Genomic data is incredibly powerful. It can reveal migration patterns, or uncover interesting details like the distance people move from their place of birth to procreate. But more importantly, genomic data allows us to ask questions about human health, like how much genetic variations account for differences in individual life-spans. Large family trees allow us to analyze both close relatives and distant relatives, teasing apart the difference between genetic variations and environmental factors. Erlich, for example, found that genes account for only 15 percent of the differences in individual life-spans, on average about five years. Speaking about these surprising findings, Erlich says, “I think there is this notion that there is some fountain of youth in our genome, and we just have to find the gene to unlock it. But it doesn’t seem this is the case.” Erlich explains that since 1960, lifespans have increased linearly by about two months every year, despite two World Wars. Despite the many catastrophes of the 20th century, lifespans continued to steadily grow. Erlich says these findings mean that our actions might matter more than our genes. “Smoking for example, determines ten years of our life expectancy, which is twice as much as what our genetics determines.”

While genes seem to have relatively little impact on our life span, genomic data has allowed us to identify risk factors for a numbers of diseases. Using genome-wide association studies (GWAS), it’s possible to link genetic variants in different individuals to particular traits. The more statistically significant the link is, the more the data looks like the skyline of Manhattan. Ten years ago, Erlich says, these Manhattan plots actually looked more like the skyline of Los Angeles. But bigger sample sizes have become easier for researchers to access, thanks to initiatives like the UK Biobank, where an increasing number of genetic risk factors are being identified. Using data from more than 100,000 donors, obtained through the website DNA.land, Erlich has himself been able to discover the genetic bases for several traits in Israeli families.

With the help of civilian genealogy enthusiasts, genomic data is changing not only the landscape of health care, but forensics too. In April, thanks to the website GEDmatch, the FBI was able to link DNA from the unidentified Golden State Killer to a third cousin of the suspect who had voluntarily provided their own DNA to the free online genealogy database. By building a large family tree, and scanning the different branches of the tree until they found a profile that exactly matched what they knew about the serial killer, they were able to track down the suspect, test his DNA, and charge him.

Erlich is impressed by the power of genomics to improve demography, healthcare, and forensics. But he agrees there are many issues that still need to be addressed. For example, since these databases primarily contain people of European descent, non-European populations with certain genetic risk factors are missed, while risk factors identified in these European populations may not have the same implications for other groups. The most obvious reason for this disparity is economics. But many genealogy websites are free, and the price of DNA tests has dropped to as little as $49. Another reason may be access to family records. As Erlich says, “My family died in the Holocaust, so I have no means to go beyond a certain number of generations. It’s all lost.” A lack of record-keeping is also a problem for many populations. There’s also the question of social influence. “If I know someone who is doing genealogy, I’m now more willing to also do it. When you start with one community, it spreads from that community unequally.” Erlich does not have the answers for how to remedy the issue of diversity in databases, but believes that governments, at least in countries equipped with the resources, should take greater responsibility for driving genomic medicine.

Another complex issue is the issue of privacy. When it comes to genetic information, many of us are concerned that employers and insurance companies may use this information unethically. According to the Genetic Information Nondiscrimination Act of 2008 (GINA), employers and insurance companies cannot use our genetic information without our consent. But there are some major loopholes; for example, GINA doesn’t apply to life insurance. There’s also the question of how law enforcement should be allowed to use genetic information. The Golden State Killer case in particular raises many questions about privacy. Interestingly, 60 percent of Americans of European heritage (because they are over-represented in databases) have relinquished genetic information that could be used by law enforcement, and within three years, this number is expected to rise to 99 percent. Erlich says he's not scared of these techniques being abused. He’s more worried about national security. “I’m more concerned about foreign governments using the same techniques to identify U.S. individuals. Think about CIA operation in some countries. The whole point is that it’s covert—you don’t know the identities of these people. It’s very easy to disguise your face and get a fake passport, but you can’t change your DNA.” At the end of the day, there are no easy answers. “It’s a tricky question of justice, and how to define that,” he says, pointing toward the need to make genetic information part of a public good, rather than be used for monetary gain. But the limits may be hard to find. He says, “I don’t know what’s the right answer.”

The composition of our gut microbiome is often thought to be established as we pass through the birth canal, and greatly modified through our immediate environment in the first few years of life. After that, the microbiome becomes largely resistant to new bacteria. Interpreting this “gut-brain” axis has been the focus of Mazmanian’s work, revealing complex interactions between the gut and the brain, which increasingly look connected to everything from thoughts and emotions, to potentially the onset of certain brain disorders including Autism Spectrum Disorder and Parkinson’s disease.

You may be wondering a few things. How do trillions of bacteria establish themselves in our gut in the first place? How do our immune systems differentiate between the bacteria that make up our microbiome, and other harmful bacteria that makes us sick? Mazmanian says, “I think our microbiome, having evolved in the context of the immune system, have learnt to co-op with the immune system.” He adds, “Instead of trying to combat or invade the immune system, they actually engage it.” The good bacteria actually have a vested interest in their hosts being able to selectively attack dangerous bacteria, either because the “good” bacteria may also be harmed, either directly, or indirectly if their hosts perish. So, instead of avoiding immune cells, these beneficial bacteria have developed properties which redirects the immune response in a way that doesn’t cripple it. The “good” bacteria are spared, and the immune system is not prevented from attacking other pathogens. In this way, an amicable symbiosis is achieved, in which the gut microbiome is able to thrive in the warm, moist, nutrient-rich intestines. In fact, research carried out by graduate student Gregory Donaldson in Mazmanian’s lab suggests that one microbe in particular, called Bacteroides fragilis, might have even achieved long-term stability in the gut because of an immune response involving an antibody called IgA, which actually helps anchor it to the gut wall.

Mazmanian believes that our microbiome may influence many diseases. A few years ago, Mazmanian and his group noticed that children with autism — a neuropsychiatric disorder where children suffer from behavioral deficits, such as decreased vocalisation and social interaction, as well as repetitive behavior — also experience digestive issues, such as abdominal cramps and bloating. This was a clue that bacteria could be involved in the disease process. Other clues were that risk factors for autism include having a caesarean section, formula feeding, and taking antibiotics in childhood, all of which change the microbiome.

Mazmanian thinks the same may be true of Parkinson’s disease, a neurodegenerative disorder where neurons in the brain die, leading to motor symptoms like tremors, difficultly in walking, and rigidity. Like with autism, Parkinson’s patients often have gut symptoms. Strikingly, 80 percent of the three million people in the U.S. that suffer from Parkinson’s disease also suffer constipation—symptoms that sometimes precede the onset of motor symptoms. Interestingly, people who have had their vagus nerve, a potential highway between the gut and the brain, removed during surgery, are less likely to develop Parkinson’s disease.

To study how the gut may influence neurological diseases, Mazmanian completely removed the gut microbiome of mice that are genetically engineered to develop autism or Parkinson's. He found these mice no longer exhibited symptoms of Parkinson's or autism, suggesting that the microbiome is involved in both diseases. Mazmanian had stumbled on a remarkable discovery. “When we made these germ-free sterile mice, it gave us a research tool that we can now use for other purposes.” Next, he took fecal samples (which contain intact microbiomes of their donors), from both Parkinson's patients and healthy controls. He put these samples into bacteria-free sterile mice genetically modified to over-express a protein called α-synuclein (αSyn, which is associated with Parkinson's disease). The mice implanted with microbiomes from people who had Parkinson's had much worse symptoms than the mice who received microbiomes from a healthy control. Similarly, when mice with autistic behaviors that had their microbiomes removed were given certain beneficial bacteria recovered from neurotypical humans , Mazmanian’s team were able to reduce their vocalisation deficits and repetitive behaviors.

