New cells lines made using “cloning” technique valuable for research

Yesterday a New York Stem Cell Foundation team reported for the first time that they had created two new embryonic stem cell lines through a technique known as somatic cell nuclear transfer (SCNT), which is sometimes called therapeutic cloning. They reported their findings in the journal Nature.

SCNT is a third avenue for creating cell lines able to form all tissues in the adult body – called being “pluripotent.” Interestingly, SCNT borrows from the two other techniques used to date.

Pluripotent cell lines were first created by extracting them from 5-6 day old human embryos left over after in vitro fertilization – hence their name human embryonic stem cell lines.

Pluripotent cell lines were later created by reverting skin cells to a pluripotent state through a process called “reprogramming” – commonly referred to as induced pluripotent cells.

SCNT is a reprogramming method that involves the creation of an embryo as a first step.  In this case, scientists took DNA from a human skin cell and placed it in a human egg, which they then stimulated to form a 5-6 day old embryo. In this environment, the DNA was reprogrammed to an earlier state and the resulting cells were extracted to create human embryonic stem cell lines.

The fact that SCNT-derived stem cell lines have so much in common with other forms of pluripotent stem cells has some opponents of the research asking why bother? Here’s why. CIRM held a conference in June 2010 to discuss the value of pursuing SCNT and posted a report on the findings in November, 2010. 

That report suggests three areas where embryonic stem cell lines generated through SCNT would clearly be valuable in three ways:

• Understanding how you reprogram any cell to become pluripotent could help us optimize the creation of iPS cells, which are so far inefficient to create in addition to being incompletely reprogrammed.
• Understanding and treating the rare diseases that are passed on from those few genes that reside outside the nucleus in the cellular organ called the mitochondria.
• Studying the very early stages of human development, which are poorly understood now, and which is when some human diseases are thought to originate.

The fact that the New York team got the technique to work in humans is a significant advance that has value for all three of those potential areas of research. However, the two cell lines reported yesterday aren’t exactly ready for therapies. Rather than having two copies of each gene, as all of us do, these cells have three copies of every gene and are therefore biologically abnormal. The Wall Street Journal described the problem like this:

While such cloning experiments have been successful in various mammals, the "de-nucleated" egg approach hasn't worked so far in humans. Now, Dr. Egli and his colleagues have—partially—achieved it via a simple move: They didn't remove the egg's own nucleus.

Not removing the egg’s nucleus resulted in the triple copy of chromosomes (one from the egg and two from the donor’s nucleus) that left the cells as “research only” cell lines. Many news stories about the work have referred to the new lines as coming from “cloned embryos”. However, because the cell lines contain more chromosomes than the donor cell they are not truly clones.

Understanding what factors in the nucleus aided in getting SCNT to work could provide clues about factors that might aid in making iPS cells more efficiently, and also provide clues as to how to create SCNT-derived lines with normal numbers of chromosomes.

The Wall Street Journal story quotes George Daly, a stem-cell researcher at Children's Hospital Boston , who summarizes the findings as “a landmark even if it isn’t a complete victory.”

In coming months we should watch for advances that turn this landmark into a victory for people hoping to use the SCNT-derived stem cells to study the earliest stages of development, understand and treat mitochondrial diseases, and learn how to create better iPS cells.

DG

Scotland week honors Scottish stem cell scientists

April 3 – 10 is Scotland Week in the U.S. and Canada, reaching its apex on April 6 with Tartan Day. That gives us all one day to dig up a kilt to honor any Scottish heritage we may have.

In celebration of the week, the Scottish Stem Cell Network is posting a series of profiles featuring Scottish stem cell scientists working in the U.S. and Canada, or international collaborations featuring Scottish scientists.

Scottish scientists played a pivotal role in the stem cell field: It was a team at the Roslin Institute in Edinburgh that cloned dolly the sheep. That breakthrough – the first cloned mammal—demonstrated that it was possible to reprogram an adult nucleus back to an embryonic state. In the case of dolly and other cloned mammals, the reprogrammed nucleus went on to form an embryo that was then implanted into a mother.

