Part 11 (1/2)
They are building the replica specific neuron by specific neuron, because every neuron is anatomically and electrically unique, with unique dendritic connections. The project is founded on an immense amount of research that has been going on for the last hundred years in neuroanatomy, beginning with the unraveling of the microstructure of the neocortical column, and in physiology, beginning with the model of ionic currents and the idea that dendritic branches of neurons affect their processing. The first goal of the project has been accomplished. That was to construct a single neocortical column (NCC) of a two-week-old rat. In preparation for this project, the researchers at EPFL, over the last ten years, have been performing paired recordings of the morphology and physiology of thousands of individual neurons and their synaptic connections in the somatosensory cortex of two-week-old rats. The replica NCC, the ”blue column,”* is made up of ten thousand neocortical neurons within the dimensions of an NCC, which is about half a millimeter in diameter and one and a half millimeters tall.3 At the end of 2006, the first column was completed; the model included thirty million synapses in precise 3-D locations! The next step is to compare simulation results of the model with experimental data from the rat brain. Areas where more info is needed can then be identified, and more research will be done to fill in these gaps. This is not a one-shot deal. The circuit will have to be rebuilt over and over again every time a section gets tweaked by new data, and the replica of the real biological circuit will become progressively more accurate.
What's the Point of Building This Model?
Markram has a whole laundry list of information that will be gleaned from these models. Just as Breazeal thinks her robots will be useful for verifying neuroscientific theories, so Markram thinks of the blue column the same way: ”Detailed, biologically accurate brain simulations offer the opportunity to answer some fundamental questions about the brain that cannot be addressed with any current experimental or theoretical approaches.”3 First, he sees it as a way to gather all the random puzzle pieces of information that have been learned about cortical columns, and put them all together in one place. Current experimental methods allow only glimpses at small parts of the structure. This would allow the puzzle to be completed. You jigsaw fans know how satisfying that can be.
Markram has hopes the continual tweaking of the details of the model will allow us to understand the fine control of ion channels, receptors, neurons, and synaptic pathways. He hopes to answer questions about the exact computational function of each element, and their contribution to emergent behavior. He also foresees insight into the mystery of how the emergent properties of these circuits-such as memory storage and retrieval, and intelligence-come about. A detailed model will also aid in disease diagnosis and treatment. Besides identifying weak points in circuits that can cause dysfunction and targeting them for treatment, simulations of neurological or psychiatric disease could also be used to check hypotheses about their origins, to design tests to diagnose them, and to find treatments. It will also provide circuit designs that can be used for silicon chips. Not too shabby!
CHANGING YOUR GENES.
Gregory Stock, director of the Program on Medicine, Technology and Society at UCLA, doesn't think the fields of technology and robotics are going to change what it means to be human. He thinks being a fyborg is where it is at. Machines will stay machines, bodies will remain carbon. The idea of hopping up onto the operating table for a bit of neurosurgery when he feels just fine doesn't much appeal to him, and he doesn't think it will appeal to many people, especially when everything you would gain could be had by wearing an external device. I know neurosurgery is not on the top of my to-do list. Why risk it, when you could strap on a watch-like device or clip something on your belt? Why give up a good eye when you could slip on a pair of gla.s.ses for night vision? Stock thinks our world is going to be rocked by the fields of genetics and genetic engineering-tinkering with DNA, man directing his own evolution. These changes aren't going to be the result of some mad scientist cooking up ideas about modifying the human race to his specifications; they are going to creep in slowly as the result of work done to treat genetic diseases and to avoid pa.s.sing them on to our children. They are also going to come from the realization that much of our temperament is due to our genes ( just like the domesticated Siberian foxes we talked about) and that those genes will be modifiable. ”We have already used technology to transform the world around us. The canyons of gla.s.s, concrete, and stainless steel in any major city are not the stomping ground of our Pleistocene ancestors. Now our technology is becoming so potent and so precise that we are turning it back on our own selves. And before we're done, we are likely to transform our own biology as much as we have already changed the world around us.”51 Biology-Based Aids-The Ways to Change Your DNA.
You can change your biology by taking medications, or you can change the instruction manual that coded how to build your body. That manual is DNA. There are two ways to tinker with DNA: somatic gene therapy and germ-line therapy. Somatic gene therapy is tinkering with the DNA a person already has in nonreproductive cells; it affects only the current individual. Germ-line therapy is tinkering with the DNA in sperm, egg, or an embryo, so that every cell in the future adult organism has the new DNA, including the reproductive cells. That means the change is pa.s.sed on to future generations.
