Could we ever genetically design a human?

Creation, second attempt

The tourists strained to look east into the low Siberian sun. For more than an hour they have been standing on a kind of watchtower. You have paid a lot for this moment and you are expecting something special. A living being that shouldn't actually exist. Then: Indeed. Something is moving. Slowly. Majestic. Almost 500 meters away. At first glance, nothing but bushy fur and huge tusks. Some take their breath away.

"Three years ago I would have said: Impossible! But right now there is revolutionary progress in many areas of molecular biology, and that's why I think today, at this point in time, that it is no longer impossible."

Since the clone sheep Dolly saw the light of day, there has been speculation that scientists might one day resurrect the extinct mammoth. But again and again the hopes were disappointed. The cells found were too bad or the methods were not fully developed. But now there is a new way in which the mammoth could return soon.

"The mammoth bull weighs more than twelve tons," explains a ranger. "Genetic researchers built this wonderful animal together in the laboratory - from genetic blueprints that are more than 10,000 years old." "Hard to believe," whispers a tourist around 65 and reaches for his binoculars. "What a blessing that I'm allowed to experience this in my life."

The basis for the resurrection of the mammoth is the complete genome: the sequence of the individual letters in the genome. More than 70 percent of the mammoth genome has been known since the end of 2008. Hardly anyone expected that it would happen so quickly. And now it is only a matter of time and money before the rest of it is stored correctly in the genetic researcher's computers. Stephan Schuster and his team at Pennsylvania State University have already started creating a second, more complete version. It should be available in 2010. The stupid work of sequencing is done by machines and computers. In the meantime, the researchers are trying to evaluate the available data. Cobbler:

"With the data we have now been able to collect, we have made comparisons with 50 vertebrate species that have already been sequenced today, most of them mammals. And there are regions in these genomes that are called ultra-conserved. That is, these regions in this genome are identical at the amino acid level in all examined animal species. And only in the mammoth do we now find areas, individual amino acids, that are different. "

That means: The mammoth genome is unique and very original. The researchers are particularly interested in the deviations and similarities between the mammoth and its closest living relatives, the elephants. Is a mammoth basically an elephant with fur? Initial genetic analyzes have shown that elephants show a high genetic similarity to mammoths. According to initial estimates, the difference is less than one percent. With the Asian or Indian elephant a little less, with the African elephant a little more.

Mammoth news. In a nutshell. The Broad Institute in Boston has deciphered the genetic makeup of the African elephant. The individual letters in the genetic blueprint of the mammal were determined a total of seven times in order to obtain a version of the elephant genome that was as complete and error-free as possible. The data will help to research the evolution and genetic diversity of elephants and their relatives. In the near future, the Broad Institute team also wants to determine the genetic blueprint of the Indian elephant.

If you were to change all the differences in an elephant genome so that they correspond to the mammoth blueprint, an elephant would become a mammoth. Initially, it is nothing more than a mind game in which the molecular biologist Stephan Schuster is also happy to participate.

"What we jokingly call: reverse engineering. So that we are trying to find out what changes we have to introduce into an Asian elephant so that it becomes more mammoth-like. So a mammutification of an Indian elephant"

For many scientists, one thing is certain: the way to the mammoth leads over the elephant. Its mammutification is probably easier and safer than recreating the mammoth from man-made DNA. Cobbler:

"To do something like this with a mammoth, you'd have to make a minimum of 400,000 changes and a maximum of several million."

Since the 1970s, genetic engineers have been able to transplant individual genes from one species to another. With the help of viruses or small rings of genetic material, so-called plasmids, they transfer small segments of genetic material made up of 1,000 or 2,000 building blocks. With this technology, one of the more than 20,000 mammoth genes could already be synthetically produced and transplanted into a different species. But just a Gen. Schuster:

"Well, you can simply multiply this copy into many, many copies with the help of the PCR method. And what would then be trivial to plant that in a bacterium. But you could also relatively easily make a transgenic mouse that then copies a mammoth gene wearing."

Instead of a mouse, however, an elephant could also serve as the receiver. The result would be an elephant with 19,999 elephant genes and one mammoth gene. For example, it could be used to investigate the specific role that a single gene plays in mammoth metabolism. But of course this has nothing to do with the reconstruction of an entire animal. Only after genetic manipulation and many generations would a mammoth gradually emerge. Cobbler:

"At the moment we are not so far advanced that this is technically possible. You can think about it on paper, and there is no longer any resistance among colleagues. But there are still several technical hurdles that have to be overcome before it is then in the end it is so far. "

So you would have to transfer many genes at the same time, so that millions of genetic components would be changed. Scientists have already given some thought to this as well. Researchers from Japan and the USA developed artificial yeast chromosomes about 20 years ago. Many hundreds or even thousands of genes can be accommodated on these so-called micro-chromosomes. There are hundreds of thousands, sometimes millions, of genetic components. The microchromosomes are used in animal breeding. At Hematech in South Dakota, they are used to raise cattle with a human immune system. The farm animals should become vaccine suppliers for humans.

