Cheryl guy stolbernov.
On the 28 th, Tucson, more than 9,450 feet M, overlooks a deep canyon, where the prickly pear cactus dotted on the desert floor gives way to the dense forest of huangsong.
It is said to be close to heaven, just like in southern Arizona.
Jesse Gelsinger loves this place.
At the beginning of November, on a sunny Sunday afternoon, Paul Gelsinger laid his 18-year-
Seven weeks after a gene, my son is resting.
The treatment experiment cost him his life.
The ceremony was simple and improvised.
24 mourners-Jesse's father;
His mother, Patty.
Micky, his stepmother.
There are two sisters, one brother, three doctors, and some friends. -
Trek five miles along a steep trail to the rocky heights at the top.
There, Paul Gelsinger shares the story of his son, who loves motorbikes and professional wrestling, and what annoys his father is the apparent lack of ambition.
Jessie is the kind of child who has saved $10.
In his bank account. -
Gelsinger explained: "You need $10 to stay open-
But those who gathered on the top of the Mountain agreed that he had keen wisdom and sensitive hearts.
At Gelsinger's request, the hikers carried Jesse's medicine bottle full of ashes, and now they gather on the edge of the top of the mountain.
The surgeon who injected Jesse with a dose of the deadly new gene, Steve Lapo, pulled out a small blue collection of poems from his pocket.
"Here, his head rests on the legs of the Earth," Raper reads an elegy by Thomas Gray, reciting a passage, "a young man of unknown wealth and fame.
The science of fairness is not against his humble birth.
Then the surgeon, the sad father, and others spread Jesse's ashes into the canyon, where they rose in a gust of wind, and again in a mighty fine gray dust
"Jess, I will be watching you here a lot," said Paul Gelsinger sadly . ".
Jesse Gelsinger was not ill before he died.
He suffered from Bird and Bird tranexaminases (OTC)
Lack, a rare metabolic disorder, but it is controlled at low
Protein diet and medicine, 32 capsules per day.
When he signed up for an experiment at the University of Pennsylvania, he knew he would not benefit;
The study was conducted to test the safety of treatment for infants with fatal diseases.
Still, it brings hope, promising that Jesse might one day get rid of the tedious drugs and diets that are so strict that half a hot dog is a treatment.
"What is the worst thing that can happen to me?
He told a friend before going to the Philadelphia Penn hospital.
"I'm dead. this is for the baby.
According to government officials, Jesse died on Tuesday.
This is the first study directly related to gene therapy.
The official cause listed on Raper's death certificate is adult respiratory distress syndrome: his lungs are closed.
The facts are more complicated.
Jesse's treatment involves injecting corrective genes wrapped in a weakened cold virus called a carrier by scientists.
Carriers are like taxis that drive healthy DNA into cells;
The only purpose of the virus is to enter the cells and infect them, and they produce useful vectors.
Researchers at the University of Pennsylvania tested their vectors in mice, monkeys, baboons, and a human patient at the same dose as Jesse, and saw the expected flulike side effects, with some minor liver inflammation, the inflammation itself disappears.
When Jesse got the vector, he suffered a chain reaction that was not predicted by the test ---
Coagulation disorders, kidney failure, lung failure, and brain death: In Raper's words, "more-organ-system failure.
The doctor is still investigating.
Their current assumption is that the virus triggered an overwhelming inflammatory response. -
Essentially, immunitysystem revolt.
What they still don't understand is why.
Every area of advertising medicine has its defining moment, usually with a face.
Jonas Sauk got polio.
Louise Brown, the world's first in vitro fertilization trialtube baby.
The transplant was performed by Seattle dentist Barney Clark, whose heart is artificial.
AIDS patient Magic Johnson
Now there's Jesse Gelsinger in gene therapy.
Gene therapy was a promising idea that has not been achieved so far before Jesse's death.
When scientists map the human genome, they are actually tripping over mutations that lead to rare genetic diseases, including the disease OTC defect of Jesse.
The initial goal is simple: cure or prevent these diseases by replacing defective genes with healthy genes.
The biotech company has invested millions of research. -
Not a rare genetic disease, but a large one.