Stanley Cohen of Stanford University and Herbert Boyer, then at the University of California, San Francisco, worked only thirty miles apart, but they met in Hawaii. They attended a conference on bacterial plasmids in 1972. A plasmid is a DNA molecule, usually in the shape of a ring. It is separate from the chromosomal DNA but is also able to replicate. It is usually found floating around in bacterial cells. One reason they are important is that these strands of DNA can carry information that makes bacteria resistant to antibiotics. Cohen had been working on ways to isolate specific genes in plasmids and clone them individually by putting them in Escherichia coli bacteria and letting them replicate. Boyer had discovered an enzyme that cut DNA strands at specific DNA sequences, leaving ”cohesive ends” that could stick to other pieces of DNA. Shop-talking over lunch, they wondered if Boyer's enzyme would cut Cohen's plasmid DNA into specific, rather than random, segments, then bind those segments to new plasmids. They decided to collaborate, and in a matter of months succeeded in splicing a piece of foreign DNA into a plasmid.52 The plasmid acted as a vehicle to carry this new DNA, which then inserted new genetic information into a bacterium. When the bacterium reproduced, it copied the foreign DNA into its offspring. This created a bacterium that was a natural factory, cranking out the new DNA strands. Boyer and Cohen, now considered to be the fathers of biotechnology, understood that they had invented a quick and easy way to make biological chemicals. Boyer went on to cofound the first biotech company, Genentech. Today, people all around the world enjoy the benefits of Boyer and Cohen's ”cellular factories.” Genetically engineered bacteria produce human growth hormone, synthetic insulin, factor VIII for hemophilia, somatostatin for acromegaly, and the clot-dissolving agent called tissue plasminogen activator. This line of research suggested that perhaps custom DNA could be added to human cells, but the problem was how to get it into the cell.
The goal of somatic therapy is to replace a defective gene that is causing a disease or dysfunction by the insertion of a good gene into an individual's cells. In somatic gene therapy, the recipient's genome is changed, but not in every cell in the body, and the change is not pa.s.sed along to the next generation. This has not been an easy a.s.signment. Although there has been a lot of research done in this area, and a lot of money spent, the successes have been few and far between.
First of all, there is the problem of just exactly how one inserts genes into a cell. Researchers finally figured out that they should use the experts in cell invasion and replication: viruses. Unlike bacteria, viruses cannot replicate on their own. In reality, a virus is merely a vehicle for DNA or RNA. It consists of DNA or RNA surrounded by a protective coat of protein: That's it. They are the quintessential houseguests from h.e.l.l.
Viruses actually sneak their way inside a host cell and then use the cell's replication apparatus to make copies of their own DNA. However, if you could make that DNA a good copy of a defective gene, and direct it to cells that have a defective copy, well then, you can see the possibilities of a virus acting as the agent of somatic gene therapy: Take the virus's DNA out, add the DNA that you want, and turn it loose.
To begin with, research has concentrated on diseases that are caused by only a single defective gene in accessible cells, such as blood or lung cells, rather than diseases caused by a host of defects that work in concert with each other. But of course, nothing is as easy as first envisioned. The protein coats of the viruses are foreign to the body, and sometimes they have triggered host reactions that have caused rejection, a problem that recently may have been solved by researchers in Italy.53 Because of the problems with rejection, different DNA vehicles are being explored. Inserting strands of DNA on a chromosome is also tricky, because it matters where it is put. If spliced next to a DNA sequence that regulates the expression of the sequences next to it, it can result in unexpected consequences, such as tumors.54 Moreover, most genetic diseases, such as diabetes, Alzheimer's disease, heart disease, and various cancers, arise from a host of genes, not just one. Also, the effects of the therapy may not last. The cells that have been modified may not be long-lived, so that the therapy has to be repeated.
Gene therapy has had a few successes, including the treatment of severe combined immunodeficiency disease (also known as bubble-boy disease)55, 56, 57 and X-linked chronic granulomatous disease,58 which is another type of immune deficiency. As I am writing this, the BBC reports that a team at London's Moorfields Eye Hospital made the first attempt to treat blindness caused by a faulty gene called RPE65 using gene therapy.59 Whether this worked or not will not be known for months. The trouble is, somatic therapy is really a quick fix. The people who have been treated still carry the mutant gene and can pa.s.s it on to their offspring. This is the problem that prompts research in germ-line therapy.
