April 14 (Bloomberg) — Scientists discovered a way to transfer DNA from one fertilized human egg to another in a pioneering effort to avert the spread of a host of genetic disorders such as learning disabilities and diabetes.
The researchers at Newcastle University in northern England extracted the genetic material contributed by the egg and sperm and implanted it into a donor egg, according to the study published today by the journal Nature. It’s the first time DNA has been transferred between two fertilized human eggs.
The approach discards almost all the defective DNA inherited from the mother that disrupts the tiny energy generators inside cells, and may prevent related disorders such as blindness and liver failure, the researchers said. They are planning further experiments to see whether the technique could help people who carry mutated genes to have healthy babies — an end result that may still be a decade away.
“We have no way of curing these diseases at the moment, but this technique could allow us to prevent the diseases occurring in the first place,” said Doug Turnbull, the lead researcher and a professor at the university’s medical school, in a statement. “It is important that we do all we can to help these families and give them the chance to have healthy children, something most of us take for granted.”
Parents contribute a total of 23,000 genes to a child. In a fertilized egg, this genetic material is housed in two pronuclei, one from the egg and one from the sperm. The egg also contains mitochondria, tiny structures found in every cell that produce the chemical fuel needed for life. Mutations in the mitochondrial DNA, which are passed on from the mother, can disrupt the functioning of these energy generators.
‘Changing the Batteries’
The Newcastle scientists were able to extract both pronuclei and implant the material that makes each child unique into a donor egg with healthy mitochondria. They created 80 fertilized eggs using the technique and grew them in a laboratory for six to eight days. That showed for the first time that eggs produced in this way could reach the stage at which they each had divided into about 100 cells.
“It’s like changing the batteries,” Turnbull said today at a news conference in London. “These are diseases where there is battery failure. Because mitochondria are everywhere, these diseases can affect all parts of the body. None of my patients is exactly the same.”
About 1 out of every 200 children is born each year with mutations in mitochondrial DNA that cause no symptoms or only mild conditions. One in every 6,500 children is born with a more serious mitochondrial disease, ranging from muscular weakness to fatal heart failure. Some disorders lead to death in early infancy.
The research was funded by the Muscular Dystrophy Campaign, the U.K. Medical Research Council and the London-based Wellcome Trust, the world’s second-biggest medical research charity.
–Editors: Phil Serafino, Angela Cullen
To contact the reporter on this story: Kristen Hallam in London at khallam@bloomberg.net
To contact the editor responsible for this story: Phil Serafino at pserafino@bloomberg.net
Article by Nicholas Wade – New York Times
Published: March 10, 2010
Two research teams have independently decoded the entire genome of patients to find the exact genetic cause of their diseases. The approach may offer a new start in the so far disappointing effort to identify the genetic roots of major killers like heart disease, diabetes and Alzheimer’s.
In the decade since the first full genetic code of a human was sequenced for some $500 million, less than a dozen genomes had been decoded, all of healthy people.
Geneticists said the new research showed it was now possible to sequence the entire genome of a patient at reasonable cost and with sufficient accuracy to be of practical use to medical researchers. One subject’s genome cost just $50,000 to decode.
“We are finally about to turn the corner, and I suspect that in the next few years human genetics will finally begin to systematically deliver clinically meaningful findings,” said David B. Goldstein, a Duke University geneticist who has criticized the current approach to identifying genetic causes of common diseases.
Besides identifying disease genes, one team, in Seattle, was able to make the first direct estimate of the number of mutations, or changes in DNA, that are passed on from parent to child. They calculate that of the three billion units in the human genome, 60 per generation are changed by random mutation — considerably less than previously thought.
The three diseases analyzed in the two reports, published online Wednesday, are caused by single, rare mutations in a gene.
In one case, Richard A. Gibbs of the Baylor College of Medicine sequenced the whole genome of his colleague Dr. James R. Lupski, a prominent medical geneticist who has a nerve disease, Charcot-Marie-Tooth neuropathy.
More common diseases, like cancer, are thought to be caused by mutations in several genes, and finding the causes was the principal goal of the $3 billion human genome project. To that end, medical geneticists have invested heavily over the last eight years in an alluring shortcut.