Diseases such as cancer, heart disease and AIDS are beneficial.
The government has reviewed 331 genes as of August
The treatment plan involved more than 4,000 patients.
Only 41 for "single gene" or "single gene"
Patients with these diseases are eager for gene therapy to save them.
At the same time, science is progressing slowly;
Researchers are having trouble designing carriers that can carry genes to the right cells and get them to work there.
Four years ago, doctor.
Harold warms, president of the National Institutes of Health, commissioned a very important report on gene therapy, accusing investigators of creating mistakes and widespread perceptions of success.
Since then, some achievements have been made: for example, a team at the University of taftz has used gene therapy to develop new blood vessels for heart patients.
But gene therapy has not cured anyone so far.
As with bioethicologist, Ruth McLean, member of the advisory committee on recombinant DNA, the National Institutes of Health team in charge of supervising genes --
To put it bluntly, the treatment study "Gene therapy has not yet been treated. ''On Dec.
8. the Commission's alleged "rac" will begin an open investigation into the death of Jesse and the safety of about one of the recombinant viruses used.
Quarter of all genes
Clinical trials for treatment.
Scientists in Pennsylvania will report their preliminary results, and at RAC's request, researchers who have submitted thousands of pages of patient safety data to the committee will discuss the side effects of the virus.
Including researchers from Schering.
Plogh Corporation conducted two experiments in patients with advanced liver cancer using a Penn-like approach.
After Jesse's death, the Food and Drug Administration suspended the registration of these trials.
Under the pressure of RAC, the company released some information showing that some patients experienced serious side effects, including changes in liver function and blood
Cell count, mental confusion and nausea;
There are two small pens, although one of them is historical.
Once all data on the recombinant adenoids were analyzed in the December.
At the meeting, RAC may suggest limiting its use, which will almost certainly slow down some aspects of the gene
Study of treatment.
There is another reason why this conference is important: it will mark an unprecedented public release of information on the safety of gene therapy ---
It is this shared RAC that has not been successful in the past.
Officials say no one was killed except for Jesse's genetic treatment.
But since his death, there have been news reports that other patients died during the experiment. -
From their disease, not treatment-
The scientists did not report the deaths to RAC as required.
This has raised growing doubts about gene therapy, raising questions about whether other scientists have withheld information that could prevent Jesse's death.
This question cannot be answered before analyzing all the data.
But one thing is for sure: Four years after Varmus's highly critical assessment rocked the pitch, it is now rocked again, this time because of a more fundamental problem than efficacy ---safety.
"I think this is a dangerous time for gene therapy," said Le Roy Walters, a bioethologist at Georgetown University and former president of RAC . ".
"So far, we can say, 'Well, it doesn't help many people, but at least it doesn't hurt people.
It has changed.
"Maybe no one is more keenly aware of the failed promise of gene therapy than Mark Batshaw, a pediatrician who has proposed a way to get Jesse Gelsinger
The 54-year-old ad from Batshaw, who left Penn University last year for the Children's National Medical Center in Washington, was tall, slightly bent over his shoulder, with a shy smile on his face, give him the feeling of an awkward boy, he used to be.
When he was a child, Buttershaw had a problem with ADHD: he didn't study until the third grade;
Fourth, his teacher became so annoyed with his constant chatter that she put his chair in the hall.
This experience left him a soft rib for children with stunted development, which is why he became one of the most important experts in urea in the world --
Cycle disorder, which is lacking in OTC.
The urea cycle is a series of five liver enzymes that help clear ammonia in the body, a toxic breakdown of proteins.
When these enzymes are missing or missing, ammonia--
"You scrub the floor with the same ammonia," explained Batshaw. -
Accumulate in the blood and enter the brain, leading to coma, brain injury and death.
The most common urea is the lack of OTC.
Cycle disorder occurs every 40,000 births.
Its genetic mutation occurs on the X chromosome, so women are usually carriers, while their son suffers from the disease.
Batshaw said the severe shortage of OTC is a devastating disease.
Normally, the newborn is in a coma within 72 hours of birth.
Most people suffer from severe brain damage.
Half of the people died in the first month and half of the survivors died at the age of five.