In germ-line gene therapy, the embryo's DNA is changed, including the DNA in its reproductive cells. When it comes time for it to reproduce, its egg or sperm cells carry the new DNA, and the changes are pa.s.sed on to their offspring. The disease-producing gene or genes are eliminated for good in a particular individual's genome. This idea could not even have been considered until 1978, when the first test-tube baby was born. In vitro fertilization involves harvesting egg cells from the woman's ovary, and mixing them on a petri dish with sperm. The resultant embryo is then accessible to manipulation. Very controversial at the time, in vitro fertilization (IVF) is now casual c.o.c.ktail-party talk. That is not to say the process is enjoyable. It is difficult and both physically and emotionally arduous. Notwithstanding the difficulties, many infertile couples benefit from the technology, to the extent that 1 percent of the babies born in the United States are the result of in vitro fertilization.
Not all in vitro fertilization is done for infertile couples. Some is done for couples who have had a child with a genetic disease, such as cystic fibrosis. It is also done when one or both of the prospective parents know they carry a copy of a defective gene. Embryos conceived in vitro, when they reach the eight-cell stage, can now be screened with the genetic tests that are currently available. Up until 2006, there were just a small handful of diseases that could be tested for. However, a new procedure known as preimplantation genetic haplotyping (PGH),60 developed at Guy's Hospital in London, has changed that. It is now possible to take a single cell from the early embryo, extract the DNA, replicate it, and then use it for DNA fingerprinting. This not only increases the number of genetic defects that can be detected in preimplantation embryos, now ranging into the thousands, but also increases the number of usable embryos and their survival rate. Before this test was available, if the concern was for X-linked disease, none of the male embryos could be tested, so they were eliminated. Now they too can be screened. Humans are the only animal that can tinker with their chromosomes (and those of other species, too) and guide their genetic reproduction.
The future implications of PGH are huge. There is a Web site called BetterHumans.com. The first page of comments about PGH seems to cover the territory pretty well: ”It's pretty important considering how much it will affect the lifelong happiness of an individual and how well they can contribute to the world.”
”It is wonderful that this is not illegal yet. Do you not love incrementalism?”
”But once again, we need to define disease. I consider the average lifespan to be a disease.”
”Perhaps it will be possible to extrapolate the genetic tendency for longer life, in which case we can engineer longer lifespans into the populace.”
”When we can clearly say that a given DNA pattern has an unacceptably high propensity for a specific disease-it would be unethical to propagate it.”
”You're right, it's not a simple process to weed out disease from socially desirable traits.... Diversity will be important to maintain.”
”However, for public policy: an international ethical board should decide which genetic options lead to medical disorders.”
Those less enthusiastic may agree with Josephine Quintavalle, member of the pro-life activist organization Comment on Reproductive Ethics, who said: ”I am horrified to think of these people sitting in judgment on these embryos and saying who should live and who should die.”61 Even before the advent of this type of testing, an earlier version that allowed screening for only a handful of diseases caused different countries to take very different approaches to legislating and regulating its use, giving rise to the phenomenon of reproductive tourism-the one vacation from which you won't appear so well rested on your return. Obviously this even more exhaustive testing will bring more ethical questions with it.62 Currently if a couple does such testing, they may be concerned only with genetic disease that causes a lifelong affliction or an early death. But the truth is, no embryo is going to be perfect. It may not have the genes coding for childhood-onset diseases like cystic fibrosis or muscular dystrophy, but suppose it had genes that indicated a high probability of developing diabetes in middle age, or heart disease, or Alzheimer's disease? Are you going to toss it, start all over again, and try for a better one? How about depression? And this is where the future of germ-line therapy and all of those headache-provoking ethical questions may come into play: Don't toss 'em, change 'em!
Changing the DNA of an embryo changes the DNA in all its future cells, from the brain to the eyeb.a.l.l.s to the reproductive organs. It changes the DNA in the future egg and sperm cells also. That means the altered DNA is pa.s.sed on to all the future offspring, which would therefore be ”genetically modified organisms.” In a sense, every organism is genetically modified just by the recombining of genes. Humans have already been guiding their evolution more than they realize, from raising crops to modern medicine. Although modern medicine has found ways to treat such things as infectious disease, diabetes, and asthma, allowing people to live longer, it has also allowed some people-who normally would not have lived to reproductive age-to reproduce and pa.s.s those genes on. Inadvertently, this affects evolution, increasing the prevalence of genes coding for these diseases. However, the term genetically modified organisms has come to mean tinkering with DNA by man for the purpose of selecting for or against specific traits. This has been done in plants and on laboratory animals, but not with humans.