Of course, these studies have only been carried out in mice, since there are ethical issues with replacing a healthy human’s microbiome with one from a Parkinson’s patient. However, Mazmanian says that dozens of papers have shown that the gut microbiome in autistic people and Parkinson’s patients are different. The cause of these differences — maybe ethnicity, geography, genetics or diet — is unclear, but Mazmanian’s mouse experiments have led him to a provocative hypothesis. He thinks some forms of autism and Parkinson’s may not arise in the brain at all, but in the gut. By targeting the microbiome, in a personalized way, he hopes to develop a viable therapeutic.

It’s not just the gut that sends signals to the brain. Weirdly, the brain also communicates with the gut, although understanding this process has been more challenging. Members of Mazmanian’s lab have been trying to better understand brain --> gut communication by working with neuroscientists using genetic engineering techniques, brain lesion studies, and studying the vagus nerve. Anecdotally, we rely on “gut-feelings” or “gut-instincts” to help us make decisions, sometimes we experience “gut-reactions” in response to an experience, and when we are overcome with anxiety or excitement, we often feel it in in our gut as a stomach-ache or “butterflies.” These turns of phrase suggest what these scientists suspect: that our brains send signals to our gut via our nervous system in response to queues in the environment.

Mazmanian’s lab are trying to not just identify the bacteria that inhabit our guts, but what these bacteria are doing. “We take a reductionist approach in the fact that we work with single organisms we can genetically manipulate,” he says. “I want to manipulate both the bacteria and the host,” isolating each on a molecular level to identify the mechanisms by which they work.

Conversely, Mazmanian likens many traditional drug treatments to pouring oil all over the engine of a car, in the hope that some might get into the right place. He thinks the future of medicine is in “drugs from bugs,” saying, “Someday, you and I may go to the doctor and be prescribed a pill with a live bacteria inside of it as the remedy.”

Viruses may actually be responsible for the ability to form memories. Shepherd’s research focuses on how our brains encode, store, and retrieve memory, enabling us to learn – and what happens when these processes are disrupted as we age. Neurons in the brain don’t actually touch; there are gaps between them called synapses, across which signals are transmitted. Specific patterns of activity can alter the strength of these synapses. Known as synaptic plasticity, these patterns mediate both learning and memory. The star of Shepherd’s research is a protein called "activity regulated cytoskeletal" protein or Arc. By carrying out memory tests in Arc-deficient mice, Shepherd and his colleagues have shown that Arc is essential for memory. “If you take the Arc gene out of mice,” Shepherd explains, “they don’t remember anything.” These mice initially appear to be capable of learning, but they aren’t capable of retaining these memories. “If you come back an hour later or a day later, there’s just no consolidation.” Based on these studies, Shepherd believes that Arc is a critical piece of the brain’s conversion of memories from short-term to long-term storage.

Arc was first discovered in the mid-90’s by two independent research groups (led by Paul Worley and Dietmar Kuhl) looking for genes that could be switched on by learning. Around the same time that Arc was discovered, another group of researchers led by Oswald Steward were investigating whether protein synthesis could occur at the synapse, rather than the cell body like in most cells. It turned out that not only was Arc uniquely switched on by synaptic activity, but Arc messenger RNA, the molecule responsible for carrying the instructions to make Arc protein, was one of the first examples of an RNA molecule that gets trafficked from the cell body to the synapse. This finding prompted researchers to ask just how cells translated Arc RNA into a protein at the synapse.

When Shepherd started looking into this, what he found was "completely unexpected." In the lab, the Arc protein kept clumping up. “It seemed to be behaving weirdly,” he recalls. “We almost stopped doing the experiments, because we thought that we were stuffing up somewhere.” After a lot of head scratching, they concluded that the protein was clumping because it was much bigger than expected, and decided to look at the protein under an electron microscope. 

What Shepherd saw reminded him of something that had nothing to do with the proteins he was used to – the Arc protein looked like human immunodeficiency virus (HIV). Retroviruses, like HIV, lack the necessary biological machinery to replicate their own RNA. So instead, they have evolved to attach to a host cell, and insert their own genomic material into the genome of the cell, where it will be replicated as part of the cell’s normal process. To protect the viral RNA from being destroyed by the host defense system, viruses enclose their RNA in a protein shell called a capsid. This allows the virus to travel from cell to cell unscathed. Like HIV, Arc forms a capsid containing its own RNA – which was completely unheard of for a human protein.

Through mouse experiments, they also found that Arc proteins behave like viruses, “infecting” cells just like real viruses do. Shepherd found that Arc capsids released from one neuron are able to share their RNA with another neuron, similar to how viruses share RNA.

Which raises an important question: how did a protein that behaves like a virus end up in humans? Though the Arc gene’s evolutionary history is still being investigated, it is found in both birds and humans but not in fish. Since a version of Arc is found in humans and mice, scientists are now assuming that it is found in every land animal. Shepherd adds, “The closest sequence [to the Arc gene] in fish is an active retrotransposon,” which are pieces of genetic material that can jump from one part of a genome to another. He thinks the Arc gene was randomly inserted by a retrotransposon in an ancestor of both fish and land mammals over 350 to 400 million years ago. He concludes “Once it was incorporated into the genome it became repurposed."

Together, these studies show that Arc is a viral-like evolutionary remnant that is extremely numerous in the areas of the brain associated with memory formation, and helps control memory. But we don’t yet know the purpose of this viral-like mechanism. Unlike mice, fish without an Arc-like gene don’t have great memories but they still learn, so what does Arc confer to them? Shepherd speculates, “One explanation is that when animals moved onto land, there were all these new environments they had to adapt to – so you needed a smarter brain, and a more plastic brain. Perhaps that is why Arc is so useful: It can give that extra plasticity or some sort of advantage.” He thinks the capsid structure might have been preserved as a protective measure when transporting RNA, since that’s what viruses use their capsids for — to protect from cell defenses.

Like many discoveries, the surprising findings about Arc have led to more questions, many of which still don’t have answers. Shepherd and his group are already beginning to think about how this pathway could be implicated in Alzheimer’s disease and cognitive decline in aging, or harnessed for developing treatments. Perhaps Arc-like capsids could be used to remove toxic proteins. Or maybe it could be harnessed to deliver gene therapies without causing an immune response. It might even be possible to manipulate brain plasticity in order to enhance memory. The way Shepherd sees it, “Arc is really the intermediate between the environment and the wiring of the brain.” He explains that any time you encounter something new, or the brain needs to learn something new, Arc expression is enhanced. He says, “Anything that boosts cognitive awareness and plasticity, we think could boost Arc expression.”