The little calf is still unsteady on its long, skinny legs. Frightened, it looks outside through a pane of glass. Veterinarian Julie Koster explains that the room has to be extremely clean. Because the calf does not have a natural immune system. Only animal keepers in white protective suits - well cleaned - can enter the room through a lock. This calf is genetically modified. It has human genetic material to build a human immune system.

"Genetic engineering is usually limited to a few thousand base pairs. But we had to smuggle in millions of base pairs."

James Robl has made a name for himself as a cattle cloning expert. The university professor is the founder of the company Hematech, based in Sioux Falls, South Dakota. As he sits at his desk, a plastic cow looks over his shoulder.

"We had to build a new chromosome that we added to the bovine genome. Normally cows have 60 chromosomes. Our cattle have 61 chromosomes. The extra chromosome has about 25 to 30 million base pairs. That makes it a very small chromosome compared to natural ones Chromosomes. But it is enough to carry the genetic information for over 1000 genes. That means it is huge for today's genetic engineering. We made this chromosome with the help of yeast cells. The important thing is that it has all the elements to be in one To double cell division so that after cell division both daughter cells receive a micro-chromosome. "

In fact, some cattle developed parts of a human immune system and produced human antibodies. The offspring of these animals, however, had lost this ability again. The artificial chromosome was lost during reproduction. The researchers were only able to breed more cattle with additional human chromosomes using cloning technology. James Robl has to admit that the original plan to use cattle as a vaccine supplier for humans has not yet materialized. Nevertheless, even after ten years of research, he is optimistic.

"The technique is not exactly easy. It is extremely complicated, even today. That is why we have been working with the Japanese food and pharmaceutical company Kirin for several years. The researchers there in Tokyo have most of the experience with microchromosomes. It is difficult that Bringing the right genes together in a chromosome and switching off the corresponding genetic make-up in the recipient. But we have already done it several times. Some of our modified cows with artificial chromosomes are already five or six years old. "

The Hematech company founded by James Robl has since been bought up by the Japanese group Kirin. Research continues, but the Kirin Group management does not want to comment on the chances of success. Should this technique one day be used to create a mammoth, all typical mammoth genes would have to be combined on an artificial microchromosome. At the same time, the corresponding genes of the elephant genome would have to be switched off. A lot of detailed work that would have to be done by hand in the laboratory. Result uncertain.

Five minutes later the mammoth is still standing motionless next to a pair of disheveled pine trees. The first tourists are getting impatient. "I hardly see anything," complains an overweight man around 60. "Couldn't they drive the mammoth a little in our direction? After all, we paid for this attraction." The ranger shakes his head. "You can be happy to see such a wonder of nature in the 21st century. You have no idea what our researchers have done to make this possible."

The American genome researcher George Church from Harvard Medical School in Boston has an idea of ​​his own on the subject of the "return of the mammoth". His philosophy is: automation. And then life constructs itself.

"You can sort of carry out the genetic changes on the fly. So while the cells are alive and dividing. It's like adding new parts to your car without stopping. It's the best way to genetically modify mammals. "

Mammoth news. In a nutshell. Geneticists from Harvard Medical School in Boston present a new method of genetic manipulation in the journal "Nature". George Church's team has developed a method with which hundreds of genetic changes can be carried out in parallel. They call their process multiplex genome technology. First of all, it was bacteria of the species Escherichia coli tried. According to developer George Church, the same method can be applied to mammalian cells. In principle, it is now possible to turn an elephant's cell into a mammoth cell, Church told the New York Times.

George Church is one of the stars of a new field of research: synthetic biology. Almost like a guru. He often speaks out on theoretical questions in science, thinks about new methods, and how they could change the world. He always seems calm and serene. Only occasionally does he enjoy provoking.