Today, in 2007, when you have a child without IVF, you really can't be held responsible for his or her DNA: You get what you get. That is, unless you know that you carry a defective gene that can produce a disease, and you choose to reproduce anyway. It is a matter of opinion how ethical that is. Now that the human genome has been sequenced, and you will soon be able to get your own personal sequencing done for a few bucks, this laissez-faire att.i.tude about the future DNA of your offspring may not be acceptable.
I can imagine the courtroom scene: ”Mr. Smith, I see here that you had your gene sequencing done in February of 2010. Is that correct?”
”Ah, yeah, I thought it would be cool to get it done.”
”I also see that you received a printout of the results and an explanation of what they meant.”
”Well, yeah, they gave me that paper.”
”Yes, but you signed this paper that said you understood you carried a gene that could cause any of your offspring to have....”
”Yeah, I guess so.”
”And you went ahead and had a child without first doing PGH? You did nothing to prevent this disease in your child?”
”Well, you know, we just got caught up in the moment, and, well, it just happened.”
”Did you tell your partner you knew you were the carrier of these defective genes?”
”Ah, well, I kinda forgot about it.”
”You kinda forgot about it? When we have the technology to prevent this sort of thing?”
But then there is the other side of the coin. Your future teenager may hold you responsible for all that she doesn't like about herself. ”Gee Dad, couldn't you have been a little more original? Like, everyone has curly blond hair and blue eyes. And maybe you could have made me more athletic. I mean, I can't even run a marathon without training.”
No one is tinkering with the human germ line just yet. Too much is still unknown about the properties of various genes and how they affect and control each other. It may turn out that it will be too complicated to mess with. Genes that control the expression of certain traits may be so linked with the expression and control of other genes that they may not be able to be isolated. Certain traits may be the result of a constellation of genes that can't be altered without affecting many other traits. Parents are going to be reluctant to interfere with their children's genes, and well they should be. Europeans and people in Marin County don't even want them altering the genes of their vegetables. That is why a different idea is being pursued: an artificial chromosome.
Artificial Chromosomes.
The first version of an artificial human chromosome was made by a group at Case Western Reserve University in 1997.63 It was to be used to help illuminate the structure and function of human chromosomes, and possibly to avoid some of the problems of viral and nonviral gene therapy. You will recall that we have twenty-three pairs of chromosomes. The idea is to add an ”empty” (and, we hope, inert) chromosome, which can be modified. The artificial chromosome is put into the embryo, and then whatever you order up will be tacked on to it. Some of what is tacked on may have on-and-off switches that would be under the individual's control when they are older. For instance, there could be a gene for cancer-fighting cells that wouldn't express itself except in the presence of a particular chemical. That chemical would be given as an injection. A person finds out he has cancer, he gets the injection that turns on the gene that produces the cancer-fighting cells, and voila, the body cleans up the mess without any further ado. Another type of injection would turn the gene off. And if better sequences are discovered, then when it comes time for your offspring to reproduce, they can replace whatever is on the artificial chromosome with the newer, better version. Some of the genes would have to be able to suppress the expression of genes on the original chromosomes, if they control the trait you want modified.
Of course, this all presupposes IVF. Will humans control their reproduction to this extent? Our current genetically coded s.e.xual urges lead to a great deal of w.i.l.l.y-nilly reproduction. In the United States, abortion eliminates half of these unplanned pregnancies. However, if this urge is suppressed by selecting for a population of people that plan everything, will we survive as a species? How much will all this cost? Will only wealthy countries, or the wealthy in each country, be able to afford it? Does that matter?
You may find this disconcerting and think we should be pulling in the reins a bit, but you also need to remember what is driving our behavior. Our genes are programmed to reproduce. Besides urging reproductive behavior, they also make us safeguard our children to ensure that they survive to reproduce themselves. Stock predicts that this safeguarding will include routine PGH, that those who can afford to will no longer reproduce that old-fas.h.i.+oned, rather haphazard way, but will resort to IVF and embryo selection.