Shepherd believes that there is a constant battle within the brain between plasticity and stability. "The young brain is extremely plastic, because you are learning about your environment. But at some point, this information must be retained, so the brain becomes more stable.” He says, "One way this could happen is that the inhibitory network of neurons gets stronger, making it more difficult to induce some of the genes required for plasticity" – like Arc. In a recent paper, Shepherd showed that if you boost Arc in normal adult mouse brains you can reopen some of the highly plastic parts of the brain in the critical period during infancy. It’s not difficult to imagine that the same might also be possible in humans. (Of course, Shepherd warns, such experiments would have to be extremely controlled.)

Furthermore, Arc is probably not the only gene of its kind. Shepherd thinks there are another 50 genes in the genome that have similar viral structure or origins. It’s unclear whether these other proteins could be involved in memory, or if there’s similar viral-like processing or pathways in other cell types. The questions Arc poses may lead us to even more exciting discoveries.

Large studies have revealed significant variation between the gut microbiome of both healthy individuals and those with health conditions, making it hard to identify associations between the gut microbiome and a person’s health. However, thanks to two recent studies (one in Amsterdam and one in Guangdong, China), the reasons for this variation are now clearer. The two studies showed that both ethnicity and geography are key factors in determining the gut microbiome. It gets even more complicated: most of the current knowledge about the connections between the microbiome and health come from studies of European and North American populations.

This new research highlights the importance of being careful when applying data about the gut microbiome to different groups of people: clearly, one size does not fit all. However, researchers still don’t know why differences in the gut microbiome are associated with ethnicity and geography. We’ll need to untangle the influence of genetics, cultural norms, and diet if we want to develop personalized microbiome-based treatments.

Now, scientists are transplanting "mini-brains" into the little brains of mice. Before you write us off as crazy cackling scientists in basements, let me explain why.

"Mini-brains," or brain organoids, the latest development in stem cell technology, are organized 3D cell structures made up of different brain cells, which resemble the complexity of the human brain. Human stem cells can be grown into brain organoids in 40 days, offering neuroscientists an unprecedented opportunity to more accurately model human brain development and disease. Until now, scientists had two choices: to study the brains of other mammals and extrapolate similarities with the human brain, or study the cells that make up the brain in a dish, which  although informative, can only tell us so much about how the human brain  works as a whole.

However, unlike our own brains, which last a lifetime, these mini-brains are relatively short-lived. The human brain has the advantage of a circulatory system, allowing it to survive and function. By supplying brain organoids with a special cocktail of factors, they can grow in a dish, develop and survive, but  only to a limited degree. But, by transplanting brain organoids into the brains of living mice, one group of scientists has shown that artificially grown organoids have the potential to resemble a real human brain even more closely when they  are sustained by a living blood supply. 

The group were able to show that the transplanted organoids can fully integrate into the mouse  brain, survive for up to 9 months, and develop to a level of maturity, which had not before been seen.

By  tagging the transplanted organoid and creating a  glass window in the skull, the group was able  to keep track of where it was in the mouse brain. The first thing they noticed was that compared to organoids kept in a dish, the organoids that had been successfully transplanted into the mouse brain shared more features with a human brain. The normal human brain has a network of cavities, which are filled by cerebrospinal fluid and is also formed up  of distinct layers of neuronal cells, which mature over time. In the  dish, organoids develop a cavity and begin to form different cell layers  like in a real brain, however, the cells that make up the layers do not  fully mature. When the researchers compared the different cell types  present in the implanted organoids vs. those that were formed in a dish,  they detected a higher number of mature neurons and also other cell  types, such as the star-shaped support cells of the brain, called astrocytes, which are not usually found in lab-grown organoids. 

The  human brain is made up of billions of neurons which need to communicate in order for our brains to function as a whole. The point at which two neurons meet is called a synapse and chemical signals are transported between neurons, across these synapses. Not only were the scientists able to show that the transplanted organoids developed mature neurons,  but also that these neurons were able to form synapses with each other,  and with resident neurons in the mouse brain.

The scientists' findings were staggering. They had predicted that providing organoids with a constant blood supply would allow the organoids to fulfill their true developmental potential, but they needed proof. By injecting a red  fluorescent dye (which can only be detected under a specific wavelength  of light  using a special microscope) into the mouse brains, which could  enter the blood stream, they were able to see the flow of blood through the blood vessels and saw that the blood vessels did indeed run throughout the  organoids.

By this point, it seemed like organoids with a living blood supply looked more like a human brain in terms of structure than they had ever looked in a dish because they were able to survive long enough to develop properly. However, the question still remained as to whether the neurons and their synapses were functional. Neurons are electrically excitable cells that receive, process and transmit information through electrical  and chemical signals. Calcium plays an important role in the transmission of electrical signals from one neuron to the next. Changes  in the levels of calcium at the end of neurons can be measured using calcium-sensing proteins that light up red. When the scientists looked through the glass window in the skulls of the mice, they were able to see that neurons did have fluctuating levels of calcium, suggesting that  neurons in the brain organoids were active. To be sure, they used electrodes to directly measure the electrical activity of the implanted organoid at different places and during different times of development, and discovered that the neurons were able to electrically stimulate each  other and respond to stimuli from the external environment.The researchers had succeeded in creating fully functional brain organoids. Then things got really interesting.

In their earlier experiments, the scientists had detected connections between neurons from organoids and neurons from the mouse brain, but they could not tell  whether or not the neurons could actually communicate with one and  other. Optogenetics is an extremely clever technique that uses light to  control neurons. By using this technique, the researchers were able to  specifically stimulate the neurons in the organoids by turning on and  off a light. When the light was on, the neurons of the organoids became  electrically active. When they used electrodes to measure the activity  of neurons outside the organoid in another part of the mouse brain, they  were able to detect electrically activated neurons there too, showing  that organoid neurons could signal to host neurons.

Those with an active imagination might picture the organoid taking over, creating some sort of "hybrid-consciousness." They wouldn't be foolish for thinking  so. Consciousness is a difficult term to grasp. It is a topic that still  has scientists scratching their heads. In fact, most scientists believe  that the origin of consciousness lies outside the realm of scientific inquiry. One thing that scientists can agree on though is that consciousness needs the brain, and that the neural circuits of which the brain is comprised are essential for certain aspects of consciousness. Therefore, if consciousness can be boiled down to neural connections then experiments like this raises interesting question about  whether consciousness can therefore be grown in the lab and it's  ethical consequences.

In a 2016 interview, organoid pioneer Madeline Lancaster at the Medical Research Council  Laboratory of Molecular Biology in Cambridge, England said of her 3D  brain tissue structures, “Just to be clear, they are not really human  brains.” At the time, she was able to recall 16 labs around the world  who had adopted her technique. But did she foresee that a year later, other labs would be injecting them into mouse brains? If neural networks  are at the root of consciousness and if we don't fully understand how consciousness arises because of them, do we need to consider the ethical implications of producing brain organoids, which are becoming better and better at forming functional connections? The president of the Allen Institute for Brain Science in Seattle, Christof  Koch, has concerns, saying in an interview last year "We are entering totally new ground here... the science is advancing so rapidly, the ethics can't keep up."

In reality, scientists develop techniques with noble intentions - to understand how our bodies work. Not to create "freaks of science." But in the process, techniques are developed which have further potential - potential that might be considered unethical. 

