Turning skin into sperm

Eggs and sperm are pretty special cells. They are the chains that link one generation to the next. In a sense they are our immortal parts, with some living on in our children, and some of theirs carrying on in yet the following generation, and so on. The scientists that study these cells consider them the most important cells of the body. Without them our species would cease to exist.

Infertility is a devastating condition for couples that desire children. They will go to great lengths to overcome the problem. About one percent of all births in the US are the result of in vitro fertilization procedures. But even these so called test tube babies can only be made if the parents produce eggs and sperm. If the male, for example, makes no sperm, then all current procedures fail.

A remarkable breakthrough in the test tube creation of sperm has been reported in the Aug. 19 issue of the prestigious science journal “Cell”. A group working at Kyoto University, including Katsuhiko Hayashi and Mitinori Saitou, discovered how to turn stem cells into sperm. They worked with the mouse model organism, but there is no reason to think that the same developed methods won’t also apply to humans.

This group and others had been previously studying the normal progressive process that creates sperm. It had been shown that in the embryo the stem cells that will normally give rise to sperm are sequentially exposed to a series of signals including the Wnt, Activin and FGF, BMP4 and LIF growth factors. By recapitulating this natural plan in the petri dish they found they were able to convert a small percentage of stem cells into primordial germ cells, the precursors to sperm. They were able to actually sort out just the primordial germ cells based on their surface properties, and then they injected them into the testicles of mice that could not make their own sperm. Amazingly, the injected cells made sperm and the mice became fertile.

This work was first carried out using embryonic stem cells, which are natural stem cells that were isolated from mouse embryos. This is great from a science perspective, but it wouldn’t be of much use for an adult male, with his embryonic stem cells long gone. The Kyoto group therefore repeated the experiments starting with stem cells that had been made from adult cells. Yamanaka had shown previously that it is possible to treat adult cells, such as skin cells, with a special gene expression cocktail and to turn them into the functional equivalent of embryonic stem cells. See my blog on “Why Yamanaka will win the Nobel Prize” for details. Anyway, they showed that the procedure worked just as well with stem cells made from adults.

The implications of the work are enormous. In a few years, as these procedures are translated from the mouse to the human, it might become possible for men that don’t make sperm to father children. This could provide considerable benefit for otherwise infertile couples.

It also opens up some interesting possibilities concerning designer genes children. Scientists are already incredibly proficient at the genetic engineering of stem cells. Over ten thousand genes have been modified in mouse stem cells, and then the cells were used to make mice, which then revealed the functions of the genes. It now appears possible to take skin cells from adults, to turn them into stem cells, which can then be genetically manipulated, and turned into sperm. That is, it now appears possible to make designer genes sperm.

As we better learn the complex relationships between DNA sequence and traits, such as longevity, health, looks, athletic performance and intelligence, it will become possible to engineer sperm that will produce children with desired features. This strategy is much more ethically appealing than more traditional designer genes baby approaches, which typically involve the genetic screening of many embryos to find those with the preferred gene combinations. The problem, of course, is that those embryos without the wanted features are discarded.

But the designer genes production of sperm, and eventually eggs, avoids these ethical concerns. All of the genetic engineering and selection occurs before any embryos are made. No life is lost. No embryos are harmed. What is not to like?

The DNA sequencing revolution and our designer genes future

Historians might refer to our current era as the Age of DNA Sequencing. There is an incredible technological revolution going on that is radically reducing the cost of DNA sequencing. The Human Genome Project, which determined the first complete Human DNA sequence, was completed about a decade ago, at a cost of over three billion dollars. It was a remarkable achievement, to be ranked with the likes of landing on the moon, and with much greater long term impact on our well being.

Yes, there was a bit too much hype, and some are disappointed that we haven’t seen more diseases cured. But there is no denying that we have set out on an incredible journey that will, in time, completely change the nature of medicine. Indeed, it is even going to change the fabric of the Human species itself.

The first thing we discovered is that people only have about 25,000 genes, a number about five fold smaller than previously thought. It is amazing to think that you can genetically program all of the complexities of a person starting with only 25,000 genes. The Human DNA sequence also allowed us to map thousands of mutations to specific genetic diseases. For many diseases this work provided the first clue as to the genetic basis, and put us on the path to finding a cure.

