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by Kasra Hassani
Up until a month ago, a Google search with the keyword organoid would mostly lead to links to animé characters. Today, a recent publication about creating human brain organoids has changed that a little bit — organoids are a trendy new theme in developmental biology research, slowly spilling out into the mainstream. Before some witty writer channels Raymond Bradbury or Stephen King and bestows on organoids a provocative nickname, I’d like to lay down some foundational information.
What exactly are organoids?
In normal organs within our body, various cell types exist concurrently. For example:
• the liver, a fairly complex organ, consists of hepatocytes (basically liver cells), some immune cells, specialized blood vessels that run through it, and still some other cells.
• the small intestine is made of enterocytes (internal cells) specialized in absorbing the digested food, mucus producing cells, antimicrobial producing cells, lots of different immune cells and again blood vessels.
However, one sort of cells that all organs (at least at some point during their development) share are stem cells. Stem cells have the ability to self-renew, meaning they divide to cells that have the ability the same ability. These cells can also specialize or as biologists say differentiate into mature cells (like brain cells, blood cells and kidney cells (Watch this short video to learn more). During development, organs are formed from division and differentiation of stem cells and from their three dimensional organization that gives the organ its structure and shape and allows it to perform its function properly. Intriguingly, if the stem cells are put in the right conditions, they are actually able to divide, differentiate and self-organize to form an organ by themselves!
Researchers are currently in the process of understanding how these events occur during the development of an organ, meaning how do stem cells know when to divide and when to differentiate, how do they choose the cell type to differentiate into and how do they organize into 3D organ structures. This research has also led to the development of a new type of research models: organ-like tissues or organoids. Organoids are like mid-way organs, not as intricate as an actual organ, but more elaborate than a flask of more or less identical cells usually used in research.
How are they made? What kinds have been made so far?
Organoids are mostly formed by culturing and differentiation of stem cells. Many of the cells in our body do not live very long and need to be replaced regularly. Examples are red blood cells that are cleared from the blood after about 100 days and skin cells that are constantly shed from the body. Thanks to stem cells, our body has the ability to repair some tissues that become damaged. It also appears that if stem cells are put in the right concentrations of nutrients and growth factors outside of the body, they could still differentiate into cells and tissues similar to their whole organism counterparts, or even more, organ-like structures or organoids. What makes organoids thrilling is that together with cellular differentiation, the cells also go through 3D self-organisation. Using this method, researchers have been able to make organoids from many body organs such as skin, small intestine, liver, kidney, retina, pituitary gland and brain.
Let’s take an example: The first report of a small intestine organoid goes back to 2009. The human adult small intestine has a structure of alternating protrusions and invaginations called villi (singular villus) and crypts respectively. These structures dramatically increase small intestine surface to maximize food absorption. The cells carpeting the small intestine are constantly being renewed with new ones being made in the bottom of the crypts and slowly migrating up while the ones on the top of the villus are being constantly shed. The whole surface of the small intestine is renewed almost every few days. Scientists believe that this constant renewal and shedding is an evolutionary mechanism to limit the time a pathogen could have for spreading if it has infected an intestinal cell (more on that maybe in another post). Additionally, this means that there are rapidly dividing stem cells present in the bottom of intestinal crypts leading to formation of the intestinal cells that slowly migrate up and replace the old ones. Back in 2009, scientists managed to create organ-like structures from stem cells purified from the small intestine. Given the right conditions and media, the researchers were surprised to see that a single intestinal stem cell could form an organoid structure containing villi and crypts with a small variety of differentiated cells! Listen to a podcast interview with the senior scientist for this discovery here.
Skin tissue has a similar story. It is also continuously being renewed and shed. So its stem cells can be used for making skin-like organoids outside of the body. Actually, organotypic skin has been available for a much longer time and researchers can now even be purchase them from different companies such as here and here for their experiments. Scientists are also trying to use this technology to help produce skin for patients with serious burns or wounds using their own stem cells. Hear more about it from researchers in Alberta here.
And finally the most exciting of them all, the brain organoid has been made also from pluripotent stem cells (stems cells that can differentiate into any kind of cell in the body). This story has been covered rather extensively so I won’t repeat it. The full paper and it’s comment in Nature magazine are behind a paywall but you can read reports here and here.
What are the benefits of using organoids in research?
