The Genetic Gamble
NOVA examines current research and its ethical implications as modern medicine confronts the era of human gene therapy.
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00:00This child is a victim of one of the very few inherited diseases that are understood
00:16in precise detail. New techniques of genetic engineering could save her life. But once
00:21we begin tampering with human genes, where do we draw the line?
00:26There is the question or the concern that some day it might be possible to in fact manipulate
00:33our genetic composition and remake human beings.
00:36As well as ethical, there are technical problems in applying this new science to human disease.
00:41These kinds of manipulations still are problematical. They do damage to cells on occasion.
00:47But some who are closely involved are impatient to begin this journey into the medical unknown.
00:52Gene therapy is perhaps a little bit of a risk, but so is everything we try on these patients.
00:59The time is now.
01:03A parent, a child and a physician willing to take the genetic gamble, next on NOVA.
01:13Major funding for NOVA is provided by this station and other public television stations nationwide.
01:20Additional funding was provided by the Johnson & Johnson family of companies, supplying healthcare products worldwide.
01:30And Allied Corporation, a world leader in advanced technology products for the aerospace, automotive, chemicals and electronics industries.
01:50A bug special for the butterflies in the stomach for a thousand dollars.
02:07Six-year-old Erin McCarthy is not one of life's big winners.
02:13She lacks the natural immunity the rest of us depend on to combat the sources of infection all around us.
02:20Seeing her like this, it's hard to realize she has a life-threatening disease.
02:26That's partly because Erin, on her bad days, would be a very disturbing sight.
02:35It's also a testimony to the tireless efforts of her parents, her doctors and expert home nurses.
02:44Let's get you started today, okay?
02:47A bug! A bug! A bug!
02:50Life in this house is dominated by the battle to keep Erin alive.
02:54Her playmates are discreetly screened. A minor cold could be lethal to her.
02:59Do you want to empty these like you usually do?
03:02Erin, do you want to empty these like you usually do?
03:05Yeah, see?
03:07The cause of her condition is the lack of a natural enzyme called ADA, a crucial chemical link in the immune system.
03:14That, in turn, was caused by an unlucky combination of genes coming together from both sides of the family.
03:23But her parents had no idea this devastating legacy lay hidden within them.
03:28No, we didn't. It had never shown up in a family history or anything.
03:33It came as a total surprise and shock.
03:37The chances of one person who's a carrier marrying another person who's a carrier would be a quite extraordinary event.
03:46And that bears out in the clinical situation.
03:48We only see perhaps 30 to 50 new cases of ADA deficiency in the United States per year.
03:55In diseases like this, simply injecting the missing enzyme does not help.
03:59Well, it has to be manufactured inside the body cells.
04:03Since the key elements of the immune system are contained in the bone marrow, total bone marrow transplant is a possible treatment.
04:11But Erin has no matched sibling to act as a donor.
04:14Now an experimental treatment called gene therapy is a scientific ray of hope for Erin.
04:20It would involve manipulating the cells of her own bone marrow using the techniques of molecular biology.
04:26In short, bringing genetic engineering out of the research lab and into the hospital.
04:32This is a fatal disease. Gene therapy is perhaps a little bit of a risk, but so is everything we try on these patients.
04:41Medicine is a science, but it's also an art.
04:45And with every decision that we've ever made with Erin, we more or less compile the information,
04:52sift through it, and go with our gut feeling as far as if we really feel it's something that would benefit her.
04:59It's almost a question of inevitability, unless you can get something permanent, some permanent immunity.
05:10You can't walk around in white clothes for a year and not get them dirty.
05:17Well, that's similar to here.
05:20We've been very fortunate for six years, and many people that we've met and known haven't been so fortunate.
05:32And the time is now.
05:40Inherited defects are responsible for about 3,000 diseases.
05:44Most are not exactly household names.
05:49There's no simple cure for any of these diseases, which account for over 25% of admissions to children's hospitals.
05:58The gene responsible for ADA deficiency is understood precisely.
06:02It's one of the 511 human genes on file at the National Genetic Data Bank.
06:08That is nice, because at a glance, you really see the variation from one sequence to another.
06:15Well, if we just take this off the gene sequence that we have here...
06:18These rows of A's, G's, C's, and T's are a gene, or the symbolic representation of one that's understood by geneticists and computers.
06:28A, G, C, and T are the initial letters of the four chemical bases that are used to form the links of the long chain which make up a real gene.
06:37It's a code, and in theory, if these scientists had enough of it in their computer,
06:42they would be looking at the specifications for a human individual down to the tiniest detail.
06:51Biology, like everything else, has entered the age of the microprocessor.
06:58This amazing machine at Caltech can actually create a gene to order.
07:03The little bottles contain the chemicals needed to make the A, G, C, and T molecules.
07:16Punch in the required sequence, and the machine automatically assembles it.
07:21It's almost, not quite, making living things to order.
07:27This is just one dramatic example of the way biology has been transformed in a single generation.
07:33The science of observing nature is on the brink of becoming the technology of modifying nature when it goes wrong.
07:43So, what's the connection between a gene and an enzyme like ADA, whose absence can have such devastating effects?
07:57These musicians are about to participate in a metaphor of genes and how they make enzymes and other proteins,
08:05which in turn make cells, which make animals like scientists, musicians, and the rest of us.
08:16Chords played by the orchestra will represent the component parts of big proteins like ADA.
