Eis a resposta de um gênio, cujo nome vou omitir por ora, para que vocês não sejam influenciados por quem ele é.
A pergunta - no título - digo logo de quem é: é minha.
Não muitos seriam capazes de propor essa pergunta após ler o texto abaixo. A razão? Falta-lhes deixar o "germe romper o duro invólucro". Em palavras mais batidas, emprestadas da religião, falta-lhes dar uma chance a Deus. O que requer que repensem - com "resolução e coragem" - a religião contrária... a Ele.
O texto foi adaptado um pouco. Por mim. Para que ao menos uns poucos consigam entendê-lo. Do jeito que eu o encontrei... pois é. Seria o mesmo que postar em grego.
E por que formular tal pergunta é importante?
Se não o fizesse, vocês sequer veriam que a resposta a ela está no texto. Uma pergunta essencial; pergunta que favorece o...
Esclarecimento
Esclarecimento (Aufklärung) significa a saída do homem de sua menoridade, pela qual ele próprio é responsável. A menoridade é a incapacidade de se servir de seu próprio entendimento, sem a tutela de um outro [homem]. É a si próprio que se deve atribuir essa menoridade, uma vez que ela não resulta da falta de entendimento, mas da falta de resolução e de coragem necessárias para utilizar seu entendimento sem a tutela de outro.
É tão cômodo ser menor. Se possuo um livro que tem entendimento por mim, um diretor espiritual que possui consciência em meu lugar, um médico que decida acerca de meu regime, etc., não preciso eu mesmo esforçar-me. Não sou obrigado a refletir, se é suficiente pagar; outros se encarregarão por mim da aborrecida tarefa.
Assim, são poucos os que conseguiram, pelo exercitar de seu próprio espírito, libertar-se dessa menoridade, tendo ao mesmo tempo um andar seguro. Esse Esclarecimento não exige, todavia, nada mais do que a liberdade.
Mas ouço clamar de todas as partes: Não raciocine(m)!
O oficial diz: Não raciocine, mas faça o exercício! O conselheiro de finanças: Não raciocine, mas pague! O padre: Não raciocine, mas creia! Em toda parte só se vê limitação da liberdade.
Mas que limitação constitui obstáculo ao Esclarecimento, e qual [limitação]não constitui ou lhe é mesmo favorável?
Respondo: O cidadão não pode recusar-se a pagar os impostos que lhe são exigidos; a crítica insolente de tais impostos, no momento em que ele tem a obrigação de pagá-los, pode até ser punida como um escândalo (que poderia provocar rebeliões gerais). Mas não está em contradição com seu dever de cidadão se, enquanto erudito, ele manifesta publicamente sua oposição a tais imposições inoportunas, ou mesmo injustas.
Do mesmo modo, um padre está obrigado, diante de seus catecúmenos e sua paróquia, a fazer seu sermão de acordo com o símbolo da Igreja à qual ele serve; pois ele foi empregado sob essa condição. Mas, enquanto erudito, ele dispõe de liberdade total, e mesmo da vocação para tanto, de partilhar com o público todas suas ideias, minuciosamente examinadas e bem intencionadas, que tratam das falhas desse simbolismo e [que tratem] de projetos visando a uma melhor abordagem da religião e da Igreja.
O uso, portanto, que um pastor faz de sua razão, diante de sua paróquia, é apenas um uso privado; pois esta é uma assembleia de tipo familiar, qualquer que seja sua dimensão. E, levando isso em conta, ele não é livre enquanto padre, e não tem o direito de sê-lo, pois ele executa uma missão alheia à sua pessoa.
Em contrapartida, enquanto erudito que fala ao verdadeiro público, isto é, ao mundo, o padre desfruta de uma liberdade ilimitada de servir-se de sua própria razão e de falar em seu próprio nome. Pois, querer que os tutores do povo nas coisas eclesiásticas [ou seja, os padres] voltem a ser menores, é um absurdo que contribui para a perpetuação dos absurdos.
Entretanto, numa sociedade de eclesiásticos, um sínodo, por exemplo, não deveriam os seus tutores ter o direito de comprometer-se mutuamente, por juramento, sobre um certo símbolo imutável, para assim manter, sob tal tutela permanente, cada um de seus membros e, desse modo, perenizar tal tutela?
Digo que é absolutamente impossível.
Tal contrato, concluído para proibir para sempre toda extensão do Esclarecimento ao gênero humano, é completamente nulo e, para todos os efeitos, não ocorrido, mesmo que tivesse sido [tal contrato] implementado pelo poder supremo, pelas Dietas do Império e pelos mais solenes tratados de paz. [Que resposta esclarecida!]
Uma época não pode se aliar e conspirar para tornar a [época] seguinte incapaz de estender seus conhecimentos, de libertar-se de seus erros e, finalmente, fazer progredir o Esclarecimento. Seria um crime contra a natureza humana, cuja vocação original reside nesse progresso. Assim, os descendentes terão pleno direito de rejeitar essas decisões tomadas de maneira ilegítima e crimonosa.
O que, então, pode ser imposto, sob a forma de lei, para um determinado povo é definido com esta questão: o povo imporia a si mesmo tal lei?
Ora, tal lei seria possível, aceitável, na espera de uma melhor, e por um breve e determinado período, a fim de introduzir uma certa ordem. E contanto que tal lei, ao mesmo tempo, autorizasse cada um dos cidadãos, principalmente o padre, em sua qualidade de erudito, a fazer publicamente, isto é, por escrito, suas observações sobre os defeitos da antiga instituição. E isso até que a compreensão de tais coisas esteja publicamente tão avançada e confirmada a ponto de, reunindo as vozes de seus defensores (nem todos, com certeza), trazer diante do trono um projeto: proteger as paróquias que se julgassem, segundo suas próprias concepções, modificadas quanto a determinada instituição da religião, sem, contudo, prejudicar aquelas que quisessem manter-se na situação antiga.
Mas é simplesmente proibido acordar-se [entrar em acordo, pacto] sobre uma constituição religiosa imutável, que impeça que se façam a ela contestações publicamente, por quem quer seja, desse modo anulando, literalmente, todo um período da marcha da humanidade em direção à sua melhoria, e torná-la não só estéril, mas ainda prejudicial à posteridade.
Um homem pode, pessoalmente, e somente por algum tempo, retardar o Esclarecimento em relação ao que ele próprio tem a obrigação de saber. Mas renunciar a ele [ao Esclarecimento], seja em caráter pessoal, seja ainda mais para a posteridade [renúncia definitiva], significa lesar os direitos sagrados da humanidade, e pisar-lhe em cima.
O que um povo não é sequer autorizado a decidir por si mesmo, um monarca tem ainda menos o direito de decidir pelo povo. Pois sua autoridade legislativa repousa, precisamente, sobre o fato de que ele reúne toda a vontade popular na sua.
Situei o alvo principal do Esclarecimentro, qual seja, a saída do homem da menoridade da qual ele próprio é culpado, principalmente no domínio da religião. Isso porque, em relação às ciências e às artes, nossos soberanos não se interessaram em desempenhar o papel de tutores de seus súditos [será que não?]. Além disso, essa menoridade à qual me referi [a menoridade em relação à religião], além de ser a mais nociva, é também a mais desonrosa.
Um príncipe que considere como um dever nada prescrever aos homens em matéria de religião; que os deixa, sobre esse ponto, em uma liberdade total, e recusa para si o orgulhoso título de tolerante, é ele mesmo esclarecido. E por ter sido, esse príncipe, o primeiro a libertar o gênero humano de sua menoridade, pelo menos no que concernia ao governo, e por ter deixado, cada um, livre para se servir de sua própria razão, em todas as questões de consciência, merece ser, tal príncipe, louvado pelo mundo que lhe é contemporâneo, e pelo futuro agradecido. Pois mostra a este, por seu exemplo brilhante, que ali, onde reina a liberdade, nada há porque temer pela tranquilidade pública e unidade do Estado. Pois os homens procuram libertar-se de sua grosseria, ainda que [seus governantes] se esforcem para mantê-los, artificialmente, em tal condição [de grosseria].
