Two Studies Cast Doubt on Adult Stem Cells - critical analysis
Newsday, Thursday, March 14, 2002
The Associated Press - Two new studies cast doubt on the tantalizing theory that adult stem cells can serve as the body's all-around repairmen, capable of converting into any type of cell to fight disease or replace faulty organs.
The findings, if confirmed, could force scientists to focus more on embryonic stem cells - whose use is highly controversial because they are taken from embryos that are killed in the process.
Scientists have long known that stem cells from embryos are all-purpose cells that can transform themselves into diferent kinds of specialized tissue, such as muscle, bone, skin and organs.
Researchers hope someday to harness this ability to treat various diseases and injuries.
In recent years, scientists have found surprising evidence that stem cells taken from adult creatures have some of the same transforming properties, or plasticity.
But the two new studies, conducted in separate laboratories at the University of Florida in Gainesville and the University of Edinburgh in Scotland and published online yesterday by the journal Nature, cast doubt on that belief.
In the two studies, embryonic stem cells from mice were put in laboratory dishes with mouse bone marrow and brain cells. But instead of transforming into their neighboring cells, the stem cells simply merged their genetic material with the marrow and brain cells.
The researchers said the same phenomenon may have occurred in earlier studies involving adult stem cells, and may have fooled scientists into thinking that the cells had transformed themselves.
Analzye the article.
- What information from within the article supports the title of this article?
- What information from within the article disputes the title of this article?
- What is the tone of the article? How does the author establish that tone?
- How could you find evidence to support or refute the attitude projected by this article?
- State TWO sources that provided you with accurate information. What did these sources state?
- Write a new title that might represent the content of the article more accurately for readers.
CA due Monday November 9th
DNA Manipulation
Carefully read the statement given below. Answer the questions in complete, concise, coherent sentences. Think of as many options/reactions as possible.
"DNA manipulation is not anti-human or unthinkable, merely an attempt to apply to human beings the techniques of selective breeding that human beings have applied efficiently to animals for centuries."
Do you feel comfortable with the possible implications of this statement?
- a. What are the possible implications of the statement?
- b. What are the pros and cons of such possible implications?
- c. What is your reaction to those possibilities?
CA due Monday November 23rd
New gene therapy halts 2 boys' rare brain disease
By LAURAN NEERGAARD, AP Medical WriterThu Nov 5, 5:12 pm ETWASHINGTON – French scientists mixed gene therapy and bone marrow transplants in two boys to seemingly halt a brain disease that can kill by adolescence. The surprise ingredient: They disabled the HIV virus so it couldn't cause AIDS, and then used it to carry in the healthy new gene.The experiment marks the first time researchers have tried that long-contemplated step in people — and the first effective gene therapy against a severe brain disease, said lead researcher Dr. Patrick Aubourg of the University Paris-Descartes.Although it's a small, first-step study, it has "exciting implications" for other blood and immune disorders that had been feared beyond gene therapy's reach, said Dr. Kenneth Cornetta, president of the American Society of Gene and Cell Therapy."This study shows the power of combining gene therapy and cell therapy," added Cornetta, whose own lab at Indiana University has long researched how to safely develop gene delivery using lentiviruses, HIV's family.The research was published in Friday's edition of the journal Science.In 20 years of gene therapy research, there have been few home runs and some headline-making setbacks — including a risk of leukemia caused by otherwise successful gene therapy for another rare disorder, "bubble boy disease." That's a risk that specialists hope a lentivirus-based gene therapy will eliminate.FYI - (Gene therapy trials for SCID were halted worldwide for a number of years when it was reported that children who had been treated for XSCID in a French gene-therapy experiment had developed a type of leukemia. It was soon discovered that the mechanism used to insert the corrective gene had placed it in a region of a receiving cell's chromosome that switched on a cancer-causing gene (oncogene).)