08:22Notes played on the piano will represent the gene sequence.
08:25But it's a bizarre piano with only four notes, equivalent to the four genetic code bases A, G, C, and T.
08:36We're ready to record.
08:381, 2, 1, 2, 3.
08:50Just as the composer can write any number of pieces with only 20 instruments,
08:55a biological cell using just 20 chemical components can assemble any of the 100,000 protein molecules that carry out the biochemical tasks of life.
09:09And the gene is a set of instructions for assembling a particular protein, decoded three units at a time.
09:16The combination G, C, T, for example, means go get a component called alanine and add it to what we're making.
09:27The musical chords on the lower staff represent the process of assembling a chain from those chemical components, the building blocks of life.
09:35The resulting chain detaches when the gene is completely decoded and wraps itself up to form the big protein molecule,
09:42which might be ADA, insulin, hemoglobin, or muscle.
09:55Superimposed on that process is the wonderfully complex hierarchy of cells, organs, animals.
10:02But the blueprint for the whole thing is in the genes, which are stored in packages called chromosomes.
10:15The human chromosome, in a sense, plays the tune of life.
10:19There is a basic code that's present in the human chromosomes that consists of three billion different notes of four different types.
10:27We divided these notes into bars and sheets of music.
10:30They would constitute a pile of music that's two and a half miles tall.
10:35In humans, there may be 100,000 different genes, that is, 100,000 different tunes.
10:40And as we go from a single egg, single-celled egg, to the adult organism with a million, billion different cells,
10:47in each of these different cell types, precise subsets of these tunes must be played to confer on those cells
10:55the characteristics of muscle cells or eye cells or red blood cells.
11:00In actual fact, genetic information is stored in the chromosomes in two complementary copies, the famous double helix of DNA.
11:17So now the connection to genetic diseases can be understood.
11:20It's wrong notes in the music that cause them.
11:27At the Medical Center at the University of California, San Diego, dividing his time between clinical practice and lab research is Dr. Ted Friedman,
11:35who has long been attracted by the concept of curing genetic disease as simply as one might correct a misprint on a musical score.
11:43Let's say this note is completely missing for some reason or other.
11:47That note has never found its way into this composition or that bass has never found its way into the gene.
11:53The consequence is to shift all the subsequent musical notation into new bars which didn't exist before,
12:04so that every bar is going to sound different.
12:08Dr. Friedman is looking at a musical representation of a gene that specifies an enzyme called HPRT.
12:15Mistakes in this music cause a disorder at least as tragic as immune deficiency.
12:25Called Leshnian syndrome, the disease is a form of cerebral palsy with a horrifying characteristic symptom of self-mutilation.
12:34Victims have to be restrained to prevent them from biting off their own fingertips.
12:51Most of the 200 Leshnian patients born every year have very short lives.
12:55Craig Weiner, thanks to the somewhat tough love of his brothers and constant home care, has made it to the age of 22.
13:03I thought I'd buy you some clothes for your birthday.
13:05Right?
13:06How about a new TV?
13:08Sure.
13:09Color?
13:10Color TV?
13:11For the top of your bed?
13:12Yeah.
13:13Okay.
13:14With a remote control?
13:15Yeah.
13:16And a VCR?
13:17Yeah.
13:18For your tapes?
13:19You can tape the baseball games?
13:20Uh-huh.
13:21You can help yourself?
13:22Right, you can help yourself.
13:23Once the disease was identified, UCSD researchers quickly tracked its cause.
13:27Surprisingly, this complex syndrome is all due to the lack of that one substance, HPRT.
13:33When Ted Friedman isolated and described the HPRT gene in 1983, Leshnian syndrome became a prime candidate for gene therapy.
13:42There is no conventional cure.
13:44That's a quarter, that's a quarter.
13:46Now, I'm going to go, I'm going to move over here.
13:49The reason for the pillows under his chin is to give him some sort of support because he has a tendency to throw his head forward.
13:55And it brought him a great deal of discomfort.
13:57And I thought it would be best to have something to support his neck.
14:00And I couldn't think of anything else.
14:02See, these kids come up with these things, one thing after another.
14:05Like, with the pillows.
14:06He would sit there and snap his neck.
14:08And snap his neck.
14:10You know, so all these different things used to come up.
14:12Like, he used to bite his lips when he was younger.
14:15But he doesn't do that anymore.
14:16He doesn't bite his fingers.
14:17He doesn't do any of that Mickey Mouse stuff anymore.
14:19Because he knows that will hurt him.
14:21Yes, he's going to go to the airport today.
14:26Friedman's lab team has been working quickly and carefully to show that they have a potential cure for Leshnian syndrome.
14:33Working with cultures of bone marrow from Craig Weiner and other patients which carry the defective HPRT gene.
14:41Is this Eric's?
14:42Yeah, this is Eric's serum.
14:45Hi, guys.
14:46So, how do you look?
14:47Hi.
14:48Hi.
14:49It's looking pretty good.
14:50I'm getting some different morphology.
14:52I don't know if it's...
14:53These scientists have already developed a reliable way of inserting a good copy of the HPRT gene into cells in culture.
15:03Since bone marrow is the factory for a whole complex suite of cells in the bloodstream and beyond,
15:09genetic transformation of marrow could have very far reaching effects.
15:14That's been confirmed by animal experiments.