Quando se pergunta, portanto: Vivemos atualmente numa época esclarecida?
A resposta é: Não, mas numa época de esclarecimento. Muito falta ainda para que os homens, no estado atual das coisas, tomados conjuntamente, estejam já num ponto em que possam estar em condições, em matéria de religião, de se valer de seu próprio entendimento, com segurança e êxito, sem a tutela de outrem. Mas que, desde já, o campo lhes esteja aberto para que eles se movam livremente, e que os obstáculos à generalização do Esclarecimento e à saída da menoridade - que lhes é autoimputável - sejam cada vez menos numerosos.
Entretanto, há aquele que, embora ele mesmo esclarecido, não temia as trevas, mas, ao mesmo tempo, garantia a tranquilidade pública tendo sob seu comando um exército numeroso e bem disciplinado. Este chefe de Estado é capaz de dizer o que um Estado livre não ousa dizer: Raciocinem o quanto quiserem, e sobre o que desejarem, mas obedeçam! Revela-se, assim, uma marcha estranha, inesperada, das coisas humanas.
Um grau mais elevado de liberdade civil parece vantajoso para a liberdade de espírito do povo. Em contrapartida, um grau menos elevado daquela [liberdade] proporciona a este [espírito] a possibilidade de estender-se de acordo com suas forças.
Portanto, a natureza [que traduzo como Deus] libertou, de seu duro envoltório, o "germe" sobre o qual ela vela mais ternamente: a inclinação e a vocação do homem para pensar livremente.
Essa inclinação age, por sua vez, sobre a sensibilidade do povo, tornando-o cada vez mais capaz de ter a liberdade de agir. Finalmente, age, tal inclinação, também sobre os princípios do governo, que encontra o seu próprio interesse em tratar o homem - que doravante é mais do que uma máquina - na medida de sua dignidade.
Königsberg, Prússia, 30 de setembro de 1784
Tuesday, July 7, 2009
Monday, July 6, 2009
Revolução na biologia - da Newsweek, em inglês
Este artigo, também da Newsweek, está com quase dois anos de publicação. Hoje ele perfaz uma excelente introdução às matérias que já postamos hoje (role a página até "Complexidades da Vida"). O tema - a revolução na biologia.
The Year of Miracles
By Lee Silver NEWSWEEK
From the magazine issue dated Oct 15, 2007
The year 1905 was an annus mirabilis, or miracle year—A rare historical moment in which key flashes of insight suddenly made the field of physics take off in new directions. That was the year Albert Einstein presented four papers that turned the conventional wisdom about how the universe works, from the infinitesimal realm of atoms to the vast reaches of the cosmos, upside down. During the next several decades, Einstein and a handful of other brilliant physicists went on to shape the 20th century and lay the foundation for all its technological accomplishments.
A century later, the year 2007 is shaping up to be another annus mirabilis. This time biology is the field in transition, and the ideas being shattered are old notions of genes and inheritance.
Ever since 1900, when Gregor Mendel's work on peas and inheritance was rediscovered, scientists have regarded the "gene" as the fundamental unit of heredity (just as the atom was regarded as the bedrock of pre-Einsteinian physics). Crick and Watson's discovery of the DNA double helix as the carrier of hereditary information did little to disturb the status quo. In recent months, however, a perfect storm of new technology and research has blown apart 20th-century dogma. The notion of the Mendelian gene as a unit of heredity, scientists now realize, is a fiction.
What's taking its place? Many scientists now believe that heredity is the result of an incredibly complex interplay among the basic components of the genome, scattered among many different genes and even the vast stretches of "junk DNA" once thought to serve no purpose. Biology has been building up to this insight for years, but some big puzzle pieces have now fallen into place. Once scientists abandoned their preconceived notions of genes and looked instead at individual DNA "letters" in the genome —the four bases A, C, T and G—they immediately began to see cause-and-effect connections to myriad diseases and human traits.
The result of this seemingly modest conceptual breakthrough has been a torrent of new discoveries. In five months, from April through August, geneticists at the Harvard/MIT Broad Institute, founded by Eric Lander; at deCODE Genetics in Iceland, founded by Kari Stefansson, and several other institutions have published papers suggesting that the key to a deeper understanding of the human genome may finally be in hand. These scientists have identified specific alterations in the sequence of DNA that play causative roles in a broad range of common diseases, including type 1 and type 2 diabetes; schizophrenia; bipolar disorder; glaucoma; inflammatory bowel disease; rheumatoid arthritis; hypertension; restless legs syndrome; susceptibility to gallstone formation; lupus; multiple sclerosis; coronary heart disease; colorectal, prostate and breast cancer, and the pace at which HIV infection causes full-blown AIDS. Unlike so many previous "disease gene" discoveries, these findings are being replicated and validated. "The race to discover disease-linked genes reaches fever pitch," declared the leading British science journal, Nature. Its American counterparts at Science chimed in: "After years of chasing false leads, gene hunters feel that they have finally cornered their prey. They are experiencing a rush this spring as they find, time after time, that a new strategy is enabling them to identify genetic variations that likely lie behind common diseases." That the world's top two scientific journals still use the old language of "genes" to describe these discoveries shows how new the new thinking really is.
These findings are just a prelude to what's shaping up as a true conceptual and technological revolution. Just as physics shocked the world in the 20th century, it is now clear that the life sciences will shake up the world in the 21st. In a handful of years, your doctor may be able to run a computer analysis of your personal genome to get a detailed profile of your health prospects. This goes well beyond merely making predictions. A new technology called RNA interference may also allow doctors to control how your DNA is "expressed," helping you circumvent potential health risks. Many common diseases that have preyed on humans for eons—devastating neurological conditions such as Alzheimer's, Parkinson's, cancer and heart disease—could be eradicated. If this sounds outrageously optimistic, so did the promise of eliminating smallpox and polio to previous generations.
Why is all this happening now? What has changed between this year and last? To answer these questions, we need to trace the story of how mainstream biomedical scientists tried to link the cause of diseases to single genes and, despite early success, hit a brick wall. Meanwhile, a handful of renegade scientists, pursuing their own pet projects, happened to develop exactly the intellectual tools needed to break through that wall. These biologists are now the leaders of the new revolution in biomedical science.
The seeds of our new understanding were first sown in the 1960s, when molecular biologists figured out how genetic information is organized, regulated and reproduced inside single-cell bacteria. In bacteria, a gene is a discrete segment of DNA that contains the "code" that tells the cell how to make a particular type of protein. Bacterial genes are arranged along a single DNA molecule, one after the other, with only tiny gaps in between. Since all organisms have DNA and work by essentially the same biochemistry, scientists assumed that a human genome would look like a larger version of a bacterium's.
Clues that something was amiss came quickly with the development of DNA-sequencing methods in the 1970s. The first surprising result was that genes accounted for only 2 percent of the human genome—the rest of the DNA didn't seem to have any purpose at all. Biologists Phillip Sharp and Richard Roberts made things worse with a discovery that won them a Nobel Prize in 1993. If the gene were the basic unit of heredity, the DNA required to make any particular protein should be contained in its corresponding gene. But Sharp and Roberts found that DNA that codes for individual proteins is often split and scattered throughout the genome.
Scientists could ignore these signs largely because they seemed to be making progress. By combining new DNA-sequencing tools with studies of inherited diseases in large families, medical geneticists identified the genetic culprits responsible for cystic fibrosis, Huntington's disease, Duchenne muscular dystrophy and a host of other diseases. Each of these "all or none" diseases is caused by a mutation in a single protein-coding region of the DNA. Few diseases, unfortunately, work so neatly. In particular, the search for genetic bases of common diseases that affect large numbers of aging people came up empty.
