GoogleNews.com, LA JOLLA, Calif., June 2 (UPI) — U.S. and Spanish scientists say they have proven, in principle, that a human genetic disease can be cured using a combination of gene and stem cell therapy.
The researchers, led by the Salk Institute for Biological Studies, said their achievement has catapulted the field of regenerative medicine significantly forward.
“It’s been 10 years since human stem cells were first cultured in a Petri dish,” Professor Juan-Carlos Izpisua Belmonte of the Center of Regenerative Medicine in Barcelona, Spain, said. “The hope in the field has always been that we’ll be able to correct a disease genetically and then make (induced pluripotent stem cells) that differentiate into the type of tissue where the disease is manifested and bring it to clinic.”
Although several studies have demonstrated the efficacy of the approach in mice, its feasibility in humans had not been established. The researchers said the Salk study offers the first proof that the technology can work in human cells.
“We haven’t cured a human being, but we have cured a cell,” Belmonte said. “In theory we could transplant it into a human and cure the disease.”
The research is reported in the early online edition of the journal Nature.
Image: Juan Carlos Izpisua Belmonte. A colony of the iPS cells created.
GoogleNews.com, DiscoverMagazine.com, June 2, 2009 — Scientists have taken another step in cellular reprogramming that points the way towards the use of a patient’s own cells to treat genetic diseases. In a proof of concept study, researchers took skin cells from patients with a rare condition, Fanconi anemia, which causes skeletal problems and bone-marrow failure, and raises sufferers’ risk of cancer..In the skin cells, the researchers fixed the genetic defects that caused the disease, and then reprogrammed the cells to act like stem cells capable of growing into any type of tissue.
The corrected stem cells could be grown into blood precursor cells for therapy. As these would carry a patient’s own DNA, except for the mutation responsible for the illness, they could be transplanted without risk of rejection by the body’s immune system. However, the patched up cells were not used to treat patients in this study, because it isn’t yet clear whether such cells are safe. Comments molecular geneticist Chris Mathew: “In future it may become possible to transfer the corrected stem cells back into the patient, but much work remains to be done before this can be transferred from the lab bench to the bedside”
Over the past year, such reprogrammed and multipurpose cells known as induced pluripotent stem (iPS) cells have been generated from patients with a wide variety of genetic disorders…. Such disease-specific stem cells offer unprecedented experimental models to investigate disease mechanisms and to screen new drug compounds. But to treat diseases with tailor-made cell therapies, such stem cells first need to be corrected to be disease-free.
In the new study, published in Nature, lead researcher Juan Carlos Izpisua Belmonte and his colleagues first used a lentivirus to deliver genes to the skin cells, which corrected the mutation that caused Fanconi anemia in the three patients. The team then tranformed the skin cells into iPS cells by using retroviruses to introduce four genes known to be active in embryo development, which in effect turned back the clock and made the adult skin cells behave like embryonic stem cells.
The technique isn’t ready for medical trials, researchers stress. “Serious concerns need addressing before attempting any clinical trial with iPS-derived cells; perhaps the most important is that of tumor formation,” says Belmonte. This is because the virally delivered genes used to reprogram the skin cells can remain embedded in the cell’s DNA even after reprogramming. These genes are thought to become active during the cell-differentiation process, considerably raising the long-term risk of cancer. However, just last week another group of researchers announced a new way to reprogram skin cells that doesn’t involve the use of viruses, raising hopes that scientists will find ways to use patients’ own cells to fight their diseases.
TimesOnLine.co.uk, The prospect of treating genetic diseases with corrected stem cells grown from patients’ own bodies has moved closer, after the results of a remarkable experiment.
Scientists have successfully reprogrammed skin tissue from people with a rare form of anaemia to create powerful stem cells, while at the same time rectifying the genetic defect that causes the condition.
The corrected stem cells could be grown into blood precursor cells for therapy. As these would carry a patient’s own DNA, except for the mutation responsible for the illness, they could be transplanted without risk of rejection by the body’s immune system.
Though the research team, from Spain and the United States, has yet to use the cells to treat patients, and several important hurdles still remain, the achievement has been hailed as a significant advance for stem cell research.
It suggests that it should eventually be possible to treat many inherited conditions by making disease-free stem cells from their own bodies.
The experiment offers “proof of concept” that the technique “can be used for the generation of disease-corrected, patient-specific cells with potential value for cell therapy applications,” the researchers write in the journal Nature.
In the study, a team led by Juan Carlos Izpisúa Belmonte, of the Salk Institute in La Jolla, California, took cells from six patients with Fanconi anaemia, a recessive genetic disorder that causes bone marrow failure and leukaemia. It is often fatal unless a bone marrow transplant is available from a perfectly matched donor.
The cells were infected with a genetically modified virus to correct the gene that causes Fanconi anaemia. These were then reprogrammed into an embryo-like state by modifying further genes, to create versatile master cells known as induced pluripotent stem cells (IPS cells).
When these IPS cells were grown in culture, they developed into blood progenitor cells of the sort that are required for transplant in Fanconi anaemia therapies.
As the IPS cells’ DNA had been corrected, they did not have the mutation that causes the disease, but they were otherwise genetically identical to the patients’ own tissue.
The reprogrammed, corrected cells are not yet suitable for transplanting into patients, because it is not yet known whether IPS cells can be safely given to patients.
The reprogramming technique currently relies on modifying genes with a virus, and there are fears that this could promote cancers. Several new reprogramming methods that do not rely on viruses, however, have recently been developed.