15:16But whether those effects reach the brain and indeed whether that would be necessary to cure Leshnian syndrome is controversial.
15:24Here goes nothing.
15:28That's lane one.
15:29Yeah, it's lane one and lane two in two different trials.
15:33Another research team working on gene therapy at the National Institutes of Health is led by Dr. French Anderson.
15:40Anderson hopes to be the first scientist to bring gene therapy to humans, victims not of Leshnian syndrome but ADA deficiency.
15:53To Anderson, ADA deficiency is the best bet because conventional bone marrow transplantation has a proven record in treating immune deficient patients who have a matched donor.
16:03That cannot be said for Leshnian syndrome.
16:07Leshnian has been the leading candidate for several years.
16:12Dr. Ted Friedman's work in San Diego has been pioneering in this.
16:16The difficulty is that the first attempt at a bone marrow transplant in a patient did not result in helping the patient.
16:25If you cannot help the patient with a full bone marrow transplant, it is unlikely that you're going to help them by correcting some of the cells.
16:35Whether gene therapy has anything to offer patients like Craig Weiner is a dilemma for Ted Friedman.
16:40Scientifically, it's too soon to tell.
16:43But medically, there's a need to act before it's too late to help.
16:47Okay, easy. Easy now.
16:49Okay, put your head back.
16:50Many of us who see patients as well as try to study disease in the laboratory feel to be in a particularly difficult situation of having that clinical pressure,
17:01knowing what the clinical urgencies are.
17:04And treatment in medicine always involves a balance of known and unknown risks against the clinical urgencies to do something,
17:13even if one doesn't have perfect knowledge.
17:19At the Whitehead Institute affiliated with MIT, Richard Mulligan is a pure research scientist who is not personally subject to that clinical pressure.
17:28The neatest thing is that down here, it's a low tiger.
17:31A leader in this field, he also considers ADA deficiency a better candidate for gene therapy than Leshnian,
17:37but contends that it's too early for any clinical trials.
17:40Suggesting that we go forward in the absence of the scientific information, I don't consider it very scientific.
17:45I know the basic difficulty is you have three groups of people.
17:49You have the patients that are very, very sick.
17:52You have the physicians who want to help.
17:55And you have the scientists who will be responsible in a technical sense for the whole method.
18:00Well, I'm sure there's a lot of disagreement on this.
18:02My feeling is that one should not leave some of the scientific issues to the physician.
18:09We don't want to make decisions about the patient particularly,
18:12but especially in this case, I think I would certainly feel very, very more responsible than the physician for the patient if someone used a method I worked on.
18:21For the last year, Mulligan in Boston, Friedman in San Diego,
18:25and French-Anderson's group in Bethesda have been seen as competitive with each other
18:30and with a few other labs working in this highly advanced and fast-moving field of research.
18:35And measuring the amount of activity in different clones.
18:37This was a positive control.
18:43Our whole group is now spending many, many hours every evening, all weekends, working in this.
18:50And it's really less the competition with other people as it is with nature.
18:56It's such an enormous question.
18:58The question of how can you get around nature's defense mechanisms and cure an incurable disease.
19:06It's very exciting.
19:08Any plans for human gene therapy will have to be approved by this group,
19:12the Recombinant DNA Advisory Committee of the NIH.
19:16Initially, what we've tried to do with our questions is to signal...
19:20A working group on gene therapy has been debating the ethics of making genetic changes to sick children who cannot consent for themselves.
19:28French-Anderson is himself on that subcommittee.
19:31Another key figure is an expert on medical law who was director of the President's Commission on Bioethics in 1982, Alexander Capron.
19:40The notion that it is only for desperate diseases, that desperate remedies are justified,
19:46actually, I think, can have a pernicious effect.
19:48Because what it means sometimes is the notion that because of the desperation, you can try anything.
19:54And indeed, some of the recent heart experiments with artificial hearts and baboon hearts and so forth
20:01illustrate where I think that can sometimes go rather far awry, that notion.
20:06That it's because we have nothing else to try, so we'll desperately try something.
20:11Sometimes a real careful examination of the risk-benefit ratio can go by the wayside.
20:19And also, particularly when children are involved,
20:22the notion that the parents may be put in a position of accepting something,
20:27which might even in the end be harmful or cause a more painful death,
20:31because there's nothing else that can be done, is a very delicate issue.
20:35It's not to say that that isn't sometimes justified,
20:38but you have to be very concerned about the quality of the consent you're going to get.
20:42The Weiner family's consent was underscored by their move from New York to San Diego,
20:47to be ready at a moment's notice.
20:49We all agreed.
20:51I think it's worth a try, but what's most important, Craig thinks it's worth a try.
20:55Do you think it's worth a try, Craig?
20:57You think so, Craig?
20:58Pick up your head.
20:59Pick up your head. Tell me. Tell me.
21:01We said yes.
21:03There's very few things that you do or that someone creates or someone invents
21:08or someone discovers that is undebatable.
21:14And simply because this issue can be debated,
21:18just like artificial hearts or anything else,
21:23to hold up the positive side of it, to me, would be a very bad thing.
21:35Comments from members of the committee.
21:38To some, the scrupulous federal committee procedures have been taking precious time.
21:43In April 1985, the working group published draft guidelines for human gene therapy
21:48and invited public comment.
21:50I very much appreciate the letters which we received.