Best known from the movie "Lorenzo's Oil", adrenoleukodystrophy, or ALD, is a rare genetic disease that, in its most devastating form, destroys the coating of nerve fibers in boys' brains. Without that coating, called myelin, the neurological system breaks down. The disease typically strikes between the ages of four and 10, leading to blindness, deafness, dementia and loss of muscle control, and killing them within a few years.Bone marrow transplants can halt ALD by letting new myelin-forming stem cells take root. But it's difficult to find a matching marrow donor, and the transplant itself is very risky.So what if stem cells from the boys' own bone marrow could be genetically corrected, eliminating the ALD mutation? To do that, Aubourg's team had to overcome a technical hurdle: Gene therapy works when scientists harness deliver a healthy new gene by attaching to a virus that can harmlessly infect cells. But none of today's so-called gene therapy "vectors" could penetrate enough of the stem cells needed for an ALD treatment to work.Unlike most viruses, HIV can penetrate stem cells, and it sticks permanently. So Aubourg's team removed the genetic parts of HIV that make it dangerous, leaving basically a scaffolding to carry the new therapeutic gene.Then they culled stem cells from two 7-year-old boys in the early stages of ALD, and mixed in the healthy gene. The boys underwent bone marrow-destroying chemotherapy and then had their genetically corrected stem cells reinserted.Two years later, the boys have shown no sign of worsening brain damage and are functioning well with 15 percent of their blood cells producing the healthy protein, said Aubourg, who plans to test the experimental procedure in more patients. An advocacy group, the Stop ALD Foundation, is working to raise money for a similar U.S. study.______On the Net:Science Web site: http://www.sciencemag.orgCancer: When The Chromosome Breaks
Science 83, Sept. 1983 p 16. writtenby Michael Gold
For the last decade, two groups of biologists have been following parallel paths, both with their sights on the puzzle of cancer, neither paying much attention to the other. The cytogeneticists were tracking human chromosomes, the rod-shaped bodies that carry the genes. They found that in the tumor cells taken from cancer patients, the chromosomes were often broken and scrambled. Meanwhile, the molecular biologists had identified the so-called oncogenes, mysterious genetic elements that usually sit quietly on chromosomes but can be "turned on" somehow to trigger the unbridled growth that makes a cell cancerous.
Suddenly these two groups have noticed they are heading in the same direction, toward what some have called the most encouraging development of cancer research in years: a link between the molecular biologist's oncogenes and the geneticist's busted chromosomes. What they found is that the broken chromosomes were rearranging themselves so that an oncogene ended up next to an "active region" which turned on the deadly gene.
"It's a kind of startling thing," says molecular geneticist Philip Leder of Harvard University. "Until now, these chromosomal defects were only a collection of sitings. The oncogene findings provide the molecular underpinning, the rationale."
In many ways the findings are preliminary; no one knows, for instance, how an active region turns on an oncogene or what the gene does to initiate a tumor. Still, now that researchers know that physical rearrangements of the oncogenes are the key, they know where to look to find out more.
"It is preliminary," says Jorge Yunis, a geneticist at the University of Minnesota, "but it could be a jackpot." Yunis has just published a report reviewing some of the exciting finds and documenting a few new results of his own.
One of Yunis' contributions is a new method of painting tiny stripes across the chromosomes, as many as 220 identifiable bands on a single chromosome. The bands help him track fragments that leave one chromosome and hook up with another. He can follow chromosomal bits so small they contain only 10 genes; a full chromosome may carry several thousand.
![Translocation]()
The chromosome-oncogene connection is seen in Burkitt's lymphoma, a childhood cancer that affects B-lymphocytes, cells that help produce antibodies. An oncogene called myc on chromosome No. 8 ends up next to immunoglobulin genes (imm) on No. 14. In B-lymphocytes the immunoglobulin genes are very active. The hypothesis is that whatever turns on the genes in that region also activates the cancer-producing oncogene in some way.
