On the College of Toronto, Alison McGuigan and her lab deal with the advanced and interesting science of tissue engineering, particularly growing instruments to not solely mimic the construction of pure tissues, however the processes that result in their group.
Her analysis covers a spread of subjects from drug resistance in most cancers therapy to using self-organized 3D tissue cultures known as organoids. These are derived from stem cells which were crafted to copy an organ or sure preparations of cells, permitting researchers to check a extra reasonable mannequin of human tissues.
Past her analysis, McGuigan believes in constructing communities inside academia; environments the place college students, researchers, and leaders care about each other and drive science by cooperation, help, and collaboration versus a deal with competitors.
Our dialog with McGuigan centered round her analysis and expertise as a mom of 4 main a tutorial analysis group. Her greatest piece of recommendation? Observe making use of for jobs recurrently since you are by no means going to really feel prepared when a chance comes your approach.
Are you able to inform us about a few of your lab’s analysis in tissue engineering?
Latest work from our lab is centered round mimicking organizational constructions that happen throughout embryonic improvement. When an embryo develops organs, just like the lungs, they undergo a collection of very particular organizational steps and constructions. We wished to know if these mechanical constructions helped outline the cell kind as a result of you’ll be able to think about it’s a approach of constructing the entire patterning system extra strong. Might we take an enormous mass of stem cells and put mechanical structural blueprints in addition to chemical substances to sample their destiny, making them particular lung cells or particular liver cells, for instance.
We collaborated with a lung surgeon on the College of Toronto named Thomas Waddell. The thought was to take lungs and measure the bronchial tubes that make up the lung from sure phases of improvement. We wished to know if we may management how stem cells differentiate if inserted into completely different tube sizes corresponding to those completely different improvement phases. We have been capable of make tubes of particular diameter utilizing the identical expertise that generates microchips. We made plastic surfaces containing holes with dimensions that match these tubes of the lung at completely different phases of improvement.
We have been capable of see that relying on the tube dimension, you get variations in the way in which these cells differentiate into specific kinds of lung cells. That’s one side of utilizing engineering instruments to basically template the bodily group of cells. You possibly can then drive how they go on to behave in these self-assembly processes the place they’re differentiating and organizing into 3D constructions.
How is your lab ready to do that microenvironment engineering with tumor cells?
Now we have a few platforms and there are two standards that drive what we do.
First, you need to put within the minimal quantity of complexity for the issue that you’re focused on fixing. We used to put in writing in our papers that 2D plastic dishes should not consultant of the tumor setting, which incorporates completely different cell varieties, molecular gradients of vitamins and waste, and blood vessels that encompass and feed a tumor cell. Tumor cells always work together with their microenvironment and [this] doubtlessly might be manipulated to drive tumor cells into specific illness states]. Nonetheless, one reviewer made a really insightful touch upon certainly one of our papers, saying fashions should not higher, it simply modifications the kind of questions you’ll be able to ask.
Clearly 2D plastic dishes have allowed many most cancers medicine to be found, so they’re very invaluable, however they solely seize sure sorts of biology.
The second standards requires that you just assemble your construction in a approach that facilitates excessive worth information. One instance we now have is that this platform known as GLAnCE, which is a tradition system we use usually with organoids. It simplifies organoid imaging because the hydrogels [used to build them] are fabricated in such a approach that they’re micro-molded, so their floor is at a really particular thickness and utterly flat.
Immediately, imaging instruments work a lot better as a result of it eliminates an issue introduced by a meniscus that types between the hydrogel and its help floor. It opened up the sorts of information and the standard you will get out your system.
Are you able to give us a selected instance of the way you construct synthetic tumor microenvironments to check illnesses?
One in every of our fashions of tumor microenvironments is a 3D software known as the TRACER System. To create this, we use a sheet taken from a tea bag — very best as a result of it’s designed to not collapse in liquid — and we infiltrate the pores of the teabag with a Jell-O-like materials, akin to collagen, with the cells inside.
We are able to then generate this skinny “tissue” strip that’s about 35 to 40 microns thick. We then roll the strip round an oxygen impermeable core [meaning the oxygen molecules cannot pass through, which effectively mimics a hypoxic or low-oxygen environment typical of tumors], and you find yourself with one thing a bit like a Swiss roll, which some individuals have been very confused about in Canada as a result of it’s a British cake.
You wrap the cell-Jell-O teabag strip round this core, like a spool of movie, and also you cap it at both finish after which the oxygen and vitamins can solely entry the stack by diffusing by from the surface in direction of the middle and in no different path. As such, there may be progressive consumption of oxygen in every layer by the cells because the oxygen strikes in direction of the middle.