21:53One of those letters was from Aaron McCarthy's doctor, Sheldon Horowitz,
21:57reminding the subcommittee that lethal diseases work to their own, more urgent timetable.
22:03Gene therapy may have only a small chance of success, he wrote,
22:07but its risks are minimal compared with certain death.
22:11We can't wait forever.
22:12We have gotten into trouble hearing that gene therapy might be available in 6, 12 months
22:17and trying to wait, and while we wait, the kid gets some terrible infection
22:21and then we're really up against the wall.
22:24French Anderson was one of many who took notice.
22:27He contacted Horowitz and the two of them began drafting the paperwork they'll need for permission
22:32once they're technically ready.
22:34If we run into a major problem, and other laboratories,
22:37other groups working on this run into major problems,
22:40it could be a year, two years, five years, it could be never.
22:43But at present, we anticipate that probably sometime early in 1986.
22:53So it seems that some very sick child will soon begin a journey into the medical unknown.
22:59Since gene therapy has not yet been tried,
23:01the patient and her mother in this scene are portrayed by actresses.
23:07The Hutchinson Cancer Center in Seattle is a leading bone marrow transplant center for leukemia,
23:12which may become involved in gene therapy.
23:14Its medical and research staff cooperated in this simulation
23:18by playing out their own roles in the procedure.
23:21And just after you taste that funny taste, you'll fall asleep.
23:26And when you wake up, we'll be all done.
23:29Okay?
23:31Okay, good night.
23:34Withdrawing a sample of bone marrow is not a major or very lengthy procedure.
23:39But the surgeons need to dig deep into the hip bones and withdraw about a pint of marrow
23:44to be sure of harvesting enough of the actively dividing cells,
23:47whose offshoots will spread throughout the body.
23:52In the biochemical lab, the marrow will be selectively cultured to favor those special cells.
23:57They're called stem cells.
23:59But since stem cells can't be isolated or even identified,
24:03it's impossible to be sure how many of them will absorb the new gene in an effective way.
24:08And nobody will really know how many is enough until they try it on the first human patient.
24:13How does the cell count look?
24:15I'm just checking it now.
24:17The gene is not simply mixed with the cultured cells.
24:20It has to be targeted to the cell nuclei.
24:23To achieve that, scientists use a natural chemical reaction
24:27To achieve that, scientists use a naturally occurring organism called a retrovirus,
24:32cleverly adapted for genetic engineering.
24:35It takes an electron microscope to actually see a retrovirus.
24:39These tiny primitive life forms reproduce by invading animal cells, often causing tumors.
24:47A retroviral gene, here symbolized by four bars of music, is actually many hundred bars long.
24:53And something in its special top and tail gives it the amazing ability
24:57to insinuate its own genes into those of an animal cell,
25:01forcing the cell to play the virus's music as well as its own.
25:06For use in gene therapy, scientists delete the virus's own harmful genes
25:11and substitute the gene for ADA or HPRT.
25:15The retrovirus goes about its work unaware that the music the cell will now play
25:20will be a passage from some other concerto altogether.
25:29The next step for the patient will be a dose of gamma radiation that would normally be lethal.
25:39The point of this drastic step is to kill all the bone marrow cells remaining in the body
25:44so that the genetically corrected cells, when re-implanted,
25:47will not compete for survival with a much larger number of unchanged cells.
25:52Patients with ADA deficiency will be spared this trauma
25:55because their already damaged immune cells have little power to compete.
26:06But treatment of other genetic diseases will involve radiation.
26:10It's the point of no return.
26:12She must now get her bone marrow back or die.
26:23The marrow, bearing its new genetic information,
26:26does not need to be re-implanted surgically inside the bones.
26:29It will infuse gently and easily by IV drip.
26:32But this will be a crucial time in the life of the patient.
26:40Vulnerable to the slightest passing infection.
26:46There are many other technical problems to be overcome
26:49before gene therapy has any guarantee of success.
26:52One potentially serious one is that the retrovirus breaks the music of the host cell
26:57and inserts its own at a totally unpredictable point.
27:01This capricious behavior is baffling even to experts like Dr. Inder Verma.
27:07We have absolutely no control on it.
27:09In fact, that's one of the weaknesses of all the work done on mammalian systems now
27:14is that we don't know where genes integrate when you put them in a cell.
27:18That means that the control of that gene is likely to be not quite normal.
27:25It also means that some of these events will result
27:28in the turning off of otherwise normal and needed gene functions.
27:35So these kinds of manipulations still are problematical.
27:38They do damage to cells on occasion.
27:42Furthermore, there's also the problem that since these retroviruses
27:47have such strong elements of control for activation of RNA, for example,
27:53that there's no guarantee that they may also integrate in the vicinity of a gene
27:59which has the potential to become a tumor gene.
28:03If genetic disease is a sour note in the score of a symphony,
28:07gene therapy is the equivalent of inserting a corrected page in the score somewhere at random.
28:13Whether the whole piece will then play well is truly a gamble.
28:17Looks like you're ahead of me.
28:20Our simulated child patient will be gambling with many ifs
28:24beyond the considerable risks of the bone marrow transplant itself.
28:29How would you describe yourself to someone who does not know you?
28:34If the gene got into enough stem cells, and if it did not disrupt another gene,
28:39and if the inserted gene makes enough of whatever enzyme she lacked before,
28:44then she will get better.