In stem cell science, the embryo formation step can be used to create new embryonic stem cell lines. Rather than implanting the embryo, scientists remove the inner cells, which go on to form stem cells with DNA identical to the animal that donated the cell nucleus. The technique hasn’t worked yet in humans, but is carried out widely in other animals. (It’s that first step, called nuclear transfer or SCNT that some Minnesota lawmakers are trying to ban in humans, rather than banning the implantation of the embryo as California has done.)

Today’s update from the Scottish Stem Cell Network is particularly interesting. They chronicle the life of a tissue sample in a clinical trial. I know, it doesn’t sound like a real page-turner, but you’d be surprised how many steps there are in simply collecting samples to find out if a clinical trial is working. At CIRM we are frequently asked why science takes so long to produce cures. Reading the SSCN piece you realize how carefully each step of a clinical trial must be carried out.

We’ve also produced a video by CIRM grantee at UC Irvine Hans Keirstead talking about hurdles that have to be overcome in developing new cures.

One thing that speeds the path to new cures is when the best scientists from around the world work together to make progress. SSCN has encouraged those collaborations through the International Consortium of Stem Cell Networks, and CIRM has agreements with 13 governmental agencies to work together toward new cures. So, whether or not you wear a kilt on Wednesday, you can take a minute to celebrate international efforts to develop new stem cell-based cures.

- A.A.

Legislating science without scientists = confusion

It sounds like the Minnesota senate could use a little help from CIRM's Stem Cell Basics as they debate a proposed ban on… well, they aren't really sure what it's on. Reproductive cloning? Therapeutic cloning? Stem cell research? 

(Hint, reproductive cloning creates a new human — CIRM, the California constitution and all states actively supporting stem cell research oppose reproductive cloning. Therapeutic cloning, if it ever works in humans, would provide an additional way of creating embryonic stem cells. These cells, contrary to some science fiction scenarios mentioned in a Minnesota Independent story, can not form a new person.)

Perhaps including scientists in the discussion would have allowed lawmakers to clear up this confusion.

The Minnesota Independent wrote about a Senate Higher Education Committee debate over an amendment proposed by Sen. Michelle Fischbach banning taxpayer funding for a technique called somatic cell nuclear transfer. The confusion comes over the fact that SCNT is the first step in reproductive cloning, and is also the first step in creating embryonic stem cells identical to the donor's cells. So far, SCNT has been successful in a number of animals but has never worked in humans. (All human embryonic stem cells currently come from embryos left over after in vitro fertilization.)

The proposed ban would eliminate both uses of SCNT, and would prevent Minnesota scientists from using stem cells created via SCNT in other states. According to the Minnesota Independent, Sen. Kathy Sheran spoke up about confusing the two uses:

“I think we are really in danger of confusing the public about the difference between human cloning using stem cells for the creation of another human being and stem cells used for therapeutic purposes,” said Sheran. “They are very different and very separate, and this rolls them all in together and confuses the public into thinking this is all about human cloning when it isn’t.”

In a blog entry last week (Ban reproductive cloning not stem cell research), my colleague Geoff Lomax, who heads CIRM's Standards Working Group, made what I thought was a great comparison between the SCNT debate and genetics. Genetic engineering has resulted in untold new drugs and disease discoveries. It also underlies the fear of genetic discrimination made famous in the movie GATTACA. Did we ban genetic engineering in order to prevent GATTACA? No, we enacted the Genetic Non-Discrimination Act to prevent such a scenario.

Lomax said:

By the same logic, we shouldn't ban basic research due to unwarranted science fiction concerns over reproductive cloning.

Apparently the Minnesota lawmakers don't agree. An attempt to explicitly ban reproductive cloning failed in favor of more general language encompassing both uses of SCNT.

For more information about SCNT, see the report from CIRM's 2010 SCNT workshop.

- A.A.