A rendering of in vitro fertilization.
Imagine two men making a baby. Or two women. Or an infertile couple. Or an older woman whose eggs are no longer viable. None of these people could have a baby today without the help of an egg or sperm donor.
Cells scraped from the inside of your cheek could one day be manipulated to become either eggs or sperm.
But in the future, it may be possible for them to reproduce using only their own genetic material, thanks to an emerging technology called IVG, or in vitro gametogenesis.
Researchers are learning how to reprogram adult human cells like skin cells to become lab-created egg and sperm cells, which could then be joined to form an embryo. In other words, cells scraped from the inside of your cheek could one day be manipulated to become either eggs or sperm, no matter your gender or your reproductive fitness.
In 2016, Japanese scientists proved that the concept could be successfully carried out in mice. Now some experts, like Dr. John Zhang, the founder and CEO of New Hope Fertility Center in Manhattan, say it's just "a matter of time" before the method is also made to work in humans.
Such a technological tour de force would upend our most basic assumptions about human reproduction and biology. Combined with techniques like gene editing, these tools could eventually enable prospective parents to have an unprecedented level of choice and control over their children's origins. It's a wildly controversial notion, and an especially timely one now that a Chinese scientist has announced the birth of the first allegedly CRISPR-edited babies. (The claims remain unverified.)
Zhang himself is no stranger to controversy. In 2016, he stunned the world when he announced the birth of a baby conceived using the DNA of three people, a landmark procedure intended to prevent the baby from inheriting a devastating neurological disease. (Zhang went to a clinic in Mexico to carry out the procedure because it is prohibited in the U.S.) Zhang's other achievements to date include helping a 49-year-old woman have a baby using her own eggs and restoring a young woman's fertility through an ovarian tissue transplant surgery.
Zhang recently sat down with our Editor-in-Chief in his New York office overlooking Columbus Circle to discuss the fertility world's latest provocative developments. Here are his top ten insights:
Clearly [gene-editing embryos] will be beneficial to mankind, but it's a matter of how and when the work is done.
1) On a Chinese scientist's claim of creating the first CRISPR-edited babies:
I'm glad that we made a first move toward a clinical application of this technology for mankind. Somebody has to do this. Whether this was a good case or not, there is still time to find out.
Clearly it will be beneficial to mankind, but it's a matter of how and when the work is done. Like any scientific advance, it has to be done in a very responsible way.
Today's response is identical to when the world's first IVF baby was announced in 1978. The major news media didn't take it seriously and thought it was evil, wanted to keep a distance from IVF. Many countries even abandoned IVF, but today you see it is a normal practice. And it took almost 40 years [for the researchers] to win a Nobel Prize.
I think we need more time to understand how this work was done medically, ethically, and let the scientist have the opportunity to present how it was done and let a scientific journal publish the paper. Before these become available, I don't think we should start being upset, scared, or giving harsh criticism.
2) On the international outcry in response to the news:
I feel we are in scientific shock, with many thinking it came too fast, too soon. We all embrace modern technology, but when something really comes along, we fear it. In an old Chinese saying, one of the masters always dreamed of seeing the dragon, and when the dragon really came, he got scared.
Dr. John Zhang, the founder and CEO of New Hope Fertility Center in Manhattan, pictured in his office.
3) On the Western world's perception that Chinese scientists sometimes appear to discount ethics in favor of speedy breakthroughs:
I think this perception is not fair. I don't think China is very casual. It's absolutely not what people think. I don't want people to feel that this case [of CRISPR-edited babies] will mean China has less standards over how human reproduction should be performed. Just because this happened, it doesn't mean in China you can do anything you want.
As far as the regulation of IVF clinics, China is probably the most strictly regulated of any country I know in this world.
4) On China's first public opinion poll gauging attitudes toward gene-edited babies, indicating that more than 60 percent of survey respondents supported using the technology to prevent inherited diseases, but not to enhance traits:
There is a sharp contrast between the general public and the professional world. Being a working health professional and an advocate of scientists working in this field, it is very important to be ethically responsible for what we are doing, but my own feeling is that from time to time we may not take into consideration what the patient needs.