But the shortcut was based on a premise that is turning out to be incorrect. Scientists thought the mutations that caused common diseases would themselves be common. So they first identified the common mutations in the human population in a $100 million project called the HapMap. Then they compared patients’ genomes with those of healthy genomes. The comparisons relied on ingenious devices called SNP chips, which scan just a tiny portion of the genome. (SNP, pronounced “snip,” stands for single nucleotide polymorphism.) These projects, called genome-wide association studies, each cost around $10 million or more.
The results of this costly international exercise have been disappointing. About 2,000 sites on the human genome have been statistically linked with various diseases, but in many cases the sites are not inside working genes, suggesting there may be some conceptual flaw in the statistics. And in most diseases the culprit DNA was linked to only a small portion of all the cases of the disease. It seemed that natural selection has weeded out any disease-causing mutation before it becomes common.
The finding implies that common diseases, surprisingly, are caused by rare, not common, mutations. In the last few months, researchers have begun to conclude that a new approach is needed, one based on decoding the entire genome of patients.
The new reports, though involving only single-gene diseases, suggest that the whole-genome approach can be developed into a way of exploring the roots of the common multigene diseases.
“We need a way of assessing rare variants better than the genomewide association studies can do, and whole-genome sequencing is the only way to do that,” Dr. Lupski said.
With 10 genomes of healthy humans sequenced, Dr. Gibbs, a specialist in DNA sequencing, decided it was time to decode the genome of someone with a genetic disease and asked his colleague Dr. Lupski to volunteer.
Mutations in any of 39 genes can cause Charcot-Marie-Tooth, a disease that impairs nerves to the hands and feet and causes muscle weakness.
Fifty thousand dollars later, Dr. Lupski turned out to have mutations in an obscure gene called SH3TC2. The copy of the gene he inherited from his father is mutated in one place, and the copy from his mother in a second.
Both his parents had one good copy of the gene in addition to the mutated one. A single good copy can generate enough, or nearly enough, of the gene’s product for the nerves to work properly. Dr. Lupski’s mother was free of the disease and his father had only mild symptoms.
In the genetic lottery that is human procreation, two of their eight children inherited good copies of SH3TC2 from each parent; two inherited the mother’s mutation but the father’s good copy and are free of the disease; and four siblings including Dr. Lupski inherited mutated copies from both parents. These four all have Charcot-Marie-Tooth disease. The results are reported in The New England Journal of Medicine.
In Seattle, Dr. Hood and Dr. Galas have also applied whole-genome sequencing to disease. They analyzed the genome of a family of four, in which the two children each have two single-gene diseases, called Miller syndrome and ciliary dyskinesia. With four related genomes available, the researchers could identify the causative genes. They also improved the accuracy of the sequencing because DNA changes that did not obey Mendel’s rules of inheritance could be classed as errors in the decoding process.
The Seattle team believes whole-genome sequencing can be applied to the study of the common multigene diseases and plans to sequence more than 100 genomes next year, starting with multigenerational families.
The family whose genomes they report in Science were sequenced by a company with a new DNA sequencing method, Complete Genomics of Mountain View, Calif., at a cost of $25,000 each. Clifford Reid, the chief executive, said that the company was scaling up to sequence 500 genomes a month and that for large projects the price per genome would soon drop below $10,000. “We are on our way to the $5,000 genome,” he said.
Dr. Reid said the HapMap and genomewide association studies were not a mistake but “the best we could do at the time.” But they have not yet revolutionized medicine, “which we are on the verge of doing,” he said.
Dr. Goldstein, of Duke University, said the whole-genome sequencing approach that was now possible should allow rapid progress. “I think we are finally headed where we have long wanted to go,” he said.
Icelandic biologists have discovered that the genetic risk of several common diseases, like Type 2 diabetes and cancer, can depend on which parent a DNA variant is inherited from.
The finding may help explain part of a serious gap in understanding the genetics of common diseases.
Using an extensive genealogy that includes almost all the present population of Iceland and many in previous generations, the Reykjavik company DeCode Genetics managed to distinguish which chromosomes came from the father and which from the mother in some 40,000 people.
The company then ran standard tests, known as genome wide association studies, the tool that scientists have hoped would track down the roots of common diseases and fulfill the promise of the Human Genome Project.