During this lull, a visionary physician-scientist named Leroy Hood, now at the Institute for Systems Biology in Seattle, was growing impatient. Genetics, he recognized, was still a cottage industry of government-funded university professors, who each directed a small group of students and technicians to study an isolated gene. At the pace research was progressing, it would have required 100,000 worker-years of concerted effort to decipher just one complete human genome.
Hood thought it was absurd that genetic scientists spent nearly all their lab time performing tedious and repetitive mechanical and chemical procedures. At the same time, he grasped the far-reaching implications of a fundamental fact: while even the simplest organism is immensely complicated, the primary structures of its most complicated parts—DNA and proteins—are very simple. The alphabet of DNA contains only the four chemical letters (or bases) A, C, G and T, and proteins are made from just 21 amino acids. Hood saw that this simplicity would make it possible for robots and computers to read and write DNA and proteins more quickly, accurately and cheaply than human beings.
The rest of the biomedical community refused to believe that robots could analyze something as complex as a living system. And in any case, no practicing geneticist had the capacity to design such machines. Unable to obtain government grants, Hood secured private funding to bring together dozens of scientists, engineers and computer programmers (far larger and more diverse than any other genetics team). They proceeded to invent the first generation of molecular-biology machines. Two read and recorded information from DNA and proteins respectively (a process known as sequencing), and two others worked backward, converting digital electronic information into newly written sequences of DNA or protein.
Hood completely transformed the biomedical enterprise. DNA-writing machines give genetic engineers an unlimited capacity to create novel genes that can be studied in test tubes or added to the genomes of living organisms. And protein-writing and -reading machines provided drug firms with the ability to create a new generation of protein-based drugs. The DNA-reading machines suddenly made it conceivable to crack the 3 billion-base sequence of an entire human genome. In 1990 the U.S. government embarked on a 15-year, $3 billion project to do just that.
Eight years later, however, the project—parceled out to many U.S. scientists—was still less than 10 percent complete. Now it was biotech entrepreneur Craig Venter who was frustrated. Convinced that government-funded workers were the problem rather than the solution, Venter enlisted private funding of $200 million to build an enormous lab filled with hundreds of automated machines, working 24/7, overseen by a handful of technicians. Within three years, the first reading of a human genome was essentially complete.
Armed with data from the genome project, scientists figured they'd surely be able to crack the really hard diseases, like cancer and heart disease. But a funny thing happened when they began to look closely at this vast storehouse of genetic information. Geneticists Andrew Fire and Craig Melo galvanized the field by discovering a key mechanism that had been completely overlooked—the cellular process of RNA interference. (They shared a Nobel Prize in 2006 for the work.)
Finding evidence of extraterrestrial life couldn't have come as a bigger shock. Geneticists had taken for granted that the machinery of cells involved genes directing the production of proteins, and proteins doing the work of the cell. Here was a process that didn't involve proteins at all. Instead, tens of thousands of hitherto mysterious regions of the human genome—part of the so-called junk DNA—directed the production of specific molecules called microRNAs (consisting of bits of RNA, a well-known component of cells). These microRNAs then oversaw a whole new process, called RNA interference (RNAi), that served to modulate the expression of DNA.
The good news was that RNAi could open up a whole new approach to biomedical therapy (more on that later). But RNAi also made it clear that the fundamental unit of heredity and genetic function is not the gene but the position of each individual DNA letter.
To make it all harder to fathom, each bit of DNA is susceptible to mutation and variation among individuals. Of the 3 billion DNA bases in the human genome, geneticists identified about one tenth of one percent (millions) that differ from one person to another. Variations in these particular letters—called "snips," or SNPs, for single nucleotide polymorphisms—have replaced genes as the unit of heredity.
Many scientists responded to this devastating realization by going into a funk. "It will be difficult, if not impossible, to find the genes involved [in common diseases] or develop useful and reliable predictive tests for them," Dr. Neil Holtzman, director of genetics and public policy at Johns Hopkins University, said in 2001.
Fortunately, another visionary scientist, Kari Stefansson of Iceland, was already blazing a trail out of this thicket. If the genome was far more complex than scientists had thought, they would need to test for many more variables, and to do that they would need more test subjects. To find the cause of diseases would now require the participation of very large groups of genetically related people.
Like Hood and Venter, Stefansson was originally motivated by frustration with the pace of research. In the United States, where most of the disease-gene-discovery projects were being conducted, most people cannot trace their ancestors back more than a few generations, and the largest families consist of a few hundred living subjects at most. Subject panels of this size failed to provide sufficient data to identify the genetic bases for complicated and variable common diseases. Stefansson decided to solve this problem by taking aim at the largest well-documented extended family that he knew—his own.
Nearly all the 300,000 citizens of Iceland can trace their ancestors back, through detailed, public genealogical records, to the Vikings who settled this desolate European island more than 1,000 years ago. Stefansson gave up his faculty position at Harvard Medical School to return to Iceland, where he founded the company deCODE Genetics in 1996. He persuaded the Icelandic government to provide deCODE with exclusive access to the health records of its citizens in return for bringing investment capital and high-tech jobs to the capital, Reykjavik. So far, more than 100,000 Icelandic volunteers have donated their DNA to deCODE.
Stefansson's project was roundly criticized by international bioethicists and other geneticists for violating the privacy of Icelanders (even though 90 percent of the population approved). Nevertheless, he persevered, placing "the genealogy of the entire nation on a computer database," together with the health and DNA records of still-living individuals. The power of large numbers was soon apparent. In a study of obesity, he directed his software to look for SNPs associated with subsets of the population who were either extremely overweight or very thin. Within just a few hours, it began finding evidence that variations among particular DNA letters indeed played a causative role, confirming SNPs as the new unit of inheritance.
As of September, deCODE has made progress in identifying SNPs that may play a role in 28 common diseases, including glaucoma, schizophrenia, diabetes, heart disease, prostate cancer, hypertension and stroke. In some cases, such as glaucoma and prostate cancer, deCODE's findings could lead to diagnostic tests for identifying people at risk of developing the disease. In other instances, such as schizophrenia, links to particular proteins have led to insight about the cause of the disease, which could lead to therapies.
Buoyed by Stefansson's success, other geneticists were eager to perform large-scale family studies, yet few had similar access to ancient genealogical records. But serendipity would deliver an epiphany: it's possible to study the entire human population as a single extended family, provided scientists collect enormous amounts of data. Eric Lander, an MIT professor and the intellectual leader of the U.S. government effort to sequence the first human genome, realized scaling up would require a new approach. In 2004, Lander persuaded MIT and Harvard to combine their enormous resources toward the creation of the Broad Institute. Backed by $200 million from billionaire philanthropists Eli and Edythe Broad, the institute is driving the development of ever more advanced genetic technologies. One technology, based on computer-chip fabrication, can identify DNA base letters present at 500,000 SNPs in the genomes of 40,000 or more people.
Think of this as a spreadsheet with 500,000 columns (each representing a specific SNP) and 40,000 rows (one for each person). To hunt for a genetic basis for, say, bipolar disease, the computer searches rows of people who have the disorder, checking column by column for an unusually high frequency of particular letters in comparison with people without the disease. As it turns out, a collaboration of American and German researchers has done this work—and found that variations of DNA letters in 20 different positions are influential in bipolar disease.
Incredibly, most disease-causing variants are the most common ones present in the human population: the strongest-acting one, for instance, exists in 80 percent of people without bipolar disease and 85 percent of people with the disease. The implication is that these variants are beneficial in some way, and cause problems only when their number exceeds a threshold.