As I mentioned above, organoids are something in between simple cell culture systems and full organs that can only be accessed via animal models. They have a bit of benefits from each and lack some drawbacks of each.
Cell culture systems are created when a type of cell (like an immune cell, liver cell or muscle cell) is immortalized usually because it is cancerous. It still keeps some of its original properties and behaviour, but it also changes in many ways due to immortalization. Cell culture is a rather simplistic model for studying biological systems. In contrast to actual organs where only stem cells continue to divide, all of the cells in most cell culture systems continue to divide indefinitely. That is a good thing when you want to have lots of them for your experiments, but a bad thing if you want to have a realistic model. Additionally, cell culture systems usually contain only one or two cell types and lack the three dimensional organisation and cell diversity that is existent in organs. In contrast, organoids are more similar to actual organs, because they have more cell diversity, self-organization and 3D structure. Moreover, organoids can be constructed from human stem cells, so they would be more similar to human tissues than animal equivalents. So a human brain or liver organoid system could potentially provide precious information in modeling human diseases.
Organoids can be extremely beneficial in tackling questions about the development of an organ: What is the role of a certain gene during organ development? How do certain cell types form and interact with one another and what signals do they send and receive? Organoids are used as models for some congenital disorders and developmental defects. One of the main objectives of the researchers who have published the recent study on the brain organoid has been to create better a model for neurodevelopmental disorders such as microcephaly.
One recent example of application of organoids in health research is studying cystic fibrosis. Cystic fibrosis is a debilitating genetic disease caused by malfunction of a single protein called cystic fibrosis transmembrane conductance regulator or CFTR, which is responsible for chloride ion transport across the cells. Researchers were able to create miniguts with deficient CFTR and not only take a closer look at its pathology but also assay different putative drugs on progression of the disease. The full study is behind a paywall, but you can read a report here.
Besides development and diseases, another important field of organoid research is using them for repairing and eventually replacing damaged organs by permitting stem cells to regrow the damaged areas inside the body. This has been already done a few times with simpler organs such as the tracheaand critical advancements have been made in making bio-engineered skin(links above) and liver for transplantation.
What are the drawbacks of using organoids in research?
Having only miniature forms compared to a complete organ, organoids are normally not larger than a few millimetres, at least until now. They (so far) do not have blood vessels to provide their internal cells with food and oxygen, so they cannot grow very large. Although they are more complex than cultured cells, organoid cell diversity, tissue complexity and developmental level are still far behind that of actual tissues and organs, making them both suitable and unsuitable as models, depending on what you are looking for. All models have their limitations. That is why research is best done when different models are used to look at the question from different perspectives and not one instead of the other.
Can they eventually replace animal testing?
Definitely not. As I discussed in a previous post, complex multi-organ interactions within the body such as systemic and longterm effects of a drug or a chronic disease, interactions of the body with the trillions of bacteria living inside it, or behaviour can only be studied in appropriate animal models. On the other hand, one could say if organoids become cheaper, more accessible and easier to handle and manipulate, they could reduce the burden of experiments done on animals. Or better say, they could potentially provide more accurate answers to some questions compared to current animal research. It will take some time until these sophisticated and trendy techniques, currently run by a minority of research labs, to be adopted by the whole scientific community. Only then the full scale of their academic and therapeutic applications can be appreciated.
P.S. While I was finalizing this post, news stories came out reporting production of first pancreatic organoids and also significant advances in production of skin tissue! Organoid research is definitely developing at an incredible speed!
Kasra Hassani is currently a postdoctoral fellow in mucosal immunology in Hannover Medical School, Germany. He uses mice and cell culture models to study the small intestine of adults and newborns. His research projects aim to understand the interactions of the cells lining the interior of the small intestine with different pathogens such as Salmonella, Rotavirus and Giardia, all of which cause significant morbidity worldwide, especially in children.
My thoughts on the film, Naturally Obsessed: The Making of a Scientist, by Richard Riftkind and Carole Riftkind
by Meredith Hanel
This is a documentary film that follows three scientist trainees, in the lab of Dr. Lawrence Shapiro at Columbia University Medical Center. I had the opportunity to view this film at the Canadian Science Policy Conference (CSPC) this past week. Unfortunately, since the documentary was running concurrently with some excellent panel discussions, only a few of us opted for the movie. I was drawn to it out of both nostalgia and curiosity. I left lab life a few years ago, having worked in molecular biology during undergraduate, graduate school, and two postdoctoral positions.
