. They have nearly (but not quite, due to anti-vax resistance) eliminated polio.
  3. The new mRNA vaccines for Covid-19 are remarkably effective, have very few side effects, and are easy to modify as the virus itself mutates over time.
  4. Vaccines protect us so thoroughly against childhood infections that many formerly common infections–including measles, mumps, and Haemophilus influenza–have almost disappeared.
  5. Child mortality from infectious has plummeted in countries with robust early childhood vaccine programs.
  6. The vaccine against human papillomavirus (HPV) will prevent many thousands of cases of cervical cancer, throat cancer, and other cancers, saving lives for decades to come.
  7. Vaccines train our immune system to recognize and fight off infections, in many cases stopping the infection before we even have symptoms.

I could go on, but the bottom line is that vaccines continue to save millions of lives every year. They also dramatically reduce non-fatal illnesses, sparing people a great deal of suffering as well as long-term harms caused by some infections. (For example, mumps can cause permanent hearing loss.)

Given all of these benefits, you might wonder why everyone doesn’t get every vaccine available. Well, some people do, and part of the answer is simply that we don’t have enough vaccines for everyone, and many countries lack the public health infrastructure to deliver vaccines. But there are a few very small minuses, so let’s consider the downsides of vaccines:

  1. The shot (or “jab”) hurts a little bit, and your arm might be sore for a day.
  2. In very rare cases with some vaccines, some people might have allergic reactions. One example is that some flu vaccines are manufactured in chicken eggs, and people with egg allergies might react to those.
  3. In a few rare cases, the live polio virus vaccine has caused some people to get polio. This vaccine was discontinued in the U.S. decades ago.
  4. In rare cases, some people might have an immune response to a vaccine that causes ongoing inflammation. This includes the Covid-19 vaccine. However, the risk is much smaller than the risks associated with an actual infection.

That’s pretty much it. I hope it’s clear that the pluses far outweigh the minuses, but I imagine that some people looking at this list are wondering why I didn’t include a host of other supposed harms of vaccines, such as an increased risk of autism.

That’s because vaccines don’t cause autism or any other neurological disorder, as I’ve written before. Studies involving hundreds of thousands of people have been done to investigate this possibility, starting in the early 2000s, and all of the science points the same way: vaccines do not cause autism.

This supposed risk, and others like it, are inventions of the modern anti-vaccine movement. I won’t go into the history of the anti-vax movement here (I’ve done that before, many times), except to point out that many people promoting anti-vax misinformation are making lots of money selling “cures” for problems that don’t exist in the first place.

Anti-vaxxers continue to invent new harms caused by vaccines, and spread these claims on social media. Even with no evidence whatsoever, some of these claims catch on, because - well, the Internet.

Now back to the title of this column: are there really two sides to the vaccine debate?

Well, no.

Among doctors, scientists, and public health professionals, virtually everyone agrees with my first point in the “pluses” list above. However, we all recognize that when a foreign substance (a vaccine) is injected into one’s body, it’s possible that something unexpected might happen, and we must continually monitor vaccines so that we’ll know if something goes awry.

Let me end with an analogy. Seat belts in cars have been around for decades, and they’ve prevented millions of injuries and deaths. And yet people have argued (and probably still do) that it’s possible that wearing a seat belt might cause harm, for example if the belt jams and one cannot escape a burning car after an accident. (This seems to happen all too often in movies.) Thus you can’t argue that wearing a seat belt is 100% risk-free. Even so, wearing a seat belt is a really good idea, because the benefits are so much greater than the risks.

The same is true of vaccines. There might be some very, very small risks, but the benefits vastly outweigh them. And modern vaccines are safer than ever. There’s no serious debate about that.

Do telomeres measure our true biological age, and can we do anything to maintain them?

Telomeres are one of the keys to aging. We’ve known this for decades, and the scientists who first figured it out won the Nobel Prize in 2009. (One of them was my former colleague at Johns Hopkins University, Carol Greider.) Not surprisingly, many people have been trying, ever since, to use this discovery to slow down or reverse the aging process.