“The recent implementation of reprogramming protocols that do not rely on viral integration, if their applicability to human cells was confirmed, would bring the realisation of this possibility closer,” the researchers said.
The combination of reprogramming cells and correcting their DNA could also have potential for treating many other conditions with a genetic component, such as Parkinson’s disease, motor neuron disease and diabetes.
Chris Mathew, Professor of Molecular Genetics at King’s College London, said: “This is an important development for families with this rare, inherited blood disorder. The patients have low numbers of blood stem cells in their bone marrow, so there are very few target cells to correct by gene therapy.
“The new research shows that it is possible to reprogramme skin cells from these patients into stem cells in which the genetic defect has been corrected. In future it may become possible to transfer the corrected stem cells back into the patient, but much work remains to be done.”
Guest post by Nick Lane, author of Life Ascending: The Ten Great Inventions of Evolution
TimesOnline.com/science, June 2, 2009 — When Matt Ridley read Nick Lane’s new book he said “If Charles Darwin sprang from his grave, I would give him this fine book to bring him up to speed.” We asked Nick to write a quick 10-point primer for the father of evolution about our current understanding of the science of life.
“Darwin knew everything and nothing about evolution. Everything, because nobody grasped the priciples of natural selection better than he. Nothing, because almost all of today’s proofs of his theory are written in the languages of genes and molecules that he knew nothing about.
Darwin would be amazed and delighted by the scope and details of our current understanding of life. In Life Ascending: The Ten Great Inventions of Evolution I take life’s most celebrated ‘inventions’, each one of which transfigured our planet, and trace what we know of how they came to be”
Here’s what Nick would tell Darwin: But first a comment from the Target Health Global Blog:
How does evolution explain that sea urchins have the same genes as humans, for sight, smell and sound, and yet sea urchins don’t use these genes in any way?
Target Health Global admires Darwin, a great genius who helped assemble a strong foundation, that we now build on, in a profound way. What’s the point of talking about 21st Century science Darwin didn’t know……just a waste of time. It only makes sense to write about the monumental advances Science has made because of Darwin.
In no way, do we ascribe to intelligent design…..these thoughts and beliefs are fading fast. we do think, however, that if we humans are ever going to approach an understanding of the universe….and where we (everything) really came from, we will have to enhance our brain power to a much higher level, perhaps through genetic engineering plus the addition of computer chips. We are going to have to evolve to a much greater extent, from the primitives we still are. Enter Ray Kurzweil!
Charles Robert Darwin ( 1809 – 1882)
1. The Origin of Life
Darwin famously speculated about life beginning in some warm pond, but recent research has framed a far grander setting – the hydrothermal vents at the bottom of the ocean. One type of vent bubbles hydrogen gas into the oceans, giving rise to a myriad of honeycomb cells with delicate mineral walls. These natural cells replicate spontaneously under the pressure of the vents. What’s more, they concentrate organic molecules, including DNA, up to amazingly high levels, and generate energy across a membrane just as living cells do today. There’s lots to learn, but as a setting for the origin of life, it brooks no equal.
In 1953, Francis Crick and James Watson walked into The Eagle in Cambridge and declared they knew the secret of life – the structure of DNA. It immediately provided the mechanism of heredity so sorely missed by Darwin. But Watson and Crick didn’t know how DNA coded for proteins. The story of the code within the DNA code is one of the best (and least known) scientific detective stories of the 20th century – and it also points to life’s origins in deep sea vents. Most unexpectedly, the detailed mechanism by which DNA is replicated implies that life actually emerged from the vents twice from a common ancestor that lived inside.
Without photosynthesis, life wouldn’t be up to much. It provides us not only with all the food we need to live, but also with the oxygen needed to burn it up to provide our energy. And yet true photosynthesis arose only once in the whole history of evolution – in bacteria that were later captured by algae and plants and put to work. The trick depends on an enzyme that splits water to extract hydrogen, releasing oxygen as waste. The core of the water-splitting enzyme is similar to a mineral in its structure. Knowing how it works at the atomic level could help to solve the energy and climate crises of our planet.
4. The Complex Cell
Complex life, like photosynthesis, arose only once on earth. The differences between plants, animals, fungi and algae suggest that plants arose from one type of bacteria and animals from another, but that’s not what happened. Compared to bacteria, our cells are virtually identical to those of a daffodil: we are in fact closely related. Complex cells arose in an unprecedented merger between bacteria. That vital step was not anticipated by Darwin, who saw organisms as diverging rather than converging. Yet without that improbable chimera, natural selection may never have got beyond bacteria, and none of us would be here.
Sex is absurd. Not only does it cost a small fortune to find a partner, but it transmits horrible venereal diseases and parasitic genes, and randomises all successful combinations of genes. Worse, sex requires males, viewed by implacable feminists and evolutionists alike as a waste of space. So why we all have sex anyway was viewed as the queen of evolutionary problems in the 20th century. An old explanation for the benefits of sexual recombination has risen in a new guise, and helps explain not only why we have so much sex, but also why it got going in the first place in simple cells.
Muscle is the invention that sets us animals apart. Yet the two molecules that make muscles work, the chain-like proteins actin and myosin, are found in all organisms, even those without any muscle. Nothing would have given Darwin more pleasure than the finding that the same molecules that power muscular contraction evolved from simpler forms that propel amoebae around, support plant cells, and help bacteria to divide. Or that they they work by forming a dynamic scaffold in cells in the same way that a variant form of haemoglobin does when it distorts red blood cells in sickle-cell anaemia. Selection fashioned such spontaneous quirks into the might of muscle.