5) On how the three-parent baby is doing today, several years after his birth:
No news is good news.
6) On the potentially game-changing research to develop artificial sperm and eggs:
First of all I think that anything that's technically possible, as long as you are not harmful to other people, to other societies, as long as you do it responsibly, and this is a legitimate desire, I think eventually it will become reality.
My research for now is really to try to overcome the very next obstacle in our field, which is how to let a lady age 44 or older have a baby with her own genetic material.
Practically 99 percent of women over age 43 will never make a baby on their own. And after age 47, we usually don't offer donor egg IVF anymore.
But with improved longevity, and quality of life, the lifespan of females continues to increase. In Japan, the average for females is about 89 years old. So for more than half of your life, you will not be able to produce a baby, which is quite significant in the animal kingdom. In most of the animal kingdom, their reproductive life is very much the same as their life, but then you can argue in the animal kingdom unlike a human being, it doesn't take such a long time for them to contribute to the society because once you know how to hunt and look for food, you're done.
"I think this will become a major ethical debate: whether we should let an older lady have a baby at a very late state of her life."
But humans are different. You need to go to college, get certain skills. It takes 20 years to really bring a human being up to become useful to society. That's why the mom and dad are not supposed to have the same reproductive life equal to their real life.
I think this will become a major ethical debate: whether we should let an older lady have a baby at a very late state of her life and leave the future generation in a very vulnerable situation in which they may lack warm caring, proper guidance, and proper education.
7) On using artificial gametes to grant more reproductive choices to gays and lesbians:
I think it is totally possible to have two sperm make a baby, and two eggs make babies.
If we have two guys, one guy to produce eggs, or two girls, one would have to become sperm. Basically you are creating artificial gametes or converting with gametes from sperm to become egg or egg to become a sperm. Which may not necessarily be very difficult. The key is to be able to do nuclear reprogramming.
So why can two sperm not make offspring now? You get exactly half of your genes from each parent. The genes have their own imprinting that say "made in mom," "made in dad." The two sperm would say "made in dad," "made in dad." If I can erase the "made in dad," and say "made in mom," then these sperm can make offspring.
8) On how close science is to creating artificial gametes for clinical use in pregnancies:
It's very hard to say until we accomplish it. It could be very quick. It could be it takes a long time. I don't want to speculate.
"I think these technologies are the solid foundation just like when we designed the computer -- we never thought a computer would become the iPhone."
9) On whether there should be ethical red lines drawn by authorities or whether the decisions should be left to patients and scientists:
I think we cannot believe a hundred percent in the scientist and the patient but it should not be 100 percent authority. It should be coming from the whole of society.
10) On his expectations for the future:
We are living in a very exciting world. I think that all these technologies can really change the way of mankind and also are not just for baby-making. The research, the experience, the mechanism we learn from these technologies, they will shine some great lights into our long-held dream of being a healthy population that is cancer-free and lives a long life, let's say 120 years.
I think these technologies are the solid foundation just like when we designed the computer -- we never thought a computer would become the iPhone. Imagine making a computer 30 years ago, that this little chip will change your life.
Researchers are looking to engineer chocolate with less oil, which could reduce some of its detriments to health.
Building a 3D tongue
The team began by building a 3D tongue to analyze the physical process by which chocolate breaks down inside the mouth.
As part of the effort, reported earlier this year in the scientific journal ACS Applied Materials and Interfaces, the team studied a large variety of human tongues with the intention to build an “average” 3D model, says Soltanahmadi, a lubrication scientist. When it comes to edible substances, lubrication science looks at how food feels in the mouth and can help design foods that taste better and have more satisfying texture or health benefits.
There are variations in how people enjoy chocolate; some chew it while others “lick it” inside their mouths.