I have fond memories of lab life and I was hoping this film would pull on my heartstrings. It did. I was curious about whether this film would be an accurate portrayal of lab life, if it could offer outsiders a true sense of what it is really like to work in a scientific laboratory and help people understand “why haven’t they cured cancer yet?”
Thankfully this documentary was not artificially staged or prettied up with colourful bottles and smoke to make science look cool. Science is cool, but the gruelling scientific process, not usually seen by those on the outside, is uncool. What this film offers is a raw look at the personal struggles that young scientists face, and a feeling for what motivates scientists to continue when things get tough. All three characters are driven by the chance to discover something or need to know how something works.
The most senior PhD student, Robert Townley, is attempting to solve the crystal structure of AMPK, an important regulator of metabolism. The film shows how a little bit of hocus pocus, superstition and a lot of faith go into getting difficult techniques to work, especially when you may not be able to monitor the subject of your experiments until after an incredible number of steps have been carried out. It was agonizing to watch Robert work for years on just getting crystals to form only to discover they were not good enough for analysis. Failure after failure, Robert carries on, and that tenacity is the key to success.
Two other characters, Gabe and Kil, show viewers why not every PhD ends up a professor, something called “leaks in the pipeline.” Kil struggles with pressures from his girlfriend and from himself to move on in life, buy a house, have kids, but is stuck in limbo living the poor student life. Gabe starts off enthusiastic but later appears lost with too little supervision for her comfort level, from Dr. Shapiro, who believes less interference from him teaches students to be independent. Gabe longs for a more defined job and more sense of accomplishment, which she eventually finds—along with a happier life—after leaving the PhD program and getting a laboratory job at a biotech company.
This documentary is a window into the rollercoaster ride that is laboratory research, highlighting the human side of scientists and showing that earning a PhD is a real endurance test.
More information about the film can be found at http://www.naturallyobsessed.com/
Meredith earned her PhD in medical genetics and spent many years in the lab doing research in molecular and developmental biology related to medicine. Meredith works in science outreach with Scientists in School. She enjoys writing about science and loves to find out the biology behind just about anything in nature. You can read her blog at http://biologybizarre.blogspot.ca
Eight months pregnant and stressed-out was how I found myself roughly two years ago, sitting in front of the computer screen. I was on the Air Canada website, attempting to book a flight from Vancouver to Winnipeg so I could visit family six weeks after my daughter’s due date. But I was terrified to click on “Book Flight.”
Everyone knows that airplane cabins are festering clouds of germs, right? There’s science to back that up: one study of microbes inside airplanes found that circulating cabin air contained an abundance of “opportunistic pathogenic inhabitants of the human respiratory tract and oral cavity.” So if I brought a newborn with a still-developing immune system on board, would I be putting her life in danger? She wouldn’t even have had her first vaccinations yet. What kind of monster would I be for taking her on this flight?
At the time, my knowledge about the infant immune system was based mainly on what my health care practitioners had told me–which was practically nothing. I had even asked a nurse about airplane flights, specifically, and she said she didn’t know whether or not it was a good idea. That probably accounted for why I couldn’t bring myself to click the button that committed me to the flight.
What I failed to realize at the time was how much the recent research on the human microbiome—the bacteria that live on and inside us–was relevant to the issue. It just required putting together a few scientific pieces.
When a baby is born, she is more-or-less a microbial blank slate. (Recent research calls into question the age-old assumption that babies are completely bacteria-free in the womb, but it’s clear that the main bacterial exposure comes during and after birth.) So the act of coming into the world is of great importance to a baby’s health, because the moment she hits the birth canal, she is exposed to a diverse set of bacteria that colonize her tiny body.
The baby’s immune system is indeed immature at that point, leaving her vulnerable to infections. In fact, a new study actually found evidence of immunosuppression in newborns, which is probably because the baby needs to remain “vulnerable to,” or open to, good bacteria taking up residence. It seems excessive inflammation caused by a sensitive immune system would do more harm than good at that point.
The microbes that colonize a newborn’s body in the first weeks basically are her immune system. When the right kinds of good bacteria are present, pathogens have more difficulty getting a foothold.