Darwin himself pondered the evolution of ‘organs of extreme perfection’ such as the eye, and it’s been an icon ever since. What use is half an eye, say detractors, yet the eyeless rift shrimp reabsorbs its fully formed larval eyes and replaces them with a naked retina – literally half an eye – as it moves down to the black-smoker vents. We now know how eyes evolved in more detail than any other organ. Surprisingly, it looks as if the critical light-sensitive protein at the centre of it all, rhodopsin, evolved from an ancestor in algae where it is used to calibrate light levels in photosynthesis. Some bacteria even use rhodopsin for a type of photosynthesis.
8. Hot Blood
Hot blooded animals keep their thermostat jammed on hard at 37°C, regardless of need. Many small mammals need to eat as much in a day as a lizard eats in a month, and a serious penalty is smaller populations. One big benefit is stamina, yet dinosaurs like Velociraptor apparently combined stamina with a low resting metabolism. But hot blood may also solve an interesting problem with diets rich in carbon and low in nitrogen, such as leaves. Vegetarians get enough nitrogen from leaves only if they eat a lot and get rid of the excess carbon. We hot bloods just burn it off, and that enables herbivores to survive on a much lower quality diet.
There’s no doubt that consciousness evolved, and that many animals are aware of themselves and their surroundings, perhaps right down to bees. But still there are deep uncertainties about what consciousness actually is. We simply don’t know yet how neurons firing in the brain can generate a feeling of anything. This is what philosophers call the hard problem, and it may be solved by studying the behaviour of animals like bees that apparantly gain neural rewards for finding nectar. I’d tell Darwin that consciousness is the last great challenge for understanding natural selection.
But death is no challenge. Without death, natural selection would count for nothing, and life could never have evolved the majesty of consciousness at all. Yet death benefits individuals, or rather their genes, in some way. Mitochondria, the power-houses inside our cells, hold the key. They generate reactive free radicals that ultimately undermine our health. The problem is that in the short term, free radicals optimise respiration, making us as strong and energetic as we can be when young. Antioxidants disrupt that. So sadly the penalty for vigour in youth is decreptitude in old age. But there’s hope. Birds leak fewer free radicals and live longer than mammals, without losing their vigour. And that means the anti-ageing pill is not a myth.
Another Darwin Movie is in the Works
Oscar-winning producer Jeremy Thomas, and writer John Collee (“Master and Commander”) are working on a movie about Charles Darwin based on the book: “Annie’s Box” written by Darwin’s descendant Randal Keynes. The movie will focus on the relationship between Darwin and his wife and children, especially his first daughter Annie, who died in 1851 at age 10. Randal Keynes said: “I find it a very moving story. I’m so glad they are doing a film because I think it is important and helpful for people to understand Darwin the man and his feelings for his wife and his children. The film will focus on that and it will be good to see Darwin’s life from that point of view.” He added: “Darwin’s experience with his daughter and her death, and his feelings afterwards influenced some of his most important ideas. I wrote the book to explain them to other people.” Thomas expects to start shooting the movie next year on location at Down House. The movie is planned for release in 2009, the bicentennial of Darwin’s birth.
New technologies will soon make it possible to sequence thousands of human genomes. Now comes the hard part: understanding all the data.
MIT Technology Review, by Emily Singer — The 12 prototypes look like prefabricated children’s forts–boxes the size of freezers, faced with bright red plastic and grouped in twos and threes on a concrete floor at Pacific Biosciences, a startup in Menlo Park, CA. But the simple exterior of the machines belies the complexity within. Each box houses a small chip packed with thousands of strands of DNA from bacteria or viruses, each strand in a nano-sized well. An enzyme stuck to the bottom of each well speedily builds a corresponding strand, stringing together the bases, or chemical subunits of DNA, that pair properly with those of the original. Each of the four types of bases, represented by the letters A, T, C, and G, is labeled with a different fluorescent marker, which is activated by the reaction that attaches a new base to the strand. Because the machine tracks the reactions as they happen, it can churn out reams of raw data on the sequences of the DNA samples as fast as a built-in camera can record them.
A computer monitor installed next to each machine displays a snapshot of the action taking place. A series of lights scatter across the screen, bursting and fading in quick succession. Each flash lasts just tens of milliseconds, but its color indicates which of the four bases has just been added to a strand of DNA, and its position indicates where. The video must be slowed for viewing: the flashes come too fast for the human eye to process. Computer algorithms convert the pattern of flashes into DNA sequences hundreds to thousands of bases long. Additional algorithms then compare millions of these stretches of DNA, identify sequences that overlap at their ends, and fit the pieces together to capture a complete genome.
When it comes to sequencing DNA, time is money, and Pacific Biosciences’ commercial machines, due out in 2010, could prove to be the fastest ever made. It took the Human Genome Project roughly $300 million and 13 years to work out the sequence of the three billion DNA base pairs in a composite human genome, a task completed in 2003. By October 2008, researchers using a variety of new types of machines were saying that they could sequence an individual genome for less than $100,000; one company promises a $5,000 genome by next spring. And Pacific Biosciences predicts that by 2013, its machines will be able to sequence a person’s genome in 15 minutes, for less than $1,000.
Up to now, scientists have sequenced the genomes of a handful of people, and that’s given them a general sense of human variability. But fast, cheap sequencing technology could make it practical to read the genomes of thousands, perhaps millions, of people. By combing through those myriad genomes and linking specific DNA sequences to different characteristics–handedness, height, blood pressure, and susceptibility to anxiety, to name a few–scientists should be able to unravel the complex interplay of genetic variants that makes each individual unique. Most important, that kind of sequencing capacity might finally reveal the inherited basis of common diseases–a riddle that has been taunting geneticists for decades.
