Liver cells that actually work have been notoriously difficult to grow in the lab. Various scientists have managed to produce liver cells, but they weren't fully functional and couldn't be used to test drugs in development. The effect drugs have on the body needs to be thoroughly tested, lest they kill us, for instance. Now a team at the Hebrew University of Jerusalem, driven by a breakthrough insight, has managed to grow large amounts of liver cells that actually behave like liver cells.
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One potential upshot could be that drug development gets cheaper, though whether that economy reaches the consumer is another matter.
Anyway - among its myriad critical functions, the liver is part of the body's "sewage treatment" system, breaking down toxins that reach it through the blood system. Drugs we take also reach the liver, where they undergo metabolism – chemical processes intended to break them down for excretion. Hence, a key part of pharmaceutical development is to see how the liver handles the drug – and/or whether the drug harms the liver.
With all due respect to rat models and extrapolations, to know if a drug does damage to the human liver, it must be tested on a human liver or at least human liver cells (called hepatocytes). The inability to mass-produce viable, functional human liver cells in the lab had been an obstacle that has now been overcome by the team, which reports its work in the July edition of Hepatology.
That ability to mass-produce useful hepatocytes could save Big Pharma big shekels: Drug companies have been spending a cool billion dollars a year on buying laboriously-harvested cells to use in drug testing.
“This is quite a revolution for pharmaceutical drug discovery,” said Prof. Yaakov Nahmias, the study’s senior author. “While other groups have been able to produce liver cells before us, their cells showed little functional activity, and could not be reliably used for drug discovery. In fact, up until now stem cell-derived hepatocytes showed little ability to predict clinical outcome.”
The lab coaxed the hepatocytes into developing from human embryonic stem cells and genetically engineered skin stem cells. (Stem cells are pre-specialized primordial cells). The question had been how to "activate" them.
When scientists have children, this can happen
Nahmias' eureka moment happened when his daughter was born earlier this year. Birth causes a lot of baby bodily systems that had been "gearing up" inside the mother's body to kick in – just think of the lungs. Baby only begins breathing after being expelled into the world and, sometimes, provoked by the doctor.
Ditto the liver. “I watched her feeding just moments after birth, and realized this is the first time her liver started working,” said Nahmias. But what exactly made the baby's liver start working? His team set out to discover that very thing, and to mimic it, in order to jumpstart liver cells grown in the lab.
And thusly the team discovered that the bacteria already existing in the baby's gut moments after birth produce vitamin K2 and bile acids, which activate the fetal liver’s dormant drug metabolism program.
Down the line, the team found that liver cells produced from either embryonic stem cells or genetically engineered skin cells can detect the toxic effect of over a dozen drugs with greater than 97% accuracy.
“The implications for liver biology and drug discovery are quite staggering,” said Prof. Oren Shibolet, Head of the Liver Unit at the Tel-Aviv Sourasky Medical Center, who was not involved in this study. “The method provides access to unlimited amounts of functional liver cells and is likely to critically improve our ability to predict drug toxicity, which was previously limited by the unavailability of liver cells."
Caesarean births – which are quite common in Israel – result in different bacterial occupation of the gut. Shibolet postulates that the mode of delivery might therefore affect newborns’ liver maturation.
"Current practice is to routinely administer Vitamin K to newborns. The data presented suggest that parents abstaining from this practice may cause liver maturation and drug metabolism in their children to develop quite differently," Shibolet observed.
Other co-authors participating in the study include Yishai Avior, Gahl Levy, Michal Zimerman, Dr. Danny Kitsberg, Dr. Ronen Sadeh, Dr. Arieh Moussaieff, Dr. Merav Cohen, Prof. Robert Schwartz from the Weill Cornell Medical College, and Prof. Joseph Itskovitz-Eldor from the Rambam Medical Center. The work was funded by the European Research Council, the British Council BIRAX Regenerative Medicine initiative, and the HeMibio consortium funded by the European Commission and Cosmetics Europe as part of the SEURAT-1 cluster.