Tongue impressions from human participants studied using optical imaging helped the team build a tongue with key characteristics. “Our tongue is not a smooth muscle, it’s got some texture, it has got some roughness,” Soltanahmadi says. From those images, the team came up with a digital design of an average tongue and, using 3D printed molds, built a “mimic tongue.” They also added elastomers—such as silicone or polyurethane—to mimic the roughness, the texture and the mechanical properties of a real tongue. “Wettability" was another key component of the 3D tongue, Soltanahmadi says, referring to whether a surface mixes with water (hydrophilic) or, in the case of oil, resists it (hydrophobic).
Notably, the resulting artificial 3D-tongues looked nothing like the human version, but they were good mimics. The scientists also created “testing kits” that produced data on various physical parameters. One such parameter was viscosity, the measure of how gooey a food or liquid is — honey is more viscous compared to water, for example. Another was tribology, which defines how slippery something is — high fat yogurt is more slippery than low fat yogurt; milk can be more slippery than water. The researchers then mixed chocolate with artificial saliva and spread it on the 3D tongue to measure the tribology and the viscosity. From there they were able to study what happens inside the mouth when we eat chocolate.
The team focused on the stages of lubrication and the location of the fat in the chocolate, a process that has rarely been researched.
The artificial 3D-tongues look nothing like human tongues, but they function well enough to do the job.
Courtesy Anwesha Sarkar and University of Leeds
The oral processing of chocolate
We process food in our mouths in several stages, Soltanahmadi says. And there is variation in these stages depending on the type of food. So, the oral processing of a piece of meat would be different from, say, the processing of jelly or popcorn.
There are variations with chocolate, in particular; some people chew it while others use their tongues to explore it (within their mouths), Soltanahmadi explains. “Usually, from a consumer perspective, what we find is that if you have a luxury kind of a chocolate, then people tend to start with licking the chocolate rather than chewing it.” The researchers used a luxury brand of dark chocolate and focused on the process of licking rather than chewing.
As solid cocoa particles and fat are released, the emulsion envelops the tongue and coats the palette creating a smooth feeling of chocolate all over the mouth. That tactile sensation is part of the chocolate’s hedonistic appeal we crave.
Understanding the make-up of the chocolate was also an important step in the study. “Chocolate is a composite material. So, it has cocoa butter, which is oil, it has some particles in it, which is cocoa solid, and it has sugars," Soltanahmadi says. "Dark chocolate has less oil, for example, and less sugar in it, most of the time."
The researchers determined that the oral processing of chocolate begins as soon as it enters a person’s mouth; it starts melting upon exposure to one’s body temperature, even before the tongue starts moving, Soltanahmadi says. Then, lubrication begins. “[Saliva] mixes with the oily chocolate and it makes an emulsion." An emulsion is a fluid with a watery (or aqueous) phase and an oily phase. As chocolate breaks down in the mouth, that solid piece turns into a smooth emulsion with a fatty film. “The oil from the chocolate becomes droplets in a continuous aqueous phase,” says Soltanahmadi. In other words, as solid cocoa particles and fat are released, the emulsion envelops the tongue and coats the palette, creating a smooth feeling of chocolate all over the mouth. That tactile sensation is part of the chocolate’s hedonistic appeal we crave, says Soltanahmadi.
Finding the sweet spot
After determining how chocolate is orally processed, the research team wanted to find the exact sweet spot of the breakdown of solid cocoa particles and fat as they are released into the mouth. They determined that the epicurean pleasure comes only from the chocolate's outer layer of fat; the secondary fatty layers inside the chocolate don’t add to the sensation. It was this final discovery that helped the team determine that it might be possible to produce healthier chocolate that would contain less oil, says Soltanahmadi. And therefore, less fat.
Rongjia Tao, a physicist at Temple University in Philadelphia, thinks the Leeds study and the concept behind it is “very interesting.” Tao, himself, did a study in 2016 and found he could reduce fat in milk chocolate by 20 percent. He believes that the Leeds researchers’ discovery about the first layer of fat being more important for taste than the other layer can inform future chocolate manufacturing. “As a scientist I consider this significant and an important starting point,” he says.