No luck so far, but that doesn’t mean you can’t spend money on your telomeres.

Over the past decade or so, a number of companies have started offering to measure your telomere length, which they suggest will tell your true, biological age. Sometimes, along with these measurements, they will offer to sell you something that they claim maintains or even lengthens your telomeres, thereby making you younger. What’s all the fuss?

Well, let’s start by explaining what telomeres are. Every cell in your body contains your DNA, arranged into 23 pairs of chromosomes. (That’s the origin of the company name for 23andMe, by the way.) Your chromosomes are very long strings of DNA letters (usually written A, C, G, and T). Through a quirk of biology, the very tips of our chromosomes are special: they contain thousands of copies, repeated end-to-end, of the 6-letter sequence TTAGGG. These are the telomeres, and they are a common feature in all animals, plants, and pretty much every living thing except for some single-celled microbes.

What’s fascinating about telomeres is that they provide a molecular “clock” that you can use to tell how old a cell is–sort of. You see, each time your cells divide, they have to copy all of that DNA, and sometimes they don’t quite copy the entire telomere. Over time, your telomeres get shorter.

This means that, in theory at least, your telomere length can tell you something about your age.

When humans are still infants, our telomeres are about 10,000 DNA letters long, and they slowly get shorter. By the time we’re in our 80s and 90s, our telomeres might be only 4000-5000 letters long–but this varies enormously. Telomere length varies from tissue to tissue–even your blood has many different types of cells in it, with different telomere lengths–and from person to person. Thus it’s entirely possible for a healthy 40-year-old to have telomere lengths that are typical of 80-year-olds, and vice versa. Here’s a graph from a scientific study that looked at telomeres in over 800 people, showing how they get shorter as you age. Length is on the vertical axis, measured in thousands, versus age on the horizontal axis:

As you can see, telomeres decline from about 10,000 letters (bases) at birth to about 5,000 in 80-year-olds, but many people have telomeres that are thousands of bases shorter or longer than the average.

When its telomeres get too short, a cell will die. So the reasoning goes, if we can keep our telomeres nice and long, we’ll live longer! It might seem simple, but it’s not.

First, it’s not clear that there’s anything we can do if we know the length of our telomeres. As my Hopkins colleagues Mary Armanios explained, “Within the normal telomere length range, it is not possible to determine a person’s exact biologic age, nor is it a good marker of a person’s ‘youthfulness.’”

The other problem is that it’s not clear that we can take any action to make our telomeres longer, or even to prevent them from getting shorter. But there are a couple of things you can try:

Exercise regularly. There is some evidence that regular exercise is correlated with longer telomeres. A study in 2017 concluded that “adults who participate in high levels of physical activity tend to have longer telomeres, accounting for years of reduced cellular aging compared to their more sedentary counterparts.”

Avoid stress. Another study in 2016 found that stress tended to make telomeres shorter.

Even if both of those studies are wrong about telomeres, the general advice to exercise and avoid stress is good for all sorts of reasons, so I’m happy to endorse these recommendations.

In addition, there are companies (like this one) that claim you can take supplements that will maintain telomere length, but I couldn’t find any solid evidence to back up those claims. So no, you can’t take a supplement or a pill that will restore your telomeres to the lengths they had when you were a baby.

Finally, there is some promising early research that uses mRNA technology–the same technology used to develop the new COVID vaccines–to deliver enzymes that rapidly increase telomere length in human cells. A huge caveat is that this only works in cells growing in a laboratory culture, and no one knows if it’s possible to do this in a living human. But it isn’t a crazy idea, so I’ll keep an eye on this research.

So what about companies that offer to measure your telomere length? Well, they really can do it, although the accuracy of various technologies will vary. Given what we know today, it seems unlikely that these tests will provide anything of value, unless you’re among a very small cohort of people who have a telomere-related genetic disorder. So my advice is, don’t waste your money. But it can’t hurt to exercise regularly and avoid stress, and both of these pieces of advice might help maintain your telomeres as well.