The actual impact on medicine, however, is far less certain and may be much less positive. For almost two decades, researchers have promised that advances in sequencing technology will enable doctors to practice personalized medicine, targeting treatments to patients on the basis of their genetic profiles. The assumption was that a limited number of common genetic variants would turn out to underlie a particular disease, and physicians would be able to prescribe drugs according to which variants their patients carried. But the latest data suggest that even the most common heritable illnesses, such as diabetes and heart disease, are linked to many different variants, each of them relatively rare. If that’s true, then practicing personalized medicine could become very complicated–and very expensive. “It would not be good to have a $5,000 genome and a $500,000 analysis,” says Francis Collins, the former director of the National Human Genome Research Institute and a leader of the Human Genome Project.
Beyond Common Variations
Genomic medicine began in earnest in the 1980s, when scientists identified genes linked to diseases such as Duchenne muscular dystrophy and cystic fibrosis. Both are so-called Mendelian diseases, meaning that they’re caused by mutations in a single gene; anyone who inherits either one or two copies of the mutated gene, depending on the disease, will be afflicted. Over the last 20 years, researchers have identified genes for a number of Mendelian disorders, and screening tests based on these discoveries have led to earlier diagnoses. In the case of disorders that develop only when a person inherits two copies of the mutation, the tests can identify healthy carriers, helping them make better-informed decisions about having children. Single-gene disorders, however, make up a very small percentage of human diseases. For most diseases, it’s much harder to pinpoint the genetic culprits.
As scientists began assembling a rough draft of the genome sequence in the late 1990s, they uncovered a useful phenomenon. Large blocks of DNA, known as haplotype blocks, tended to be passed down intact through generations. Different versions of these blocks, which were linked to an individual’s ancestral origins, had characteristic patterns of common genetic variations known as single-nucleotide polymorphisms (SNPs), in which the genetic sequence varies by just one DNA letter. Thus, a telltale SNP could serve as a marker for its surrounding DNA. The discovery was a boon to geneticists–if each block tended to occur in a limited number of varieties within the human population, it would be unnecessary to check every base in the genome for variations linked to common diseases such as asthma or schizophrenia. The presence of a particular SNP would indicate which haplotype block an individual carried.
Researchers developed genetic microarrays that could quickly detect the presence of these common SNPs throughout the genome; by scanning for the telltale variations, a relatively inexpensive process, the microarrays have enabled the largest genomic studies to date. Scientists have used them to efficiently search tens of thousands of human genomes for SNPs more common in people with autism or Alzheimer’s, for example, than in healthy people. Over the last two years, a flood of studies have been published, identifying more than 300 genetic variations linked to an assortment of common traits and diseases.
But finding these variations has not led to the breakthrough that some scientists had hoped for in understanding the genetic basis of common diseases. That’s because they turn out to account for only a small fraction of the genetic risk for many illnesses. Researchers have identified 18 genes linked to type 2 diabetes, for example, and tests to identify the variations have been introduced. Yet many other heritable risk factors for the disease remain unidentified. That means that the new tests give an incomplete picture of how likely someone is to develop diabetes, making it difficult to use them to tailor medical decisions. “There is very little reason to be encouraged that prevention strategies can be revolutionized with what we’ve discovered so far [on the genetic basis of common diseases],” says David Goldstein, director of the Center for Population Genomics and Pharmacogeneticsat Duke University in Durham, NC.
The hunt for SNPs makes sense if the inherited risk for diseases like type 2 diabetes results from a combination of many common genetic variations, each exerting a small effect. But what if that is only part of the story? What if other, rarer types of genetic mutations are also playing a role? Because microarrays were designed to detect common SNPs, they miss variations that appear in less than 1 percent of the population. These mutations are the focus of an alternative hypothesis, in which–as in the Mendelian model–high-impact individual variations contribute heavily to a disease. Any one of the variations may occur infrequently, according to this thinking, but if they affect the same or related biochemical pathways, they may produce similar outcomes. Collectively, they could make a disorder relatively common.
Until recently, only limited efforts had been made to search for rare variants linked to common diseases. This search may involve sifting through every letter of DNA–something that can only be done by sequencing. With the old technology, that was too expensive to be practical. But in view of the disappointing results from microarray studies, scientists are turning to the fast new sequencing technologies to rigorously test the rare-variant hypothesis. It’s likely that “much of the rest of the heritability [of disease] is hiding in rare variants with high impact,” Collins says. “If we really want to understand the genomics of disease, we need complete genome sequences.”
It’s still unclear how much rare variations contribute to disease, but evidence is starting to trickle in. In a study published this summer, biologists at the University of California, Berkeley, sequenced the gene for an enzyme called MTHFR, which converts the B vitamin folate (folic acid) from one form into another. Scientists had previously identified a common genetic variant that produces a weakened version of the enzyme, increasing the risk of birth defects and possibly of heart disease. By sequencing the MTHFR gene in 564 people of different ethnicities, Nick Marini and colleagues found four new variants that also impair the enzyme’s function; present in fewer than 1 percent of the subjects, these variants would have been undetectable in microarray studies.