To do evaluation, you simply unroll the strip and accumulate cells alongside its size, tracing again the place they have been alongside a 3D gradient. You possibly can quickly accumulate cells from completely different sorts of microenvironments established on account of this gradient.
Our unique system required a whole lot of cells, however we actually wished to combine the patient-derived organoid materials to seize that extra reasonable kind of tumor variety that you just get in these populations. We thought it will be straightforward to only combine them in, however the variety of cells you wanted to make one mannequin was prohibitive, so we spent a whole lot of time determining the right way to make the machine smaller. The issue is you’ll be able to solely go as small as your potential to roll and deal with this strip of tea bag, which is already very small and skinny.
A pupil in my lab, Jose Cadavid, got here up with a terrific thought of filling within the tea bag paper with an oxygen impermeable polymer which leaves areas the place you’ll be able to seed cells. While you roll up the strip, all of the areas with cells align and you’ve got a slice of the cake versus the entire round cake. It’s bodily the identical dimension as the unique mannequin however requires approach fewer cells.
How do you assess the conduct of those tumor cells? Is it context particular?
It’s context particular. With the TRACER software, we tried three completely different organoid traces and noticed whether or not they would develop an oxygen gradient and present oxygen responsive patterns and gene expression, which all of them do. Tumor cells in sure areas of the tumor (usually the place therapies don’t work) are always disadvantaged of oxygen and the TRACER software can mimic that situation after which examine how the cells reply at an RNA and ultimately protein degree.
Now we have additionally lately carried out a single cell RNA-Seq evaluation [a technique used to examine the gene expression in only one cell at a given time] by our TRACER platform for one organoid line. This generates an enormous quantity of knowledge to mine and we are able to discover attention-grabbing expression patterns in our information set which appear to be replicating in different organoid fashions. Nonetheless, the place we now have regarded extra at variations in tumor cell behaviors between sufferers is within the GLAnCE platform as a result of it has a a lot larger throughput.
Issues come up once you deal with a affected person with a drug which kills some proportion of the [cancerous] cells whereas some stay after which regrow. This recurrence then means these cells might now not reply to the unique drug — you begin this “survival of the fittest” cycle.
What our group can do to imitate that is deal with our mannequin micro-gels with a drug after which watch them over time. We discover conditions the place we all know a sure dose of the drug can kill extra cells however the induced modifications within the leftover cells really make them extra aggressive and develop again faster. Now we have began evaluating microenvironments between sufferers and have discovered variations on this regrowth conduct.
Many different parameters [of the tumor microenvironment] may also impression how a affected person will tolerate a drug [during chemotherapy]and we hope our modeling instruments will ultimately have the ability to predict conduct by correct simulations for use in a scientific context, not simply within the laboratory.
Cell migration results in the group of tissues and organs. How and why does your lab examine cell motion and tissue formation?
Collective migration is prime to many processes, and we have been learning a few of these fundamental guidelines however then in some unspecified time in the future there was a need to consider making use of our information to completely different illness conditions.
We did some modeling of collective cell migration and decided the foundations of conduct in an in vitro system very early on. We additionally did a whole lot of theoretical evaluation, like monitoring how cells transfer in collective sheets, how they’re guided by structural options like topography, and the way that steerage might be transmitted between neighboring cells.
In a crowd, if somebody is being pulled alongside and everybody within the crowd is holding fingers, you’d pull the entire crowd alongside. In some unspecified time in the future, we thought we actually wished to use this to a extra disease-relevant state of affairs, so our try at that was to take a look at the tumor-stroma interface. The stroma is the area discovered across the tumor and in a number of cancers, that is primarily fibroblasts. In quite a few cancers, you see the breakdown of the tissue construction because the fibroblasts invade into the tumor cells area, and the tumor cells invade out into the stroma compartment.
Now we have used GLAnCE to check this breakdown of construction within the context of cancer-associated fibroblasts and tumor cells.
Are you able to share some future analysis plans?
One paper got here out lately that’s in a really attention-grabbing space I hope our lab can increase into. We used the teabag and as an alternative of engineering a tumor, we engineered a sheet of human fats with adipocytes [fat cells] solely — there aren’t any different cell varieties at first. We are able to then deal with this with a excessive lipid “food plan”, simulated within the media, and this induces overweight phenotypes. I believe this mannequin goes to be an attention-grabbing factor to increase on.
