February 21, 2003
Human Embryonic Stem Cell Gene Insertion and Deletion

Scientists at U Wisc Madison have developed a technique for humans to add or delete genes from embryonic cells. (bold emphases added)

MADISON - The technique that helped revolutionize modern biology by making the mouse a crucible of genetic manipulation and a window to human disease has been extended to human embryonic stem (ES) cells.

In a study published today (Feb. 10) in the online editions of the journal Nature Biotechnology, a team of scientists from the University of Wisconsin-Madison reports that it has developed methods for recombining segments of DNA within stem cells.

By bringing to bear the technique, known in scientific parlance as homologous recombination, on DNA in human embryonic stem cells, it is now possible to manipulate any part of the human genome to study gene function and mimic human disease in the laboratory dish.

"Indeed, homologous recombination is one of the essential techniques necessary for human ES cells to fulfill their promise as a basic research tool and has important implications for ES cell-based transplantation and gene therapies," write Wisconsin researchers Thomas P. Zwaka and James A, Thomson, the authors of the new study.

The technique has long been used in the mouse and is best known in recent years for its use to generate mice whose genomes have been modified by eliminating one or more genes. Known as 'knockouts,' genetically altered mice have become tremendously important for the study of gene function in mammals, and have been used to explore everything from the underlying mechanisms of obesity and other conditions to the pinpointing of genes that underpin many different diseases.

Significant differences between mouse and human embryonic stem cells have, until now, hampered the application of the technique to human ES cells, according to Zwaka, the lead author of the Nature Biotechnology report and a research scientist working in the laboratory of James Thomson. Thomson was the first to isolate and culture human embryonic stem cells nearly five years ago.

"This is a big benefit for the human ES cell field," Zwaka said. "It means we can simulate all kinds of gene-based diseases in the lab - almost all of them."

To demonstrate, the team led by Zwaka and Thomson were able to remove from the human genome the single gene that causes a rare genetic syndrome known as Lesch-Nyhan, a condition that causes an enzyme deficiency and manifests itself in its victims through self-mutilating behavior such as lip and finger biting and head banging.

The study of genes derived from human ES cells, as opposed to those found in mice, is important because, while there are many genetic similarities between mice and humans, they are not identical. There are human genes that differ in clinically significant ways from the corresponding mouse genes, said Zwaka. The gene that codes for Lesch-Nyhan is such a gene, as mice that do not have the enzyme do not exhibit the dramatic symptoms of the disease found in humans whose genes do not make the enzyme.

Another key aspect of the new work is that it may speed the effort to produce cells that can be used therapeutically. Much of the hype and promise of stem cells has centered on their potential to differentiate into all of the 220 kinds of cells found in the human body. If scientists can guide stem cells - which begin life as blank slates - down developmental pathways to become neurons, heart cells, blood cells or any other kind of cell, medicine may have access to an unlimited supply of tissues and cells that can be used to treat cell-based diseases like Parkinson's, diabetes, or heart disease. Through genetic manipulation, 'marker' genes can now be inserted into the DNA of stem cells destined for a particular developmental fate. The presence or absence of the gene would help clinicians sort cells for therapy.

"Such 'knock-ins' will be useful to purify a specific ES-cell derived cell type from a mixed population," Zwaka said. "It's all about cell lineages. You'll want dopamine neurons. You'll want heart cells. We think this technique will be important for getting us to that point."

Genetic manipulation of stem cells destined for therapeutic use may also be a route to avoiding transplant medicine's biggest pitfall: overcoming the immune system's reaction to foreign cells or tissues. When tissues or organs are transplanted into humans now, drugs are administered to suppress the immune system and patients often need lifelong treatment to prevent the tissue from being rejected.

Through genetic manipulation, it may be possible to mask cells in such a way that the immune system does not recognize them as foreign tissue.

This press release is as notable for what it doesn't say as for what it does say. First lets review what it does say the technique will be useful for.

Yes, this technique will be useful for doing cloning to create cell lines that have knock-outs of genes in order to study the effects of eliminating individual genes. This is routinely done with mouse cell lines. It can even be used with reproductive cloning to find out whether a mouse can still live without a gene and to see what effects the absence of the gene has on whole organisms. Of course it is unlikely (at least in Western countries) that scientists are going to do reproductive cloning on humans with gene knock-outs to discover what effects a gene knock-out has on full human organisms.

The technique will probably be useful in helping to guide cellular differentiation and to solve immuno-compatibility problems in order to create replacement organs.

The press release doesn't mention the possibility that this technique will also probably be useful for the creation of non-embryonic stem cell lines in order to do replenishment of non-embryonic stem cell reservoirs. That will be useful for treating some genetic diseases (e.g. sickle cell anemia) and some types of cancer (e.g. leukemia). But the biggest benefit to come from making non-embryonic stem cells is as a rejuvenation therapy to partially reverse aging.

The biggest potential use of this technique that the press release doesn't mention is like the huge elephant in the room that everyone pretends not to notice: This technique will be useful for human germ line genetic engineering for the purpose of creating genetically engineered human offspring. The ability to delete and insert genes means the ability to replace one version of a gene with a different version of the same gene. It also means the ability to add new genes. Also, additional copies of existing genes could be added in order to get more expression of those genes in the embryo, child, or adult human.

A technique to change embryonic stem cell genes is unlikely to be limited only to embryonic stem cells produced in a single way. It seems likely that the technique will work on embryos produced by cloning or by in vitro fertilization of an egg or by regular sexual reproduction where the embryonic cells would be removed from a woman's womb. Therefore regardless of how a viable embryo is created it will be possible to do genetic engineering to it before it develops into a fetus and baby.

Share |      Randall Parker, 2003 February 21 03:24 PM  Biotech Manipulations

Bob said at February 21, 2003 4:25 PM:

It doesn't mention the giraffe either. I'm sure that body builders and "world-class" athletes will be all over this in no time.

Curry Master said at June 5, 2003 7:47 PM:

Hey i would just like to point out to the creator of this site that pundit is the name for a indian (hindu) priest.

Stuart Evans said at March 7, 2004 5:20 PM:

As an old S.F. reader, I can usually relate new technology to old stories I read years ago. This one I can relate to supermen and women who were 10%Jack's,20%Harry's,8%Helen's etc. But mostly,I think of the continual degradation of the human genome caused by the practise of medicine since time immemorial,and the chance to repair some of the damage. Take haemophilia for instance:- This can be completely avoided by aborting male fetuses but at the same time as producing many carrier females which perpetuate the necessity of future screening. This is commonly done right now. Or in earlier times think of a doctor,giving a cesearian to a woman with small hips who was herself delivered by cesearean of a small-hipped mother.Why should we accept this medical tinkering with our genes and yet object to attempts to repair it? As a starter, I would like to see the gene for baldness completely expunged from the human genome!

Stuart Evans said at March 7, 2004 5:25 PM:

Here is a chance to repair some of the damage to the human genome that the practice of medicine has been doing since time immemorial. Support it! Start with the gene for baldness!

Randall Parker said at March 7, 2004 5:52 PM:

Stuart, I am in your chorus cheering on this idea of putting an end to the gene for baldness. Then right after that I want gene therapy to repair the cells that generate hair color so that grayness can be put to an end as well.

patel said at April 7, 2004 3:07 AM:

Respected sir,
I and my brother has a problem of baldness(In my family no one has this problem) so sir I want to know what is the problem with me and my brother??
pls reply soon sir...WITH THANKS...

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