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© 2011, 2012 Health Futures Digest
| The cost of sequencing an entire human genome was US$800 million in 2003, $20 million in early 2005, $1-2 million today, and may soon reach $20,000. (In the July issue we reported that a $5,000 whole genome sequence could be possible in 2007.) However, the full benefits of sequencing an entire genome will not be realized until we know every gene’s function. Europe is embarking on a project to do just that.
Even when that is completed, the task will barely have begun of unraveling the complexity of the genome multiplied by the proteome multiplied by a new factor, the epigenome. It seems Lamarck was not entirely wrong in proposing that acquired traits are inheritable, and the recent discovery not only that the environment and other factors can influence an individual’s genes but also that the genetic change can be passed on to offspring must now be factored into the Darwinian/Mendelian Modern Synthesis. Epigenomics requires, and is getting, its own Human Genome Project-like Human Epigenome Project. While such megaprojects take the combined resources of university, government, and corporate labs around the world, some democratization of research can be discerned in the discovery by a small community-based clinic of the genetic causes of several diseases, using gene chips (“labs-on-a-chip”) that give small clinics the equivalent of an enormously expensive high-end genetics lab. Gene chips have also helped identify a key skin cancer gene, and that is just the foot in a door the technology is about to force wide open. Given the massive arsenal of weapons such as gene chips arrayed against it, cancer is losing the war. One expert anticipates genetically engineered cancer vaccines to become “blockbusters” within a decade. The combinatorial complexity of genomes, proteomes, and epigenomes does not deter systems biologists, who aim to create a complete, functioning, virtual E. coli from the (digital) molecule up, genome and all. The project is visionary enough to recognize explicitly that it is only conceivable in the context of accelerating power in computing, and will only be do-able if Moore’s Law holds. It reminds us of the digital neocortical column project reported in our last issue, of which we now have a small update. Our ability to create new lifeforms (real as well as virtual) via systems biology, genetic engineering, and synthetic biology (creating new life from old, using genes from multiple organisms) has so far escaped serious ethical scrutiny and public interest. That may be OK as long as the new lifeforms are beneficent. The trend to “personalized medicine” gathers steam with the introduction of pharmacogenomic tests of an individual’s likely receptivity to specific drugs. Further impetus to the trend may soon be provided by a handheld lab (yet another “tricorder” candidate) that enables doctors to test patients for genetic predisposition to disease. If ever there was a time to talk about “new paradigms” in medicine, this is one of them; especially when you add the therapeutic potential of “RNA interference” to the diagnostic potential of pharmacogenomics. RNAi’s extraordinary potential is beginning to be realized barely six years since it was mooted only as a remote possibility. The potential of genetic therapies is illustrated by the curing of mice of a disease that blinds 1 in 5,000 boys. One more gene-related note: If Alzheimer’s could be cured or at least easily contained, the boomer-driven healthcare cost explosion could be mitigated to some extent. A gene therapy on trial in Chicago offers hope that the disease can be contained. |
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| Cheaper Sequencers
Hard on the heels of a potentially far cheaper and quicker way of decoding DNA, invented by a company called 454 Life Sciences, Harvard Medical School researchers have invented another, similar, method, reports the New York Times. Either method could put “essentially … the equivalent of a $50 million genome-sequencing center on the desk of every researcher and physician.” Both methods involve loading the DNA fragments to be sequenced onto ultrasmall beads then visualizing the sequence of each fragment through reactions that cause the beads to light up. 454 Life Sciences’ equipment costs US$500,000, far less than the $50 million cost of a conventional sequencing center, but considerably more than the Harvard machine, which uses off-the-shelf instrumentation and reagents and whose most expensive component is a $140,000, computer-controlled digital microscope that many labs already possess. Harvard says its method is more accurate and far cheaper. 