Using such handling techniques, Yunis and others have shown that chromosomeal breaks are not just occasional features of cancer cells, but are almost always present in tumors. Yunis reports that he examined tumor cells from 240 patients and found defective chromosomes in 98% of them. Moreover, for most of the patients, he found particular rearrangements that consistantly show up in certain cancers. Twenty-six out of 32 patients with a certain type of nodular lymphoma, for example, had a "translocation" between the No.14 and No. 18 chromosomes. That is, a piece of the No.18 broke off, reattaching to the No. 14 and vice versa. Others have reported consistent defects in dozens of different cancers. The defects include translocations, associated mostly with leukemias and lymphomas, deletions on missing pieces, which occur in solid tumors such as lung and kidney cancer and extra chromosomes, which are linked to various others tumors.
In fact, the cytogeneticists have catalogued far more chromosomal defects than the molecular biologists can explain. Several breaks occur near known oncogenes, but at the moment only one has been worked out in detail-by groups at Harvard, the National Cancer Institute and the Wistar Institute in Philadelphia. The rearrangement seen in the tumor cells of most victims of Burkitt's lymphoma is between the oncogene on the No. 8 chromosome and the active site on the No. 14.
If the chromosome-oncogene connection holds up, then the spots where breaks occur are the obvious places to look for new oncogenes and possible activation sites. Following that strategy, Yunis and Carlo Croce of the Wistar Institute are investigating break points in two non-Burkitt's lymphomas hoping to find previously unidentified oncogenes where fragments from chromosomes No. 11 and No. 18 attach to the activation site on chromosome No.14.
One of many questions posed by these findings is whether the breaks are random or somehow preordained. Janet Rowley, a cytogeneticist at the University of Chicago, favors the random process. "It may be that chromosomal rearrangements are occurring all the time," she says, "and if it happens at the right place in the right cell it may lead to cancer." Rowley concedes, however, that some of Yunis' latest results may cause her to modify her opinion.
The findings involve "fragile sites", points where chromosomes often break, which show up as gaps or weakly stained spots in chromosomes of healthy people. Many of these fragile sites are inherited. Yunis has found sites in normal blood cells of leukemia patients that match the break points of chromosomes in their leukemic cells. He has also found fragile sites where others have located chromosomal defects in tumors linked to some chemicals and to smoking. Soon, Yunis suggests, simple blood tests could determine if individuals have fragile sites that predispose them to certain cancers. They could reduce their risks by avoiding occupations that expose them to suspected carcinogens, for example, or by giving up smoking.
Other possible applications for these characteristic defects include diagnosing certain cancers, making prognoses and recommending treatments.
Patients with one type of acute leukemia, whose No. 16 chromosomes show an inversion or upside-down segment, may live for five years or more, says Yunis. Those who lack the inversion live only a few months unless they receive a bone marrow transplant.
Such applications may soon be practical, once correlations between defects and specific cancers are confirmed in large numbers of patients. Researchers say they are likely to come sooner than the finding of many new oncogenes or the understanding of how they are activated-if that's what really happens.
"It's going to be very complicated and there will be lots of different answers," says Rowley. "But this is an area that's not been fully explored in the past and it has to be very fruitful." Special Report
Focus questions for First Impressions
- 1. Defining the Terms. Indicate meaning based on context clues and text check.
- a. cancerous
- b. oncogene
- c. translocation
- d. fragile sites
- 2. What is the main idea of this article?
- 3. What two fields of Biology have been carrying out cancer research?
- 4. What did each group discover?
- 5. What knowledge has been revealed by combining the findings of these two groups?
- 6. What is meant by the term "banding techniques"?
- 7. Explain two disorders these techniques can identify.
- 7. How can this knowledge by used to help or harm humanity? Consider both pro and con aspects
Cracking Cancer's Code
Researchers are learning how genes start tumors - or stop them
written by J. Madeleine Nash, Time Magazine, Science section, 1990
Just 10 days earlier, the laboratory cultures had all contained the same number of microscopic cancer cells. Now even an untutored eye could tell the difference. Globs of wildly dividing cell colonies filled half the flasks, while in the others the cells refused to multiply. Reason: a research team, led by Johns Hopkins University oncologist Bert Vogelstein, had endowed the quiescent cells with a protective device that the dividing ones lacked, in this case a normal copy of a gene that acts as a circuit breaker, shutting down growth. The scientists had found a way, at least in theory, to stop a tumor after it gets started.