The Personal Genome
At a recent conference at the venerable Cold Spring Harbor Laboratory on Long Island, James Watson, codiscoverer of the structure of DNA, sat slouched in the front row of the auditorium beneath a large portrait of himself. Watson, who for a time headed the Human Genome Project, had his genome sequenced in 2007. His was only the second individual genome to be completely mapped. (Craig Venter, who led the private effort to sequence the genome, used his own DNA as the sample.)
Watson isn’t known for sitting through successive conference presentations. But a good portion of this conference was about him. He attended talk after talk, as scientists presented their analyses of what has become affectionately known as “Project Jim.” Watson is a seemingly healthy 80-year-old man, and the results of scrutinizing his genome have so far been fairly mundane. He has extra copies of genetic variations shown in previous studies to protect against heart disease and macular degeneration, for example. An initially worrying mutation in the BRCA1 gene, which is linked to breast cancer, turned out to be harmless. But the vast majority of Watson’s genome remains uninterpretable. Scientists have yet to find a genetic component to his intelligence or his curiosity or his tendency toward politically incorrect outbursts. Perhaps most important to Watson, it’s not yet clear whether he harbors a genetic vulnerability to schizophrenia that he passed along to his son, who has the disease.
The Human Genome Project’s reference sequence, which is a composite of genetic information from more than 20 individuals, gave scientists a basic blueprint of the genome. But a single genome has its limits. It’s only by comparing multiple genomes that scientists can begin to get a handle on the genetic variability that underlies the vulnerability to disease or madness, the tendency to athletic prowess or mathematical genius, the drive toward altruism or aggression.
Even Watson, who has spent his career trying to understand DNA, seems less than impressed to see the details of his genome presented. “We’ll see if any of it adds five minutes to my life span,” he remarked at the conference. Indeed, the meaning of most of his genetic quirks will remain a mystery until many more people join him in having their genomes sequenced.
Harvard Medical School geneticist George Church, who has been working on sequencing technology since his PhD research at Harvard in the early 1980s, aims to speed that process along. Three years ago Church launched the Personal Genome Project (PGP), which aims to collect genetic and medical data from thousands of people over the next five years. The project indicates not just the technical and scientific challenges that might be posed by large-scale sequencing of human genomes, but the ethical issues as well.
In the pilot phase, the project will focus on 10 volunteers, including Church, Harvard psychologist Steven Pinker, and entrepreneur Esther Dyson. To start, it will sequence the coding regions of their genomes–the 1 percent of DNA that directs the production of proteins. That information, along with the participants’ medical histories (including prescription regimens) and information about their height, weight, handedness, and other traits, will be deposited in a public database. Church’s team hopes that this database will serve as a resource for scientists, or even members of the public, who want to search for links between specific genetic variations and diseases or other traits.
The first set of data–released to participants in October–hints at both the promise of sequencing and the current limitations of genetic analysis. John Halamka, CIO of Harvard Medical School and another one of the 10 original volunteers, learned that he carries a mutation for Charcot Marie-Tooth disease, an inherited neurological disorder. This rare variation would not have been found with existing SNP arrays. But since Halamka survived childhood unscathed, and only three other people in the world have been shown to carry that particular mutation, it’s hard to know what impact, if any, it has had on his health. Perhaps many people carry the variation with no ill effect, and the link between the disease and the mutation has been overstated. Or perhaps the gene has a broader impact than expected, raising the risk of other neurological diseases. (Or, as George Church notes, the finding may simply be an error.)
The greater the number of entries in the database, the easier it will be to understand a finding like Halamka’s. And in April 2008, Church’s team received approval from Harvard to expand the project from 10 to 100,000 participants. (Church plans to scale up slowly, multiplying the number of subjects by 10 each year.) This next phase will seriously test both the technology used to sequence the genomes and the strategies used to interpret the resulting data. As of November, about a year into the project, PGP scientists had gotten only about a fifth of the way through sequencing the coding regions of the original volunteers’ genomes. (Church plans to expand the PGP to the entire genome once sequencing becomes cheap enough.) If they’re to sequence thousands more genomes, sequencing technology will need to become as fast and robust as Church believes it can be.
Too Much Information
Making use of the data from the PGP will pose problems of its own. First, Church and his team will need to figure out the best way to give the larger group of volunteers their results. The first 10 received one-on-one genetic counseling from Joseph Thakuria, the project’s medical director and a clinical geneticist at Harvard Medical School. But Thakuria won’t be able to counsel the thousands of new subjects. Given the shortage of geneticists and genetic counselors with appropriate training, that problem is almost certain to be echoed much more broadly as personal genomics becomes more accessible.
But the greatest challenge in the next phase of human genomics is likely to be interpreting the meaning of the seemingly endless array of variations that will be uncovered. Individual genetic changes occur by chance, and some are harmless. Others happen to be dangerous, disrupting some vital cellular process and raising the risk of disease. And some may even be beneficial–enhancing the breakdown of toxins, for example, and thus protecting against certain ailments. But it’s often impossible to tell which class a variation falls into just by looking at it. And as new technologies allow scientists to sequence the genomes of large numbers of people, the list of known variants will quickly grow. “This information is going to be thorny and problematic in terms of interpretation,” says James Evans, a professor of genetics and medicine at the University of North Carolina at Chapel Hill. “We all have mutations and alterations that we simply don’t understand. As usual, the technology will be ahead of our ability to use it.”
The complexity of the new genomic information may also be an obstacle to the personalized medicine that gene sequencing was supposed to usher in. Researchers have hoped to create tests that predict an individual’s risk for a specific disease or reveal which drug is likely to work best for him or her. But genetic tests that detect newly discovered variations won’t be very useful until scientists can figure out what those variations mean. And if many common diseases are caused by rare variants, the task will be enormous. “Understanding risk based on rare variants is going to take us years,” says Dietrich Stephan, founder and chief science officer of Navigenics, a personal-genomics startup.