Mixed with that, we now have a technique of automation with a robotic which may fabricate as much as 384 of those engineering fats tissues in parallel. We’re going to have the ability to scale and construct these tissues whereas introducing manipulations to know how that impacts diet-induced phenotypes. We’re additionally beginning to discover the molecular pathways that management these processes.
Now we have some papers coming that introduce immune cells into the most cancers system and the way we apply these scaled platforms. You possibly can then start to consider discovering new targets or doing extra mechanistic biology.
You’re a mother of 4. Do you face many challenges as each a tutorial and a mom?
As a mom, you might be compelled to prioritize the way you need to spend your time. How are you going to manage your time and establish issues that may be as good as they will presumably be and different issues that may be ok?
It forces you to get very environment friendly. I don’t know if my work output modified with every youngster added, however I believe I bought extra environment friendly every time. My thoughts has to regulate between science after which lunches and play dates and this thoughts switching might be fairly factor to your mind. It presumably simply modifications the way in which you might be seeing these very completely different worlds and getting snug with that switching might be useful once you then should collaborate with individuals which might be in very completely different fields to you.
Persons are all the time going to really feel responsible that they can not compete with the metrics of convention attended and hours labored. On the similar time, a number of the metrics should not related to match anymore since you may go to at least one convention however be rather more focused about what you might be doing at that convention to get the perfect worth.
Journey is actually tough for me, which may make it tough to get extra visibility, however a number of the conferences being digital has in all probability helped with that, permitting individuals to attend extra conferences with out really having to journey.
I additionally suppose constructing communities on social media is democratizing our potential to get visibility as a result of there isn’t a want for costly conferences, and folks can as an alternative work together with others in the neighborhood through Twitter, for instance.
Is there one thing that universities and establishments may do to offer the help system for ladies as principal investigators?
Many locations present mentorship packages, and I believe they require variety when it comes to the mentorship recommendation as a result of there may be not one path to comply with. The purpose ought to be to offer individuals confidence to navigate their decisions and perceive their profession choices. It will be helpful to have some useful resource that helps you “put out fires” with childcare or elder care, for instance.
Being conscious of workload in academia is very vital. There may be very clear proof close to the necessity for variety on award panels, for instance, however if in case you have a smaller fraction of sure demographics in your division, and also you want that demographic on each committee, these people do rather more committee work than different people, and that may go unnoticed or is solely not rewarded.
Constructing a neighborhood the place individuals are and care about each other versus placing an enormous deal with competitors can also be vital. Through the COVID-19 pandemic, one professor messaged me asking if I used to be okay. Truthfully, there was nothing they might do, however the truth that they despatched the e-mail was superb.
What’s…
A pastime you pursue in your free time?
I’d say inventive initiatives, like photograph initiatives or making mini-movies or artwork.
Do you might have a favourite dish?
In Toronto, we’re fairly spoiled for meals. I’d say on the completely different UberEATS choices, the whole-chili pakoras are excellent. I’m vegetarian, so I like a whole lot of vegan and vegetarian meals.
A music you can’t get out of your head in the intervening time?
I like old style techno home Spotify playlists.
Is there ebook you’ll be able to suggest?
I lately reread after a few years, Tuesdays with Morrie. It’s a very unhappy story stuffed with perception a couple of man who reconnects together with his professor 15 years after being out of college. The professor is dying from Lou Gehrig’s illness, so he needs to offer all these classes to his pupil, who’s author, earlier than he dies. It’s an attention-grabbing perspective. I had learn it in my mid-20s, and I discovered it impactful at the moment, and it was attention-grabbing to learn it once more and see if I’ve lived by a few of these classes or not.
An individual (well-known or not) you want to have espresso with?
I believe it will be attention-grabbing to speak to certainly one of these iconic innovators, like Steve Jobs or Elon Musk. Might you might have a coherent dialog? Do individuals like Invoice Gates see this nugget of the long run? Did they actually see the tip purpose from the start? Katalin Karikó is a superb fashionable instance of somebody I’d like to have espresso with. It will even be very attention-grabbing to know a number of the feminine innovators who actually drove a imaginative and prescient, like Marie Curie.
Who would play you in a biopic?
One reply from my husband was Drew Barrymore just because individuals have instructed me earlier than that I seem like her doppelgänger. The opposite particular person I considered is my oldest daughter who kind of seems like me and is barely 9, and proper now she needs to be an actress and may be very dramatic.
Function picture credit score: Neil Ta
Study extra about McGuigan’s work within the Superior Supplies “Girls in Supplies Science” Digital Subject — a set of excellent work created, steered, and led by feminine scientists around the globe.