454 Life Sciences claims its machines can sequence novel genomes whereas the Harvard method can only find variations in a genome of known sequence. The Times estimates it cost about $800 million for the Human Genome Project to sequence the first human genome in 2003. Using the same method, it would now cost around $20 million. The two new methods bring the cost down to $1-2 million, and could get it down to $20,000, and possibly to the Holy Grail of $1,000, in the future. The European Union will spend US$16 million to test the function of almost every gene in the 25,000-gene mouse genome. The project will generate 20,000 mutations in mouse embryonic stem cells and make them available to researchers worldwide to study their function. The project will use “gene trapping” and “gene targeting” to randomly mutate genes in live mice by inserting a DNA element into the gene to “knock it out” and identify where it has been knocked out from, and to disrupt genes in specific locations. A similar project — the Knockout Mouse Project — has been proposed in the US. “A new world is opening up, one that is so much more complex than the genomic world,” said a Canadian epigeneticist of his new field — epigenetics, the study of biochemical reactions that turn genes on and off, of the processes involved in the unfolding development of an organism, of inheritable changes in gene function that occur without a change in the sequence of nuclear DNA. It includes the study of how a parent’s environment can affect the way genes are expressed in children. “Epigenetics is one of the fastest-moving areas of science, period,” said another, both quoted in a Wired article. Epigenetics helps explain why “identical” twins are not, and why the children and even grandchildren of women who suffered malnutrition during pregnancy are likely to weigh less at birth. It may help explain whether parents’ socioeconomic status has an impact on future generations. It also helps explain — and may therefore help predict — some human cancers and other diseases from the effect of the environment. Recent studies have shown that an individual’s epigenome changes in response to the environment, that those changes can be passed from parents to children, and that some cancers follow from the deactivation of tumor-suppression genes. Last year, notes Wired, the US Food and Drug Administration approved the first epigenetic drug, azacitidine, which treats a form of leukemia by reactivating those genes. Scientists need a large-scale map that shows how epigenetic patterns relate to disease, which would enable them to predict which individuals are more at risk, how to reduce their risk through changes in diet and environment, and how they are likely to respond to drugs. One major difficulty is that the map would need to be dynamic, since the epigenome itself changes over time in response to various factors. Adding to the difficulty is the fact that the epigenome differs in every one of some 200 or so major cell types. The task would seem to call for a major concerted effort, like the Human Genome Project, but without all the patent nonsense that bedeviled that effort. And in Europe, that is what it has got, in the form of the Human Epigenome Project, a massive private-public consortium. The epigenomic map unfolding from this project is free and available to anyone, though it is to date “well under 1 percent finished.” Acceleration in Genetic Discoveries A tiny, non-profit, community-based Clinic for Special Children has discovered the genetic causes of more than a half dozen diseases in the past 12 months using Affymetrix GeneChip(R) microarrays. The small non-profit focuses on research into rare pediatric genetic diseases among the Amish and other relatively closed communities in the Plains area of Pennsylvania. Their discoveries have wider relevance. For example, one disease-causing genetic mutation they discovered among the Pennsylvanians turned out to be the identical one that causes Salla disease in the Finnish population. Physicians can now diagnose Salla disease simply by testing for the mutation in symptomatic patients. Among other discoveries are some relating to Cortical Dysplasia and Focal Epilepsy, “Pretzel” syndrome, Down Syndrome, Patau Syndrome, and Sudden Infant Death with Dysgenesis of the Testes (SIDDT). Taking advantage of gene chips able to analyze thousands of genes at once, British scientists have identified the gene primarily responsible for basal cell carcinoma, a common form of non-melanoma skin cancer. Lead researcher Professor David Kelsell told BBC News the gene chips were a “vast improvement on previous technologies, which could not pick up certain differences”. Identifying genes contributing to cancer should lead to better treatments. Gene therapy can cause cancer, but can probably cure it as well, writes Carl June, director of translational research at the Abramson Cancer Center at the University of Pennsylvania, in The Scientist. Evidence of the latter can be seen in Shenzhen SiBiono GeneTech Co., Ltd.’s gene therapy for head and neck squamous cell cancer, which was approved in China in 2003. Though no gene therapies have yet been approved in Europe or the United States, Dr. June believes that one may “soon” be used to augment cancer vaccines, which have had generally disappointing, though not negative, results. At