Animals are used in research without us fully understanding their consciousness, so why should we worry about creating artificial 3D brain-like structures? Maybe we shouldn't. This is something we, both the scientific community and the public, need to work out. A variety of 3D organoids including a colon, small intestine, liver, retinal cells (cells in the eye), and pancreas have been implanted into living organisms, in some cases, to repair and rescue tissue damage (colon, liver, and pancreas). Meaning that organoids may have potential for cell therapy. Stem cell therapy is  already being tested in a number of clinical trials, and organoids could be the next step. We are not that many steps away from organoids reaching a human brain, therefore, it is worth considering how they  impact the brains of other living creatures.
 

In his book, Berbiguier recounted his meeting with Pinel, saying, "After listening with great attention, this doctor told me that he knew of the type of disease affecting me, and that he had successfully treated people with it." However, Berbiguier continued feeling tormented by the imps and accused Pinel of making false claims.

Berbiguier wasn't wrong. The concept that hallucinations were not a disease per se but a "symptom" of different diseases developed in the 19th century after what one leading psychiatrist called a "long and barren" debate. Although hallucinations are now regarded as symptomatic of a number of disorders, they are not themselves necessarily harmful. As a symptom, they can indicate that the brain is not functioning properly, which may lead to other harmful symptoms, but hallucinations are not categorically good or bad.

The consequences of experiencing hallucinations vary from one experience to the next. For example, "low-level" auditory hallucinations experienced in the general population are usually mundane and cause little distress, while auditory hallucinations experienced by some schizophrenia patients during episodes of psychosis can be violent and extremely distressing, perhaps even leading to dangerous behavior that could harm the individual or others. (That said, violent behavior is rare, and the idea of people with schizophrenia being dangerous is largely a myth perpetuated by ill-informed media.)

Some people, both those with and without mental illness or a neurological disorder, actually enjoy their hallucinations. People who experience visual hallucinations following a bereavement, for example, can find them comforting. In one study, 86 percent of widowers described their hallucinations as good or helpful. Individuals with Charles Bonnet syndrome, a common condition among people who have lost their sight which causes them to see things that are not there, report mixed experiences. According to the late Oliver Sacks, seeing faces — which are sometimes deformed — is the single most common hallucination, an experience many people with the condition are averse to. The second most common hallucination is cartoons, which some patients do not mind.

Furthermore, many people deliberately induce hallucinations. In recent years, people in the west have started taking part in ayahuasca ceremonies, a traditional practice among indigenous groups of the Amazon, as a way to experience a "spiritual awakening" through experiencing visions. 

The use of hallucinogenic drugs have also been used as inspiration and a way to reach new levels of creativity. The book Riding So High, The Beatles and Drugs by Joe Goodden, describes how LSD greatly influenced The Beatles' music between 1965 and 1968, leading to the creation of the 1966 and 1967 albums, Revolver and Sgt Pepper's Lonely Hearts Club Band.

Hallucinations force us to question the very nature of reality. Unlike imagination, hallucinations don't seem to be of our own creation, are often outside of our control, seem to come from the outside world, and mimic perception. One might argue that it is easy to define reality in a way that rules out hallucinations by considering "normal" to be what appears to a large group of people. However, hallucinations can be experienced by large groups of individuals. 

Take Koro for example, a culture-bound syndrome in South East Asia that is characterized by a panic anxiety state that one's penis is shrinking or retracting into the abdomen, or even disappearing. Just because lots of people perceive something does not make it real. So what does?

I really do love corn, but not as much as one woman: Barbara McClintock. For nearly 70 years, she could not get enough of the stuff and, in 1983, her fixation won her a Nobel Prize.

By meticulously crossbreeding corn, McClintock showed that DNA is far more complicated than scientists originally thought. DNA, the blueprint of life, is about two meters long when unfurled and packaged into tightly coiled, thread-like structures called chromosomes, of which we have 23 pairs. You may have been told that our genes are instructions stored on DNA in our chromosomes like information stored on magnetic tape in the 1980s. Read out those instructions and voilà! You can build an organism.

However, in the 1930s and 40s, McClintock's work showed that some genes did not exist in fixed position on chromosomes, but could actually jump around from one part of the chromosome to another. These “jumping genes” are now called transposable elements. She also found that the genome is not just a passive database of information but a sensitive and dynamic system, containing a whole host of elements that interact with their environment and each other. Her ideas were completely radical at the time and met with “puzzlement, and even hostility” as she described it. It took everyone else over 20 years to catch up.

Early education and research

McClintock was born in 1902 in Hartford, CT. Her father was a homeopathic doctor whose parents emigrated to America from Britain, and her mother was a housewife, poet, and artist from an upper-middle-class Bostonian family. Growing up, McClintock, one of four children, liked being alone, often reading by herself in an empty room for hours. Her comfort with solitude was also true in adulthood, where she became a pioneer in corn cytogenetics, the combination of classic genetic techniques and microscopic examination of corn chromosomes.

Her love affair with genetics started in 1921, when she took a genetics course as an undergraduate at Cornell's University of Agriculture led by plant breeder and geneticist C.B. Hutchison. Hutchison was impressed by McClintock and invited her to participate in the graduate genetics program. That was it. In 1923 she received her bachelors, in 1925 her masters, and in 1927 a PhD - a feat quite commendable for a 24-year-old woman at the time.

After earning her PhD at Cornell, McClintock stayed on as an instructor and assembled a close-knit group of plant breeders and cytologists in the Department of Plant Breeding there, including two fellow graduate students, Marcus Rhoades and George W. Beadle (who went on to also win a Nobel Prize) and the department head Rollins A. Emerson. 

"We were considered very arrogant," she said. "We were ahead of all these other people, and they couldn't understand what we were doing. But we knew, and we were really a very united, integrated group." 

Back in the 1930s, the tools that we now have available to simply read a genetic code and link it to a particular trait did not exist; the fact that genes were encoded in DNA had not even been discovered yet. To understand the mechanisms of inheritance in plants, Barbara McClintock had to rely on cross-breeding corn and developing hybrids. Her research focused on finding a way to visualize corn chromosomes and characterize their shape in the resulting hybrids, igniting the field of corn cytogenetics at Cornell. In 1932, McClintock moved to the University of Missouri to work with geneticist Lewis Stadler, who taught her how to use X-rays to introduce mutations into chromosomes. She turned out to be very gifted at doing so.

Nobel-caliber research

In 1941, McClintock took up a research position at Cold Spring Harbor on Long Island and later became a permanent faculty member there, becoming known for her tenacity. My favorite story about McClintock is the one about her telling off a group of students – including a young James Watson, one of the scientists who would go on to discover the double helix structure of DNA – for wayward balls landing in her crop during their baseball games. Watson described McClintock as “like your mother” - and not in the good way. Little did he know that her research on corn genetics would go on to challenge the simplified version of DNA his work would later support.

McClintock remained at Cold Spring Harbor for the rest of her career. She spent much of her time there studying the relationship between color patterns on corn plants and the look of their chromosomes under a microscope. Drawing upon what she had learnt in Missouri, she used X-rays to destroy sections of chromosomes in order to work out where genes were, what they did and how they mutated, linking changes in genes on the chromosomes to changes in traits on the plant.