So what gives a newborn a healthy collection of microbes that provide immunity? Studies consistently find that infants who have been delivered vaginally, rather than by cesarean section, have microbiomes that contain a greater number of species. Ditto for those who were breastfed–they got a bunch of good bacteria packed into every meal (though certain probiotics can easily substitute). Gestational age at birth also seems to matter, as the colonization happens differently in a preterm baby’s gut. Other bacteria, both good and bad, come from the baby’s environment–the people and surfaces that she touches.
The science seemed to say that as long as baby’s good bacteria are thriving, the chances of her getting a terrible bacterial infection on an airplane flight should be quite low. Great news.
But on the other hand, there’s still a problem. Despite the gargantuan importance of the microbiome early in life–with some calling it the “forgotten organ” of the human body and arguing that the effects of early microbial colonization last a lifetime–why are health practitioners not prepared for questions about it? My (anecdotal) survey of friends who’ve recently had babies uncovered not a single report of a care provider who had brought up the topic. It’s a huge oversight, given the volume of research on the topic over the past two years or so. Doctors, nurses, and midwives need to get up-to-date on this, and quickly. Especially because a few good ideas are bouncing around that may help save some newborns from serious infections. In my case, giving me all the facts might just have saved me from unnecessary anxiety.
The end of the story is this: I took the flight, and the baby was fine. In fact, we took 18 flights the first year, and all of them were fine. The risk of taking a baby on an airplane, or anywhere that’s microbially unfamiliar, can be mitigated by ensuring good colonization in those early weeks.
Unfortunately, I can’t say the same for the risk of dirty looks from fellow passengers when your baby cries. Good luck with that, parents.
Kristina Campbell, a.k.a. “The Intestinal Gardener”, writes about gut bacteria research at http://intestinalgardener.blogspot.ca/
by Brian Owens
The NDP is making a play for the science vote. At last week’s Canadian Science Policy Conference the party’s science critic, Kennedy Stewart, unveiled the third plank in the opposition’s slowly developing science policy: an independent Parliamentary Science Officer (PSO).
Stewart will table his proposal in the house this week as a private member’s bill – it would create a position whose job would be to both provide independent, nonpartisan scientific information to MPs on demand, but also to scrutinize and pass judgement on the scientific basis for any proposed bill or policy.
I’m not entirely convinced how this would work. The independent advice part is based on the UK’s Parliamentary Office of Science and Technology (POST), but that office never passes public judgement on government policy the way the PSO seems to be intended to do. In fact, in my eight years in London reporting on science policy I rarely had much reason to pay attention to POST. They produced nice, concise summaries of scientific matters like vaccines or geoengineering, which MPs could use to get a quick grip on an issue, but were mostly invisible outside of Westminster.
The other model Stewart mentioned was the Parliamentary Budget Officer, but after Kevin Page’s rocky ride in that role, it’s pretty clear that another person whose job it is to point out inconsistencies in government policy would not be welcomed with open arms in Ottawa. Sometimes (well, let’s be honest, a lot of the time) governments need to make decisions for reasons that can’t always be supported by science, and having a PSO calling them out on that isn’t going to be viewed as helpful.
The first option, a POST-like role, is probably the more realistic, and arguably more constructive. Having a reliable, trusted and, most importantly, an adequately funded source of scientific information available to MPs would be useful. But giving the office any more power to scrutinize government more broadly is going to be a hard sell, no matter who is in power.
In any case, as a private member’s bill the proposal has essentially zero change of passing, but it does show that the NDP takes science issues seriously, and is making a play for the votes of people concerned about how the Conservatives are handling the file. And Stewart says there is more to come, as the party rolls out its science strategy over the next year or so before the 2015 election.
One thing that struck me at the conference was the contrast between Stewart’s presentation and science minister Greg Rickford’s speech. Stewart and his deputy, Laurin Liu, spent more than an hour discussing and explaining their proposal with a small room of policy nerds, while Rickford’s keynote was your standard list of bland political platitudes and massaged stats, with no opportunities for questions from the floor (I saw that The Globe & Mail’s Ivan Semeniuk did manage to corner him afterwards, but since no fresh quotes from Rickford appeared in Ivan’s story on the PSO, Rickford either said nothing interesting, or Ivan got a major scoop we should all look out for). Not surprising perhaps, given that opposition politicians always need to work harder to get attention, but it was also a pretty clear demonstration of both parties’ approach to media relations and public consultation.
