Salk scientists implant human cells in monkey embryos as a step toward easing future transplants

Salk Institute for Biological Studies professor Juan Carlos Izpisua Belmonte
Salk Institute for Biological Studies professor Juan Carlos Izpisua Belmonte says engineering human and/or monkey cells to communicate with pig cells and eventually use them to help grow organs compatible with humans is “a far way away.”
(Courtesy of Salk Institute for Biological Studies )

To better understand how human cells communicate with those from other animals and potentially ease the process of cultivating tissue and organs for human transplantation, scientists at the Salk Institute for Biological Studies in La Jolla have taken the next step in research of chimeras — organisms that contain cells from two or more species.

Led by Salk professor Juan Carlos Izpisua Belmonte, researchers have reached out to one of our nearest genetic and evolutionary neighbors, the monkey, to demonstrate a new integration of human cells into animal tissue by successfully growing monkey embryos with human cells. A new study, published April 15 in the journal Cell, builds on the Izpisua Belmonte lab’s previous work with chimeric mice and rats.

The lab uses animal models to study the cellular division process but recognizes that nothing compares to the natural process of development in utero.

“We have gathered a lot of knowledge on animal models … but that knowledge doesn’t always translate to humans because we are different from other animals,” Izpisua Belmonte said. “About 20 years ago, the scientific community was able to get some of these cells from these early embryos [known as] totipotency cells that can generate the 250 cell types that a human is composed of. … We were able to take them out of a human embryo, put them in a petri dish and maintain them. In these 20 years, we have taken these cells and are trying to mimic what nature will do: Inside the mother, these cells will start to form all the tissues and organs, so we are trying to mimic that process in a petri dish.”

Scientists have since been able to cultivate isolated liver cells, neurons, intestinal cells and more in the lab. These cells can be used to repair or replace cells damaged by accident, disease or aging. However, they are not identical to cells created by living creatures because they don’t follow the same biological process.

Looking to improve the function of the cells, Izpisua Belmonte questioned whether they could be put inside an animal and grown organically instead of growing them in a petri dish.

Having had success with chimeric mice and rats, the lab questioned whether human cells could be incorporated into the embryos of other animals, which could then grow and develop human-size and genetically modified organs for humans. Pig tissue has been used in certain organ transplants or supplements, such as a pig heart valve in a human heart.

But, Izpisua Belmonte said, human cells have a receptor on the exterior and another protein called a ligand that connects them to other cells. “If the cells were of the same species, the ligand and the receptor would fit perfectly,” he said. “But with the human and the pig, the ligand will not connect with a receptor.”

With humans and monkeys being closer together evolution-wise than other animals, he theorized that the communication among cells might be easier. He was right. For the first time, scientists grew monkey embryos containing human cells in a petri dish for about 20 days to see how they would communicate.

“This communication was much more efficient than the communication between human cells and pig cells,” Izpisua Belmonte said. He likened the process to communicating with different languages: Human cells in pig tissue was akin to the cells trying to find common ground between Chinese and French, for example, whereas human cells in monkeys operated more like two closely related languages, such as Spanish and French.

However, he said, “our goal is not to have human cells growing inside monkeys; this is not what we’re after. The idea would be with the molecular knowledge of how these monkey and human cells communicate, this knowledge can bring it back to the pig cells and re-engineer the pig cells so it can communicate better with [other] cells.”

Izpisua Belmonte added that engineering human and/or monkey cells to communicate with pig cells and eventually use them to help grow organs compatible with humans is “a far way away” and “we will need some time to understand at the molecular level that communication and apply it to a pig. The concept has been proven; achieving this with human cells will take longer.”

The discovery has drawn criticism from some in the scientific community, particularly regarding the ethics of such a process.

Primates are protected by stricter research ethics rules than certain other animals, and some scientists worry that such work could trigger public opposition.

“There are much more sensible experiments in this area of chimeras as a source of organs and tissues,” Alfonso Martinez Arias, a developmental biologist at Pompeu Fabra University in Barcelona, Spain, said in an article published by the journal Nature. Experiments with livestock animals such as pigs and cows are “more promising and do not risk challenging ethical boundaries,” he said.

Izpisua Belmonte said “we understand there are concerns, but every day we do an experiment in the lab, we have to pass local and worldwide regulations. Many of the things that were impossible yesterday are possible today, and this comes with critiques. What was considered inappropriate yesterday is considered appropriate today.”

“A few hundred years ago,” he said, “one of the major theologists ... proposed respiration and the interchange of gases in our lungs that allow people to breathe. The church could not accept that, so he was burned alive. … We just need to ... embrace science because it can make us better, but with certain ethical regulations that all institutions have in place.” ◆