28:45Does that sound good?
28:46Yes.
28:47Okay, it's your turn.
28:49I don't feel like playing anymore.
28:52And those are the questions that will hang over the first gene therapy trials.
28:56The real patient is certain to be a child with one of the handful of rare diseases
29:00whose genetic basis is understood.
29:03The vast majority of diseases on this list are said to be genetic
29:07only because they're observed to run in families.
29:10The missing substance or the defective gene are unknown.
29:14There's perhaps a paradox that the initial candidate for gene therapy is such a rare disease.
29:21It could easily have been a much more common disease,
29:23but we have so little knowledge about most human genetics
29:28that we really need to have a great deal more information about human genetics in general
29:33before it will be possible to apply these sophisticated techniques like gene therapy
29:39to a broad range of very common genetic diseases.
29:43Further progress depends on unraveling more of the mystery locked up in the double helix.
29:49This is DNA itself spilled from the single chromosome of a bacterium.
29:54Human DNA is packaged in 23 pairs of chromosomes,
29:58each of which may carry some 10,000 genes.
30:02The detective work involved in tracking down a gene to a precise location in all this
30:07is complex and fascinating.
30:13Since chromosomes are a family affair,
30:15the starting point of the detective work is to go out and talk to families with a genetic defect.
30:26These researchers are from the Howard Hughes Medical Institute in Salt Lake City.
30:30Since they give an absolute guarantee of anonymity to the families they work with,
30:34this scene is a simulation using a volunteer family that is not part of the study.
30:39Now I understand that Stephen has seven children?
30:42Seven. No, eight.
30:44He left Joshua. Where did Joshua go?
30:47He goes between the Enoch and the Nekai.
30:51Once the family tree has been sorted out, it's time for some bloodletting.
30:55Well, it may look like we have a lot of tubes here,
30:57we only collect about maybe a quarter of a cup.
31:00I'll go. I want to do it.
31:06We'll look at your left arm, okay?
31:08I've got a wound in my left arm.
31:10Oh, wow, for good sakes.
31:12I just got that today from the rose bush.
31:17There we go.
31:27The white blood cells, which contain the chromosomes,
31:30are separated out and added to their cell library,
31:34a miniature high-rise city of 10,000 citizens in deep freeze.
31:43Move them around when we get four.
31:46If you're looking for a gene and you don't know what it is or where it is,
31:50the only possible approach is to sample a large family
31:53and see what differences you can find between the chromosomes
31:56of those that have the disease and those that don't.
32:00In fact, it is now known that up to 90% of the music of the gene
32:05is not decoded bar by bar, but is unstructured and unannotated.
32:10By comparing the different way family members
32:13play those long passages of apparent nonsense,
32:16researchers get important clues as to where disease genes may lie.
32:23Chopping up chromosomes and decoding the pieces,
32:26they hope to find one particular pattern somewhere in the nonsense music
32:30that always crops up in the chromosomes of disease victims.
32:34And then next, last stage...
32:37If healthy family members always have a different pattern
32:40at that position on the chromosome,
32:42then that position is said to be a marker for the disease.
32:46Beginning with a general search of all 23 chromosomes,
32:50computer analysis eventually finds one chromosome
32:53for which this relationship almost always holds good.
32:57No, uh-uh. They're dead. They're all dead.
33:01Let's say a large family has three different marker positions
33:04on chromosome number 11.
33:06Call them A, B, and C.
33:08A form of diabetes also runs in this family.
33:11If everyone who has the diabetes also has marker pattern B
33:15and nobody who is healthy has B,
33:17that's evidence that the diabetes gene is on chromosome 11.
33:21But that's only narrowed down the search to one chromosome,
33:24which carries perhaps 10,000 genes.
33:27Pinpointing the gene to an exact place
33:30depends on a curious feature of the way chromosomes are inherited.
33:35Here's an imaginary family of two grandparents,
33:38four children, and three grandchildren.
33:40And here's the biology textbook version
33:42of how any pair of chromosomes is handed on,
33:45starting with grandfather and grandmother.
33:47Each of their children inherits one from each of them,
33:50chosen at random.
33:51So let's say the eldest daughter gets a pink from father
33:54and a green from mother.
33:56The next-born son gets a yellow and purple,
33:59and so on down the generations.
34:02Well, it's not quite that simple.
34:04In the formation of the all-important sex cells,
34:06the sperm or egg of any individual,
34:09the chromosomes actually merge in a complicated double-X formation.
34:14When they separate,
34:15the Xs are found to have exchanged parts in some random way.
34:21So what a son inherits would almost never be pure pink,
34:24but a mostly pink chromosome
34:26with some stripes of yellow from his other parent.
34:29The next generation gets a chromosome salad of all the family DNA.
34:34These crossovers, as they are called,
34:36have profound consequences for the inheritance
34:39of those markers that geneticists follow.
34:44If we represent a bad gene by a black square
34:47and a marker by an arrow,
34:48it's obvious that unless they're extremely close together,
34:51they risk being separated by crossovers.
34:54The number of times a marker and a gene
34:56wind up on different chromosomes
34:58is a measure of how far apart they are.
35:00So geneticists turn these random crossover events to their advantage,
35:04patiently counting how many members of a large family get the gene
35:08but not the marker, or vice versa,
35:10and deducing exactly where the gene must be.