Rickford did, at least, ask for input into the development of his new science and technology strategy, which will replace the largely abandoned 2007 version. Anyone with strong opinions on the subject needs to pay close attention to this process over the next few months.
Overall, though, I thought the conference was an extremely hopeful sign of the healthy state of science policy discourse in Canada. The fact that 600 people, including politicians from all three major political parties, spent three days discussing and debating what role science and technology should play in the country’s future bodes well for the quality of any eventual submissions to Rickford’s new strategy. The NDP proposal is an important part of this process – it’s exactly the kind of thing we need to be debating as the government decided what it wants from science and the scientific community.
Brian Owens is an experienced science journalist and editor who spent eight years in London working as the online news editor for the leading science journal Nature and as a reporter and news editor for the influential policy magazines Research Fortnight and Research Europe. Now back in Canada, he is working as a freelance writer and editor for Nature, New Scientist, BBC Future, and Research Fortnight, among others.
Tagged with: 2013 • Brian Owens • Canadian science • Canadian Science Policy Conference • Conservatives • Globe and Mail • government • Greg Rickford • Ivan Semeniuk • Kennedy Stewart • NDP • Parliamentary Office of Science and Technology • Parlimentary Science Officer • POST • PSO • science • science policy
Quilting in space is hard. We know this because one of the six human beings currently living in outer space, NASA astronaut Karen Nyberg, has been working on a 9” quilted star block, and was so kind as to send us a how-to from the space station.
Thanks to Nyberg we now know that:
- Since everything floats around in zero gravity, you have to use Velcro to keep your supplies together. You need a Ziploc bag to hold any extras.
- You can’t just cut a pattern flat like you would on Earth.
- There aren’t any sewing machines.
Nyberg’s been sewing by hand, using spare needles instead of pins. Her block is a little uneven, since she wasn’t able to simply cut a straight line on a flat piece of fabric. But it’s beautiful, and she’d like us to help her make a full-size quilt. If you want to get crafty, Nyberg is taking 9.5” star-patterned blocks anytime before August 2014. Check out this press release for the address where you should send your stellar creations.For anyone who hasn’t made one before, the process for quilting yourself a little star block is reassuringly easy down here on Earth thanks to gravity, and hundreds of years of technological innovation.
Just for starters, we have access to extremely sharp scissors, rotary cutters, and mats that ensure clean cuts. Each of these is a specialized tool, available widely and cheaply.
Then there’s the matter of sewing, for which we have the celebrated portable sewing machine–a piece of technology that transformed American homes in the mid-1800s. In 1860, people called it “The Queen of Inventions.” It was big.
The more modern portable sewing machine is a descendant of Thomas Saint’s 1790 sewing machine, which used a chain stitch with one string to tie canvas or leather together. An awl poked the hole, then a machine moved the string in an over-under loop. It worked, theoretically. But it never went up for sale.
Forty years later, Barthélemy Thimonnier gets the credit for pushing the first automated sewing machine to market, which was great, until a mob destroyed his clothing factory.
Come 1850, the right entrepreneur, the now synonymous-with-sewing Isaac M. Singer, patented a rigid-arm, portable sewing machine. It was innovative on several levels. Singer’s machine had two strings (which was actually the innovation of Walter Hunt, who also invented the safety pin), a needle that moved separately from its arm, and a foot- rather than hand-powered mechanism. That last trick left both hands free for directing the fabric through the machine with accuracy.
Suddenly, it became affordable for factories to employ hundreds of seamstresses, and the clothing market moved from private home to grand corporations. Clothes got cheaper, but pay for seamstresses tanked. Sweatshops were born.
But for others, sewing machines introduced the possibility of purchasing ready-made rather than home-made clothing. Buying rather than hand-sewing a dress shirt saved the average housewife 14 hours a day. If she had still opted to make her shirt, but she made it on a new machine, it would take only about an hour. This freed up a lot of time for leisure, or for in-home mending businesses.
The world was changing.
But now, awash in an oasis of modern technology, Karen Nyberg is going back to basics, sewing by hand–in outer space.
Victoria Martinez is a writer and editor interested in science and poetry. You can follow her work on Twitter @eigenmotion.