Batshaw was a young postdoc when he first met urea. cycle-
Patients in 1973, when most other doctors had never heard of the disease, correctly diagnosed it.
Within two years, he and his colleagues designed the first treatment,
A protein formula called ketoneacid.
Later, they came up with something that is still standard therapy so far: preservative benzoate sodium and another sodium that binds to ammonia and helps eliminate ammonia from the body.
However, this therapy does not prevent coma, which is usually the first sign of OTC and is rampant in affected infants.
When Buttershaw joined Penn College in 1988, he dreamed of a cure ---gene therapy.
The patient is also dreaming, says former colleague Tish Simon.
Chairman of the National urea cycle disorder Foundation, his son died of OTC deficiency three years ago.
"We all think that gene therapy is a hope for the future," Simon said . ".
"Of course, if someone is going to do that, it must be Mark Batshaw.
Gene therapy has become a reality in Singapore.
1990, in a ward of the National Institutes of Health in Bethesda, Maryland. , when a 4-year-
Old girl with severe immunity
System defect received 30-
The tiny white blood cell infusion, these white blood cells were designed to contain copies of the genes she lacked.
In modern medicine, few experiments are full of hope;
The news of the treatment spread quickly on front pages around the world.
The scientist who conducted the studyW.
French Anderson was soon called the father of gene therapy.
Anderson now admits, "We 've hyped ourselves up and thought there would be a quick, easy, early treatment . ".
"The people who closely watched Anderson's debut included Jim Wilson in the Square --jawed, sandy-
The Midwest with thick hair, when he realized that he would not succeed in football, decided to follow his father's footsteps in medicine.
As a graduate student in biochemistry, Wilson is very interested in rare genetic diseases.
"Everything I do is about the dream of gene therapy," he said . "
"Today, as director of the Institute for Human Gene Therapy at the University of Pennsylvania, Wilson is in a great position to make this dream come true.
Based in a century-
An old building between a tree-lined maple and brick sidewalk at the picturesque Penn campus, six-year-
Old Institute with 250 employeesof-the-
The art lab and the annual budget of $25 million are the biggest academic genes.
Treatment programs in the United States.
Wilson is considered the first in a field full of selfrate.
Anderson said that the company is now excluded and he is the best person in the field.
"Buttershaw was knocking on Wilson's door even before Wilson arrived in Pennsylvania on March 1993, and within a month they started working on OTC-deficient mice.
Their first task is to develop a vector.
It seems like a logical choice.
There are some early security issues in advertising. -
When a patient was hospitalized for inflammation of his lungs, a 1993 cystic fibrosis experiment was closed-
But Wilson and Batshaw said they figured out how to make safer vectors by removing additional viral genes.
When the virus gene is removed, the OTC gene is suitable.
There is a "zip code" on it that can take it directly to the liver, Batshaw said.
Although its effect does not last long, it works very quickly, which means it may be able to reverse the coma and avoid brain damage to the baby.
"It won't be a treatment soon, but it may be a treatment soon," Batshaw said . ".
The experiment of mice was encouraging.
The treated mice survived for two to three months while feeding high-fat foods. protein diet.
People who lack treatment die.
"It's not subtle," Wilson said . "
"It makes us feel necessary.
But when teams consider testing people, they come across a moral dilemma: who should be their subject?
The answer seems obvious to Wilson: A sick baby.
Arthur Kaplan, a bioethics expert at the University, believes this is not the case.
Caplan said parents of babies on the verge of death could not give informed consent: "They were forced by their child's illness.
He advised Wilson to test only stable adults with partial enzyme defects, whether female carriers or men like Jesse.
The National Foundation for urea cycle disorders agreed.
When Batshaw asked for volunteers at 1994 annual meeting, many mothers offered to screen OTC genes so much that it took him four hours to get all the blood out.
When Mark Batshaw and Jim Wilson submitted their experiments to the reorganization DNA Advisory Committee for approval, the group was in danger of being dissolved. Varmus, the N. I. H.
The director who won the Nobel Prize for discovering a cancer family.
The cause of the gene does not hide his aversion to genetic behavior --
He felt that science was too poor to advance human testing and that few experiments focused on genetic diseases, which bothered him.