least three companies have Phase III trials underway in patients with metastatic, hormone-refractory prostate cancer and with follicular lymphomas. There has been progress too in the design of viral vectors (viruses modified to attack cancer cells instead of healthy cells). Advanced lung and oropharyngeal cancer patients treated with injections of retroviral or adenoviral vectors were “unexpectedly” successful. One company is in Phase III trials of a similar treatment for recurrent and refractory squamous cell carcinoma of the head and neck. And even better vectors are in the works. Potential roadblocks ahead for cancer gene therapy include the time and expense of clinical trials. Phase I pilot trials alone cost more than US$1 million and require “large teams of scientists, clinicians, lawyers, and involvement with biotechnology companies to navigate the regulatory environments in the United States and Europe.” Nevertheless, June is confident that “therapeutic cancer vaccines employing gene therapy to enhance immunogenicity will be FDA-approved modalities in this decade. Moreover, some of these genetically engineered vaccines may well turn out to be blockbuster drugs.” Systems Biology: Building E. Coli An international team of biologists is working to create a virtual Escherichia coli bacterium, which could be used for drug testing and genetic engineering, among other things. E. coli’s 4,288 genes were mapped in 1997, and researchers have since focused on discovering what the genes, alone and in combination, actually do. They still have “probably around 1,000 genes” left to figure out before they can reliably emulate the interactions of all 60 million molecules in a single bacterium. The International Escherichia Coli Alliance was formed in 2002 to farm out among hundreds of labs work that no single lab could achieve alone. Results so far include an ability to predict, with 78 percent reliability, how fast the microbe will grow on various sources of food, as well as how its growth changes if individual genes are knocked out. That success was based on understanding the functions of 1,000 genes, and work is now under way to improve the accuracy by expanding the model to 2,000 genes. Other researchers in the Alliance have worked out the precise mechanisms by which E. coli swims and how it navigates in response to feedback from sensors on its outer membrane. Their virtual E. coli can sense its simulated surroundings and then swims very much like a real E. coli would — towards food, for example. Towards the ultimate goal of a complete virtual model of E. coli that does everything a real one does — swim, eat, fight viruses, make copies of its DNA, and so on, often simultaneously — a US-Japan team is aiming to complete a “minimal” or “stripped-down” version of just 1,000 genes within two years. But they will build it at the molecular level, and current computing power is not enough to handle that much complexity. They are gambling that the computing power will grow as their project grows, and will be there at the right time. The joint US-Swiss effort built a virtual neocortex (reported in our last issue) will require up to two terabytes of storage just for a graphical representation of just the 10,000 neurons in a rat neocortical column. But “if all goes well,” one of the scientists involved told Technology Review, “we will be able to see where the information [in the neocortex] goes, how it is represented, and how it is stored on a [neural] tree. Then we can understand what can go wrong,” and that understanding could yield possible targets for drugs to treat brain diseases “in 10 years.” Synthetic Genomics is a designer-life company. It makes microorganisms to order, by synthesizing entirely new DNA strands to control a specific life function and inserting the DNA into cells, where they then execute that function. Its first forays are into microorganisms that generate ethanol and hydrogen, presumably to make them more productive, with other potential applications in organic chemicals, carbon sequestration, and pollution remediation. “To the extent that you can program how individual cells function, you can change global industries on a very large scale,” a company executive told the Boston Globe. Synthetic biologists, says an article in MIT’s Technology Review, seek “to separate cells into their fundamental components and then rebuild new organisms, a much more complex way of genetic engineering.” Examples of their early efforts, some of which have been achieved:
But is all this ethical? Is it safe? Could terrorist, or just teenage, “biohackers” create new agents of mass death? Could dangerous organisms produced for benign purposes be accidentally released from the confines of the lab? No-one, it seems, is prepared to say, but the questions are under study. It seems to us the answer is Yes to all of the above. Personalized Medicine/Pharmacogenomics Iressa, Tarceva, Gleevec, and other drugs targeted to attack cancer cells while leaving healthy cells alone work wonderfully — for a few patients. Identifying those patients has hitherto been largely a matter of trial and error, but tests are emerging that put us squarely on the path to pharmacogenomics — drugs tailored to the individual. Among them, the Wall Street Journal reports, are