One important offshoot of the DNA sequencing work is the field of personalized medicine. Our genetic differences make us respond differently to medicines. A drug that might cure one patient could kill another. Already we find certain cancer treatments are guided by the genetic basis of the individual’s disease.

Another result is the appearance of several companies that offer individual genetic analysis services. These companies, like 23and me, Pathway Genomics and Navigenics, all use a relatively simple “SNP Chip” technology that looks at thousands of bases, of the 3 billion total, that have been associated with specific interesting traits. The cost is generally a few hundred dollars, and the companies promise to provide “insight into your traits, from baldness to muscle performance. Discover risk factors for 97 diseases. Know your predicted response to drugs, from blood thinners to coffee. And uncover your ancestral origins.” https://www.23andme.com/.

But the real revolution is yet to come. The truth is that our current understanding of the genetic basis of most traits is fragmentary at best. We don’t really know which gene combinations define our features, such as appearance, intelligence, longevity, athletic performance and predisposition to disease. What we really need is the DNA sequences for lots of people, so we can then begin to relate their traits to their DNAs.

And this is why the current revolution in DNA sequencing technology is so important. While the first Human DNA sequence took many years to complete, at a cost of over three billion dollars, it is now possible to sequence a person’s DNA in a matter of weeks for a cost of a few thousand dollars. That is, the price has dropped about a million fold. And there is no end in sight. I was recently speaking with a representative of a company that makes the Ion Torrent DNA sequencing machine. It uses a modified computer chip to sequence DNA. He told me that the goal of his company is to increase the capacity of the machine by a factor of ten every six months. This absolutely blows Moore’s law out of the water. Gordon Moore, one of the founders of Intel, stated in 1965 that the capacity of computer chips could be expected to double about every two years. Interestingly, the first person to have their DNA sequenced with the Ion Torrent machine was Gordon Moore.

In the near future, as the price continues to plummet, we will each of us have our DNAs completely sequenced. Our DNA sequence will be an important part of our medical record, helping guide lifestyle choices, and telling the doctor which diseases to be on the lookout for.

We will then have DNA sequences for millions of people, instead of the thousands that we have today. The DNA sequencing revolution is going to allow us to crack the code, and to figure out which sequences are responsible for which traits. As we relate the sequences of all of these people to their traits we will be able to connect the dots, and learn the genetic equations that define health, longevity and intelligence.

And, as we combine the DNA sequencing revolution with concurrent revolutions ongoing in the fields of genetic engineering and stem cells, the Human race will for the first time be able to take conscious control of its own genetic destiny.

It could well mean the end of the Human race as we know it, but perhaps the beginning of something better.

About the Author: Steve Potter, PhD, is a Professor of Pediatrics, in the Division of Developmental Biology, at Children’s Hospital Medical Center in Cincinnati. He has authored Designer Genes: A New Era in the Evolution of Man, published by Random House 2010 http://www.amazon.com/Designer-Genes-New-Era-Evolution/dp/140006905X/ref=sr_1_1?s=books&ie=UTF8&qid=1310842010&sr=1-1. In addition he has written over one hundred science papers, and co-authored the third edition of the medical school textbook, Larsen’s Human Embryology.

DNA Proves Evolution

In many ways our DNA defines us. Consider identical twins, which are the result of an embryo splitting in early life. They are actually a single individual that divided into two parts during the early stages of embryonic development. They don’t call them identical for nothing. Studies show that in addition to looking the same they are also extremely similar in almost all other measurable respects, including intelligence. And, of course, the reason that they are so alike is that they have identical DNA.

But what makes most people so different from each other? We are only beginning to understand how our DNA differences distinguish us. The Human Genome Project, finished about a decade ago, was a huge first step. It defined the sequence of the A, T, G and C building blocks of our three billion bases of DNA. Like the Moon Project, it was an amazing accomplishment for mankind.

In a sense it was like our DNA defined itself, through us. Our DNA, which encodes us, was actually able to determine its own sequence, using people as a tool for the process. A very smart molecule indeed.

One of the most incredible discoveries to come from the Human Genome Project was the remarkably small number of genes we have. It turns out that we only have about 25,000 genes!! This seems a pitifully puny number.