He had to sign the RAC-approved agreement, which annoyed him and, even more, saw biotech companies selling those approvals like some kind of N. I. H.
On the business page of the newspaper.
"Some days," said the doctor.
Nelson Wivel, a former executive director of the committee, now works for Wilson in Pennsylvania, "it feels like RAC seems to be helping raise money in the biotech industry. Dr.
James hates it.
Meanwhile, the pharmaceutical industry and AIDS activists complain that RAC is redundant: F. D. A.
Genes that have been reviewed
Treatment advice. So in mid-
1995. Varmus restructured the RAC after soliciting input from the panel of experts, cutting its membership from 25 to 15 and depriving it of its approval authority ---
Some say this decision makes genes
The treatment researchers ignored the group and kept the security information confidential.
Dr. RAC complained
Robert Eriksson, a medical geneticist at the University of Arizona who served in the group, became a debate society. ''The Batshaw-
The Wilson protocol was one of the protocols that was finally ratified by the Commission.
The plan is for 18 adults (
Including Tish Simon, it was finally signed, but the last patient was never treated for Jesse's death)
The infusion of the OTC gene was received through a catheter located in the liver artery, which is hidden in the recombinant viral vector and leads to the liver.
Our goal is to find what Wilson calls the "maximum tolerance dose", a dose that is enough to make the gene work, and a dose that is enough to protect the patient from serious side effects.
Subjects will be divided into six groups, each receiving a slightly higher dose than the last.
This is the standard fare for safety testing.
Wilson explained, "enough increments, you can unplug people before they get hurt.
"This experiment is in sharp contrast to other experiments that won the contempt of Varmus.
This is paid by N. I. H.
This means that it has withstood the severe test of scientific peer review.
It aims for a rare genetic disease, not cancer or AIDS.
It is supported by a large number of animal studies: Wilson and his team have conducted more than 20 mouse experiments to test the efficacy and a dozen safety studies of mice, macaques and Babs.
Still, it upset Eriksson, one of the two scientists assigned by RAC.
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He was upset that three monkeys had died of a bloody incident, according to data.
Coagulation disorders and severe liver inflammation, when they received an earlier, stronger recombinant viral vector, were 20 times the highest dose of the study plan.
No one had previously injected recombinant adenoids into the blood directly through the liver or otherwise, and scientists admitted it was difficult to accurately judge how people would react.
They plan to limit the infusion to the right leaf of the liver, so that if an injury occurs, the infusion is contained there, thus retaining the left leaf.
They outlined the main risks: bleeding caused by both genes
The site of treatment or subsequent liver biopsy that requires surgery;
Or severe inflammation of the liver, which may require organ transplants and may lead to death.
Eriksson and other science critics have argued that the experiment is too risky for asymptomatic volunteers and suggested a rejection.
But Batshaw and Wilson won in the end.
They made Caplan's argument that the baby test was inappropriate.
They agreed to inject the vector into the blood instead of directly into the liver.
However, the decision was later overturned by F. D. A.
It insists that since the virus will spread through blood anyway and eventually enter the liver, the initial plan is safer.
Ad rac has not seen each other for a year in the chaos of Varmus restructuring, but has never been told about the change.
Jesse Gelsinger, a pediatrician at the age of 17
Randy Hayden first told him about the Penn proposal.
He wants to sign up right away.
But he has to wait until he is 18.
Paul Gelsinger is also very enthusiastic. A trim 47-year-
Gelsinger, with strong blue eyes, made a living as a handyman and nine years ago, when he divorced his mother with manic depression, he received custody of four children.
He had some difficulties with Jesse at that time;
The boy was in an adolescent rebellion and refused to take medicine.
"I said, 'Wow, Jess, they're getting ready for your illness.
Maybe they will come up with a treatment.
"Jesses is not a typical case of OTC defects: his mutation appears to occur spontaneously in the uterus.
Jesse was diagnosed with the disease when he was 2 years old, and scientists call it Mosaic ---
A small portion of his cells produced the missing enzyme.
When he saw what he had taken and what medicine he had taken, he was fine.
But one day in last December, Paul Gelsinger returned home and found his son curled up on the sofa.
