Testing a drug is safe before you give it to a pregnant woman

Pregnant woman holding medicine.

When a doctor gives you a medication you like to think that it’s safe, that it has been tested to make sure it will do you some good or, at the very least, won’t do you any harm. That’s particularly true when the patient is a pregnant woman. You hope the medication won’t harm her or her unborn child. Now scientists in Switzerland have found a new way to do that that is faster and easier than previous methods, and it uses cell cultures instead of animals.

Right now, drugs that are intended for use in pregnant women have to undergo some pretty rigorous testing before they are approved. This involves lots of tests in the lab, and then in animals such as rats and rabbits. It’s time consuming, costly, and not always accurate because animals never quite mimic what happens in people.

In the past researchers tested new medications in the lab on so-called “embryoid bodies”. These are three-dimensional clumps of cells developed from embryonic stem cells from mice. The problem is that even when tested in this way the cells don’t always reflect what happens to a medication as it passes through the body. For example, some medications can seem fine on the surface but after they pass through the liver can take on toxic qualities. 

So, scientists at ETH Zurich in Basel, Switzerland, developed a better way to test for toxicity.

They took a cell-culture chip and created several compartments on it, in some they placed the embryoid bodies and in others they put microtissue samples from human livers.  The different compartments were connected so that fluid flowed freely from the embryoid bodies to the liver and vice versa.

In a news release, Julia Boos, a lead author of the study, says this better reflects what happens to a medication exposed to a human metabolism.

“We’re the first to directly combine liver and embryonic cells in a body-on-a-chip approach. Metabolites created by the liver cells – including metabolites that are stable for just a few minutes – can thus act directly on the embryonic cells. In contrast to tests on mice, in our test, the substances are metabolised by human liver cells – in other words, just as they would be in the human body when the medication is administered.”

To see if this worked in practice the researchers tested their approach on the chemotherapy drug cyclophosphamide, which is turned into a toxic substance after passing through the liver.

They compared results from testing cyclophosphamide with the new liver/embryoid body method to the older method. They found the new approach was far more sensitive and determined that a 400 percent lower concentration of cyclophosphamide was enough to pose a toxic threat.

The team now hope to refine the test even further so it can one day, hopefully, be applied to drug development on a large scale.

Their findings are published in the journal Advanced Science

Pregnant women’s stem cells could help battle brittle bone diseases like osteoporosis

pregnant

Sometimes I wonder how a scientist ever came up with an idea for a potential treatment. Case in point is a study in the journal Scientific Reports, where researchers use stem cells from the amniotic fluid of a pregnant woman to cure osteoporosis in mice! What researcher, seeing a pregnant woman, thought to her or himself “I wonder if…..”

Regardless of how they came up with the idea, we might be glad they did because this study showed that those stem cells could reduce the number of fractures in mice with brittle bone disease by 78 percent. And that’s raising hopes they might one day be able to do the same for people.

Researchers at University College London took mesenchymal stem cells (MSCs) that had been shed by babies into the amniotic fluid of their mother, and injected them into mice with brittle bone disease. Previous studies had suggested that MSCs, taken at such an early age, might be more potent than similar cells taken from adults. That certainly seems to have been the case here where the treated mice had far fewer fractures than untreated mice.

Pascale Guillot, the lead researcher of the study, told the Guardian newspaper:

“The stem cells we’ve used are excellent at protecting bones. The bones become much stronger and the way the bone is organised internally is of much higher quality.”

 

What was also interesting was not just what they did but how they did it. You might think that the injected stem cells helped reduce fractures by forming new bones. You might think that, but you’d be wrong. Instead, the stem cells seem to have worked by releasing growth factors that stimulated the mouse’s own bone cells to kick into a higher gear, and help build stronger bones.

In the study the researchers say using MSCs from amniotic fluid has a number of distinct advantages over using MSCs from adults:

  • They are easier to expand into large numbers needed for therapies
  • They don’t create tumors
  • The body’s immune system won’t attack them
  • They are smaller and so can move around with greater ease
  • They are easier to reprogram into different kinds of cells

Next Guillot and his team want to explore if this approach could be used to treat children and adults with brittle bone disease, and to help adults with osteoporosis, a problem that affects around 44 million people in the US.

 “The discovery could have a profound effect on the lives of patients who have fragile bones and could stop a large number of their painful fractures.”

Breast Cancer Commandeers Mammary Stem Cells for Own, Nefarious Purposes

Most instances of breast cancer happen later in life—often after menopause. In many cases, the cancer progresses slowly, over a period of months or even years, often giving physicians precious time to implement a treatment plan, successfully battling that cancer into remission.

A section from a mammary 'outgrowth' harvested at lactation. [Credit: UC San Diego School of Medicine]

A section from a mammary ‘outgrowth’ harvested at lactation. [Credit: UC San Diego School of Medicine]

But there is another far more aggressive form of breast cancer that tends to develop earlier, often immediately following pregnancy. And now, researchers at the University of California, San Diego (UCSD) have discovered how this form of cancer hijacks a woman’s own stem cells to grow quickly and spread throughout the body.

Reporting in the latest issue of the journal Developmental Cell, UCSD stem cell researchers Drs. David Cheresh and Jay Desgrosellier and their teams have found a link between the molecular signaling switches that spur this aggressive, post-pregnancy breast cancer—and mammary stem cells that are normally activated during pregnancy.

These findings, say Cheresh, offer key insight into how scientists may develop better treatments for this form of breast cancer. As he stated in a news release:

“By understanding a fundamental mechanism of mammary gland development during pregnancy, we have gained a rare insight into how aggressive breast cancer might be treated.”

