Thalidomide has gone down in history as one of the worst cases of devastating side effects caused by a drug. Although there is no official figure of how many people were affected on a global scale, it is estimated that more than 10,000 babies were born with terrible malformations during the years in which this drug was marketed.
Synthesized in 1953 by Wilhem Kunz, from the Swiss pharmaceutical company CIBA, when he was looking for new antibiotics, the molecule was transferred to another laboratory, the German Grünenthal, which ended up developing it as a non-barbiturate sedative. It was approved and launched on the market in 1957. And it was almost miraculous: the package insert indicated that it was used to treat irritability, lack of concentration, premature ejaculation, menopausal pain, tuberculosis, and even nausea. It was even recommended for “unusually restless” children.
The medicine, sold without a prescription, was an enormous commercial success and, in a few years, it became the third best-selling drug in the world.
However, at the end of the 1950s, in Germany, where it was most consumed, pediatricians confirmed that more babies were born with malformations or without limbs, and in the early 1960s they linked its consumption during pregnancy with those congenital anomalies. The drug was banned, Spain was one of the last countries to do so, in 1963. But the irreparable damage was done.
Thalidomine, sold without a prescription, was an enormous commercial success and in a few years it became the third best-selling medicine in the world.
Although the pharmacist Grünenthal had carried out experiments with monkeys, dogs and rabbits, to whom she administered this substance for weeks, and even in pregnant rodents, she did not realize that the animals were less sensitive to this substance.
More and stricter controls to reach the market
The thalidomide catastrophe, as it was called, meant that countries imposed very strict control on drugs before putting them on the market. Since then, for its approval it is mandatory that pharmacological trials be carried out, that they be tested on animals and ultimately on humans before being marketed. A long process, usually lasting more than a decade and exhaustive.
However, pregnant women, and also nursing children, have traditionally been excluded from these medical tests supposedly for ethics. Administering a substance to evaluate whether or not it is toxic to a pregnant person can potentially harm the fetus. This has meant that, at least until 2025, less than 0.4% of clinical trials underway in the EU will include pregnant women.
If you do not participate in these trials, there is no information about the benefits and risks of a medication during pregnancy and breastfeeding. And yet, many pregnant women must take medications because they have chronic conditions, infections, or complications during pregnancy, such as fever or severe pain. In this sense, you will surely remember the controversial announcement first by Trump and then by the US Food and Drug Administration, the FDA, about the possible association between the use of acetaminophen during pregnancy and subsequent diagnoses of children with autism or ADHD.
“It is incredible, but today there is no reliable model to evaluate the safety of drugs during pregnancy, which represents an absolute lack of knowledge that leaves both women and children at risk,” considers researcher Kristina Haase, who since 2019 has been researching at the European Molecular Biology Laboratory (EMBL) in Barcelona.
This mechanical engineer began researching blood vessels when she was at the Massachusetts Institute of Technology (MIT) and became interested in the placenta, a temporary organ that is highly vascularized to be able to supply the fetus with nutrients and oxygen. Since arriving in Barcelona, Haase has been working on the development of a 3D model of the placenta on a chip as a tool to investigate which molecules are capable of crossing it and reaching the baby.
Today there is no reliable model to evaluate the safety of drugs during pregnancy, which represents an absolute lack of knowledge that leaves both women and children at risk.
Kristina Haase EMBL Barcelona
“Until now, toxicological studies were all basically done on placental cells in the laboratory and in animal models, which, despite being useful and providing some information about the effects of medications, do not represent the complexity of the physiology of the human placenta,” says this researcher because, to begin with, she remembers Haase, pregnancies against mice; Nor does hormonal synthesis have anything to do with it.
Furthermore, “animals also do not suffer from the health problems that can appear in human pregnancies, such as preeclampsia”, a disease that can be very serious and fatal, and which is exclusively human, adds Marta Cherubini, researcher at the Copenhagen BioInnovation Institute and co-developer.
An underappreciated organ
The placenta is undoubtedly a fascinating organ. The body creates it from scratch at the beginning of a pregnancy, it works at full capacity for 9 months, protecting the baby, providing it with nutrients and oxygen, and regulating the exchange of waste and blood between mother and child. It is now known that it is a key long-term health organ, influencing the mother’s cardiovascular risk, the baby’s future metabolic health, and fetal programming. However, this wonder’s days are numbered and after approximately 40 weeks, it stops working. Planned obsolescence of nature. Furthermore, it is an organ that belongs to both the mother and the fetus, and can vary greatly between women.
This has made it difficult to fit into classic models of biomedical research and has been little studied. Furthermore, historically, it was considered little more than waste or residue that was simply thrown away. It is quite a paradox to think about how a woman’s body is medically controlled during pregnancy and, on the other hand, for a long time the mechanism that precisely sustains pregnancy, the placenta, has been ignored.
Haase and Cherubini want to contribute to putting an end to this lack of knowledge, one more example of the gender biases that have surrounded women’s health, undervalued by science and medicine. Both researchers have been able to reproduce on a chip a simplified placenta where the mother’s part is located, separated by specialized trophoblast cells that act as an interface between maternal blood and the chorionic villi of the placenta. And the part of the fetus, the fetal vasculature. In addition, it is perfusible, that is, it allows fluids to pass through.
“We have already tried to pass molecules of different sizes and we have been able to reproduce what happens in human physiology,” Cherubini proudly points out.
A boost of three million euros
Now the Copenhagen BioInnovation Institute has just funded this project with three million euros with the aim of researchers being able to develop a commercially viable service to test toxicity within a three-year period. “Each individual chip requires a long time to perform and for each experiment, between 40 and 60 are needed,” says Cherubini, who points out that “it is an enormous effort and not very reproducible.” Since the chip is made up of different types of living cells, it takes at least three days to make. “The biggest limitation is precisely that we must wait for the cells to grow. We cannot accelerate this process,” adds Haase.
In addition to allowing us to evaluate whether drugs reach the fetus and whether they are toxic, the placenta on a chip will also be used to analyze other substances, such as caffeine. And it opens the door to shedding light on the impact of other fetal exposures on the future health of children and adults. “We began to look at particles from pollution and PFAs or persistent organic pollutants present in plastics to study their influence on pregnancy,” says Haase.
Another potential application of this device will be to be able to better understand the physiological processes that occur in this organ by observing it. on site. This would shed light on some of the problems related to this organ that can cause pregnancy losses. Currently, two out of every 10 confirmed pregnancies still end in spontaneous abortion, especially during the first trimester.
Or diseases that can put the lives of the mother and baby at risk, such as preeclampsia, which is one of the most common pregnancy conditions. In this sense, the researchers have a project funded by La Marató de TV3 in which they collaborate with a team of doctors from the Vall d’Hebron Hospital to better understand the origin of this disease using samples from pregnant women, with and without the disease, and these 3D placental chips.
Pregnancy is medicalized, but the mechanism that makes it possible has not been sufficiently investigated. With this placenta on a chip, these researchers want to change that.