Some scientists think that the real value of genomics may not lie in personalized medicine at all. Where it will really pay off, they say, will be in deepening our understanding of disease and helping researchers discover new targets for drugs. “The primary value of genetic mapping is not risk prediction, but providing novel insights about mechanisms of disease,” wrote David Altshuler, a physician and geneticist at the Broad Institute in Cambridge, MA, in a recent article published in the journal Science. In fact, Altshuler points out, identifying even rare genetic changes can end up helping a large number of patients. For example, studies of an inherited form of high cholesterol found in less than 0.2 percent of the population led to the discovery of the low-density lipoprotein (LDL) receptor, which helps to remove excess cholesterol from the bloodstream. That in turn led to the development of the blockbuster drugs known as statins, cholesterol-lowering medications that trigger an increase in the number of LDL receptors on the surfaces of liver cells.
No one knows when the next blockbuster will arrive. Making predictions about the benefits of genomics has become as thankless as trying to predict disease risk itself. And the easier it gets to sequence a genome, the harder it becomes to make sense of the complexity the sequences reveal. As Francis Collins puts it, “The Human Genome Project was perhaps a simple undertaking compared to what we face next.”
A small population of glioma-initiating cells (green cells in
the large circle) arises from a small area of the adult brain
(marked by a circle) that harbors neural stem cells.
(Credit: Image courtesy of University of Michigan Health System)
University of Michigan Health System (2009, June 1). Most Common Brain Cancer May Originate In Neural Stem Cells. ScienceDaily.com – University of Michigan scientists have found that a deficiency in a key tumor suppressor gene in the brain leads to the most common type of adult brain cancer. The study, conducted in mice that mimic human cancer, points the way to more effective future treatments and a way to screen for the disease early.
Appearing June 2 in Cancer Cell, the U-M team’s findings in mice show for the first time that:
- Glioblastoma, the type of cancer that afflicts U.S. Sen. Edward Kennedy and is diagnosed in about 10,000 Americans each year, may originate in neural stem cells located in a brain region known as the subventricular zone, or SVZ.
- In mice, neural stem cells that normally live in this niche give rise to more specialized nerve cells that migrate out of the niche. Cancer could begin with a single genetic mutation in the p53 gene, which makes stem cells migrate out of the niche like their specialized progenies.
Much research on cancer has focused on the p53 gene, known as the “guardian of the genome” because it initiates a wave of other gene actions that normally thwart cancer.
The finding of a specific zone of origin could lead to treatments that may improve the dire median survival rate of 12 months for this type of brain cancer, says Yuan Zhu, Ph.D., the study’s senior author and assistant professor in the departments of internal medicine and cell and developmental biology at the U-M Medical School.
“We have to pay more attention to the stem cell niche” in both early detection and treatment, says Zhu. If glioblastoma originates in neural stem cells in the subventricular zone in humans as it does in mice, the study suggests that doctors need to direct treatments there, as well as to the tumor, to eliminate the source of the cancer and keep it from returning, Zhu says.
The findings in mice also may lead in time to effective early screening tests for glioblastoma. The U-M scientists show that the expression of mutant p53 protein is a marker for glioma cells in all stages of the disease.
“Now, if we believe that the SVZ is the location of the cells of origin, with enhanced resolution we could detect tumor cells there,” says Zhu. If it’s possible to detect the disease early, the chances of treatment success should improve.
The link between neural stem cells and this aggressive type of cancer is a warning sign for scientists to proceed carefully with new treatments for neurodegenerative diseases such as Parkinson’s disease, where the hope is to use neural stem cells to help regenerate lost nerve function, says Zhu.
“Our results in mice show that these neural stem cells in the brain have high potential to accumulate genetic lesions and to become a cellular target for cancerous cells,” he says. ” To some degree, the cancerous cells in early stages are not much different from normal stem cells, but aberrantly combine the key features of neural stem cells (self-renewal) and specialized progenies (migration). We have to understand these stem cells more extensively before we can harness them to treat disease.”
Glioblastoma, also called glioblastoma multiforme, is notoriously hard to treat. It returns in most cases despite virtually all current therapies, which include surgery, radiation and chemotherapy. Survival rates have not improved for two decades, a fact that the new insights into p53 may help explain.
The results found in mice add specific new insights to an unfolding picture of how genes go awry to result in brain cancer. Scientists recently learned that certain genes and pathways of cell action are altered in glioblastoma. One of these key alterations involves mutations in genes that are players in the p53 pathway. But until now, scientists have not known what cell type initiates the cancer, or precisely how a deficiency in p53-mediated pathways works with other mutations to transform brain cells into cancerous ones.
In the last six years, studies have shown that stem cell-like cells are involved in a number of cancers, including glioblastoma. But the new study specifically reveals that glioblastoma begins in neural stem cells that have a p53 mutation. These cells then give rise to mutated, fast-multiplying cells down the line of cell differentiation – a class called transit-amplifying progenitor cells.
“We found that the cells with p53 mutations are highly plastic. If a treatment blocks one path of action, they may learn other ways to grow,” Zhu says. That helps explain why glioblastoma multiforme returns in drug-resistant forms.
Zhu’s team conducted a series of experiments using mice engineered to have a p53 mutation in the central nervous system. They found that a majority developed malignant brain tumors, and that a mutant form of p53 was present in the tumor cells, a phenomenon that is commonly found in human glioblastoma.