Normally, pregnancy activates a special group of stem cells in the mammary gland. Their job is to ready the expectant mother for feeding the newborn baby. By the time the baby is born, however, these stem cells go back into hibernation.

However, in some women, these mammary stem cells get hijacked by cancer cells. Rather than the mammary stem cells shutting down by the time milk production begins, cancer cells keep them switched on—which then contributes to the progression of cancer.

These findings shed much-needed light on the complex relationship between breast cancer and pregnancy. However, the authors caution that these findings don’t imply that becoming pregnant causes breast cancer. Rather, as Cheresh explained:

“Our work doesn’t speak to the actual cause of cancer. Rather, it explains what can happen once cancer has been initiated.”

Cheresh, who has received CIRM support for related work, has pinpointed a protein called CD61 that may promote the progression of breast cancer. CD61 has already been implicated in cancer metastasis and resistance to cancer drugs, so it makes sense that it would play a role in breast cancer as well.

Importantly, the discovery of a potential connection between CD61 and this form of breast cancer may ultimately open up new avenues for treating this type of cancer more successfully.

“Detecting CD61 might help doctors determine what kind of therapeutic approach to use, knowing that they might be dealing with a more aggressive yet treatable form of breast cancer. For example, there are existing drugs that block CD61 signaling, which might be another potential aspect of treatment.”

Want to learn more about breast cancer and stem cells? Check out our Solid Tumor Fact Sheet.

New Videos: Downton Abbey, preeclampsia, and the search for a cure using stem cells

(Downton Abbey Spoiler Alert: skip ahead to the video if you haven’t seen Season 3!)

If you’re one of the estimated 10 million devoted Downton Abbey TV viewers, then you most probably have heard of the word “preeclampsia.” In a heart-wrenching episode from season 3 of the early 20th century British drama, one of the characters dies while giving birth due to the complications of preeclampsia.

A fan myself, I too watched in shock as the plot unfolded. But I was at least comforted by the thought that surely this disease no longer has tragic outcomes today in the early 21st century. Boy was I wrong. As CIRM-grantee Mana Parast pointed out during her Spotlight on Disease presentation to the CIRM Governing Board two weeks ago (now viewable on our website), preeclampsia and related disorders are still a widespread problem for expecting mothers:

“They complicate 5-8% of all pregnancies worldwide, and they cause multiple maternal and neonatal complications. So in fact preeclampsia is the leading cause of maternal mortality in the developed world. It’s also the leading cause of fetal growth restriction and there’s no cure … except to deliver the baby. In fact preeclampsia is the number one cause of induced preterm delivery in the U.S.”

Preeclampsia is often called “the Silent Killer” because the symptoms often arise suddenly in the second half of pregnancy. The main noticeable symptoms for the expectant mother are high blood pressure and high protein levels in the urine, or proteinuria. Silvia Michelazzi, a preeclampsia survivor, shared with the Board her daughter’s birth story:

“My pregnancy, I was thinking, was going well. I knew Mia was a little bit smaller than average but that was pretty much it. But at a doctor’s appointment, it was found out that I had high blood pressure and proteinuria and I was rushed to the hospital and the baby was delivered 48 hours later [at 29 weeks] because there’s really nothing else to do but delivery the baby. I can’t tell you how hard it was to see the baby so small. It turned out she weighed 2 pounds 8 ounces.”

Mia, now three, spent two months in the neonatal intensive care unit but is now doing remarkably well. But some babies aren’t so lucky. They can have intestinal problems, bleeding in their brain, retinopathy of prematurity (a condition that can lead to blindness), and the list goes on. Even when they survive the neonatal stage they still have an increased risk of heart disease and diabetes over the course of their lives. And all of these scary, sometimes fatal complications are basically due to, as Dr. Parast puts it, “just having a bad placenta.”

The placenta is a transient organ that only appears during pregnancy and is critical for exchange of food, blood and oxygen between the mother and fetus. Dr. Parast, a perinatal pathologist at UC San Diego, studies the development of the placenta with the ultimate hope of finding treatments for preeclampsia. If you imagine the early embryo as a tiny hollow ball of cells, it’s the outer cells called trophoblasts that ultimately form the placenta while a clump of cells inside the hollow “ball” go on to form the fetus.

Examination of a preeclamptic placenta after delivery shows that preeclampsia is a disease marked by a malfunction in trophoblast maturation leading to abnormal placenta development. The aim of Dr. Parast’s team is to mimic preeclampsia in the lab but it’s been a tricky disease to model because preeclampsia is unique to primates so experiments in mice is not an option. Instead, with the help of CIRM-funding, Parast’s lab is embarking on a project to bank tissue from preeclamptic placentas and derive trophoblasts using the induced pluripotent stem cell (iPS) technique. With these iPS-derived trophoblasts in hand, the team can screen for drugs that restore proper trophoblast maturation and placental development.

And in a strange twist that you usually only see on a TV show – it turns out that Dr. Matteo Moretto-Zito, a researcher in Parast’s lab, is the father of little Mia. Moretto-Zito had joined the lab shortly before his wife Silvia was diagnosed with preclampsia. He also spoke to the Board and had this to say about his unique perspective:

“I consider myself extremely lucky for two reasons: number one, Mia’s story ended up really well so that is great and reason number two, because I am part of a team that can make a difference.”

Here’s to hoping that Matteo and the entire Parast team make a difference and find a treatment to end preeclampsia complications for future moms and babies.