However, there were two genetic elements that McClintock could not locate on the chromosome and concluded that this was because they were not fixed to one particular position – they appeared to be jumping around the chromosomes and explained why some corn had a mosaic pigmentation pattern rather than being one solid color. This phenomenon had been described before – they were called ‘transposable elements’ – but McClintock had a new theory about them: she thought that they were responsible for controlling and regulating how the genes that they found themselves next to were expressed, and that this was a deliberate feature of how the genome worked not just in corn but in other organisms like humans.

McClintock was not completely right. Firstly, jumping genes – transposons – do exist in abundance; today we know that they make up 50 percent of the human genome. Secondly, though there are controlling elements in the genome that are responsible for switching genes ‘on’ and ‘off’ like molecular switches, they're not transposons. These elements, which regulate the expression of different genes and traits at different stages of development and allow different cell types with the same genome to have different patterns of gene expression, actually sit next to the genes they control and stay put. Still, she had stumbled upon an important fundamental idea about genetics. But when she presented what she believed to be the most important findings of her career at Cold Springs Harbor annual symposium in 1951, her work was not well received; her peers could not follow her theories, which they considered to be preposterous.

Disheartened, she decided not to bother publishing her work again after that. But she did not stop working on corn genetics – “When you know that you are right, you know that sooner or later it will come out in the wash,” she said.

In the 1960s and 70s, independent groups of scientists began to describe genetic regulation and the phenomenon of transposition in bacteria. In 1960, Francois Jacob and Jacques Monod described genetic regulation in bacteria. (Not missing a beat, McClintock responded in 1961 with a paper: "Some Parallels Between Gene Control Systems in Maize and in Bacteria".) McClintock’s earlier work started to gain credibility and finally, in 1984, at the age of 82, she got the recognition she deserved and was awarded the Nobel Prize in Physiology or Medicine for "The discovery of mobile genetic elements." Apparently, McClintock had no telephone at the time and happened to hear the news on the radio.

Gender Discrimination?

McClintock’s profound discovery was dismissed by her male colleagues for years. In the book A Feeling for the Organism: The Life and Work of Barbara McClintock, Evelyn Fox Keller paints this as gender discrimination, putting her late recognition down to the fact that she was a woman. This a story we hear a lot. Watson and Crick vs Rosalind Franklin and the Nobel Prize in Physiology in Medicine, Hewish and Ryle vs Jocelyn Bell Burnell and the Nobel Prize in Physics.

However, this may not have been the case for McClintock. As research for his book The Tangled Field: Barbara McClintock’s Search for the Patterns of Genetic Control, historian of biology Nathanial Comfort spent many hours looking through McClintock’s correspondences, research notes, and interviews and argues that this notion of gender discrimination is not consistent with the facts. She was enormously well respected in her time by both her male and female colleagues.

Describing this story of gender discrimination as mythology, arising only when she gained popularity in the run up to her Nobel Prize in the 70s and 80s and began to give more interviews, he explained in an interview on the BBC in April 2018 that her late recognition really was down to the fact that movable elements were reinvented in the 1960s when they were discovered in bacteria and given a different context. 

Barbara McClintock died in 1992, eight years after her Nobel Prize. Whatever the reason for her late recognition, she didn’t seem to mind – saying to People magazine 1983, “It might seem unfair to reward a person for having so much pleasure over the years.”

To better understand the link between exercise and aging, biomedical researcher Stephen Harridge of King's College in London and his colleagues looked at whether changes in the characteristics of skeletal muscle result from the aging process itself or the affects of lifestyle choices that are strongly associated with aging — like the tendency to adopt a more sedentary lifestyle. Because of the latter, the current perception of muscle structure and age come from studies in people whose physical activity is low. In these individuals, a number of characteristics "typical" of older muscle have been identified, such as changes to muscle fibers, but few studies have gone as far as to investigate the underlying cause of those changes.

Harridge and his group recruited 125 male and female amateur cyclists aged 55-79, who had been cycling regularly for about 26 years. The scientists predicted that since these athletes would have a similar level of high physical activity, any changes in their muscle as they aged could not be explained by inactivity, but rather than an inherent aging process. 

Biopsies were taken from one of the large muscles at the side of the thigh that we use during cycling — the vastus lateralis. Part of the biopsy was cut into thin slices so that its structure could be assessed under a microscope, and part of it was mashed up into a liquid so that its protein content could be calculated.

To investigate how the structure of muscle differs between cyclists aged 55 - 79 years of age, Harridge needed a set of easily measurable, clear muscle properties: capillaries, muscle fiber, and mitochondria, the highly specialized structures within our cells that use oxygen to make energy.

Capillaries supply the muscle with blood carrying oxygen, which is needed to make energy for muscles to function. Endurance exercise improves the delivery of oxygen to the muscle through increasing the number of capillaries that supply it. When the number of capillaries in the muscle biopsies were evaluated, Harridge and his colleagues discovered that there was no relationship between the age of female cyclists and capillary density, but there was a reduction in capillary density with increasing age in male cyclists. This finding, published recently in the journal Aging Cell, was one of the most important in the study, because it may prove that this change is affected by the aging process, and not because of the interaction between aging and inactivity.

Unlike capillary density, the effect of aging on muscle fiber composition was not as closely linked. Skeletal muscle is composed of two broad fiber types; slow twitch (type I) fibers, which contract slowly and allow us to carry out endurance activities like long-distance running, and fast twitch (type II) fibers, which contract in quick bursts, fatigue rapidly, and are used for power activities like sprinting or weight lifting. Older muscle tends to have smaller type II muscle fibers — partly explaining why elderly people find if difficult to make fast sudden movements. 

The main characteristic of type I muscle is that it uses oxygen, and therefore, it is not surprising that there were more type I fibers in the vastus lateralis of the younger male and female cyclists who participated in this study compared to type II fibers. Harridge and his colleagues discovered that this ratio of more type I to type II fibers stayed the same as cyclists aged. The scientists found that mitochondria, which function better in younger master athletes, also did not change with age among their study participants. These findings suggest that using our muscles to exercise into old age prevents them from deteriorating and maintains their function.

However, one important question still remained for Harridge and his colleagues: How these properties actually relate to the physiological functions that allow us to perform physical exercise — in this case, cycling.

In 2015, Harridge and his lab carried out another study on the same group of cyclists focusing exclusively on physiological functions, those physical mechanisms relevant to endurance and explosive muscle function, and found no strong relationship between them.

Endurance exercise is dependent on aerobic metabolism — the way the body generates energy by burning carbohydrates, proteins, and fats in the presence of oxygen — which can be measured by VO2max, the maximum amount of oxygen a person can use during intense exercise. Back in 2015, the scientists measured VO2max during a continuous progressive exercise test on a cycle ergometer. Harridge and his group discovered that the greater the proportion of type I to type II fibers the participants had, the better their VO2max. They also found that VO2max linearly increased with capillary density in males. In contrast to endurance exercise, explosive physical activities engage fast twitch type II muscle fibers.

To investigate the relationship between type II fibers and the generation of force and high power outputs, the participants were also asked to perform a number of explosive, high-power exercises, such as cycle sprinting and knee extensor exercises. These tests revealed that in male cyclists, type II fiber proportion and size was associated with peak power output during sprints and the rate of force development during maximum voluntary contraction, when extending the knee.