To make sense of this complexity, scientists would like ultimately to build a vast international database that contains the complete sequence of DNA bases in the genomes of hundreds of millions of people. Ideally, such a database would be available for analysis by all biomedical researchers and would provide the foundation for understanding the genetic components of all human traits. That sounds like a lot of data—think of a spreadsheet with 3 billion columns and 100 million rows—but computing power is getting cheaper by the year. Within a decade, the cost of obtaining a sequence of all 3 billion DNA letters in an individual's genome will drop from $2 million now to $1,000. It will be a routine part of a person's health record, enabling physicians to prescribe genome-specific preventions and treatments.
The discovery of RNAi, meanwhile, suggests a completely new personalized form of disease therapy. Whereas drugs act on proteins, RNAi therapy would act on the expression of DNA itself, potentially preventing or reversing diseases such as Alzheimer's, Parkinson's, Huntington's, bipolar disorder, schizophrenia and others. Old-school pharmaceutical firms have taken notice. The largest ones are betting heavily on the gene-targeted RNAi therapeutic approach to fill product pipelines, as the discovery of traditional chemical drugs becomes more elusive. Novartis and Roche have both signed nonexclusive licensing deals with the biotech firm Alnylam (founded by Phillip Sharp) for new therapeutic techniques that are valued at up to $700 million and $1 billion respectively; Merck paid $1.1 billion to buy another biotech company outright, solely to obtain its contested portfolio of RNAi intellectual property, and the London-based drug firm AstraZeneca has a $405 million licensing deal with Alnylam's competitor Silence Therapeutics.
The explosion of genetic discoveries shows no sign of letting up any time soon. New diseases are being added to the list every month, and biologists are rapidly parlaying gene- and SNP-disease links into a deeper understanding of how proteins and other molecules can misbehave to cause different medical problems in different people. And other scientists are working to advance the biology revolution (accompanying interviews). As a result of their efforts, many children born this year could very well be alive and healthy at the dawn of the next century, when they may look back in awe at the annus mirabilis of biomedical genetics in 2007.
Silver is a professor of molecular biology at Princeton. He is the author of "Challenging Nature." He has no financial ties to any biotech or drug firm.
http://www.newsweek.com/id/42525
The Year of Miracles
By Lee Silver NEWSWEEK
From the magazine issue dated Oct 15, 2007
The year 1905 was an annus mirabilis, or miracle year—A rare historical moment in which key flashes of insight suddenly made the field of physics take off in new directions. That was the year Albert Einstein presented four papers that turned the conventional wisdom about how the universe works, from the infinitesimal realm of atoms to the vast reaches of the cosmos, upside down. During the next several decades, Einstein and a handful of other brilliant physicists went on to shape the 20th century and lay the foundation for all its technological accomplishments.
A century later, the year 2007 is shaping up to be another annus mirabilis. This time biology is the field in transition, and the ideas being shattered are old notions of genes and inheritance.
Ever since 1900, when Gregor Mendel's work on peas and inheritance was rediscovered, scientists have regarded the "gene" as the fundamental unit of heredity (just as the atom was regarded as the bedrock of pre-Einsteinian physics). Crick and Watson's discovery of the DNA double helix as the carrier of hereditary information did little to disturb the status quo. In recent months, however, a perfect storm of new technology and research has blown apart 20th-century dogma. The notion of the Mendelian gene as a unit of heredity, scientists now realize, is a fiction.
What's taking its place? Many scientists now believe that heredity is the result of an incredibly complex interplay among the basic components of the genome, scattered among many different genes and even the vast stretches of "junk DNA" once thought to serve no purpose. Biology has been building up to this insight for years, but some big puzzle pieces have now fallen into place. Once scientists abandoned their preconceived notions of genes and looked instead at individual DNA "letters" in the genome —the four bases A, C, T and G—they immediately began to see cause-and-effect connections to myriad diseases and human traits.
The result of this seemingly modest conceptual breakthrough has been a torrent of new discoveries. In five months, from April through August, geneticists at the Harvard/MIT Broad Institute, founded by Eric Lander; at deCODE Genetics in Iceland, founded by Kari Stefansson, and several other institutions have published papers suggesting that the key to a deeper understanding of the human genome may finally be in hand. These scientists have identified specific alterations in the sequence of DNA that play causative roles in a broad range of common diseases, including type 1 and type 2 diabetes; schizophrenia; bipolar disorder; glaucoma; inflammatory bowel disease; rheumatoid arthritis; hypertension; restless legs syndrome; susceptibility to gallstone formation; lupus; multiple sclerosis; coronary heart disease; colorectal, prostate and breast cancer, and the pace at which HIV infection causes full-blown AIDS. Unlike so many previous "disease gene" discoveries, these findings are being replicated and validated. "The race to discover disease-linked genes reaches fever pitch," declared the leading British science journal, Nature. Its American counterparts at Science chimed in: "After years of chasing false leads, gene hunters feel that they have finally cornered their prey. They are experiencing a rush this spring as they find, time after time, that a new strategy is enabling them to identify genetic variations that likely lie behind common diseases." That the world's top two scientific journals still use the old language of "genes" to describe these discoveries shows how new the new thinking really is.
These findings are just a prelude to what's shaping up as a true conceptual and technological revolution. Just as physics shocked the world in the 20th century, it is now clear that the life sciences will shake up the world in the 21st. In a handful of years, your doctor may be able to run a computer analysis of your personal genome to get a detailed profile of your health prospects. This goes well beyond merely making predictions. A new technology called RNA interference may also allow doctors to control how your DNA is "expressed," helping you circumvent potential health risks. Many common diseases that have preyed on humans for eons—devastating neurological conditions such as Alzheimer's, Parkinson's, cancer and heart disease—could be eradicated. If this sounds outrageously optimistic, so did the promise of eliminating smallpox and polio to previous generations.
Why is all this happening now? What has changed between this year and last? To answer these questions, we need to trace the story of how mainstream biomedical scientists tried to link the cause of diseases to single genes and, despite early success, hit a brick wall. Meanwhile, a handful of renegade scientists, pursuing their own pet projects, happened to develop exactly the intellectual tools needed to break through that wall. These biologists are now the leaders of the new revolution in biomedical science.
The seeds of our new understanding were first sown in the 1960s, when molecular biologists figured out how genetic information is organized, regulated and reproduced inside single-cell bacteria. In bacteria, a gene is a discrete segment of DNA that contains the "code" that tells the cell how to make a particular type of protein. Bacterial genes are arranged along a single DNA molecule, one after the other, with only tiny gaps in between. Since all organisms have DNA and work by essentially the same biochemistry, scientists assumed that a human genome would look like a larger version of a bacterium's.
Clues that something was amiss came quickly with the development of DNA-sequencing methods in the 1970s. The first surprising result was that genes accounted for only 2 percent of the human genome—the rest of the DNA didn't seem to have any purpose at all. Biologists Phillip Sharp and Richard Roberts made things worse with a discovery that won them a Nobel Prize in 1993. If the gene were the basic unit of heredity, the DNA required to make any particular protein should be contained in its corresponding gene. But Sharp and Roberts found that DNA that codes for individual proteins is often split and scattered throughout the genome.
Scientists could ignore these signs largely because they seemed to be making progress. By combining new DNA-sequencing tools with studies of inherited diseases in large families, medical geneticists identified the genetic culprits responsible for cystic fibrosis, Huntington's disease, Duchenne muscular dystrophy and a host of other diseases. Each of these "all or none" diseases is caused by a mutation in a single protein-coding region of the DNA. Few diseases, unfortunately, work so neatly. In particular, the search for genetic bases of common diseases that affect large numbers of aging people came up empty.
During this lull, a visionary physician-scientist named Leroy Hood, now at the Institute for Systems Biology in Seattle, was growing impatient. Genetics, he recognized, was still a cottage industry of government-funded university professors, who each directed a small group of students and technicians to study an isolated gene. At the pace research was progressing, it would have required 100,000 worker-years of concerted effort to decipher just one complete human genome.