35:14I guess it wouldn't matter,
35:15because with the recombinant,
35:16their kids would just take the genes as they come,
35:20with the recombinant in it.
35:22Nowhere in the world is there a better example of that process
35:25than the shores of Lake Maracaibo in Venezuela.
35:47In the spring of every year since 1979,
35:50an American-led and funded expedition
35:52has set off for a remote corner of this huge inland sea
35:56ten degrees north of the equator.
35:58The expedition leader is Dr. Nancy Wexler,
36:01president of the Hereditary Disease Foundation,
36:04which was endowed in memory of her mother,
36:06who died of Huntington's disease.
36:10The gene Dr. Wexler is tracking down with such passion
36:13is the gene that killed her mother
36:15and causes the lingering and undignified death
36:18of a thousand other Americans a year.
36:29Their destination is a small village
36:31perched on stilts over a shallow lagoon.
36:49Hola.
36:51Look at me.
36:53That's lovely.
36:55The traditional life of this community
36:57has been modified by a few gifts
36:59from the high-tech world elsewhere,
37:01notably the Japanese-built outboard motor.
37:13But there is no fast food,
37:15no air conditioning,
37:16and no medical care whatsoever.
37:18The diet, the culture, and the way of life
37:21revolve around one commodity, fish.
37:36Another fact of life here
37:38is the scourge of Huntington's disease.
37:40A single woman brought it to this area in the 1880s.
37:44The gene is dominant.
37:46Inheriting it from only one parent
37:48is sufficient to give the disease.
37:50And the random shuffling of the chromosomes
37:52over the generations since
37:54has distributed the disease
37:55to some thousand people in this region.
37:58Nobody in this village is without many relatives
38:01who suffer from it.
38:02And because the symptoms rarely appear
38:04until quite late in life,
38:06these people are condemned to live 40 years
38:08in the knowledge that genetic fate
38:10may have dealt them a very bad hand.
38:15My room.
38:19And as the 40-year-old child of a victim herself,
38:22Nancy Wexler understands that predicament
38:25from a very personal point of view.
38:27Each child of a parent with a disorder
38:29has a 50-50 risk of inheriting the disease.
38:33So I have a 50-50 risk of inheriting it.
38:36My sister has her own 50-50 risk of inheriting it.
38:40And there is no way at the moment
38:43to tell, there has been no way to tell
38:47who is carrying the lethal gene
38:49until you actually develop the symptoms of the disease.
38:59It causes uncontrollable movements
39:01in all parts of the body.
39:03It causes massive personality changes,
39:06often severe depression, suicidal depression,
39:10sometimes hallucinations, delusions.
39:12It causes cognitive decline,
39:15but patients have still very good insight
39:19into the fact that they are slowly
39:21and progressively losing all of their faculties.
39:27It's invariably fatal,
39:29and as of yet, there's no effective treatment.
39:33Every day while she's here,
39:35Wexler sets off in search of missing links
39:37in the vast family tree
39:39that she and her colleagues have compiled over six years.
39:44The interlinked families of this region
39:46are a research goldmine.
39:48Thanks to data collected here,
39:50the Huntington's disease gene
39:52has already been linked to a marker
39:54on chromosome number 4
39:56that inherits with the gene 95% of the time.
39:59And this has already given a way of predicting
40:02for this family who has the bad gene.
40:06Nancy Wexler explains how,
40:08using another imaginary family tree.
40:12Imagine that these dominoes here are people.
40:17The black ones have Huntington's disease.
40:20In fact, this one has died of this disease.
40:24The white ones here are unaffected.
40:27These are three children
40:29who want to know what their fate will be.
40:32Each one of these children has two chromosome 4s,
40:35one from the mother, one from the father.
40:37They have a different DNA pattern
40:39on each chromosome 4.
40:42In this case, you don't know
40:44which pattern came from which parent.
40:47You can see that these two children have the same patterns.
40:50This one has a little different one.
40:52The question for these children is,
40:54each of them has a 50-50 risk,
40:56which is going to get the disease?
40:58If you have the parents,
41:00you can see what patterns they have.
41:03This healthy mother has a four-point pattern
41:06on each of her chromosome 4s.
41:08All she can do is pass on
41:10the four-point pattern to her children,
41:13which she has done right here.
41:15The question is,
41:17which of these two patterns in the sick father
41:20is sitting next to his Huntington's disease gene?
41:23You need to look at another generation.
41:26Luckily, this man's mother is still alive.
41:28His father has died of the disease,
41:30so his genetic information is unavailable to us.
41:33The mother has a two-point pattern
41:35on each of her chromosome 4s.
41:37The two-point pattern has to be the healthy pattern
41:40because she didn't have the Huntington's gene.
41:42The two-point pattern went to him.
41:44This was his healthy chromosome 4.
41:46He gave his healthy chromosome 4 to these two children.
41:49In fact, these two children are free.
41:51The five-point pattern has to be
41:53sitting next to the Huntington's disease gene.
41:56In giving his five-point pattern to this child here,
42:00this child will develop Huntington's disease.
42:09It takes no great expertise
42:11to see that Carmen Soto is a black domino.
42:14The neurological tests are not for diagnosis,
42:17but to record the progress of the disease since last year.
42:20Carmen is a direct descendant of the original carrier,
42:23and she married another Huntington's victim,
42:26so her offspring with two black dominoes stacked against them
42:29have a 75% chance of getting the disease.