But with most of these common diseases, the tests have so far identified genetic variants that account for only a small percentage of the risk. This is in contrast to simple diseases, most of them rare, where a single gene is the cause and the disease has a clear family pedigree.
The failure has left biologists puzzled about the missing heritability, which some have jokingly attributed to “dark matter” within the human genome, an analogy with the dark matter invoked by cosmologists to explain the missing mass of the universe.
Some experts believe the missing risk might be carried in a large number of rare DNA variants not included in current scans of patients’ genomes. Because it costs too much to decode all three billion units of DNA in a patient’s genome, biologists use chips that scan just the 500,000 sites where variation is most common. These sites were expected to explain the genetic component of common diseases like cancer or schizophrenia, but mostly do not do so.
Another explanation is that the missing heritability lies in aspects of cell biology that are not yet understood.
Decode scientists have found one such instance. They report in Friday’s Nature that a DNA variant increases a person’s risk of Type 2 diabetes by 30 percent if inherited from the father, but reduces the risk by 10 percent if comes from the mother.
Because the two effects tend to cancel each other out, they have not been picked up by the standard tests that do not identify the parental origin of each section of DNA.
DeCode found that five of seven variants tested made different contributions to disease depending on the parent of origin. In most cases the effect was of differing degrees of severity, depending on the parent involved.
To increase the chances of seeing such an effect the researchers tested known disease-associated variants that lay close to so-called imprinted genes, ones where the copy from one parent is suppressed. They now plan to survey the rest of the genome.
Kari Stefansson, DeCode’s chief executive, said he could not predict how large a percentage of the missing heritability the parent-of-origin effect might account for. “But I think it’s going to be substantial,” he said.
DeCode Genetics recently filed for bankruptcy, but the company plans to continue operations in another form. Dr. Stefansson said that its access to the Icelandic genealogical database would give it an advantage in searching for disease genes in circumstances where it is essential to know the genetic structure of a population.
Mark Daly, a medical geneticist at Massachusetts General Hospital, said that DeCode’s result was “a significant finding” and that it confirmed the idea that effects of this nature would account for some of the missing heritability.
BAKERSFIELD, Calif. — In the war on cancer, scientists are battling the disease right where it begins: within tiny strands of DNA. There are many different kinds of mutations in DNA that can cause cancer, and each specific change provides new clues about how the illness starts and potential ways to treat it. In two new studies, British researchers found evidence that our behavior alters some genes and these changes may trigger cancers.
Doctors studying tumor cells from a man with melanoma found DNA damage caused by ultraviolet light — and UV rays from the sun are a known risk factor for skin cancer. Other research on lung cancer cells revealed mutations caused by carcinogens in tobacco smoke. Scientists saw evidence that the DNA had tried to repair itself but it was unsuccessful. Experts said these findings show the interplay between our genes and our environment — people are born with risks for certain diseases due to their genes, but then their lifestyle choices act on those same genes, changing them for the better or the worse.
Copyright 2009 by TurnTo23.com. The Associated Press contributed to this report. All rights reserved. This material may not be published, broadcast, rewritten or redistributed.
ScienceDaily (July 31, 2009) — A group of nanoengineers, biologists and physicists have used innovative approaches to deduce the internal structure of chromatin, a key player in DNA regulation, to reconcile a longstanding controversy in this field. This new finding could unlock the mystery behind the origin of many diseases such as cancer.
The details of this breakthrough discovery are highlighted in a paper in the Proceedings of the National Academy of Sciences (PNAS). The authors include Gaurav Arya, a nanoengineering professor at the UC San Diego Jacobs School of Engineering, as well as researchers from Penn State University, University of Massachusetts, and New York University.
The internal structure of chromatin is not known—a mystery that has baffled scientists for more than three decades. Chromatin is a complex combination of DNA and proteins that makes up chromosomes. The function of chromatin is to package DNA into a smaller volume to fit in the cell. Chromatin also plays an important role in the regulation of genetic processes like DNA replication, transcription, recombination, and repair because all these processes depend critically on the accessibility of the DNA, which is directly controlled by chromatin. A loosely folded chromatin fiber allows easy access to DNA sequences while a tightly folded fiber prevents or inhibits such access.
