Of Stem Cells and Neanderthals

Last October, word leaked out that something might be seriously amiss with the embryonic stem cell lines approved by President Bush for federally funded research. Today, the full details were published on line in Nature Medicine. It’s an important paper, and not only because it points out a grave problem with the current state of stem cell research. It also shows how scientists who do cutting-edge medical research are looking back at two million years of human evolution to make sense of their work. At a time when antievolutionists are trying hard to wedge creationist nonsense into science classrooms, this is something worth bearing in mind.

This new research focuses on the sugar molecules that coat our cells like frosting on a cake. Two of these sugars are common on virutally every mammal. They are abbreviated as Neu5Ac and Neu5Gc. These sugars are clearly essential to survival. When scientists altered the genes of mice so that they couldn’t produce them, the mice died. The sugars probably have several vital roles. They probably work as identity badges, judging from the fact that mammal cells also have receptors that can lock onto these particular sugars and only these particular sugars. Cells need to recognize each other for many reasons, such as when they are developing together to form a complex organ like a liver or a brain.

A surprise was in store for scientists who began looking for these two sugars in the human body. They found plenty of Neu5Ac, but they found practically no Neu5Gc. This is no minor difference, abbreviations aside. Neu5Gc is very common in other mammals. In gorillas, our close relatives, it makes up between 20% to 90% of this group of sugars. In us, zip. We are unique, in fact, among mammals for lacking this molecule.

Ajit Varki of UCSD led the research that established that Neu5GC is missing from humans. He decided to figure out how it disappeared. Other mammals make Neu5Gc by tinkering with Neu5Ac. The enzyme that does the actual tinkering is known as CMAH. This enzyme is pretty much identical in mammals ranging from chimpanzees to pigs. In humans, Varki and his colleagues discovered, the gene for CMAH is broken. It produces a stunted version of the enzyme which can’t manufacture Neu5Gc, and so our cells end up with none of these sugars on their surfaces.

The CMAH gene is broken the same way in every person that has been studied. That strongly suggests that all living humans inherited the mutation from a common ancestor. Since chimpanzees, our closest living relatives, have a working version of the gene, that ancestor must have lived less than six million years ago. Scientists can even say exactly how the gene mutated. A parasitic stretch of DNA known as an Alu element produced a copy of itself which got randomly inserted in the middle of the CMAH gene.

But Varki didn’t stop here. He joined with experts on extracting ancient biomolecules from fossils. They ground up bits of bones of Neanderthals, which split off from the ancestors of living humans about 500,000 years ago. In 2002 they reported that they found Neanderthal Neu5Ac, but no Neu5Gc. Neanderthals probably inherited the same mutation as we carry. Thus, the mutation must have struck hominids before 500,000 years ago.

To narrow their estimate further, the researchers looked closely at the Alu element that had caused the mutation. They compared its sequence to the original version from which it had been copied. They also looked at related versions in other primates. Studies have shown that this parasitic DNA mutates at a relatively steady rate. So by comparing the mutations in the different versions, they could estimate how old the sugar-disrupting mutation was. They came up with 2.7 million years ago, plus or minus 1.1 million years. While this estimate spans a couple million years, it still falls nicely between the range suggested by earlier research.

This study was the first to pinpoint a mutation that produced a signficant biological change in the hominid lineage. Just three years later, we have hundreds to choose from. But the loss of Neu5Gc still remains an important discovery because it is a loss. As I wrote in an earlier post, losing genes may actually be as important to human evolution as gaining new ones. Losing genes can sometimes release us from restraints that prevented our ancestors from exploring new ways of living. Exactly what advantage giving up Neu5Gc provided isn’t clear, according to Varki, but he has some suspicions. Parasites have evolved receptors that can grab onto both sugars, an important step in invading a cell. It’s possible that losing one of these sugars helped our ancestors become more resistant to some disease.

Varki also points out that the elimination of Neu5Gc might have been particularly important for the hominid brain–which, perhaps not coincidentally–went through a huge expansion roughly around the time that the Neu5Ac mutation occurred. In other animals, Neu5Gc is abundant on the cells of most organs, but exceedingly rare in the brain. It is very peculiar for a gene to be silenced in the brain, which suggests that it might have some sort of harmful effect. Once a mutation knocked out the gene altogether, hominids didn’t have to suffer with any Neu5Gc in the brain at all. Perhaps Neu5Gc limited brain expansion in other mammals, but once it was gone from our ancestors, our brains exploded.