“Then we asked, does mutant p53 have any role in tumor initiation and progression? If so, we can use this as a marker for brain cancer in brain cells,” says Yuan Wang, the study’s first author and a U-M Ph.D. student in cell and developmental biology. The team found that mutant p53 was detectable in a minority of highly proliferative neural stem cells of p53-deficient mice two months after birth, and that the expansion of the mutant-p53-expressing cell population with features of transit-amplifying cells underlies the tumor initiation. The evidence supports the idea that mutant p53 can be a useful marker to trace the glioma cells at all stages.
Before any treatments based on these discoveries can benefit people, scientists will need to do more animal studies and verify the animal findings in human studies.
Zhu and his team plan to continue experiments in mice to see if p53 function can be restored in tumor cells. They are also examining whether inhibiting neural stem cells in the SVZ has promise as a potential therapy. Given the plasticity of these cancer-initiating cells, targeting a single signaling pathway may not be sufficient, says Zhu. This trait adds to the complexity of cancer therapy.
Besides Zhu and Wang, other authors are Jiong Yang, Huarui Zheng, Gerald J. Tomasek, Peng Zhang, U-M Department of Internal Medicine, Division of Molecular Medicine and Genetics and Department of Cell and Developmental Biology; Paul E. McKeever, U-M Department of Pathology; and Eva Y-H. P. Lee, University of California, Irvine.
Citation: Cancer Cell, June 2, 2009 Ref: CC-D-08-00286R5
Funding was provided by the National Institutes of Health.
Adapted from materials provided by University of Michigan Health System.
Sea Urchins’ Genetics Add To Knowledge Of Cancer, Alzheimer’s And Infertility
University of Central Florida – Researchers are using sea urchins to study and understand diseases like cancer, Alzheimer’s disease, Parkinson’s disease and muscular dystrophy. Although they are invertebrates, the creatures share a common ancestor with humans and have more than 7,000 of the same genes. With a complete map of their DNA, scientists can learn how to treat and prevent diseases in humans better.
They’re small, spiky and spineless. But what do prehistoric sea urchins have in common with humans? Uncovering their mysteries may help solve some of science’s most difficult and deadly problems.”At a genetic level, they’re actually related to us. So sea urchins and humans share a common ancestor,” Cristina Calestani, a developmental geneticist at University of Central Florida in Orlando, says….Even though they don’t look like us.
Sea urchins and humans share more than 7,000 genes, and biologists are now using these sea creatures to unlock the mysteries of human diseases. In fact, there are several genes in the sea urchin involving Alzheimer’s, Parkinson’s disease, muscular dystrophy and many other cancer-related genes. And infertility may be another problem the sea urchin helps solve.
No wonder — each urchin can produce 20 million eggs.
When you compare the human and sea urchin genes, quite a few of the amino acid sequences are a perfect match.
“You really need a relatively simple system in order to study … but still, also you want it to be complex enough and closer enough to vertebrates in order to use this information,” Calestani says.
Sea urchins are one of the few invertebrates on our branch of the evolutionary tree, sharing more genes with humans than fruit flies and worms — and can be reproduced for research faster than other animals. Calestani says that means researchers can produce large amounts, practically unlimited amounts of material. And with a complete map of the urchin’s DNA, they can better understand how genes work, so when diseases like cancer strike, maybe someday doctors will know exactly how to treat and even prevent them.
Another fascinating (and profound) fact is sea urchins don’t have eyes, ears or a nose, but they have the genes humans have for vision, hearing and smelling.
BACKGROUND: Sea urchins might not seem to have much in common with human beings, since they are small and spiny, have no eyes, and eat only kelp and algae. But scientists with the Sea Urchin Genome Sequencing Project, funded by the National Institutes of Health, recently completed sequencing of the genome. They found that the sea urchin genome is very similar to that of humans, and may hold the key to preventing and curing several human diseases.
ABOUT SEA URCHINS: Sea urchins are echinoderms, marine animals that originated more than 540 million years ago. Sea urchin “roe” (actually the gonads that produce the creature’s roe) are popular in Korean and Japanese cuisine, and is also a traditional food in Chile. Beyond their culinary attractions, sea urchins are known for strong immune systems and long life spans; some can live up to 100 years The project scientists are especially interested in how the sea urchin’s immune system works. Humans are born with innate immunity and also acquire additional immunities over time, as the body produces antibodies in response to infections. Sea urchins only have innate immunity, with 10 to 20 times as many such genes than humans. The hope is that studying sea urchins will provide a new set of antibiotic and antiviral compounds to fight various infectious diseases.
WHAT IS A GENOME? A genome is all of the DNA found in an organism, including its genes and DNA that does not contribute to genes. Every animal and plant has its own unique genome. Genetic DNA carries information for making the proteins required to sustain a living organism. The genome of the purple sea urchin is comprised of 814 million “letters” that code for 23,300 genes. Of those, it has 7,000 genes in common with humans, including genes associated with Parkinson’s, Alzheimer’s, and Huntington’s diseases, as well as muscular dystrophy. Despite having no eyes, nose, or ears, the creature has genes involved in vision, hearing and smell in humans.
Examples of Humans With Sea Urchin Genes
Why is no one brave enough to stand up to the fishing industry?
By George Monbiot. Published in the Guardian, 2nd June 2009
I live a few miles from Cardigan Bay. Whenever I can get away, I take my kayak down to the beach and launch it through the waves. Often I take a handline with me, in the hope of catching some mackeral or pollock. On the water, sometimes five kilometres from the coast, surrounded by gannets and shearwaters, I feel closer to nature than at any other time.