This newfound discovery by Arya and his colleagues could help scientists better understand how chromatin folds and unfolds to regulate gene activities, as well as understand the origin of genetic diseases like cancer. For example, he said, lots of diseases including cancer are directly linked to abnormal regulation of chromatin.
The structure of chromatin has been a subject of many controversies during the last 30 years, with two different models being the focus of debate. The new findings by Arya and his collaborators suggest that the structure of chromatin is actually a combination of both of these models.
Some researchers suggest that its structure is like a solenoid, where the chain of nucleosomes follows a helical path along the chromatin axis such that adjacent nucleosomes along the chain lie side by side on the chromatin fiber also and thus the linker DNA connecting the two needs to maintain a highly bent conformation. Other researchers suggest that chromatin has a zigzag structure where the nucleosome chain follows a zigzag path along the chromatin fiber such that adjacent nucleosomes on the chain actually lie on opposite sides of the fiber such that the linker DNA is straight. (The nucleosome is the basic unit of chromatin that consists of two turns of DNA wrapped around a protein spool).
Arya and his team have developed a very sophisticated model of chromatin that is computationally accessible yet detailed enough to provide insights into its structure and dynamics. By simulating this model under physiological conditions using fast computer algorithms, Arya has provided the first evidence that chromatin does not exist uniquely in solenoid or zigzag forms but rather exhibits a “heteromorphic” structure where both types of structures are in balance with each other. Arya’s collaborators have developed an innovative experimental approach called Electron microscopy assisted nucleosome capture technique to corroborate Arya’s findings.
“What we did was extract the most important features of DNA and the associated proteins in the model, using techniques called coarse-graining,” Arya explained. “You cannot simulate something as large as a chromatin fiber containing tens of nucleosomes at molecular detail for periods of time longer than a few nanoseconds. That will not tell you much. You need to reduce the complexity of the system without sacrificing important details, which is exactly what we have done. We’re trying to reduce the total number of variables in the system by eliminating the variables that are not important at the length and time scales of interest.
“This research emphasizes how engineering tools can provide new insights into biology,” he added.
“When we talk about cancer and its link to abnormal gene regulation, we have to ask the question why are these genes misfiring? In the end, it boils down to the protein machinery that makes up and regulates chromatin,” he explained. “You could have mutations in the oncogenic or tumor suppressor genes that lead to cancer or you could have abnormalities in the proteins that regulate chromatin around these genes leading to cancer.”
The next step for Arya and his team is to study the mechanisms by which chromatin is regulated, and how those lead to genes being switched “on” and “off,” genes being repaired in response to mutations, and genes being replicated during cell division. Arya believes that a molecular-level understanding of such mechanisms could lead to the development of better drugs that will directly target the chromatin around abnormally regulated genes to correct their activity.
“In fact, there are already drugs being developed called HDIs (histone deacetylase inhibitors) that can modulate structure of chromatin around oncogenic genes so as to inhibit cancer progression, though their exact mechanisms are not fully known,” Arya said.
“The scientific community is quite fascinated by DNA and they tend to forget that DNA is rarely present in its naked double-stranded helix form in higher organisms like humans, but that it is always associated with proteins in this complex aggregate we call chromatin,” he added. “Undoubtedly, DNA codes for nearly all the proteins and RNAs manufactured inside our cells but how, when, and which genes are turned on and off is almost completely determined by the structure, dynamics, and chemical properties of chromatin. …We now know how chromatin compacts and what its internal structure looks like. “But we are far from solving the mystery of the mechanisms by which chromatin exercises dynamic control over DNA.”
Journal reference:
Grigoryev et al. Evidence for heteromorphic chromatin fibers from analysis of nucleosome interactions. Proceedings of the National Academy of Sciences, 2009; DOI: 10.1073/pnas.0903280106
By:Barbara Basler | Source: AARP Bulletin Today | – June 6th 2008
From the June 2008 print edition
In the last year and a half alone, scientists have discovered more than 100 genetic variations associated with many of the medical conditions that affect older people, including type 2 diabetes, Alzheimer’s disease, asthma, osteoporosis, high blood pressure and heart disease.