Hood thought it was absurd that genetic scientists spent nearly all their lab time performing tedious and repetitive mechanical and chemical procedures. At the same time, he grasped the far-reaching implications of a fundamental fact: while even the simplest organism is immensely complicated, the primary structures of its most complicated parts—DNA and proteins—are very simple. The alphabet of DNA contains only the four chemical letters (or bases) A, C, G and T, and proteins are made from just 21 amino acids. Hood saw that this simplicity would make it possible for robots and computers to read and write DNA and proteins more quickly, accurately and cheaply than human beings.
The rest of the biomedical community refused to believe that robots could analyze something as complex as a living system. And in any case, no practicing geneticist had the capacity to design such machines. Unable to obtain government grants, Hood secured private funding to bring together dozens of scientists, engineers and computer programmers (far larger and more diverse than any other genetics team). They proceeded to invent the first generation of molecular-biology machines. Two read and recorded information from DNA and proteins respectively (a process known as sequencing), and two others worked backward, converting digital electronic information into newly written sequences of DNA or protein.
Hood completely transformed the biomedical enterprise. DNA-writing machines give genetic engineers an unlimited capacity to create novel genes that can be studied in test tubes or added to the genomes of living organisms. And protein-writing and -reading machines provided drug firms with the ability to create a new generation of protein-based drugs. The DNA-reading machines suddenly made it conceivable to crack the 3 billion-base sequence of an entire human genome. In 1990 the U.S. government embarked on a 15-year, $3 billion project to do just that.
Eight years later, however, the project—parceled out to many U.S. scientists—was still less than 10 percent complete. Now it was biotech entrepreneur Craig Venter who was frustrated. Convinced that government-funded workers were the problem rather than the solution, Venter enlisted private funding of $200 million to build an enormous lab filled with hundreds of automated machines, working 24/7, overseen by a handful of technicians. Within three years, the first reading of a human genome was essentially complete.
Armed with data from the genome project, scientists figured they'd surely be able to crack the really hard diseases, like cancer and heart disease. But a funny thing happened when they began to look closely at this vast storehouse of genetic information. Geneticists Andrew Fire and Craig Melo galvanized the field by discovering a key mechanism that had been completely overlooked—the cellular process of RNA interference. (They shared a Nobel Prize in 2006 for the work.)
Finding evidence of extraterrestrial life couldn't have come as a bigger shock. Geneticists had taken for granted that the machinery of cells involved genes directing the production of proteins, and proteins doing the work of the cell. Here was a process that didn't involve proteins at all. Instead, tens of thousands of hitherto mysterious regions of the human genome—part of the so-called junk DNA—directed the production of specific molecules called microRNAs (consisting of bits of RNA, a well-known component of cells). These microRNAs then oversaw a whole new process, called RNA interference (RNAi), that served to modulate the expression of DNA.
The good news was that RNAi could open up a whole new approach to biomedical therapy (more on that later). But RNAi also made it clear that the fundamental unit of heredity and genetic function is not the gene but the position of each individual DNA letter.
To make it all harder to fathom, each bit of DNA is susceptible to mutation and variation among individuals. Of the 3 billion DNA bases in the human genome, geneticists identified about one tenth of one percent (millions) that differ from one person to another. Variations in these particular letters—called "snips," or SNPs, for single nucleotide polymorphisms—have replaced genes as the unit of heredity.
Many scientists responded to this devastating realization by going into a funk. "It will be difficult, if not impossible, to find the genes involved [in common diseases] or develop useful and reliable predictive tests for them," Dr. Neil Holtzman, director of genetics and public policy at Johns Hopkins University, said in 2001.
Fortunately, another visionary scientist, Kari Stefansson of Iceland, was already blazing a trail out of this thicket. If the genome was far more complex than scientists had thought, they would need to test for many more variables, and to do that they would need more test subjects. To find the cause of diseases would now require the participation of very large groups of genetically related people.
Like Hood and Venter, Stefansson was originally motivated by frustration with the pace of research. In the United States, where most of the disease-gene-discovery projects were being conducted, most people cannot trace their ancestors back more than a few generations, and the largest families consist of a few hundred living subjects at most. Subject panels of this size failed to provide sufficient data to identify the genetic bases for complicated and variable common diseases. Stefansson decided to solve this problem by taking aim at the largest well-documented extended family that he knew—his own.
Nearly all the 300,000 citizens of Iceland can trace their ancestors back, through detailed, public genealogical records, to the Vikings who settled this desolate European island more than 1,000 years ago. Stefansson gave up his faculty position at Harvard Medical School to return to Iceland, where he founded the company deCODE Genetics in 1996. He persuaded the Icelandic government to provide deCODE with exclusive access to the health records of its citizens in return for bringing investment capital and high-tech jobs to the capital, Reykjavik. So far, more than 100,000 Icelandic volunteers have donated their DNA to deCODE.
Stefansson's project was roundly criticized by international bioethicists and other geneticists for violating the privacy of Icelanders (even though 90 percent of the population approved). Nevertheless, he persevered, placing "the genealogy of the entire nation on a computer database," together with the health and DNA records of still-living individuals. The power of large numbers was soon apparent. In a study of obesity, he directed his software to look for SNPs associated with subsets of the population who were either extremely overweight or very thin. Within just a few hours, it began finding evidence that variations among particular DNA letters indeed played a causative role, confirming SNPs as the new unit of inheritance.
As of September, deCODE has made progress in identifying SNPs that may play a role in 28 common diseases, including glaucoma, schizophrenia, diabetes, heart disease, prostate cancer, hypertension and stroke. In some cases, such as glaucoma and prostate cancer, deCODE's findings could lead to diagnostic tests for identifying people at risk of developing the disease. In other instances, such as schizophrenia, links to particular proteins have led to insight about the cause of the disease, which could lead to therapies.
Buoyed by Stefansson's success, other geneticists were eager to perform large-scale family studies, yet few had similar access to ancient genealogical records. But serendipity would deliver an epiphany: it's possible to study the entire human population as a single extended family, provided scientists collect enormous amounts of data. Eric Lander, an MIT professor and the intellectual leader of the U.S. government effort to sequence the first human genome, realized scaling up would require a new approach. In 2004, Lander persuaded MIT and Harvard to combine their enormous resources toward the creation of the Broad Institute. Backed by $200 million from billionaire philanthropists Eli and Edythe Broad, the institute is driving the development of ever more advanced genetic technologies. One technology, based on computer-chip fabrication, can identify DNA base letters present at 500,000 SNPs in the genomes of 40,000 or more people.
Think of this as a spreadsheet with 500,000 columns (each representing a specific SNP) and 40,000 rows (one for each person). To hunt for a genetic basis for, say, bipolar disease, the computer searches rows of people who have the disorder, checking column by column for an unusually high frequency of particular letters in comparison with people without the disease. As it turns out, a collaboration of American and German researchers has done this work—and found that variations of DNA letters in 20 different positions are influential in bipolar disease.
Incredibly, most disease-causing variants are the most common ones present in the human population: the strongest-acting one, for instance, exists in 80 percent of people without bipolar disease and 85 percent of people with the disease. The implication is that these variants are beneficial in some way, and cause problems only when their number exceeds a threshold.
To make sense of this complexity, scientists would like ultimately to build a vast international database that contains the complete sequence of DNA bases in the genomes of hundreds of millions of people. Ideally, such a database would be available for analysis by all biomedical researchers and would provide the foundation for understanding the genetic components of all human traits. That sounds like a lot of data—think of a spreadsheet with 3 billion columns and 100 million rows—but computing power is getting cheaper by the year. Within a decade, the cost of obtaining a sequence of all 3 billion DNA letters in an individual's genome will drop from $2 million now to $1,000. It will be a routine part of a person's health record, enabling physicians to prescribe genome-specific preventions and treatments.