"We have developed a method that carries out several hundred genetic changes in parallel. The DNA hereditary molecules that are created in this way are not really synthetic. We could now take gene sequences from the elephant and automatically change them. After that, it is no longer elephant DNA, but anything else. Whatever you want. You transplant the genetic material into an elephant stem cell, which becomes a new animal. You can then make a whole mammoth out of a single cell. "

The secret is in an inconspicuous device on a laboratory bench in the room next to George Church's office. The device is no bigger than a laser printer. Several dozen thin tubes connect different reaction vessels. Nothing moves, only sometimes a red or white signal lights up. Connected to it is an ordinary notebook. This can be used to control the wonder box. Church:

"The whole process is automated. The DNA is on a chip. It's not a few hundred base pairs, but 100,000. The genetic information is gradually changed as the computer dictates. Then we put this changed DNA into an elephant cell - with the standard methods of genetic engineering. We do this several times and slowly the elephant cell becomes a mammoth cell. "

It sounds like you can simply change the genome of an elephant, like individual letters in a computer word processor. Delete a G and replace it with a C. For George Church - no problem at all. How the apparatus always makes the changes in the right places remains unclear. He also mentions another difficulty in a subordinate clause: in order to turn a single cell into a whole elephant, this cell must have embryonic properties. She must be totipotent. That means: the biological switches in the genetic material must be set so that a whole living being can emerge from the cell. Only a few cells have this property. Fertilized egg cells, but also embryonic stem cells. Recently there has been another cell type that comes into question: reprogrammed body cells, so-called IPS cells.

Mammoth news. In a nutshell. Chinese researchers are creating mice from reprogrammed body cells for the first time. The production of these so-called IPS cells caused euphoria in 2007. By introducing genetic factors into skin cells, scientists at Kyoto University had made new cells with properties similar to those of embryonic stem cells. Now viable animals could be made from it for the first time. The first mouse created by this method was named: Xiao Xiao. That means tiny.

George Church speaks as if his research was already about recreating the mammoth. He never worked with elephant cells. The techniques developed in his laboratory were only tried out on bacteria. Still, George Church is convinced that his procedure paves the way for the return of the Ice Age giants. He is happy to be photographed with a "synthetic" plush mammoth. No question about it: Church himself is looking forward to the mammoth's return.

“We might do a little test run first. How about an elephant with longer tusks and a little hair growth. Then we'll see how the public reacts to this animal emerge, will live in zoos. But we also have to think about how we can reintroduce them. Only in this way will we really bring back extinct species. "

After all, he adds, man is responsible for the disappearance of many species, and he could bring some back.

"Many ecological studies have shown how important biodiversity is for our ecosystems. We need as much diversity as possible. And that's why we should learn to bring back old species or create new ones."

In Berlin at the Leibniz Institute for Zoo and Wildlife Research people shake their heads at such statements. It would be much more efficient to preserve as much of today's diversity as possible. Nevertheless: The Mammut project is also generating interest here.

"I think it's an extremely interesting project. And it shows that many things that were previously unthinkable with regard to genetic engineering and the reconstruction of the genome can be realized today or in the near future."

Thomas Hildebrandt is often called for help when a difficult elephant birth is imminent in a zoo. His office is teeming with elephants: painted, photographed and as models made of wood, plastic or metal. Most of them are gifts from various zoos as thanks for successful obstetrics.

"When a mammoth project is launched, we are there because we are the reproduction specialists in the world."

Thomas Hildebrandt is interested in all elephants, and for him a mammoth is first and foremost an elephant. In principle, elephants of different species can even mate with one another. Even if they look as different as Asian and African elephants.

"And there was also the successful birth of a hybrid, which unfortunately died ten days later. So there is the theoretical possibility that a mammoth could be carried into an Asian elephant."

The choice would fall on the Asian elephant, since according to the latest findings it is somewhat more closely related to the mammoth than the African. Thomas Hildebrandt sees few problems with genetics. But there is still reproductive biology.Artificial insemination has made great strides in the last few decades. Most of the new methods, however, were developed in farm animals or directly in humans. Without further ado, they cannot be used on elephants, says Thomas Hildebrandt. For example, if a mammoth embryo is to grow in a surrogate elephant mother, the embryo would first have to be transplanted into her uterus. A tried and tested, widely used technique in humans, but not in elephants. Hildebrandt:

"This is extremely difficult with elephants because the embryo transfer into the upper section of the fallopian tube, into the tip of the uterine horn, is a completely different challenge than it would be with sheep, cattle or even humans. The problem we have with elephants: The lungs are enlarged in all elephant species, which means that the pressure in the abdomen is extremely high, and you can use the classic embryo transfer procedure, where gas is poured into the abdominal cavity to push the intestines aside to gain access to the uterus to get that hardly apply to the elephant. "

Even with artificial insemination, Thomas Hildebrandt needs a very long catheter. The long, thin hose has to penetrate the elephant cow 2.50 meters. A difficult undertaking. Hildebrandt:

"But we would have to go at least 70 centimeters further for the embryo transfer and get into the fallopian tube. This is a challenge that has seemed extremely difficult so far, because the fallopian tube only has an outer diameter of four millimeters and an inner lumen of 0, 1 or 0.2 millimeters. That means: We have to operate on a length of over three meters with catheter technology, which is almost the thickness of hair, in order to deposit this embryo there.