By combining findings from the two studies, Harridge and his colleagues were able to show that there is no age-related decline in selected properties of the vastus lateralis that are relevant to aerobic function and explosive muscle power. Instead, these factors are more influenced by a person's level of activity regardless of age.

While the general benefits of exercise are indisputable, there are a number of important caveats to consider before deciding to become a triathlete in the quest for eternal youth. The age range studied was relatively narrow, and participants already cycled regularly. Therefore, an important question that remains unanswered is whether or not it would be sufficient to take up cycling later in life. 

They also only studied one type of exercise. Could it be the case, for example, that some muscles "age" while others do not depending on the type of frequent physical activity? Indeed, the findings from Harridge's study differ from other studies looking at sprinters, endurance runners, and swimmers or just older people who regularly take part in moderate to vigorous physical activity of different ages. One study showed that in sprinters aged 18-84, for example, an age-related loss of type II fast twitch fibers was observed, suggesting that caution should be taken before concluding that any physical activity can stave of age-related changes in the characteristics of skeletal muscle in old age.

In the male-dominated field of physics, Burnell, who was born in Belfast in 1943, has won countless awards, became a Dame of the British Empire in 2007 and, shortly after, was appointed as the first female president of the Institute of Physics. Not bad for a woman once described as "meek" by a male colleague.

Looking closely at the cosmos

It all began at Glasgow university, where she studied physics, the only female in her class during a time when it was an accepted tradition for the male students to stamp their feet when a woman entered the room. After achieving her bachelors in 1965, she went on to pursue a PhD in radio astronomy at the University of Cambridge.

As part of her PhD under the supervision of Anthony Hewish and Martin Ryle, Burnell helped to construct a huge radio telescope, the size of 57 tennis courts, designed to measure quasars - rare celestial objects of massive proportions, which emit huge amounts of energy. Following its completion in 1967, Burnell was tasked with analyzing the data produced by the radio telescope. After countless hours looking at charts, she spotted a quarter-inch smudge on a graph hidden within three miles of printed paper charts that didn't fit the patterns usually produced by quasars. When she reported the anomaly to Hewish, he dismissed it, insisting that it could only be man-made interference.

But Burnell, a conscientious, thorough and pedantic 24 year old, couldn't let it go. She had to understand why she was seeing the signal. Slightly anxious about the fact that she herself had been responsible for connecting up the 125 miles of wires and cables and could have made a mistake, she spent months repeating tests to convince Hewish of her findings.

It turns out that she hadn't made a mistake: in fact, she went on to find a second, third, and fourth pulsar. Thanks to her curiosity, we now know that when big stars reach the end of their life and their outer layers explode into a supernova, they do not disappear into space but rather, their core becomes compressed in the explosion to form small neutron stars called pulsars (aka White Dwarfs). Pulsars spin at immense speeds, sending out beams of electromagnetic radiation, which can be detected when they are facing the earth - and this is what the telescope picked up.

In 1968, their findings were published in the journal Nature, but the resulting attention was bittersweet. In one interview, Burnell recalls an article entitled "Girl Discovers Little Green Men", featuring her vital statistics, height, chest, waist and hip measurements. "They did not know what to do with a young female scientist," she says.

That's been a theme of her long career – between discovering the second and third pulsars, Jocelyn Bell had become engaged to Martin Burnell, a recent Cambridge graduate who had taken a job on the south coast of England. They married just before her PhD thesis defense, then Burnell did what was expected of a wife: she moved to where her husband was and gave up work to concentrate on starting a family.

It didn't take her long to realize that giving up work to stay home and look after a baby was not for her. She decided to start working again part time in order to keep her career afloat, believing that she could have a career and a family. But, for the next 20 years, that career would be governed by the location of her husband's job first and her research interests second. With few role models and no mentor, Burnell was very much on her own.

A Nobel denied

In 1974, the Nobel Prize for Physics went to her PhD supervisor, Anthony Hewish, and department head Martin Ryle for their role in the discovery of pulsars. Burnell, who had just had a child and was working part-time at the university of Southampton studying and teaching a different branch of astrophysics, was not included in the prize. This caused a lot of controversy in the field at the time, with many academics objecting that Burnell should have been honored alongside Hewish and Ryle – without her attention to detail and persistence, that initial anomaly may have never been caught or taken seriously. Hewish responding by saying: "I mean, my analogy really is a little bit like when you plan a ship of discovery and you go off and somebody up the mast head says 'land-ho,' that's great, but who actually inspired it and conceived it and decided what to do when and so on... there is a difference between skipper and crew"

Burnell herself professed to be unfazed by the oversight, saying that being robbed of a Nobel put her in good company.

Beyond the Prize

In interviews, Jocelyn Bell Burnell is humble, gracious, and even good humored when she is asked about missing out on the Nobel Prize. Looking at her list of awards and long career, it is easy to see why. Making the most of of her first job out of Cambridge in 1968, a teaching fellow position at the university of Southampton that was not initially the best fit, Burnell spent five years learning how to teach and forging her own research interests before becoming a professor at University College London (UCL), where she spent almost 10 years. She also made other important contributions to astrophysics, including work on Cygnus X-3, a star system that represents one of the brightest sources of x-radiation in the sky. 

Over the years Burnell has held many important positions, making her one of the most respected university educators in the world. She has been a physics professor at the Open University, a visiting professor at Princeton, and dean of science at the University of Bath. She is currently a visiting professor of astrophysics at the University of Oxford.

She is also a fellow of The Royal Society – very few women are given this honor – and was the first female president of the Institute of Physics (2008-2010). 

Burnell is a science hero in many ways, not only for her massive contribution to the field of physics but for the tremendous grit she had to demonstrate in the pursuit of a career not designed for women. Should someone ever turn her into a comic book science hero, 'Badass Bell Burnell' would be a fitting name.

Williams syndrome is a genetic disorder that results in a particularly striking departure from what is considered normal behavior: people with it are hypersocial, extremely empathetic, and indiscernibly friendly towards strangers, especially as children – sometimes to the detriment of their own safety. Scientists have been able to pinpoint that the disorder, which affects 1 in 20,000 to 1 in 7,500 people, results from a deletion of 26 to 28 genes. In recent years, they've begun using Williams syndrome to study the influence of this select group of genes on our social behaviors.

Genetic manipulations in mice are frequently used as a tool in neuroscience to uncover the function of genes and their alterations. But single-gene ‘knock-out’ mice, in which a specific gene is lost, haven't really been able to show the role individual genes play in Williams syndrome. This is largely because the mutations in these genes don’t actually mirror the gene networks responsible for the characteristics that present in people with the disorder. Imagine the Royal Philharmonic Orchestra performing Tchaikovsky’s "Symphony No. 4" with just the string players missing – it might sound a bit off, but you’d probably still be able to make out the tune. If the woodwinds and the piano – two classes of instruments that also play a central role in the symphony – were missing too, the tune would be completely lost.

Unlike the diseases I study, for which a single gene is responsible, working out how a collection of 26 to 28 genes interact with external factors to shape social behavior is a lot more challenging.

In 2009, years after the first 25 Williams syndrome-causing genes were identified, a group of scientists decided to functionally pick apart the gene deletions that cause Williams syndrome by creating three different types of mouse models – two missing one copy of a different portion of the 25 implicated genes and a third mouse model lacking all 25 genes like in the human disease. 