Chocolate is rich in polyphenols, naturally occurring compounds also found in fruits and vegetables, such as grapes, apples and berries. Research found that plant polyphenols can protect against cancer, diabetes and osteoporosis as well as cardiovascular ad neurodegenerative diseases.
Not everyone thinks it’s a good idea, such as chef Michael Antonorsi, founder and owner of Chuao Chocolatier, one of the leading chocolate makers in the U.S. First, he says, “cacao fat is definitely a good fat.” Second, he’s not thrilled that science is trying to interfere with nature. “Every time we've tried to intervene and change nature, we get things out of balance,” says Antonorsi. “There’s a reason cacao is botanically known as food of the gods. The botanical name is the Theobroma cacao: Theobroma in ancient Greek, Theo is God and Brahma is food. So it's a food of the gods,” Antonorsi explains. He’s doubtful that a chocolate made only with a top layer of fat will produce the same epicurean satisfaction. “You're not going to achieve the same sensation because that surface fat is going to dissipate and there is no fat from behind coming to take over,” he says.
Without layers of fat, Antonorsi fears the deeply satisfying experiential part of savoring chocolate will be lost. The University of Leeds team, however, thinks that it may be possible to make chocolate healthier - when consumed in limited amounts - without sacrificing its taste. They believe the concept of less fatty but no less slick chocolate will resonate with at least some chocolate-makers and consumers, too.
Chocolate already contains some healthful compounds. Its cocoa particles have “loads of health benefits,” says Soltanahmadi. Dark chocolate usually has more cocoa than milk chocolate. Some experts recommend that dark chocolate should contain at least 70 percent cocoa in order for it to offer some health benefit. Research has shown that the cocoa in chocolate is rich in polyphenols, naturally occurring compounds also found in fruits and vegetables, such as grapes, apples and berries. Research has shown that consuming plant polyphenols can be protective against cancer, diabetes and osteoporosis as well as cardiovascular and neurodegenerative diseases.
“So keeping the healthy part of it and reducing the oily part of it, which is not healthy, but is giving you that indulgence of it … that was the final aim,” Soltanahmadi says. He adds that the team has been approached by individuals in the chocolate industry about their research. “Everyone wants to have a healthy chocolate, which at the same time tastes brilliant and gives you that self-indulging experience.”
Probiotic bacteria can be engineered to fight antibiotic-resistant superbugs by releasing chemicals that kill them.
In recent years, researchers have been exploring a promising avenue: the use of synthetic biology to engineer new bacteria that may work better than antibiotics. The need continues to grow, as a Lancet study linked antibiotic resistance to over 1.27 million deaths worldwide in 2019, surpassing HIV/AIDS and malaria. The western sub-Saharan Africa region had the highest death rate (27.3 people per 100,000).
Researchers warn that if nothing changes, by 2050, antibiotic resistance could kill 10 million people annually.
To make it worse, our remedy pipelines are drying up. Out of the 18 biggest pharmaceutical companies, 15 abandoned antibiotic development by 2013. According to the AMR Action Fund, venture capital has remained indifferent towards biotech start-ups developing new antibiotics. In 2019, at least two antibiotic start-ups filed for bankruptcy. As of December 2020, there were 43 new antibiotics in clinical development. But because they are based on previously known molecules, scientists say they are inadequate for treating multidrug-resistant bacteria. Researchers warn that if nothing changes, by 2050, antibiotic resistance could kill 10 million people annually.
The rise of synthetic biology
To circumvent this dire future, scientists have been working on alternative solutions using synthetic biology tools, meaning genetically modifying good bacteria to fight the bad ones.
From the time life evolved on earth around 3.8 billion years ago, bacteria have engaged in biological warfare. They constantly strategize new methods to combat each other by synthesizing toxic proteins that kill competition.
For example, Escherichia coli produces bacteriocins or toxins to kill other strains of E.coli that attempt to colonize the same habitat. Microbes like E.coli (which are not all pathogenic) are also naturally present in the human microbiome. The human microbiome harbors up to 100 trillion symbiotic microbial cells. The majority of them are beneficial organisms residing in the gut at different compositions.