This discovery is so striking that even cautious scientists are finding it difficult to rein in their excitement. It is among the latest in a chain of discoveries that have rapidly confirmed what for a long time scientists have only suspected: mutations in specific genes are the underlying cause of cancer. As knowledge about these genes expands so too does the likelihood researchers will devise new treatments that may one day target cancer cells as selectively as antibiotics attack bacteria. "Cancer cells," says gene mapper David Housman of M.I.T., "are too damn close to normal cells, and that's been the basic problem in attacking this disease. Finally, we are beginning to learn what makes cancer cells different."
A decade ago, scientists puzzling over cancer cells resembled 18th century Egyptologists in their struggle to decipher ancient hieroglyphics. Now they have assembled a biological Rosetta stone that has enabled them to lay out in sharp detail the changes that cause a cell to go from normal to malignant. "The cancer cell used to be a black box," says Vincent T. De Vita Jr., physician in chief of New York City's Memorial Sloan-Kettering Cancer Center. "But the lid of the black box has been opened, and we can see the wheels turning inside." The "wheels" are genes that regulate growth. Some called oncogenes, activate the process of cell division; others, known as tumor-suppresser genes, or anti-oncogenes, turn the process off. In their normal form, both kinds of genes, working together, enable the body to perform the critical function of replacing dead or defective cells. But slight alterations in the genetic material, whether inherited or caused by environmental insult, can provoke the rampant cell division that leads to cancer.
The first oncogene known to exist inside animal and human cells was discovered in 1976 by Drs. J. Michael Bishop and Harold Varmus of the University of California at San Francisco. Since then, scientists have fond more than 50, some of which appear to be more important than others in human cancers. Mutation in RAS oncogene, for instance, are believed to play a role in a majority of pancreatic and colon cancers, and some lung cancers as well. Mutations in other oncogenes have been linked to leukemia and the most lethal forms of breast and ovarian cancer.
But oncogenes are just one piece in this genetic jigsaw puzzle. In 1986 scientists, including molecular biologist Robert Weinberg of M.I.T., identified the first human tumor-suppresser gene, dubbed the RB gene because, if it ceases to function, the result is retinoblastoma, a rare childhood eye cancer. Problems with the RB gene have since been tied to cancers of the lung, breast and bladder. "What was initially thought to be involved in one obscure tumor," observes Weinberg, "is a player in commonly occurring cancers as well."
Now that they recognize the importance of the genes, medical researchers are faced with the mind-bending task of figuring out how they work, singly and in tandem. "A damaged oncogene is like having the accelerator pedal stuck to the floor," notes Johns Hopkins' Vogelstein. "A damaged tumor-suppresser gene is like losing the brakes." Increasingly, scientists think cumulative damage to both sorts of genes must occur before full-blown cancer results. Cells strongly resist malignant transformation, which is the reason most cancers require 20 or more years to develop. According to Vogelstein, colon cells must accumulate damage in at least one oncogene and three tumor-suppresser genes before becoming truly malignant. The earliest of these mutations gives rise to a benign polyp; subsequent changes cause this polyp to expand in size and become more and more irregular in shape. At least one of the cells that make up the polyp then undergoes an additional genetic break that transforms the tissue into the progenitor of an aggressive tumor.
For many of the most common forms of malignancy, including colon cancer, the crucial damage is believed to occur in the so-called p53 gene, the same tumor suppresser that prevented cancer cells from growing out of control in the Johns Hopkins laboratory cultures. Like others of its ilk, this gene appears to act as a master switch that regulates many important activities, including the receipt of chemical messages originating outside the cell. Thus, speculates M.I.T.'s Weinberg, cells with defective tumor-suppresser genes may longer heed growth-control signals sent by surrounding cells. The first hard evidence that p53 may play a key role in human cancer came from Vogelstein's group at Johns Hopkins, which last year identified a mutant form of the gene in colon cancer cells. Since then, mutant p53 has shown up in breast-, lung-, brain-, and bladder-cancer cells. Many researchers believe p53, because it is so ubiquitous, offers an unusually promising platform from which to launch a major assault on cancer. For instance, drugs that mimic the action of a normal p53 gene could conceivably cause cancers to revert to a premalignant phase. One day, albeit in the very distant future, it may even be possible for molecular surgeons to replace faulty p53 genes.