And of course, next up after disease prevention will be embryo modification or enhancement. As more is learned about how our brain activity is controlled by our personal genetic code, how mental illness results from specific sequences of DNA, and how different temperaments are coded for, the temptation to tinker may prove irresistible. At first, the motivation will be to prevent disease, but while you're at it..., how about...? Stock quotes a comment made by James Watson, codiscoverer of DNA's double-helix structure, at a conference on human germ-line engineering in 1998: ”No one really has the guts to say it, but if we could make better human beings by knowing how to add genes, why shouldn't we?”64 Modification and enhancement will be a fuzzy zone, depending on your point of view. ”If you are really stupid, I would call that a disease,” Watson said on a British doc.u.mentary. ”The lower 10 percent who really have difficulty, even in elementary school, what's the cause of it? A lot of people would like to say, 'Well, poverty, things like that.' It probably isn't. So I'd like to get rid of that, to help the lower 10 percent.”65 Both Watson and Stock realize we are going to have to understand that many of the psychological differences between people (and the similarities) have biological roots.
These technologies will originally be explored for the treatment and prevention of disease, for developing genetically tailored drugs, and for genetic counseling. But obviously they will have applicability to modification and enhancement of the human genome. ”OK, I got a couple of embryos here. What did you guys want added? Oh, yeah, here is your order form. I see you have checked tall, symmetrical, blue eyes, happy, male. Hmm, are you sure about that? Everyone is ordering tall males. Jeez, there goes horse racing. Oh, you want the athletic package, and the anticancer, antiaging, antidiabetes, antiheart disease package. That's standard. Comes with the chromosome now.”
So humans may soon be taking a hands-on approach to their own evolution. However, tincture of time will not be an aspect of this type of change. Selected-for traits will not be honed by hundreds of thousands of years of physiological, emotional, social, and environmental interactions. Our track record for preserving finely balanced interactions has not been so stellar. Think rabbits in Australia: Introduced in 1859 for hunting on an estate, within ten years the twenty-four original rabbits had multiplied to such an extent that two million could be shot or trapped annually with no noticeable effect on the population. Rabbits have contributed to the demise of one-eighth of all mammalian species in Australia, and an unknown number of plant species. They also munch on plants to the point where plant loss has contributed to ma.s.sive amounts of erosion. All that to be able to bag a few on the manor. You don't even want to know how much money has been spent dealing with those rabbits.
Apparently the rabbit lesson wasn't enough. Another supposedly good idea gone bad was the one hundred cane toads that were introduced to Australia in 1935 because they were thought to be good for controlling beetles in the sugarcane fields of Central and South America. Now there are more than one hundred million across New South Wales and the Northern Territory. They are not popular. Loud and ugly with a voracious appet.i.te and ducts full of poisonous bile, they eat more than beetles. They have had a disastrous effect on indigenous fauna in Australia. Or consider the Indian mongoose, brought to Hawaii to control the rats that had come to Hawaii as stowaways. Not only did they not control the rats, they killed all the land fowl. Or how about the recent introduction of zebra mussels, native to the Black, Caspian, and Azov seas, which were dumped into the Great Lakes in the mid-1980s in the ballast water of vessels from Europe. They are now one of the most injurious invasive species to affect the United States, and have been found as far as Louisiana and Was.h.i.+ngton. Zebra mussels have altered the ecosystems of the Great Lakes by reducing phytoplankton, the foundation of the local food chain. They have other negative economic impacts, causing damage to the hulls of s.h.i.+ps, docks, and other structures and clogging water-intake pipes and irrigation ditches. Need I go on? And these finely balanced systems were visible ones.
What will come of all this genetics research? Exuberant technological scenarios have us becoming so intelligent that we will be capable of solving the entire world's problems, eradicating disease, and living for hundreds of years. Are the things that we consider problems really problems, or are they solutions for larger problems that we haven't considered? If a deer had the capacity to enumerate some of the problems it faces, we might hear, ”I feel anxious all the time, I always think there is a puma watching me. I can't get a restful night's sleep. If I just could get those d.a.m.n pumas to become vegans, half my problems would be solved.” We have seen what happens when the puma populations wane: forests become overpopulated with deer, which wreak havoc on the vegetation, leading to erosion...on and on. Problems for the individual may be solutions in the big picture. Would animal-rights activists want to tinker with the genomes of carnivores to change them into herbivores? If they think it is wrong for a human to kill and eat a deer, what about a puma?