The chemicals that these “good bacteria” produce do not pose any health risks to us, but can be toxic to other bacteria, particularly to human pathogens. For the last three decades, scientists have been manipulating bacteria’s biological warfare tactics to our collective advantage.
In the late 1990s, researchers drew inspiration from electrical and computing engineering principles that involve constructing digital circuits to control devices. In certain ways, every cell in living organisms works like a tiny computer. The cell receives messages in the form of biochemical molecules that cling on to its surface. Those messages get processed within the cells through a series of complex molecular interactions.
Synthetic biologists can harness these living cells’ information processing skills and use them to construct genetic circuits that perform specific instructions—for example, secrete a toxin that kills pathogenic bacteria. “Any synthetic genetic circuit is merely a piece of information that hangs around in the bacteria’s cytoplasm,” explains José Rubén Morones-Ramírez, a professor at the Autonomous University of Nuevo León, Mexico. Then the ribosome, which synthesizes proteins in the cell, processes that new information, making the compounds scientists want bacteria to make. “The genetic circuit remains separated from the living cell’s DNA,” Morones-Ramírez explains. When the engineered bacteria replicates, the genetic circuit doesn’t become part of its genome.
Highly intelligent by bacterial standards, some multidrug resistant V. cholerae strains can also “collaborate” with other intestinal bacterial species to gain advantage and take hold of the gut.
In 2000, Boston-based researchers constructed an E.coli with a genetic switch that toggled between turning genes on and off two. Later, they built some safety checks into their bacteria. “To prevent unintentional or deleterious consequences, in 2009, we built a safety switch in the engineered bacteria’s genetic circuit that gets triggered after it gets exposed to a pathogen," says James Collins, a professor of biological engineering at MIT and faculty member at Harvard University’s Wyss Institute. “After getting rid of the pathogen, the engineered bacteria is designed to switch off and leave the patient's body.”
Overuse and misuse of antibiotics causes resistant strains to evolve
Adobe Stock
Seek and destroy
As the field of synthetic biology developed, scientists began using engineered bacteria to tackle superbugs. They first focused on Vibrio cholerae, which in the 19th and 20th century caused cholera pandemics in India, China, the Middle East, Europe, and Americas. Like many other bacteria, V. cholerae communicate with each other via quorum sensing, a process in which the microorganisms release different signaling molecules, to convey messages to its brethren. Highly intelligent by bacterial standards, some multidrug resistant V. cholerae strains can also “collaborate” with other intestinal bacterial species to gain advantage and take hold of the gut. When untreated, cholera has a mortality rate of 25 to 50 percent and outbreaks frequently occur in developing countries, especially during floods and droughts.
Sometimes, however, V. cholerae makes mistakes. In 2008, researchers at Cornell University observed that when quorum sensing V. cholerae accidentally released high concentrations of a signaling molecule called CAI-1, it had a counterproductive effect—the pathogen couldn’t colonize the gut.
So the group, led by John March, professor of biological and environmental engineering, developed a novel strategy to combat V. cholerae. They genetically engineered E.coli to eavesdrop on V. cholerae communication networks and equipped it with the ability to release the CAI-1 molecules. That interfered with V. cholerae progress. Two years later, the Cornell team showed that V. cholerae-infected mice treated with engineered E.coli had a 92 percent survival rate.
These findings inspired researchers to sic the good bacteria present in foods like yogurt and kimchi onto the drug-resistant ones.
Three years later in 2011, Singapore-based scientists engineered E.coli to detect and destroy Pseudomonas aeruginosa, an often drug-resistant pathogen that causes pneumonia, urinary tract infections, and sepsis. Once the genetically engineered E.coli found its target through its quorum sensing molecules, it then released a peptide, that could eradicate 99 percent of P. aeruginosa cells in a test-tube experiment. The team outlined their work in a Molecular Systems Biology study.
“At the time, we knew that we were entering new, uncharted territory,” says lead author Matthew Chang, an associate professor and synthetic biologist at the National University of Singapore and lead author of the study. “To date, we are still in the process of trying to understand how long these microbes stay in our bodies and how they might continue to evolve.”
