Science As We Know It

Ah, the wonders of pursuing knowledge… The ambition of achieving more and more…

We might be led to think that scientific progress is a straight line. But science, as we know it, (see what I did here?) is a path made of ups and downs. Things do not always work out well. And as important as it is to highlight the successes and achievements from the past, it is also valuable to talk about the wrongs, the errors, the mistakes. Because, as every cheap self-help book will tell you, we are meant to learn from our mistakes. And what is science if not a learning process?

“What seems like a plot from a science fiction novel”

Paolo Macchiarini, at that time a researcher at Karolinska Institute, claimed he had developed a groundbreaking technology in bioengineering: the ability to replace a patient’s trachea with a synthetic one. This brought a huge amount of hope for patients who, for different reasons including some forms of cancer affecting the trachea, were in life-threatening need of a transplant.

The thing about transplants is that they usually rely on external donors. Someone else who can donate the tissue or organ in question. In this case, a trachea. Which, unlike kidneys (which we have two of), can only be taken by a cadaver. And this, as you might imagine, raises many problems. The first challenge is donor availability, as one cannot just get a catalog of recently deceased people to choose from (is this metaphor a little too much?). But even after this, there are always concerns about immune rejection. Our immune systems are very good at flagging and fighting things that are external to them. This works for viruses or bacteria, but also for perfectly fine human tissues or organs that come from someone else. Therefore, prior tests must be made to assess the “compatibility”, checking how much the donor and receiver are “similar” enough not to cause a huge dangerous immune reaction on the receiver’s organism. These tests are not only expensive, but might actually not even be 100% accurate, and end up in a rejection reaction on the receiver’s despite some apparent compatibility.

With Macchiarini’s new technology, these issues were no longer a concern. The trachea structure for transplantation was fully artificially made of a nanofiber scaffold, which mimicked the natural tissues. Then, these artificial trachea were coated with cartilage cells from the patient. For this, stem cells were taken from the patient’s own bone marrow. These stem cells have the potential to give rise to any other cell of the body and, in this case, were differentiated into cartilage cells which then would seed the synthetic structure. And since they come from the patients themselves, there are no concerns for any kind of rejection reaction.

This new approach seemed “nothing short of miraculous”, and would, hopefully, soon be expanded to the generation of other organs for transplantation: kidneys, livers, hearts…

The only problem was that… it was all a lie.

Many patients were subjected to this transplant. However, after surgery, their conditions kept worsening. Some of them started accumulating “mucus and blood which had to be pumped out several times a day” (we apologize if you are having a meal while reading this). And, at some point, they started dying. Despite this, Macchiarini kept performing these surgeries around the world, claiming patients’ good responses and diverging from any possible raised issues.

Why was it not working? The reasons could be many. Although in theory the idea of making an artificial organ that is fully coated with real cells from a patient seems completely plausible (even you, probably, reading this thought it was great! That it solved all the issues), there are many things that we cannot predict. This is why procedures like these must be very well studied and validated before moving on to actual patients.

News pieces started appearing about possible issues, and by 2016, Swedish TV channel SVT made a documentary piece, which set the ground for the situation to be fully exposed, culminating in Macchiarini’s final incarceration.

Macchiarini’s fraudulent behavior went way beyond its formal academic side. His personal involvement with an American news producer elevated this to a worldwide story of love, money, and scam. This mediatic side of the story has been covered in many works, including a recent documentary on Netflix.

This initially though “groundbreaking” scientific discovery created hope, a hope which Macchiarini exploited and used as a ramp for his popularity amongst the general public which, unfortunately, also affected his scientific peers.
Part of a scientist’s duty is to bring it to the general public. And this, just like the science done in the lab, has to be done with the same amount of ethics, transparency, and integrity. 

Scientists are, at the end of the day, not superheroes. They are humans. Humans which, inherent to their occupation, work with knowledge. And we know knowledge is power. So please allow me an exception and let me quote a super-hero proverb: with great power comes great responsibility.

As we approach the eagerly awaited New Year of 2024, let’s rewind the clock and reflect on years-long research that has been revolutionizing our understanding of human development. Scientists keep creating embryos in a dish solely from stem cells, bypassing the use of human embryos. This approach offers hope for addressing questions once deemed impossible. Why and how so many pregnancies end in loss? How can we prevent this? How tissues and organs are formed? And how can this knowledge aid in repairing and constructing organs in the lab for patients in need? While knowing the answers edges into the future, let’s delve into the past and present to understand how it can be achieved.

In nature, the union of a male gamete (sperm) and a female one (egg) results in the formation of a zygote, marking the beginning of a new life. As the zygote divides, it transforms into a blastocyst—a ball of cells that eventually implants into the inner lining of the uterus (endometrium). At this point, cells within the embryo specialise into extraembryonic tissues, serving to safeguard and provide essential resources during development. Simultaneously, they organize into germ layers that will eventually give rise to diverse tissues and organs of the organism. The challenge with understanding the earliest stages of human development is that it occurs hidden from our view, inside the mother.