Paul knew that he had been vomiting beyond his control, suggesting that Jesse's ammonia was rising.
Jesse fainted in the hospital and relied on her life.
After he recovered, he never took any medicine again.
On June 18, when Jesse was 18,-
Paul, Mickey and the kids. -
Fly to Philadelphia to see Paul's family.
They play tourists, visit the Liberty Bell and rock statue, where Jesse is photographed and raised his fist, a photo that will be circulated in the newspaper after his death.
On the 22nd, they went to the University of Pennsylvania, where they met the surgeon Raper, who explained the experiment and did blood and liver --
Function test to see if Jesse is eligible.
He is, his treatment is scheduled for the fall.
Jesse will be the youngest patient to register. On Sept.
Jesse returned to Philadelphia alone.
He took a bag full of clothes and a bag full of wrestling videos.
Paul Gelsinger, who plans to fly to the liver biopsy a week later, sees this as the most serious risk in the trial.
Treatment began on Monday. 13.
Jesse gets the highest dose.
Raper said that 17 patients, including a woman, had already been treated and that she had received the same dose that Jessie would have received, despite being from different places and doing "well ".
Jesse was taken to the interventional therapy center that morning.
He was injected with a calming agent, tied to a table, and a group of radiologists inserted two tubes into his groin. At 10:30 a. m.
Raper drew a vector of 30 ml and injected it slowly.
Half by noon, he is finished.
Jesse had an uncomfortable stomach that night and had a fever of 104. 5 degrees.
Raper was not particularly surprised: other patients responded the same way.
Request by Paul Kissinger;
He spoke briefly with Jessie in exchange for I love you.
This is the last word they said.
Early Tuesday morning, a nurse called Raper at home;
Jesse seems to be lost.
When Raper arrived at the hospital, it was about 6: 15. m.
He noticed that Jesse's eyes were yellow.
This means jaundice, not a good sign.
"This is not what we have seen before," Raper said . ".
A test confirmed that bilirubin in the red blood cell breakdown product Jesse was four times the normal level.
Raper called Gelsinger and Batshaw in Washington and they said he would take the train and get there in two hours.
Both doctors know that high bilirubin means one of two things: either Jesse's liver failure or he has a coagulation disorder in which his red blood cells break down faster than the liver's metabolism.
This is the same disease that scientists see in monkeys, which is given a stronger carrier.
Condition is life
It's a threat to anyone, but it's especially dangerous for people with Jesse's disease, because red blood cells release proteins when they break down.
On Tuesday afternoon, more than 24 hours after the injection, coagulation disorders caused Jesse to be in a coma. By 11:30 p. m.
His blood ammonia content is 393 micromoore per liter. Normal is 35.
The doctor began to do dialysis.
Paul Gelsinger ordered a red one. eye flight.
When he arrived at the surgical intensive care unit at 8 in the morning on Wednesday, Raper and Batshaw told him that dialysis had reduced Jesse's ammonia level to 72, but other complications were occurring.
He is overbreathing, which will increase the amount of ammonia in his brain.
They wanted to paralyze his muscles and let him go deeper in a coma so the ventilator could breathe for him.
Then he put on the scrubs, gloves and masks and went in to see his son.
By Wednesday afternoon, Jesse seemed to have settled.
Buttershaw returned to Washington.
Paul felt comfortable meeting his brother for dinner.
But later that night Jesse got worse again.
His lungs became stiff.
The doctor gave him 100% oxygen, but there was not enough oxygen to get into his blood.
They consulted a liver.
The transplant team learned that Jesse was not a good candidate.
Raper is next to it.
He consulted with Batshaw and Wilson, who decided to take a special step, a procedure called ECMO, for in vitro membrane lung oxidation, essentially, the external lungs that filter the blood remove carbon dioxide and add oxygen.
Raper said only 1,000 people had been tested before.
Only half survived.
"If we can buy his lungs in a day or two, they will think, maybe he will continue to recover," Raper said later . ".
Thursday and Thursday the next day.
Hurricane Floyd hit the East Coast.