More teams followed the same path. In a 2013 study, MIT researchers also genetically engineered E.coli to detect P. aeruginosa via the pathogen’s quorum-sensing molecules. It then destroyed the pathogen by secreting a lab-made toxin.
Probiotics that fight
A year later in 2014, a Nature study found that the abundance of Ruminococcus obeum, a probiotic bacteria naturally occurring in the human microbiome, interrupts and reduces V.cholerae’s colonization— by detecting the pathogen’s quorum sensing molecules. The natural accumulation of R. obeum in Bangladeshi adults helped them recover from cholera despite living in an area with frequent outbreaks.
The findings from 2008 to 2014 inspired Collins and his team to delve into how good bacteria present in foods like yogurt and kimchi can attack drug-resistant bacteria. In 2018, Collins and his team developed the engineered probiotic strategy. They tweaked a bacteria commonly found in yogurt called Lactococcus lactis to treat cholera.
Engineered bacteria can be trained to target pathogens when they are at their most vulnerable metabolic stage in the human gut. --José Rubén Morones-Ramírez.
More scientists followed with more experiments. So far, researchers have engineered various probiotic organisms to fight pathogenic bacteria like Staphylococcus aureus (leading cause of skin, tissue, bone, joint and blood infections) and Clostridium perfringens (which causes watery diarrhea) in test-tube and animal experiments. In 2020, Russian scientists engineered a probiotic called Pichia pastoris to produce an enzyme called lysostaphin that eradicated S. aureus in vitro. Another 2020 study from China used an engineered probiotic bacteria Lactobacilli casei as a vaccine to prevent C. perfringens infection in rabbits.
In a study last year, Ramírez’s group at the Autonomous University of Nuevo León, engineered E. coli to detect quorum-sensing molecules from Methicillin-resistant Staphylococcus aureus or MRSA, a notorious superbug. The E. coli then releases a bacteriocin that kills MRSA. “An antibiotic is just a molecule that is not intelligent,” says Ramírez. “On the other hand, engineered bacteria can be trained to target pathogens when they are at their most vulnerable metabolic stage in the human gut.”
Collins and Timothy Lu, an associate professor of biological engineering at MIT, found that engineered E. coli can help treat other conditions—such as phenylketonuria, a rare metabolic disorder, that causes the build-up of an amino acid phenylalanine. Their start-up Synlogic aims to commercialize the technology, and has completed a phase 2 clinical trial.
Circumventing the challenges
The bacteria-engineering technique is not without pitfalls. One major challenge is that beneficial gut bacteria produce their own quorum-sensing molecules that can be similar to those that pathogens secrete. If an engineered bacteria’s biosensor is not specific enough, it will be ineffective.
Another concern is whether engineered bacteria might mutate after entering the gut. “As with any technology, there are risks where bad actors could have the capability to engineer a microbe to act quite nastily,” says Collins of MIT. But Collins and Ramírez both insist that the chances of the engineered bacteria mutating on its own are virtually non-existent. “It is extremely unlikely for the engineered bacteria to mutate,” Ramírez says. “Coaxing a living cell to do anything on command is immensely challenging. Usually, the greater risk is that the engineered bacteria entirely lose its functionality.”
However, the biggest challenge is bringing the curative bacteria to consumers. Pharmaceutical companies aren’t interested in antibiotics or their alternatives because it’s less profitable than developing new medicines for non-infectious diseases. Unlike the more chronic conditions like diabetes or cancer that require long-term medications, infectious diseases are usually treated much quicker. Running clinical trials are expensive and antibiotic-alternatives aren’t lucrative enough.
“Unfortunately, new medications for antibiotic resistant infections have been pushed to the bottom of the field,” says Lu of MIT. “It's not because the technology does not work. This is more of a market issue. Because clinical trials cost hundreds of millions of dollars, the only solution is that governments will need to fund them.” Lu stresses that societies must lobby to change how the modern healthcare industry works. “The whole world needs better treatments for antibiotic resistance.”