All three mice were able to replicate crucial aspects of the human Williams disorder, including increased sociability, to varying degrees.

To explore the involvement of the two groups of genes in social disinhibition, a variety of social interaction tests were carried out in these mice. For example, in the partition test where a clear plastic wall is placed between cages that contain holes and the behavior and level of interest towards either a novel or familiar mouse on the other side is scored, all three deletion mice spent significantly more time close to the new mouse compared to normal mice. 

This suggested that multiple genes within the whole deletion region give rise to this behavior. However, for the tube test, where two mice meet in a narrow tube and the dominant one makes the other reverse, the full-deletion mice and only the mice that were missing the first portion of the 25 genes frequently lost to the normal mouse. 

Although mouse studies are clearly very helpful, providing a powerful way to study the effects of individual and combinatorial gene disruption, mice are genetically different from us and therefore do not perfectly represent our genetic landscape. To make things more complicated, this landscape is highly diverse between individuals. 

Stem cells derived from real patients with complex neurodevelopmental disorders such as schizophrenia can be turned into 2D and 3D cell structures and studied in a dish. Unlike mouse models, patient-derived stem cell models allow us to investigate the true, rather than similar, cellular effects of our genes. 

In the last few years, this strategy has been used by a number of research groups working on Williams syndrome to create brain cells that essentially have the human disorder, with their findings being published in Nature.

The gene GTF2I  has been studied in numerous patient-derived cellular models, revealing multiple functions. GTF2I is a transcription factor – a protein that controls how genetic information is expressed from DNA – and has been shown to play a key regulatory role by directly controlling other genes in the deletion region. Different cell lineages have been created, including the precursors of the telencephalon (telencephalic neural progenitor cells), the seat of all higher brain functions, and neural crest stem cells from which our facial structures derive. By studying these different brain cell types, scientists discovered that GTF2I is particularly bad at carrying out its job of controlling other genes in cells like the ones just described. As might be expected, these pathways are relevant to some of the characteristics associated with Williams syndrome.

These factors influence not just the social aspects of the disorder, but the physical characteristics associated with it as well. People with Williams syndrome have a striking set of facial features, traditionally described as "elfin," with an upturned nose, high cheekbones, big smiles, and pointy chins.  Taken together, it is not so surprising that some folklorists speculate that real people with Williams syndrome may have inspired many fictional works throughout history, such as William Shakespeare's Puck in A Midsummer Night’s Dream.

So what has studying Williams syndrome taught us about normal social behavior? Disease-causing genes that have been linked to particular traits of those with the disorder can offer clues for us to better understand variations in behavior within the general population. Differences in our DNA don't always cause disease. In fact, they are quite normal. These DNA "polymorphisms" can be single changes, deletions, or insertions or changes in the number of nucleotides, the building blocks that make up our DNA. Such polymorphisms can give rise to differences in certain human behaviors, and this is where Williams syndrome comes in.

'Social' genes

Through studying its multigenetic basis, Williams syndrome has helped us to identify which genes have an impact on our social behavior. For example, common polymorphisms in the gene GTF2I, found in the Williams syndrome deletion area, are associated with reduced anxiety in the general population and warmth, a facet of extraversion, in women. Offering a functional basis for variations in this gene, these polymorphisms have been specifically linked to reduced amygdala reactivity, a brain region involved in fear responses.

Williams syndrome hasn’t only helped us to understand our own social behavior, but also that of other species. Have you ever wondered why a dog is more likely to lick your face and wolf more likely to bite it off? Giving new meaning to the phrase "man's best friend," a study into the genetic basis of the various characteristics associated with domestication of dogs has found that our friendly canine pals have a genetic deletion in the equivalent genomic region linked to Williams syndrome in humans. They found that hypersociability, a key characteristic of the disorder, is a fundamental element of domestication that distinguishes dogs from wolves. Remarkably, they have also been able to identify structural variants in GTF2I and GTF2IRD1 that they propose contribute to extreme sociability in dogs, highlighting the conservation of these genes and their associated behavior between man and his best friend.

There are many rare diseases that go unnoticed. While often devastating for the people who live with them, they can seem irrelevant to everyone else because what leads to them is so hard to relate to. Hopefully though, what Williams syndrome can reveal about the way we interact with each other will encourages us to look a little closer at other rare and mysterious diseases and ask what they might teach us.

The fact that they're easy to make and behave a lot like the organs they resemble make them an exciting tool in the scientific study of health and disease. And, while they are still in their infancy in terms of development, organoids have a lot of potential in investigating the cause of neurodevelopmental disorders that haven't yet been cracked using more well-established methods, such as studying mice or two-dimensional cell cultures.

We have mice to thank for much of what we know about neurodevelopmental diseases. You may not think you have much in common with a mouse, besides a love of cheese, but we are quite similar at the genetic level. When common genes get messed up in mice, they end up with diseases that look similar to the way they do in people. However, this type of study doesn't work as well when looking at diseases that are caused by more than one genetic mutation – diseases like schizophrenia or autism, which are caused by multiple genes, are almost impossible to fully model in mice.

Enter organoids. Made out of stem cells, in their first incarnation (back in 2001) scientists figured out how to turn them into neural progenitor cells, self-renewing cells that can develop into the cells that make up the brain, like neurons and glia, but are not yet committed to one fate. These neural progenitor cells self-organized in 2D structures called rosettes that displayed features of the embryonic neural tube, the precursor to the nervous system. Ten years later, scientists found a way to go a step further: it became possible to create structures that look somewhat like the developed brain as a whole – or distinct regions of the developed brain, which could be fused together.

Making organoids

To make these 3D structures, you basically have to recreate the same environment within which the brain develops. We don't fully understand all the processes involved in neurodevelopment but, based on what we do know, it has been possible to recreate some important aspects of the process. For example, the protein SMAD, which is responsible for muscle and skin formation, can be inhibited, while the WNT signaling pathway, which involves numerous molecules responsible for regional patterning, can be carefully controlled, giving rise to different anatomical brain parts.

With that technological know-how, and the ability to turn a patient's cells back into pluripotent stem cells, it's possible to turn cells from patients who have complex diseases like schizophrenia into brain organoids, in a dish. We've been reprogramming and culturing patient-derived cells into pluripotent stem cells – with the kind of idiosyncratic genetic composition that is true to the nature of the genetic basis of schizophrenia – for years. But the ability to do this together with organoid technology is a step forward.

New models for psychiatric study

This technology provides an incredible opportunity for us to better model diseases, as the more complex tissue structure offers new possibilities for cellular and molecular analysis. It hasn't been extensively used to study neuropsychiatric disorders yet. But the few studies that have been done, like one in which organoids were generated from four patients with Austism Spectrum Disorder to reveal genetic abnormalities, are promising. Scientists speculate that self-patterning 3D brain organoids will allow for more accurate study of the cell-to-cell interactions that are involved in the formation of synapses, myelination (wrapping up nerve cells in a fatty white substance, which is crucial for proper signaling) and circuit maturation, all of which have been implicated in schizophrenia.

It's not just psychiatric diseases that could be better understood with the help of organoids. They are also being used to investigate the underpinnings of neurodevelopmental disorders. Because organoids resemble early stages of development, they have a lot of potential for studying developmental diseases that manifest in early embryonic fetal stages.