42:41Dora is one of Carmen's daughters.
42:43She's at the age when every time your eyelid twitches
42:46or you drop something,
42:47you worry that it's the onset of what they call here el mal.
42:51The blood and skin samples she is now consenting to give
42:54will tell an expert half a world away what her fate is.
43:00Dora's blood test results
43:05But Dora will not get the news.
43:07Even if she tests positive for the bad gene,
43:10that would not be a diagnosis.
43:12There's a 5% chance of error,
43:14and there's no treatment to offer,
43:16especially in this remote region.
43:18It's a major ethical problem which needs to be resolved,
43:21since many experts believe predictive tests
43:24will have at least as much impact on medicine as gene therapy.
43:29In this case, the researchers have decided for the time being
43:33to keep the information contained
43:35in these gifts of skin and blood to themselves.
43:42In a race against deterioration from the tropical heat,
43:45the samples are flown to the lab of Dr. James Gazzella
43:48at Massachusetts General Hospital.
43:51Technicians immediately begin the process
43:54of chemically chopping up the chromosomes,
43:56looking for a closer marker.
44:06Somewhere among these fragments of Venezuelan DNA
44:09is their ultimate goal, the gene itself.
44:12And that could be found in two ways.
44:14Either find out what it does, or how it works.
44:18Either find out what it does,
44:20or how mistakes in it cause the disease.
44:22Or track it down so tightly with these methods
44:25that you can find it and decode it.
44:34Either way, Dr. Gazzella cannot promise gene therapy
44:37for Huntington's disease.
44:39It's extremely hard to predict whether it's a candidate or not,
44:42because it depends totally on what the defect is.
44:45If the defect is the production of something that is toxic,
44:49it's very unlikely that putting in a good copy of the gene
44:52is going to eliminate that production.
44:55Other techniques, which also involve gene therapy,
44:58are, however, being developed to eliminate activities of genes
45:01that are present, and those could then be used.
45:04If, however, the defect is the absence of production
45:07of some protein, then it is a potential candidate
45:09for gene therapy.
45:11Meanwhile, does the success of this project
45:13offer any hope to Nancy Wexler personally?
45:17Absolutely, but not immediately.
45:22In order to look at a family
45:24and see whether or not a person has the marker
45:27which says that the gene is there,
45:29you have to have enough of these relatives to look at,
45:31and unfortunately in my family,
45:33everyone was wiped out by the disease.
45:36So for me personally,
45:38it will take the actual discovery of the gene itself
45:42to be able to do a diagnosis for me and for my sister.
45:47But there are ways that we can now tell
45:52if a fetus is carrying the chromosome for,
45:56say, for my mother,
45:58in which case the fetus would have a 50-50 risk like I do,
46:02or for my father, in which case the fetus has no risk
46:05because he's not carrying the gene.
46:07So it's possible for me and for other people
46:10who don't have sufficient family,
46:12it is possible to give us some information
46:14about the health of future generations.
46:20In the future of genetic research
46:22lies the possibility of not merely predicting
46:25but actually controlling the health of future generations.
46:29When more of these diseases are genetically unraveled,
46:32a corrective gene could be inserted
46:34not just into general body cells
46:36but into the sperm or egg, the germline.
46:39That gene would then be passed on
46:41to the patient's descendants forever.
46:44Bacterial gene factories in Dr. Leroy Hood's lab
46:48are producing millions of copies of the gene
46:50for a protein called myelin basic
46:53as part of a futuristic experiment in germline engineering.
46:57The gene for myelin is defective
46:59in a mutant strain of lab mice called shiver mice.
47:09They shiver because they have no myelin
47:11to insulate their nerve fibers.
47:18Under a dissecting microscope,
47:20the uterus removed from a recently fertilized female shiver mouse
47:24is carefully torn to release the fertile mouse eggs
47:27bathed in a milky fluid.
47:30One nucleus of each egg
47:32is going to be injected with a myelin gene
47:34and every single cell in a mouse that develops from it,
47:37including its sex cells, will contain the foreign gene.
47:40So the change will be permanent and inheritable.
47:48The myelin gene wrapped in a virus-like carrier
47:51is drawn up into a hollow glass needle,
47:54the finest that can possibly be made.
48:00This experiment is futuristic not only in its implications
48:03but in terms of sheer technique.
48:06The target, the upper nucleus,
48:08is less than ten thousandths of a millimeter across.
48:21When everything's in place, the gene is injected.
48:24Hundreds of copies whose exact destination in the chromosomes is unknown.
48:30A short time later, the eggs are inserted into the uterus
48:33of the anesthetized host female to develop normally.
48:40One of the most interesting results of this experiment
48:42was that early attempts failed.
48:44There was no doubt that the myelin gene
48:46did get inserted in the chromosomes,
48:48but that was not good enough.
48:50The gene was not turned on,
48:52and so did not make myelin.
48:54Within those billions of notes of the genetic concerto
48:57that are apparent nonsense,
48:59there are themes that have the vital role
49:01of controlling the genes that do code for proteins.
49:05Indeed, we've begun to learn
49:08that there are important motifs in and around the gene
49:12that tell a gene how fast to work,
49:16tell a gene where to work,
49:18what particular cell type to be expressed in,
49:21and when to work in some cases.