This is not merely a just-so story. In Varki’s lab, researchers are breeding mice that can’t produce Neu5Gc and others that make too much. If Varki is right, the alter mice should wind up with altered brains.

Now for the stem cells.

Varki has been puzzled by the fact that some scientists over the years have reported detecting tiny amounts of Neu5Gc in humans. If, as Varki has found, the genetic machinery for making this sugar is broken beyond repair, how are they getting it? He and his researchers have spent several years attacking the problem. Their experiiments indicate that we pick up the sugars from the foods we eat–in particular beef and other meat from mammals. Our cells absorb the foreign Neu5Gc and stick them on their surfaces, alongside their normal Neu5Ac sugars. It’s possible that their similarity fools our cells into making this mistake. This happens only rarely, but often enough that we develop antibodies to Neu5Gc. In other words, our bodies know that Neu5Gc is the enemy.

It occurred to Varki that something similar might be happening in the production of embryonic stem cells. Once these cells are taken from an embryo, scientists traditionally lay them on top of a layer of mouse embryo cells and calf serum, which provide a supply of food for them. This food, it turns out, is loaded with Neu5Gc, and Varki–working with Fred Gage of the Salk Institute–discovered that it ends up on the human stem cells like frosting on a cake. And Varki and Gage found that human antibodies against Neu5Gc readily attack the stem cells.

If these stem cells were put in people, they might well be destroyed by antibodies. And even if they weren’t, the foreign Neu5Gc on their surfaces could cause problems. Both Neu5Gc and the normal Neu5Ac help cells recognize each other, which is crucial during development, when cells stick together to form new structures. Confused cells could wind up producing developmental defects.

Now I suppose that opponents of embryonic stem cell research might seize on this research. Most of the embyronic stem cell lines now being studied could never be implanted in people to provide a new supply of neurons or heart tissue, because they’d be attacked as foreign tissue–exactly the sort of trouble that stem cells were supposed to avoid. Better to scrap the whole line of research and just focus on adult stem cells. (This article in Forbes seems to push this line.)

But this doesn’t really make sense on strictly scientific grounds. Scientists could just scrap their existing lines of stem cells and start new ones, making sure that they can’t take up Neu5Gc. This would be a challenge, but not an impossible one. Varki and Gage suggest feeding stem cells on serum taken from the person who is going to receive them, for example. Since we really don’t know whether embryonic or adult stem cells are going to work as cures, why should scientists simply walk away from embryonic stem cells in the face of a challenge?

The irony is that scientists who rely on federal funding have no choice but to walk away. Starting a new stem cell line is expressly verboten under Bush’s decree, because it crosses the moral line he has drawn in the sand. Varki and Gage’s results will spell certain doom for embryonic stem cell research only if the government wants it to.

I have noticed that members of the Discovery Institute, the headquarters for lobbying for Intelligent Design, are also speaking out against embryonic stem cell research. It will be interesting to see if they try to embrace Gage and Varki’s research while still trying to cast doubt on evolution. How on Earth, I wonder, could someone promoting Intellgent Design or Young Earth creationism make sense of these scientific results? How could they explain away so many facts that line up to present us with an evolutionary history taking us down through millions of years, from our common ancestor with other apes, to the first hominids to evolve large brains, to the rise of Neanderthals and our own species, to the latest breakthroughs in medicine? I do try to imagine how they would do this from time to time, but without much luck. I think I’ll keep track of real science instead.

Update, Monday January 24, 2005: The paper is not on the Nature Medicine site yet. I will post a good link as soon as one becomes available.

Update, Monday, 3:00 pm: Welcome, citizens of Slashdot and Metafilter. There sure are a lot of you!

Nature Medicine has made the PDF of the Varki paper available for free on their home page. (Scroll all the way down.)

Update, Friday, 5 pm: Here’s a follow-up post on why I don’t think this proves the handiwork of an Intelligent Designer.