In fact, organoids have been useful following the outbreak of Zika virus in 2016. Zika caused birth defects in babies born to infected pregnant mothers, including microencephaly, where babies are born with smaller-than-average heads and brain damage. Using organoids, it was possible to identify a causal relationship between Zika infection and the destruction of neural progenitor cells; one study showed that organoids exposed to Zika underwent growth reduction, consistent with the observation of microencephaly in affected infants. Another reported reductions in the number of neural progenitor cells and neurons as a result of cell death.

Organoids are also being used to explore the mechanisms behind human cortical expansion and surface folding, which give brains their funny convoluted, appearance and cannot be properly explored in mice, which have smooth, simple brains. Gyrification, the process of forming folds, can be partially achieved in human brain organoids.

The biggest question facing researchers when it comes to organoids is how well they model human development. The answer, at present, is: not quite. But they are getting better.

Limits of mini-brains

The brain continues to develop after birth. While organoid development resembles the prenatal period quite well, many aspects of brain development, including the maturation of cortical circuits, takes years to develop in growing humans, making it impractical to model these processes in organoids. There also remains much work to be done in terms of achieving more complex aspects of cortical organization, such as gyrification, establishing proper neural connections, and proper cortical layering.

On a more intricate level, genes are not expressed in exactly the same way in brain organoids as they are in human brains. The fact that the genetic identity of the different cell populations in brain organoids do not perfectly reflect the genetic identity of the different cell populations in the human brain needs to be addressed before organoids can be considered an airtight way to research human diseases. The difficulty is that during development, genes are turned on and off in an extremely controlled manner, both temporary and spatially, to create the brain as we know it, and these patterns are difficult to achieve artificially, because the complicated processes involved are not yet fully understood.

Despite their current limitations, organoids represent the next generation in artificial cell-based models of the human brain. These "mini-brains"offer a complex system for studying the neurobiology of countless brain disorders – in a dish. Over the coming years, more and more scientists are likely to adopt these 3D mini-brains, expanding their application and in the process giving rise to improvements in current methods.

I cannot wait to see where the field goes. I work on a stem cell project which aims to cure a rare, genetic childhood neurobiological diseases called Sanfilippo syndrome Type B by supplying the brain, which lacks a particular protein, with neural stem cells that can provide a long-term supply of that protein. These neural stem cells have the potential to differentiate into different neuronal cell types. By injecting organoids into the brains of experimental models, it may be possible to provide the brain with a useful combination of already-differentiated cell types, increasing the therapeutic potential of our stem cell therapy. Not only are mini-brains helping scientists find answers to intractable genetic questions – they may also help to solve them.

That's the cutting edge of research into Batten disease, the rare childhood brain disease I studied for my PhD. An inherited disease that affects about 1 in 100,000 children worldwide but represents the most common cause of pediatric neurodegenerative disease, Batten disease is incredibly cruel. Named after Frederick Eustace Batten, a British neurologist and pediatrician who first discovered it in 1903, the disease is caused by genetic mutations that affect the cells' ability to get rid of metabolic waste. However, how this actually leads to disease is a mystery.

Without notice, an otherwise "healthy" child with the illness starts to lose vision between ages five and 10. It rapidly worsens. Other symptoms include personality changes such as becoming aggressive, other behavioral issues, and learning delays.

Seizures, sometimes violent, usually start around age nine and are followed by a gradual loss of movement and speech, initially appearing as clumsiness, unsteadiness, and Parkinson-like symptoms. Eventually, kids with Batten disease become blind, bedridden, and physically and mentally debilitated. They require 24-hour care until they die, usually in their early 20s.

The first time I heard about Batten disease, I was doing a masters in neuroscience. It was winter, the heat was on full blast, and I was sitting in a stuffy lecture theater thinking about whether it was jacket potato day at the cafeteria. Standing in the way of me and my potato was a lecture on rare childhood diseases. However, the professor giving the lecture was so incredibly passionate about his work that I soon forgot about lunch. I never forgot about Batten disease though, and when presented with an opportunity to study it years later, I couldn't turn away.

For years, there has been no effective way to treat this horrible disease. Most treatments have been symptom-orientated as part of an overall palliative care approach. For example, doctors often prescribe anticonvulsant drugs to control the seizures, and other medications to help alleviate psychiatric symptoms like hallucinations. To treat the underlying causes of disease, one promising candidate is gene therapy, which supplies cells that are missing or replaces defective genes with normal, working ones.

Although scientists have made incredible progress in terms of working out how to do this theoretically, some genetic diseases are more challenging to treat using gene therapy than others. Few studies have attempted to directly address the genetic defect behind Batten disease by using gene therapy, mainly because it becomes more complicated to target a mutation when, as in Batten, the faulty gene makes a protein that sits in the membrane of a cell rather than floating freely within it. And getting it wrong could be worse than taking no action: previous studies have raised concerns that the over-expression of the gene, CLN3, would cause more harm than good because it is normally expressed at very low levels that are tricky to match.

But a study last year pushed the boundaries of what's possible, presenting the possibility that gene therapy could ultimately save lives devastated by a Batten diagnosis.

In 2016, a paper by University of Nebraska pharmacology grad student Megan Bosch and colleagues hypothesised that if the CLN3 gene that is missing in Batten disease can be replaced in cells at the right level, the devastating symptoms that result from its absence will be alleviated.

To assess the idea, scientists genetically modified mice to remove the CLN3 gene, mimicking how Batten disease works in humans. The animals were injected with viruses containing the gene replacement at one month of age, and researchers assessed their behavior over the next five months as compared to untreated and control mice. Researchers used mice who already showed disease symptoms, rather than injecting them at birth, because children who may eventually receive the therapy are unlikely to be diagnosed before they become symptomatic.

The key part of the study is that they used two different forms of a virus to deliver the gene. In one virus, they expressed the CLN3 gene at a level three to eight times greater than the in the other. It was in mice where a lower level of expression was observed that neurons, which are usually severely affected, were infected by the virus at higher levels – and the mice appeared to suffer less from the disease. Researchers were able to show the importance of the level of CLN3 expression once the gene was delivered to the cells.

Taken together, this study identified a promoter – which turns on gene expression – that can turn on human CLN3 at a level that restores normal movement and decreases pathology in the brain of mice with Batten disease. These scientists showed for the first time that this type of gene therapy can help alleviate symptoms, a critical first step toward a viable treatment for Batten disease and its relatives.

This paper is so promising that the pharmaceutical company Abeona Therapeutics is preparing to launch a clinical trial in the next 12-24 months with the aim of reversing the genetic errors responsible for juvenile Batten disease.

One Batten disease story that will stick with me forever is the story of two parents who had what they thought was a perfectly healthy little girl, until they noticed that she was struggling to see clearly. After years of trying to get to the bottom of their daughter's vision loss, they received a misdiagnosis of Macular dystrophy, a rare eye disorder that causes blindness. The mother told me about how she was just about able to make peace with the fact that her daughter would have to go through life blind only to find out that this was only the beginning.

Imagine the devastation that followed when the parents learned she had an incurable disease. It's like being hit by a truck, getting up, then having it reverse and strike again at double the speed. No child, or parents, should have to endure this. And it's looking increasingly like, in the future, nobody will have to.