The first two tests are already available; the third is in development. Such tests could help pharmaceutical companies revive failed drugs. When it was found that Iressa, for example, worked in only about 10 percent of patients with advanced non-small-cell lung cancer, it was largely taken off the market in the US. In patients who responded positively to the EGFR test, however, a “much higher” percentage (the Journal did not quote the actual percentage) responded positively to Iressa therapy, though these results apparently still need to be validated by clinical trials. The EFGR test itself is available to doctors in the US now for $975. It can not only help them make better-informed decisions for patients with very advanced lung cancer for whom other therapies have failed, but also for newly diagnosed patients who (assuming Iressa or Tarceva are available) will not have to undergo and fail several rounds of other treatment. Nanotech Genetic Tester for Doctors’ Offices A prototype biosensing device called OPTONANOGEN, based on micro- and nanotechnologies and developed in Spain, is designed for doctors to assess their patients’ genetic risk of developing diseases. It will initially be used to detect mutations of the BRCA1 gene that can cause breast cancer in some women, but could eventually detect virtually any genetic anomaly as well as proteins linked to viruses, chemical contamination in food or water pollution. The final product, which will be available “within one or two years,” will be palm-sized and will perform a genetic analysis in minutes. It contains an array of 20 microcantilevers coated in nucleic acid that react when they come into contact with a DNA sample displaying the genetic anomaly. Quiz: “If [X] starts clinical trials as planned in 2006, that would be a lightning-fast turnaround for a biochemical process that wasn’t even thought possible just six years ago. The mechanism itself was only discovered in mammalian cells in 1999. Although it has quickly become a valuable tool in every molecular biology lab, it’s been slow in showing up at your doctor’s office. That might be about to change.” What is “X” in this quote from a Wired article? Answer: It’s both a company — Sirna Therapeutics – and an interventional technology called siRNA, for “short interfering RNA,” which is a key component in RNAi (RNA interference) therapy. Treated with RNAi, mice with chronic hepatitis B saw their viral load decrease by up to 95 percent. Instead of trying to kill diseased cells with chemotherapy, radiation, or gene therapies — all of which can have dangerous side effects — RNAi simply “interferes” with the messenger, so the harmful message is simply not delivered. There were no side effects in the mouse study, and very low doses were effective. The therapy was first proposed at the Weizmann Institute, and Sirna’s real breakthrough contribution was in getting the RNAi through the membranes of the targeted cells, which it did by encapsulating the interfering RNA inside molecules of fatty acids. The company’s next target is B’s deadlier cousin, the hepatitis C virus (HCV), which affects some 2.7 million Americans. Clinical trials are planned for 2006. And all this is just the beginning. RNAi sequences can be made to block just about any gene, and could therefore cure or contain just about any disease, from HIV to Parkinson’s disease to many cancers. Alnylam Pharmaceuticals is already working on an RNAi-based treatment for flu, and human trials of an RNAi therapy for macular degeneration are already underway. Genetic Therapy for Retinoschisis University of Florida researchers have cured retinoschisis, a rare and incurable genetic disease that causes blindness in about one of every 5,000 boys, in mice, using a genetic therapy to replace a faulty gene that causes the condition. In February this year, US researchers injected up to 40 billion viruses each into the brains of six mild to moderate stage Alzheimer’s patients, to deliver copies of a repair gene to certain neurons involved in memory, and thus slow or halt the memory loss caused by the disease. The results of the high-risk experiment may not be known for about a year, but the husband of one of the patients said he could see a difference in his wife “almost immediately” after the surgery. “Before the surgery, more than half of the time she didn’t know who I was. She wouldn’t remember. Since the surgery, she’s almost always remembered. Two weeks ago she did something she hasn’t done in years: She made a cake. It was a mix, but she did it herself.” Doctors caution this could be a placebo effect, but if not, it is very encouraging news for all Alzheimer’s sufferers and their families. |
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