The discovery of RNAi, meanwhile, suggests a completely new personalized form of disease therapy. Whereas drugs act on proteins, RNAi therapy would act on the expression of DNA itself, potentially preventing or reversing diseases such as Alzheimer's, Parkinson's, Huntington's, bipolar disorder, schizophrenia and others. Old-school pharmaceutical firms have taken notice. The largest ones are betting heavily on the gene-targeted RNAi therapeutic approach to fill product pipelines, as the discovery of traditional chemical drugs becomes more elusive. Novartis and Roche have both signed nonexclusive licensing deals with the biotech firm Alnylam (founded by Phillip Sharp) for new therapeutic techniques that are valued at up to $700 million and $1 billion respectively; Merck paid $1.1 billion to buy another biotech company outright, solely to obtain its contested portfolio of RNAi intellectual property, and the London-based drug firm AstraZeneca has a $405 million licensing deal with Alnylam's competitor Silence Therapeutics.
The explosion of genetic discoveries shows no sign of letting up any time soon. New diseases are being added to the list every month, and biologists are rapidly parlaying gene- and SNP-disease links into a deeper understanding of how proteins and other molecules can misbehave to cause different medical problems in different people. And other scientists are working to advance the biology revolution (accompanying interviews). As a result of their efforts, many children born this year could very well be alive and healthy at the dawn of the next century, when they may look back in awe at the annus mirabilis of biomedical genetics in 2007.
Silver is a professor of molecular biology at Princeton. He is the author of "Challenging Nature." He has no financial ties to any biotech or drug firm.
http://www.newsweek.com/id/42525
Complexidades da Vida
Aqui está a íntegra das matérias recém-publicadas na Newsweek sobre biologia e tecnologia genética. A capa da edição impressa traz... Michael Jackson, o que talvez faça muitos ignorarem estes bons textos.
Life’s Complexities
The genome's bounty is further off than expected, but it may yet yield deeper and wider insights.
Fred Guterl
From the magazine issue dated Jul 13, 2009
If a person's genes are his destiny, why do Sunney Xie's twin daughters have different personalities, and even different fingerprints? The girls share identical genes and nearly identical upbringings, and yet somehow, as they developed through toddlerhood, their biological paths diverged. Biologists have been pondering the relative influence of nature and nurture since long before Crick and Watson discovered the basic structure of DNA in 1953, but is it possible, after all these years, that they've been missing a third influence? Xie, a biologist at Harvard, has for the past three years performed experiments in his Cambridge, Massachusetts, lab aimed squarely at this question, and he thinks he's found the overlooked factor. It is pure chance.
The idea that randomness may play a role in the life of the cell is still largely conjectural, but it is typical of the kind of intellectual ferment in the life sciences of late. It's been nine years since Craig Venter and others decoded the human genome, the panoply of genes that govern the workings of each and every human cell, and declared that the "book of life" had been revealed. Since then, biologists have found that the genome is only the beginning to life's complexities. Only slightly more than 1 percent of the genome consists of genes that produce proteins, which do the day-to-day job of running the cell's operations. Scientists are pretty sure the other 99 percent plays a big role, but what that might be is still being sorted out. Although biologists have known since the 1980s that only a few diseases are caused by a single gene, some are now thought to arise from varying subsets of tens of thousands of genes. And as if the genome weren't complex enough, the way these genes are packaged in the cell may have as much to do with development and disease than the genes themselves. This phenomenon, called "epigenetics," may even account for traits that are passed down from one generation to the next—in other words, inheritance without DNA.
These developments mean that the full bounty of the genomics revolution is going to take longer than most people thought 10 years ago. But there's reason to believe that the route out of the present confusion will lead to deeper and wider insights, as the stories in this special report on the life sciences show. For one thing, significant practical breakthroughs are already brewing in the labs. Epigenetics has already led to some startling leads in the war on cancer and other diseases, and drugs for some forms of leukemia, for instance, are already in the pipeline. Scientists have figured out how to take adult stem cells from the skin and other organs and reprogram them genetically, the first step toward turning them into replacement tissue tailor-made to the patient's immune system. The realization that the cell is a complex entity that is greater than the sum of its parts has forced doctors on the forefront of medical research to consider their patients as biological "systems." This awareness is now transforming the way medicine is practiced and taught, as Dr. Leroy Hood points out in an essay.
Medicine isn't the only field that's set to benefit from the new genomics, as our report shows. A better understanding of the biological underpinnings of plants is giving scientists ways of improving the yields and nutritional content of crops without having to tinker directly with the genetic makeup of plants. It's also opened the door to the possibility of meddling with the biosphere itself by introducing genetically modified creatures, such as mosquitoes with immunity to the malaria parasite, into the wild. Research along these lines is causing something of a furor in environment circles, as health officials look to technology to improve global health.
Randomness hasn't yet emerged into the mainstream of biology, but its recent appearance in scholarly journals adds a certain symmetry to science. Probabilities played a role in the huge upheaval in physics in the early 20th century. In 1926 Erwin Schrödinger declared that an atom isn't anything like a tiny solar system, and that electrons, unlike planets, are best described in terms of the likelihood of their appearing at any one place and time. The idea raised Albert Einstein's hackles: "God doesn't play dice with the universe," he objected. But it made the equations come out better, and equations are hard to argue with, especially when they produce nuclear weapons and iPods. If it turns out that God also rolls the dice each time a stretch of DNA does its work, it could mean that biology needs a new mathematics that takes probabilities into account, just as physics did after Schrödinger. To say that biology stands today where physics stood in 1926—on the verge of rewriting its equations—is pure conjecture, but it's got the feel of truth.
URL: http://www.newsweek.com/id/204236© 2009
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Beyond the Book of Life
By Stephen S. Hall NEWSWEEK
From the magazine issue dated Jul 13, 2009
Roll over, Mendel. Watson and Crick? They are so your old man's version of DNA. And that big multibillion-dollar hullabaloo called the Human Genome Project? To some scientists, it's beginning to look like an expensive genetic floor pad for a much more intricate—and dynamic—tapestry of life that lies on top of it.
There's a revolution sweeping biology today—begrudged by a few, but accepted by more and more biologists—that is changing scientific thinking about the way genes work, the way diseases arise and the way some of the most dreadful among them, including cancer, might be diagnosed and treated. This revolution is called epigenetics, and it is not only beginning to explain some of the biological mysteries that deepened with the Human Genome Project. Because of a series of accidental events, it is already prolonging the lives of human patients with deadly diseases.
Over the past several years, and largely without much public notice, physicians have reported success using epigenetic therapies against cancers of the blood and have even made progress against intractable solid-tumor malignancies like lung cancer. The story is still preliminary and unfolding (dozens of clinical trials using epigenetic drugs are currently underway), but Dr. Margaret Foti, chief executive officer of the American Association for Cancer Research, recently noted that epigenetics is already resulting in "significant improvements" in cancer diagnosis and therapy. "It's really coming into its own now," she said. Leaping on the bandwagon, the National Institutes of Health made epigenetics the focus of one of its cutting-edge "Roadmap" initiatives announced last fall.
"I think we were all brought up to think the genome was it," says C. David Allis, a scientist at Rockefeller University whose research in the 1990s helped catalyze the current interest in epigenetics. "But even when the genome was a done deal, some people thought, 'Is that the whole story?' It's really been a watershed in understanding that there is something beyond the genome."
The emergence of epigenetics represents a fundamental rethinking of how molecular biology works. Scientists have learned that while DNA remains the basic text of life, the script is often controlled by stage directions embedded in a layer of biochemicals that, roughly speaking, sit on top of the DNA. These modifications, called epimutations, can turn genes on and off, often at inappropriate times. In other words, epigenetics has introduced the startling idea that it's not just the book of life (in the form of DNA) that's important, but how the book is packaged.