Indeed, genetic science is moving so swiftly that, experts say, people now in their 60s, 70s and even 80s will see medical breakthroughs that will touch their lives.
“What’s happened in just this short period of time is dizzying to contemplate,” says Francis Collins, M.D., the scientist who directed the international Human Genome Project for the National Institutes of Health—and made news around the world.
Just five years ago Collins’ team completed the monumental project—mapping and sequencing all the genetic information encoded in DNA, the “instruction manual” for humans.
Using this astonishing guide, researchers can now compare the genes of groups of people who have a particular condition with groups of people who don’t, surveying the entire genome to find where the genetic differences lie. Such research is vital: Virtually every human ailment, except trauma caused in accidents, has some genetic basis.
The Human Genome Project, experts agree, is a watershed achievement in science.
It was Collins, a guitar-playing, motorcycle-riding geneticist, who brought the project in two years early and under budget. In an interview with the AARP Bulletin, the affable 58-year-old—who will leave his post Aug. 1—talks about the avalanche of information triggered by the genome, particularly in relation to older people.
To see the power and quickness of genomic science, he says, look at age-related macular degeneration, an eye disease that has left nearly 2 million Americans visually impaired.
“We’ve come a huge distance with this disease in the last few years,” Collins says. “Using new genomic tools, we’ve discovered two genes that account for about 60 percent of the risk—the rest is smoking. But we were surprised. These genes are involved in inflammation, and everybody was thinking macular degeneration was caused by aging in the back of the eye.”
Now, doctors are testing for ways to prevent the disease with anti-inflammatory drugs that “have been around for a long time,” Collins says. “Even something as simple as aspirin might have value. This is the best insight into this disease we’ve ever had, and it has completely changed the way we look at it.”
Scientists are optimistic that they’ll find similar breakthroughs for a host of other conditions.
“We knew many common diseases had hereditary links because we knew they tend to run in families,” Collins says. Over the years, scientists have pinpointed some 1,700 genes linked to disease, many of them powerful mutations of single genes. Each variation is responsible for a rare disease, such as Huntington’s, a degenerative brain disease. “But with the genome we are learning the underlying causes at work in complex diseases like diabetes or high blood pressure, which involve many genes, each with a modest effect,” Collins says. “It’s with these more common diseases that we’ve had the recent deluge of discoveries.”
A lanky Virginian, Collins earned a doctorate in chemistry at Yale and his M.D. at the University of North Carolina. He became a dedicated hunter of disease genes as a faculty member at the University of Michigan. Since 1993 he has worked at the epicenter of the genomic revolution, on the leafy NIH campus in Bethesda, Md. The National Human Genome Research Institute is tucked into a suite of beige-colored offices that look more like a dentist’s practice than the headquarters of a world-renowned research center. From here, Collins, who led a team that found the gene for Huntington’s and the gene for cystic fibrosis, oversees 500 scientists on the NIH campus and others at universities.
“Our best hope for curing diseases comes out of genomics,” Collins says, because it points to the problem of disease at the molecular level, rather than at symptoms or secondary effects.
Genomic discoveries are already pointing the way to new drugs that disrupt processes at the molecular level and to tests that predict one’s risk for a disease.
The research is also opening the way for a new “personalized medicine” that allows doctors to test a patient to determine which drugs will work most effectively with the patient’s genetic makeup. Last year the Food and Drug Administration recommended genetic tests for patients taking the blood thinner warfarin (also sold as Coumadin, Jantoven, Marevan and Waran) to help doctors prescribe the right dosages.
Studies show that 40 percent of those who take the drug have genetic variations that make them more sensitive to its effects and so need smaller doses. The genetic test can identify those at risk for bleeding complications from the drug.
“Soon, this kind of testing will be happening for asthma medications, antidepressants and cholesterol-lowering statins,” Collins says. “We should be able to do better with genetic evaluations of these drugs within three to four years.
“And boy, do we need more of this,” says Collins, who in September will be given the Andrus Award, AARP’s highest honor, for his contributions to science.
“Most of the time you go to the doctor, and the drug you’re given is one we arrived at empirically—we tried something and it seemed to work,” he says. “It’s one-size-fits-all medicine, and that’s not ideal. Now, with the genome, we have a whole new paradigm. It’s very exciting.”
Social Links