Just before the airport was closed, Mickie Gelsinger flew in from Tucson. (
Jesse's mother, Patty Gelsinger, was treated in a psychiatric hospital and could not leave. )
Batshaw spent the day stranded outside Baltimore on the American Railroad train.
The phone he called Raper turned off.
He persuaded another passenger to lend him his.
ECMO seems to be working, Raper reports.
But then there was another problem: Jesse's kidney stopped producing urine.
He slipped to more than one. organ-
The system failed, Raper said.
In his hotel that night, Paul Gelsinger couldn't sleep.
He left a note for his wife and walked half a mile to see Jesse at Penn Medical Center.
The boy was swollen beyond recognition;
His ears are swollen.
Gelsinger noticed blood in Jesse's urine and he knew it indicated the kidney was shutting down.
Who, he thought, could survive all this?
On Friday morning, 17 th, a test showed Jesse had brain dead.
No need to tell Paul Gelsinger: "I already know.
He called on a priest to serve by the bedside and prayed for the removal of life support.
The room was packed with equipment and personnel: 7 of Paul's 15 siblings came in, along with a range of doctors and nurses.
The Raptors and Batshaw stood behind and were exhausted.
The priest smeared Jesse's forehead with oil and then read the Lord's Prayer.
The doctor held back tears.
One step forward with Raper, the nursing specialist flipped two toggle switches, one to turn off the ventilator and the other to turn off the ECMO machine.
He checked his heart.
Rate monitor, watch the line flat and note the time: 2: 30. m.
He put the stethoscope on Jesse's chest, more out of habit than necessary, and announced the death officer.
"Goodbye, Jess," he said.
We will solve this problem.
Wilson immediately reported the death and was praised by government officials, but Arthur Kaplan criticized him at a press conference, saying they should make the news public.
Over the next few weeks, the University of Pennsylvania research team placed every detail of Jesse's treatment under a microscope.
It has re-checked the carrier to make sure it is not contaminated and did the same test on the monkey, re-
Laboratory and autopsy results were examined.
Wilson's biggest fear is that Jesse died of human error, but there is no evidence to prove it so far.
"It's terrible," said Anderson of France . ".
"You feel a little safer if they make a mistake.
"Death has upset three doctors in various ways.
Wilson asked himself over and over again whether he should do anything different.
"I said no at this point, but I continued
He has been troubled by concerns about the morale of his staff, whether the financial sponsors of his institute will withdraw, whether the patient will continue to volunteer, and whether he will lose courage. -
For a scientist at the cutting edge, the death knell.
One night, he admitted while having dinner in Philadelphia, "What I'm worried about is that I'll be timid and I'll be risk-averse.
Raper devoted himself to his work in an attempt to deliver on his promise to "solve the problem ".
There are many possible explanations, he said: carriers may not respond well to Jesse's drug;
Jesse's status as a mosaic may play a role;
Or, early tests on monkeys show that stronger carriers have harmful side effects, which is more dangerous than doctors realize.
It may take months for an answer, but he is determined to find one.
This study can only continue if you understand what happened to Jesse and how to prevent this from happening to others.
Raper said, "This will be the best tribute to Jesse.
"Of the three, Batshaw seems to be the hardest.
He is not a particularly religious person, but a few days after Jesse's death he went to the synagogue to say the prayers of the Jewish mourners.
He struggled with the idea of personal responsibility.
During his career, he raised many children who were about to die, but he said that no patient ever got worse because of his care.
What is the oath of hipokradi?
Batshaw asked, as his fingers hit the table top, he looked at the distance.
He paused, as if to grind himself into steel, and then said, "I have done bad things.
"Paul Gelsinger does not believe that doctors are responsible, although he is very interested in learning about the understanding of the virus by other scientists before Jesse's death.
After losing his son, he experienced a deep spiritual awakening;
In death, Jesse taught him how to live, he said.
He often talks about God and the "purity of intention", which is the way he says Jesse is showing altruism and the rest of us may follow suit.
"I hope," he said on the top of the mountain that Sunday afternoon, "I can die like my son.
"We are constantly improving the quality of text archives.
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A version of the article appeared on page 6006137 of the National edition in November 28, 1999, titled The Death of Jesse Gelsinger's biotechnology.
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