A recent solution to this challenge is the development of various systems for culturing human embryos outside the uterus until 14 days after fertilization. This aligns with the internationally agreed limit for human embryo culture.

In one approach, researchers led by Magdalena Zernicka-Goetz genetically-modified human embryonic stem cells to guide their development towards formation of extraembryonic tissues. These modified cells were then combined with unaltered human embryonic stem cells, resulting in the self-organization of embryo-like structures. Alternatively, a team spearheaded by Berna Sozen took a distinct route, opting to grow cells in medium containing specific factors to program the fate of extraembryonic tissues. But these models are not flawless, they lack trophoblast-derived cells, crucial stem cells that eventually contribute to the formation of placenta.

As we forge ahead in crafting more advanced in vitro models of human embryos, there is a growing need for tools that let us study them in setting closely resembling the natural environment of the uterus. This marks an exciting moment as scientists from diverse fields – embryologists, bioengineers and computational biologists – join their forces to unravel the intricacies how embryo is developed inside mother’s womb and figure out ways to mimic this process outside the body. But that’s just a glimpse into the future of science…

Despite the ethical and technical considerations arising from advances in modelling human development, these breakthroughs open up tremendous possibilities in addressing pregnancy-related disorders and gaining insights into the formation of tissues and organs.

Methods for modelling development were named Method of the Year 2023 by renowned scientific journal, Nature.

By Maria Jassinskaja

A friend of mine who recently went through a long period of uncertainty regarding his work situation noted an undesired side effect of this stressful time – his hair was going gray, way too fast to be considered normal aging. Indeed, the phrase “You’re going to give me gray hair!” implies a connection between someone stressing you out and premature loss of hair pigmentation. Plenty of anecdotal evidence exist for this phenomenon, but the biology behind it has long remained a mystery. Recently, a group of researchers at Harvard University set out to solve this long-standing question, and published their findings in the prestigious scientific journal Nature in January 2020¹. The answer? Stressed out stem cells.

After a bad haircut, one can often find some consolation in the fact that hair (usually) grows back. Just like in many other tissues where we see this kind of regeneration (such as blood or skin), hair regrowth is made possible by stem cells – in this case, hair follicle stem cells (HFSCs). However, while HFSCs ensure that we don’t go bald, they have little to do with the actual color of the hair. The color, or pigment, in hair comes from another set of stem cells – the melanocyte stem cells (MeSCs). Just like most other adult stem cell types, MeSCs are normally in a resting stage, which protects the cells and ensures their longevity. MeSCs are activated during hair growth to divide and produce mature pigment cells (melanocytes) which give our hair (and skin) its color². Depletion of MeSCs with age has been suggested to be the reason behind why humans (as well as other animals) go gray as we approach our golden years³.

In the Nature study¹, Zhang and colleagues found that stress caused the fur of black mice to become white significantly faster than in non-stressed animals. This effect was most pronounced when the stress was caused by pain, but was also evident when the stress was caused by restraining the animals or subjecting them to so called chronic unpredictable stress, such as quick switches between isolation and crowding. Upon closer examination of the cells responsible for hair growth and pigmentation, the researchers found that while HFSCs were unaffected by stress, MeSCs were quickly depleted from the hair follicle. In other words, the hair of the stressed mice grew out as normal, but had lost its black color. This was due to an abnormal increase in the rate at which the MeSCs divide, which caused the pool of stem cells to gradually become depleted and finally disappear. This in turn lead to a complete and permanent loss of pigmentation in the affected hairs. The main culprit behind this effect turned out to be noradrenaline, which is the hormone responsible for initiating a fight-or-flight-response in animals faced with danger. The secretion of noradrenaline was caused by stimulation of the sympathetic nervous system, which is part of the autonomous (unconscious) nervous system and is responsible for sensing and responding to danger. Molecularly, human MeSCs responded similarly to the mouse cells, indicating that noradrenaline may have a similar effect on human hair pigmentation as it has in mice.

Although there is a lot of evidence that these biological processes occur also in humans, one should keep in mind that this study was done mainly in mice. It is difficult to translate the stress experienced by the mice into human stress factors. Are a couple of bad weeks at work enough to damage human melanocyte stem cells permanently, or is a much more severe type of stress required to produce this, often undesired, effect? Regardless of the exact mechanism, stress has previously been shown to negatively affect other adult stem cell types, such as hematopoietic stem cells⁴, which can potentially lead to much more severe side effects than a couple of unwanted gray hairs. With that in mind, enjoy a lazy summer vacation this year – your stem cells could really use a break.