49:24Richard Palmater, working with Dr. Ralph Brinster
49:27of the University of Pennsylvania,
49:29came to the world with a dramatic demonstration
49:31of these control motifs in 1982
49:34when they inserted growth hormone genes into mouse eggs.
49:37Attached to the growth hormone gene
49:39was a powerful control sequence from a different gene,
49:42one that responds to trace metals in the diet.
49:48Sure enough, when given zinc,
49:50the mice grew to giant size,
49:52and the experiment made scientific headlines.
49:59This experiment was sensational
50:01for what it taught us about gene control,
50:03but it does not necessarily herald the age
50:05in which inheritable changes can be made to human germ cells.
50:09The technique is not yet reliable, even in animals.
50:13So, from the ethical perspective,
50:15Alex Capron would support a ban on human germline therapy
50:19in the present state of knowledge, but not forever.
50:24Beyond that, however, I think some of the notion
50:27that there should be an absolute prohibition
50:29on germline therapy is very puzzling.
50:33If there were certain conditions,
50:35and I think that there are,
50:37lechinion might be an example,
50:40which apparently have no benefit for the individuals,
50:43and either the affected individuals
50:45or the carriers of the disease,
50:48and which are devastating,
50:51and which may be complex to intervene with and so forth,
50:55why not want to eliminate them,
50:57not only in the patient,
50:58but in the patient's children and grandchildren and so forth?
51:01Dr. Hood, who directed the Shiver Mouse experiment,
51:04is the first to agree that social dilemmas
51:06raised by the kind of work he's doing
51:08cannot be resolved by scientists alone.
51:11I think all of us have opinions,
51:13and I don't think any of us necessarily
51:15is going to be right in our opinions,
51:17and it's my strong feeling
51:18that one is going to have to get together
51:20a panel of different people
51:22with different interests and different expertises
51:25to consider these questions in detail.
51:28Myself, as an experimental biologist,
51:31I think these kinds of opportunities
51:33afford absolutely mind-staggering possibilities for the future,
51:37and because of the exponential growth
51:39and the potential and the way
51:41in which we can carry out molecular biology,
51:43I suspect in the very near future
51:45we're even going to have more staggering opportunities.
51:49A model for an ethical panel already exists,
51:52the working group of the NIH Recombinant DNA Advisory Committee.
51:56These meetings are open to the public,
51:58and members have been made forcefully aware
52:00of the deep fears that human genetic engineering can stir up.
52:04Jeremy Rifkin is an author and advocate of extreme caution.
52:08Fearful that decisions will be made by a scientific elite,
52:11he has taken full advantage of the committee's open policy.
52:14A wide range of people.
52:15This is not just a medical issue.
52:17Human genetic therapy is a social issue.
52:19It's a cultural issue.
52:21It has long-term repercussions for the future of the human race,
52:25and even though we're at a very initial stage,
52:27the precedence we set over the next five years in this country
52:30will be looked to over the next 25 years by other countries.
52:33Indeed, what may become possible in 25 years
52:36is very much on people's minds here,
52:38as they debate the ethics of using gene therapy
52:41on hopelessly sick children.
52:43There is the additional ethical question
52:47of using therapeutic techniques
52:50for simply enhancing characteristics
52:53for people to try to be more intelligent
52:55or bigger or better looking or whatever.
52:58The technical ability to do that
53:00really isn't present at the present time
53:03because so many of the major characteristics
53:06like personality and character and so on
53:09are dictated by hundreds of genes
53:12interacting in totally unknown ways,
53:15interactions with the environment and so on.
53:17But there is the question or the concern
53:20that some day it might be possible to, in fact,
53:23manipulate our genetic composition
53:26and remake human beings.
53:28Every time there is a potential to introduce a gene,
53:31there is no saying that what kind of gene can be introduced.
53:35Right now we are talking today of the genes
53:37which have a human potential of disease therapy
53:40because they're deficient.
53:42But I see it's perfectly possible
53:44somebody might want to introduce in the same way a gene
53:47which has a totally different motive behind it.
53:50So I think, I personally think
53:53the public has a reasonable fear for it
53:56and I think it is our job, the scientists,
53:59to explain to them that there are benefits of this one
54:02and that there are safeguards
54:04which at least morally we try to apply.
54:07We can't really force on everybody.
54:09I can't say that this kind of technology
54:11is going to be,
54:14is going to be safe from abuse.
54:19On the other hand,
54:21who of us can really look at a child with Leishmanian disease
54:25or ADA deficiency
54:27or cystic fibrosis for that matter
54:30and feel that that's normal
54:32and that that's not screaming out for correction.
54:36I think it really becomes very questionable
54:39whether it's right for third parties to come in and say
54:42we have some generalized concerns that in 20 years
54:45this may have some bad effects
54:48because we may learn something which could be misapplied
54:50by some malevolent scientist someday.
54:53Therefore, your child should not get a treatment
54:56which you and a review committee and an NIH committee
54:59have all said is an appropriate step to try to cure that child.
55:03Anything in this world that's abused
55:05can have negative consequences.
55:08The issue that we're dealing with from our perspective
55:11is that this could save lives
55:16and create futures.
55:19The dilemma is in taking this first step
55:22along the road to control of our genetic destiny
55:25we would be creating futures not just for Aaron McCarthy
55:29but for mankind in general.
55:31Do we have the wisdom to take that step?
56:01Do we have the wisdom to take that step?
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