If the embryo is not rejected, but implanted in the uterus, it would be done. The gestation period, which for elephants lasts around 22 months, could begin. However, problems could arise again at birth. Because a mammoth is probably bigger than a baby elephant at birth. In the institute's computer tomography room, Thomas Hildebrandt explains the possible complications of a mammoth birth.

"A caesarean section for an elephant has never worked. We had fifteen attempts and all of them ended fatally - for both sides. That means: We must absolutely try, if a mammoth should actually grow in an Asian elephant, that the size ratio is observed, and really gives the mammoth the chance to come out and not have to be sawed up. "

How to solve this problem is something that Thomas Hildebrandt does not want to commit yet. In any case, the word "impossible" is not part of his vocabulary. For him, however, it is clear that the return of the mammoth can only be had with extreme effort and after a lot of effort. The human wish to meet his companion, the mammoth, is understandable, however.

"The relationship between humans and the elephant-like is a very special relationship. There was this saying from Schopenhauer, who said: The idea of ​​the elephant is infinite. That means: We humans even take the elephant into our philosophical world, and the relationship between humans and mammoths 10,000 years ago was extremely intense, because a mammoth killed enabled the group to survive over the winter. "

In addition to the wishes of humans, there are of course also the needs of the mammoth. Nobody can ask the mammoth whether it wants to return - and if so, how it would like to live. Hildebrandt:

"The elephant - and it can be assumed that it is similar to the mammoth - is a highly social, intelligent animal. We see it in classic zoo keeping, until twenty years ago, that animals were kept individually, that they developed extremely severe depression So the elephant needs the social context, the interaction between the individuals. That means: A mammoth is likely to get mentally ill. So we need at least three or four young animals to stimulate the group. That is a challenge to science, which is still is more complex than just retrieving an animal. "

Even the research optimist George Church becomes thoughtful when he looks at the small, lonely plush mammoth. He reaches into the shelf and places an Indian porcelain elephant next to it.

"When we bring back a species, we are responsible for its well-being. We have to be humane to the animals and make them feel just as comfortable in their new genome as they are in their old genome."

Mammoth news. In a nutshell. In the province of Yakutia in northeast Siberia, the ice age is set to begin again. The Russian geologist Sergej Zimov has been pursuing the goal of transforming a large uninhabited area into an Ice Age steppe for years. At the moment the area is about 40 by 40 kilometers. According to Zimov's plans, a landscape is to be created there that shaped large areas of Eurasia until around 11,000 years ago. Many of the animal species that were widespread at the time are to be settled there: reindeer, bison, wisents, steppe horses, wolves and, if possible, mammoths at some point.

The majority of all animal species that ever lived on earth no longer exist today. Most of them are extinct. Species living today probably make up less than one percent of all species ever created by evolution. For the Berlin zoologist Alex Greenwood, extinction is just as much a part of nature as the emergence of new species.

"Mammals are widespread because the dinosaurs are extinct. And this cycle happens again and again. If we stop this process and nothing becomes extinct, then there will be no species development, because all niches are occupied. We do not come to evolution."

"We're going to Kenya again next year," says a woman wrapped in a fur coat and looks reproachfully at her husband, who is quietly chattering his teeth. "You get much closer to the animals. Besides, it's not that cold there." "Maybe it's not a mammoth at all," interjects a young woman from under a bearskin hat. "They just took an elephant and let it grow hair, I read somewhere."

Whether the mammoth was once driven from the earth by humans is a matter of dispute among scientists. Alex Greenwood suspects that pathogens played an important role back then. It is different with the African and Asian elephants. They are clearly threatened because humans are destroying their habitat. Bringing back the mammoth while other elephants are being decimated at the same time makes no sense to Berlin zoologists Alex Greenwood and Thomas Hildebrandt.

Greenwood:

"I'd rather see it: we keep our elephants than we bring back extinct elephants."

Hildebrandt:

"If that much money is to be spent on an extinct species, we'd first like to see a little more effort from the public to take care of the animals, which may then be attractive in 10,000 years."

There is silence for a while. Questioning looks in the direction of the ranger. He buries his hands deeper in his pockets. "Right, that used to be an elephant," he mumbles. "But now it's a mammoth. Our scientists have clearly confirmed that." Some tourists nod. Others don't seem convinced. A trick? Did you spend your savings on an illusion?

Note: You can read the first part of the double feature "Creation, 2nd attempt - the mammoth returns" here.