In the meantime, tests that detect mutations in this critical gene could be an invaluable diagnostic tool. At a meeting of top cancer-gene researchers at M.I.T. last September, Vogelstein created quite a stir when he noted, almost in passing, that his laboratory had detected cells with abnormal p53 genes in the urine of patients with advanced bladder cancer. A similar scan might pick up such cells in the stools of patients with colon cancer, the cause of more than 60,000 deaths in the U.S. each year.
At first, these tests would be used to guide physicians in selecting therapies. In fact screening for oncogenes is beginning to help clinicians identify a few particularly aggressive forms of cancer and tailor treatments accordingly. Eventually, scientists may be able to fashion tests sensitive enough to detect the presence of abnormal genes in undiagnosed patients well before the cancer has embarked on its Shermanesque march through the body. Such tests would no doubt be lifesavers: if caught early enough, many cancers can be cured by surgery alone.
Focus questions for Cracking Cancer's Code
- 1. Define the Terms. For each term explain the meaning from context clues. Then look up the term in text or dictionary to confirm or expand meaning.
- a. quiescent
- b. polyp
- c. ilk
- d. ubiquitous
- 2. What is the main idea of this article?
- 3. What is meant by the term "oncogene"?
- 4. What is a proto-oncogene?
- 5. What are tumor-suppresser genes?
- 6. What is the basic problem in treating cancer?
- 7. How does "full-blown" cancer develop?
- 8. What type of gene is each of the following and what types of cancer are caused by each: RAS, RB and p53.
Smoking leaves Fingerprints on DNA
"Science News", Nov. 2. 1996 vol. 150, page 284.Few people outside the tobacco industry remain skeptical abut the link between lung cancer, the leading cancer killer in the United States, and smoking. A new study examining the DNA damage caused by a single compound in tobacco smoke should cast out any lingering doubts.When physicians study people with lung cancer, they find the same gene mutated in patient after patient. In particular, about 60 percent of lung cancer patients have mutations in the p53 gene. The protein encoded by this gene normally prevents cells from growing out of control and can even command a cell to commit suicide if it becomes cancerous.In recent years, physicians have documented the curious fact that p53 mutations in lung cancer patients usually occur at three specific sites, known as codons 157, 248, and 273, on the gene's DNA sequence. Those genetic hot spots are exactly where a common compound in tobacco smoke prefers to mutate p53, scientists now report in the Oct. 18 Science. A research group headed by Gerd. P. Pfeifer of the Beckman Research Institute of the City of Hope in Duarte, Calif., treated lung and other kinds of cells with benzo[a]pyrene, a compound of tobacco smoke that belongs to a family of cancer-causing agents known as polycyclic aromatic hydrocarbons. The scientists found that p53 genes in such cells were laden with mutation-causing adducts, sites where a metabolite of benzo[a]pyrene had attached itself to the gene's DNA. When they examined the locations of the adducts, the scientists found that codons 157, 248 and 273 were affected most often.While epidemiological studies have provided all but conclusive evidence that tobacco smoking causes lung cancer, the new results appear to provide the first direct evidence associating carcinogens in smoke with specific lung cancer mutations. "It's a bit harder to deny the connection now," says Pfeifer. His group intends to study the patterns of p53 adducts formed by other suspected carcinogens to see whether the compounds are linked to additional types of cancer. Examining how such adducts form is also a priority, says Pfeifer.Focus Questions for Smoking leaves Fingerprints on DNA
- 1. Defining the Terms. Indicate meaning based on context clues and text check.
- a. p53 gene
- b. codons
- c. epidemiological studies
- d. carcinogen
- 2. What is the main idea of this article?
- 3. What does the p53 gene do for a cell?
- 4. What is an adduct?
- 5. How has tobacco smoke been linked to lung cancer?