At one level, this higher order of control makes perfect sense. Biologists have long known that developing organisms—humans included—need a full complement of genes at the moment of fertilization, but that many genes subsequently get turned on and off as the embryo develops. In humans, this is a lifelong process. There are genes for a fetal version of hemoglobin, for example, and then an adult version that kicks in after birth; through epigenetic control, the fetal genes are permanently turned off at a certain stage of development, and the adult genes are permanently activated. As each one of us developed from a fertilized egg, stem cells in the early embryo matured into brain cells, liver cells and indeed several hundred specialized cells and tissues; at each step of that maturation process, our DNA was modified. When we entered puberty, quiescent genes were suddenly activated. And as we age, the dings of earlier life experiences seem to shape the activity of our DNA. Many if not most of those changes are epigenetic in nature, where the DNA itself remains unchanged, but the packaging has been dramatically perturbed; animal experiments suggest that environmental factors, from childhood diet and maternal care to stress, can play epigenetic havoc with our basic DNA hardware.
The interest in epigenetics has assumed critical mass in the past 10 years for several reasons. The Human Genome Project, often touted as "biology's moonshot," provided the basic text of life, in the form of the complete human sequence of DNA, but scientists have had a hard time linking specific genetic causes to many common illnesses. The role of "misspelled" DNA (in the form of both classic mutations and genetic variation, first teased out in the 19th century by the monk Gregor Mendel) has turned out to explain, in the words of a recent New England Journal of Medicinecommentator, "only a small fraction of disease." "We were all raised on the Watson and Crick concept of DNA-driven inheritance," Allis says. "It turns out that epigenetics may be even more responsible for gene expression and disease than DNA alone, especially in more advanced multicellular organisms." In the 1990s, meanwhile, scientists like Allis reported basic but breathtaking discoveries that showed how several groups of enzymes, common to every cell, could create epimutations without ever changing the DNA script.
Basic research has shown that enzymes can tamper with genetic information in at least two distinct ways. In some cases, the on-off switch of a gene can be smothered when an enzyme attaches chemicals to the DNA; known as DNA methy-lation, this process essentially silences a gene that should be on. In other cases, a separate class of enzyme improperly disrupts the normal cellular packaging of DNA. Typically, the gossamer thread of DNA is wound around a spool of protein called histone; when this second class of enzymes strips away part of the packaging, the DNA becomes so tightly wound up that it can't loosen up enough to be read by the cell. In effect, the slip jacket for specific genes is so tight that it's impossible to crack open the spine and get a glimpse of the genetic text. Conversely, sometimes genes that should remain permanently interred in a tomb of histone suddenly come back to life, like some cellular version of Night of the Living Dead.
In the past five years, the evidence has become "absolutely rock solid" to cancer researchers that epigenetic changes play a fundamental role in cancer, according to Robert A. Weinberg, an elder statesman of cancer biology at the Whitehead Institute in Cambridge, Mass. DNA methylation, he adds, "may ultimately be far more important than gene mutation in shutting down tumor suppressor genes," one of the cell's main mechanisms to short-circuit an incipient cancer.
Each epigenetic change seems to leave a chemical flag, or "mark," on the DNA, and hence researchers are intensely cataloging these marks into "epigenomes" as a possible clue to diagnosis, prognosis and perhaps even prevention of disease. Unlike genetic markers, which reveal small "typographic" variations in the spelling of genes, epigenetic markers indicate places where entire genes have been silenced or activated. Paula Vertino of the Emory University School of Medicine, for example, has identified patches of DNA that seem especially prone to be inappropriately silenced or activated in breast and lung cancer; researchers at Johns Hopkins have used epigenetic markers in brain-cancer cells to predict which patients are likelier to benefit from chemotherapy. Recent laboratory findings suggest that deciphering the layers of genetic control modifying DNA has implications not just for cancer, but also for chronic diseases associated with aging, like heart disease and diabetes; for mental disorders like autism and depression; for stem-cell biology; and even for our notions of what constitutes an inherited disease. Everything is up for grabs.
"There's only one genome," says Wolf Reik, professor of epigenetics at the University of Cambridge in England, "but hundreds of epigenomes." And unlike string theory in physics, for example, epigenetics is neither an exotic intellectual idea nor a theory awaiting verificationby future data. The biology is real, and the practical effects have already reached the bedside.
In the 1990s, Stephen Baylin of Johns Hopkins University led the effort showing that epigenetic changes in DNA were associated with cancer; in fact, disruptions in tumor suppressor genes, which normally protect cells against cancer, are more often due to epigenetic silencing than outright mutation. In May, Baylin and Peter Jones of the University of Southern California received a three-year, $9.1 million grant to launch accelerated testing of epigenetic therapy in patients with lung, colon and breast cancer, with interim results promised within a year. The Hopkins group has presented preliminary results at recent meetings showing that a combination of two epigenetic drugs produced several responses (including one complete remission) in patients with advanced lung cancer. "The trials are still ongoing, and we don't know what percentage of patients will respond, if it will be 10 or 20 percent," says Baylin. "But we have had very robust responses, of both primary tumors and metastases, in non-small-cell lung cancer." "That's just extraordinary," says Foti of AACR, noting the poor prognosis for patients with these advanced cancers.
If the amount of clinical testing seems surprising, it's probably because the medical part of the epigenetics story is unfolding in reverse: doctors had the drugs long before they had a theory suggesting how to use them properly. Indeed, several of the drugs now being tested against cancer have been around for decades, but in the past were used in the wrong way for the wrong reason. Azacitidine, for example, was first discovered in Czechoslovakia in the 1960s as a traditional chemotherapy drug, and doctors used it to kill cancer cells the old-fashioned way: giving as much as patients could tolerate. Jones, a South African by birth who now heads the Norris Comprehensive Cancer Center at USC, discovered in the 1980s that the drug had another mode of action: it could turn genes back on by stripping away the "duct tape" of DNA methylation that muffled genes. This suggested a different kind of attack on cancer—not by killing cancer cells outright, but by reversing the epigenetic changes that make a cell cancerous in the first place.
In the 1980s, as a young oncology fellow at Mount Sinai School of Medicine in New York, Lewis Silverman proposed testing azacitidine as an epigenetic drug—that is, at lower doses than is typical for traditional chemotherapy, where it still might be effective reversing silenced genes. Silverman has since shown that low doses of the drug reduce the symptoms of a type of leukemia and allows patients to live longer. The Food and Drug Administration approved azacitidine in May 2004; the drug is now marketed as Vidaza.
A different class of epigenetic drug has emerged from work at Harvard, Columbia and Memorial Sloan-Kettering Cancer Center in New York. In addition to the silencing effect of methylation, genes can be turned on and off by enzymes that tighten or loosen the packaging of DNA. Paul Marks and Ronald Breslow at Columbia created a small molecule, called vorinostat, that blocks the action of the enzymes that tamper with DNA's packaging, thus turning inactivated genes back on. That drug was approved by the FDA in 2006 for a rare form of lymphoma and is now being tested against a number of other cancers; Merck markets the drug as Zolinza. Part of the current clinical excitement is that there are already hints that combinations of these and second-generation drugs may be more effective at reversing the epigenetic changes in cancer cells.
Researchers remain guarded in their optimism. Issa concedes that the first-generation epigenetic drugs have not included a home run like Gleevec, the molecular treatment for chronic myeloid leukemia that produces dramatic and lasting remissions. And it is not unusual for deleterious side effects to become more apparent as drugs are used more widely—a particular concern in the case of drugs that have the potential to modify gene expression broadly in normal cells. But people who have witnessed the explosion of promising results in the past year have difficulty suppressing their excitement. "The promise is staggering," says Allis.