Think of it. We all start a single cell, a fertilized egg, a very small speck of protoplasm barely visible to the naked eye. And this one cell somehow turns itself into a complete person. And people are incredibly complicated. They can weigh one or two hundred pounds or more. They have arms and legs and complex organs like the liver, heart and kidney. And they have a brain, which has about 100 billion neurons with over 100 trillion specific interneuronal connections. Wow!! All of this from just a single cell equipped with a genetic program of only 25,000 genes in its nucleus. Truly amazing.

And then we sequenced the DNAs of several people, and compared them. It turns out that our sequences are about 99.9% identical, from one person to the next. Our individual differences are defined by the 0.1% sequence variation, the several million bases that fluctuate among the three billion total. As we sequence the DNAs of more and more people we will begin to define the complex equations that relate these sequence differences to specific traits.

And when we sequenced the DNAs of other animals we made more interesting discoveries. It turns out that all mammals-including lions, cows, pigs and elephants- also have three billion total bases of DNA, and about 25,000 genes. Indeed, we all have pretty much the same set of genes. To paraphrase Mario Capecchi, a Nobel laureate, who I once published a paper in Nature with, mouse and man are 99% genetically identical. What he meant by this is that for every gene a person has there is about a 99% chance that the mouse will have a corresponding very similar gene. All mammals have the same genes, but those genes will differ in exact base sequence from each other. His point was that the mouse is an excellent genetic model system for scientific study, because it so closely recapitulates man.

But another key conclusion is obvious. All mammals are very closely related.

Of course the chimpanzee is the extreme example of this, with DNA sequence that is about 99% identical to that of man http://www.seattlepi.com/local/article/Chimp-human-DNA-comparison-finds-vast-1181942.php. The chimp doesn’t just have the same set of genes as man, indeed about one third of chimp genes encode proteins that are exactly the same as their human counterparts http://en.wikipedia.org/wiki/Chimpanzee_genome_project. This sort of result is exactly what evolution predicts, and creationist/anti-evolutionists have to struggle very hard to explain it http://www.christiananswers.net/q-aig/aig-c018.html

But instead of looking at close relatives, let’s look at very distant relatives, like the fruit fly. Shockingly there is some fascinating evidence that we are even genetically related to these little bugs.

Geneticists discovered some crazy mutant fruit flies about a century ago. One mutation, for example, gave a fly that had legs growing out of the head where the antennae were supposed to be. Imagine that! During development the cells that were supposed to make antennae instead made legs that now protruded from the head! Another interesting mutation gave a fly with no eyes.

As technology advanced it became possible for us to manipulate the genes of the fly. We could alter the gene involved in leg/antennae development and re-create a fly with legs coming out of the head. But even more remarkable, we learned how to introduce human genes into the fly. And when we made similar alterations to the human counterpart of the fly gene, and put it in the fly, we got the same result, a fly with legs on the head! The human gene seemed to be functionally equivalent when placed in the context of the fly. A truly surprising and amazing discovery!

We could also take the fly gene found to be critically important for making eyes and cause it to be mis-expressed during development. It was found that if this gene was activated on the legs, for example, one could make a fly with extra eyes on its legs! Indeed it was possible to make a fly with lots of eyes, on the legs, on the antennae, and at other places on the body. But, once again, the most remarkable result came when we took the human gene most closely related to the fly eye gene and placed it in the fly. Just like for the fly eye gene, we found that if we turned on the human gene at various locations during development we could make a fly that had fly eyes all over its body. Once again, the fly and human eye genes appeared to be functionally equivalent.

These results show a remarkable, and quite unexpected, conservation of developmental genetic programs stretching across enormous evolutionary distances. Many human genes seem to work quite well, thank you, when functionally tested in fruit flies, where they initiate genetic cascades that drive the formation of discrete fly body parts. That is, in many cases fly and human genes are functionally interchangeable.

These experiments demonstrate evolutionary relatedness not only between chimps and people, but also between insects and people.

And this is one way that DNA proves evolution.

About the Author: Steve Potter, PhD, is a Professor of Pediatrics, in the Division of Developmental Biology, at Children’s Hospital Medical Center in Cincinnati. He has authored Designer Genes: A New Era in the Evolution of Man, published by Random House 2010 http://www.amazon.com/Designer-Genes-New-Era-Evolution/dp/140006905X/ref=sr_1_1?s=books&ie=UTF8&qid=1310842010&sr=1-1. In addition he has written over one hundred science papers, and co-authored the third edition of the medical school textbook, Larsen’s Human Embryology.