Last year I was returning to shore through a lumpy sea. I was 200 metres from the beach and beginning to worry about the size of the breakers when I heard a great whoosh behind me. Sure that a wave was about to crash over my head, I ducked. But nothing happened. I turned round. Right under my paddle a hooked grey fin emerged. It disappeared. A moment later a bull bottlenose dolphin exploded from the water, almost over my head. As he curved through the air, we made eye contact. If there is one image that will stay with me for the rest of my life, it is of that sleek gentle monster, watching me with his wise little eye as he flew past my head. I have never experienced a greater thrill, even when I first saw an osprey flying up the Dyfi estuary with a flounder in its talons.
The Cardigan Bay dolphins are one of the only two substantial resident populations left in British seas. It is partly for their sake that most of the coastal waters of the bay are classified as special areas of conservation (SACs). This grants them the strictest protection available under EU law. The purpose of SACs is to prevent “the deterioration of natural habitats … as well as disturbance of the species for which the areas have been designated”(1).
That looks pretty straightforward, doesn’t it? The bay is strictly protected. It can’t be damaged, and the dolphins and other rare marine life can’t be disturbed. So why the heck has a fleet of scallop dredgers been allowed to rip it to pieces?
Until this Sunday, when the season closed, 45 boats were raking the bay, including places within the SACs, with steel hooks and chain mats. The dredges destroy everything: all the sessile life of the seabed, the fish that take refuge in the sand; the spawn they lay there, reefs, boulder fields, marine archaeology – any feature that harbours life. In some cases they penetrate the seafloor to a depth of three feet. It is ploughed, levelled and reduced to desert. It will take at least 30 years for parts of the ecosystem to recover; but the structure of the seabed is destroyed forever. The noise of the dredges pounding and grinding over the stones could scarcely be better calculated to disturb the dolphins.
The boats are not resident here. They move around the coastline trashing one habitat after another. They will fish until there is nothing left to destroy then move to the next functioning ecosystem. If, in a few decades, the scallops here recover, they’ll return to tear this place up again.
The economic damage caused by these 45 boats is far greater than the money they make. They wreck all the other fisheries; not only because they destroy the habitats and kill the juvenile fish, but also because they rip out the crab and lobster pots they cross. We deplore slash and burn farming in the rainforests for its short-termism and disproportionate destruction. But this is just as bad.
Ever since the boats arrived, local people, led by the Friends of Cardigan Bay, have been campaigning to stop this pillage. After months of dithering, in March the Countryside Council for Wales advised the regional fisheries committee to stop the dredging. The committee’s chief executive refused on the grounds that its powers “are not terrifically explicit” and “the precautionary principle is a vague term, and we don’t really know how we define it.”(2) He postponed any decision until June 12th – which is a fortnight after the season ended. In 24 years of journalism I have not come across a starker example of bureaucratic cowardice.
What hold does the fishing industry have over our ministers and officials? Does it sink the bodies of their political opponents? Does it supply them with call girls and cocaine? The UK fishing sector has an annual turnover of £570m a year(3). This is less than half the size of the potato processing industry(4). Yet no one has the guts to defy it.
The story is the same all over the world. Next week, on June 8th, The End of the Line will be released in UK cinemas(5). It’s an excoriating, shocking film about the collapse of global fisheries, and the utter uselessness of the people who are supposed to protect them. It follows the journalist Charles Clover as he struggles to understand why no one is prepared to act. After several years of trying, he talks to the manager of Nobu restaurants, to ask why he is still selling meat from one of the most endangered species on earth, the bluefin tuna. The man refuses to take it off the menu, but says he’ll warn his customers that bluefin is “environmentally challenged”(6). But why is it left to restauranteurs to decide whether or not an endangered species should be allowed to survive?
As the film shows, the EU’s scientists recommend a bluefin catch one and a half times as big as it should be; the European Commission then doubles it and the fishermen then take twice as much as the Commission allows. The Mediterranean fleet now catches one third of that sea’s entire bluefin tuna population every year: at current catch rates, it will be extinct by 2012(7). There’s a total absence of enforcement, as even the most blatant illegal practices, like using spotter planes to find the shoals, are ignored by fisheries officials. Worse still, these pirate boats are subsidised by us. Aside from payments by national governments, fishing fleets in Europe are being given E3.8bn of EU money over seven years(8). There has been a total failure to make these payments conditional on fishing sustainably or even legally.
The EU now recognises that its fisheries management has been a disaster. Its green paper admits that 88% of European fish stocks are overexploited and 30% have collapsed(9). Its quota system encourages the dumping of millions of tonnes of dead fish at sea, while its efforts to reduce the fishing fleet’s capacity haven’t kept pace with technology. “In several Member States,” the paper reports, “the cost of fishing to the public budgets exceeds the total value of the catches.”(10) Last week, European fisheries ministers agreed a radical reform of the Common Fisheries policy by 2012, just in time for the extinction of the bluefin tuna.
Of course, as I have seen in Cardigan Bay, it doesn’t matter what they say they’ll do if no one is prepared to enforce it. Our marine ecosystems will continue to be ripped apart until governments stand up to the mysterious power of the fishermen.
George Joshua Richard Monbiot is a British journalist, columnist, author, academic, and environmental and political activist. Now based in Wales, he writes a weekly column for The Guardian newspaper. Several of his books have been best sellers.