The stakes in epigenetics go well beyond clinical therapies, however. There have been hints from laboratory experiments and epidemiological studies that epigenetic changes in one generation—caused, for example, by smoking or diet—can be passed on to children and even grandchildren. Reik, who is also associate director of the Babraham Institute in Cambridge, is investigating how the overlay of epigenetic changes is erased from DNA when mice make their germ cells—how all the epigenetic changes, like some microscopic version of duct tape, get stripped off the DNA that goes into the sperm in males and eggs in females. "People are now beginning to realize that there are probably things that don't get wiped out or erased in the germ cells," he says, "so these are so-called epimutations that can be passed on from parents to children and to grandchildren—not genetic changes passed on, like Mendel, but an epimutation.
"We don't know how common this might be," Reik adds, choosing his words carefully, "but it's potentially quite revolutionary. It's not only challenging Mendel, but potentially challenging even Darwin. We are very careful when we talk about these things."
© 2009 If the amount of clinical testing seems surprising, it's probably because the medical part of the epigenetics story is unfolding in reverse: doctors had the drugs long before they had a theory suggesting how to use them properly. Indeed, several of the drugs now being tested against cancer have been around for decades, but in the past were used in the wrong way for the wrong reason. Azacitidine, for example, was first discovered in Czechoslovakia in the 1960s as a traditional chemotherapy drug, and doctors used it to kill cancer cells the old-fashioned way: giving as much as patients could tolerate. Jones, a South African by birth who now heads the Norris Comprehensive Cancer Center at USC, discovered in the 1980s that the drug had another mode of action: it could turn genes back on by stripping away the "duct tape" of DNA methylation that muffled genes. This suggested a different kind of attack on cancer—not by killing cancer cells outright, but by reversing the epigenetic changes that make a cell cancerous in the first place.
In the 1980s, as a young oncology fellow at Mount Sinai School of Medicine in New York, Lewis Silverman proposed testing azacitidine as an epigenetic drug—that is, at lower doses than is typical for traditional chemotherapy, where it still might be effective reversing silenced genes. Silverman has since shown that low doses of the drug reduce the symptoms of a type of leukemia and allows patients to live longer. The Food and Drug Administration approved azacitidine in May 2004; the drug is now marketed as Vidaza.
A different class of epigenetic drug has emerged from work at Harvard, Columbia and Memorial Sloan-Kettering Cancer Center in New York. In addition to the silencing effect of methylation, genes can be turned on and off by enzymes that tighten or loosen the packaging of DNA. Paul Marks and Ronald Breslow at Columbia created a small molecule, called vorinostat, that blocks the action of the enzymes that tamper with DNA's packaging, thus turning inactivated genes back on. That drug was approved by the FDA in 2006 for a rare form of lymphoma and is now being tested against a number of other cancers; Merck markets the drug as Zolinza. Part of the current clinical excitement is that there are already hints that combinations of these and second-generation drugs may be more effective at reversing the epigenetic changes in cancer cells.
Researchers remain guarded in their optimism. Issa concedes that the first-generation epigenetic drugs have not included a home run like Gleevec, the molecular treatment for chronic myeloid leukemia that produces dramatic and lasting remissions. And it is not unusual for deleterious side effects to become more apparent as drugs are used more widely—a particular concern in the case of drugs that have the potential to modify gene expression broadly in normal cells. But people who have witnessed the explosion of promising results in the past year have difficulty suppressing their excitement. "The promise is staggering," says Allis.
The stakes in epigenetics go well beyond clinical therapies, however. There have been hints from laboratory experiments and epidemiological studies that epigenetic changes in one generation—caused, for example, by smoking or diet—can be passed on to children and even grandchildren. Reik, who is also associate director of the Babraham Institute in Cambridge, is investigating how the overlay of epigenetic changes is erased from DNA when mice make their germ cells—how all the epigenetic changes, like some microscopic version of duct tape, get stripped off the DNA that goes into the sperm in males and eggs in females. "People are now beginning to realize that there are probably things that don't get wiped out or erased in the germ cells," he says, "so these are so-called epimutations that can be passed on from parents to children and to grandchildren—not genetic changes passed on, like Mendel, but an epimutation.
"We don't know how common this might be," Reik adds, choosing his words carefully, "but it's potentially quite revolutionary. It's not only challenging Mendel, but potentially challenging even Darwin. We are very careful when we talk about these things."
If the amount of clinical testing seems surprising, it's probably because the medical part of the epigenetics story is unfolding in reverse: doctors had the drugs long before they had a theory suggesting how to use them properly. Indeed, several of the drugs now being tested against cancer have been around for decades, but in the past were used in the wrong way for the wrong reason. Azacitidine, for example, was first discovered in Czechoslovakia in the 1960s as a traditional chemotherapy drug, and doctors used it to kill cancer cells the old-fashioned way: giving as much as patients could tolerate. Jones, a South African by birth who now heads the Norris Comprehensive Cancer Center at USC, discovered in the 1980s that the drug had another mode of action: it could turn genes back on by stripping away the "duct tape" of DNA methylation that muffled genes. This suggested a different kind of attack on cancer—not by killing cancer cells outright, but by reversing the epigenetic changes that make a cell cancerous in the first place.
In the 1980s, as a young oncology fellow at Mount Sinai School of Medicine in New York, Lewis Silverman proposed testing azacitidine as an epigenetic drug—that is, at lower doses than is typical for traditional chemotherapy, where it still might be effective reversing silenced genes. Silverman has since shown that low doses of the drug reduce the symptoms of a type of leukemia and allows patients to live longer. The Food and Drug Administration approved azacitidine in May 2004; the drug is now marketed as Vidaza.
A different class of epigenetic drug has emerged from work at Harvard, Columbia and Memorial Sloan-Kettering Cancer Center in New York. In addition to the silencing effect of methylation, genes can be turned on and off by enzymes that tighten or loosen the packaging of DNA. Paul Marks and Ronald Breslow at Columbia created a small molecule, called vorinostat, that blocks the action of the enzymes that tamper with DNA's packaging, thus turning inactivated genes back on. That drug was approved by the FDA in 2006 for a rare form of lymphoma and is now being tested against a number of other cancers; Merck markets the drug as Zolinza. Part of the current clinical excitement is that there are already hints that combinations of these and second-generation drugs may be more effective at reversing the epigenetic changes in cancer cells.
Researchers remain guarded in their optimism. Issa concedes that the first-generation epigenetic drugs have not included a home run like Gleevec, the molecular treatment for chronic myeloid leukemia that produces dramatic and lasting remissions. And it is not unusual for deleterious side effects to become more apparent as drugs are used more widely—a particular concern in the case of drugs that have the potential to modify gene expression broadly in normal cells. But people who have witnessed the explosion of promising results in the past year have difficulty suppressing their excitement. "The promise is staggering," says Allis.
The stakes in epigenetics go well beyond clinical therapies, however. There have been hints from laboratory experiments and epidemiological studies that epigenetic changes in one generation—caused, for example, by smoking or diet—can be passed on to children and even grandchildren. Reik, who is also associate director of the Babraham Institute in Cambridge, is investigating how the overlay of epigenetic changes is erased from DNA when mice make their germ cells—how all the epigenetic changes, like some microscopic version of duct tape, get stripped off the DNA that goes into the sperm in males and eggs in females. "People are now beginning to realize that there are probably things that don't get wiped out or erased in the germ cells," he says, "so these are so-called epimutations that can be passed on from parents to children and to grandchildren—not genetic changes passed on, like Mendel, but an epimutation.
"We don't know how common this might be," Reik adds, choosing his words carefully, "but it's potentially quite revolutionary. It's not only challenging Mendel, but potentially challenging even Darwin. We are very careful when we talk about these things."
http://www.newsweek.com/id/204233
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A Doctor’s Vision of the Future of Medicine
By Leroy Hood NEWSWEEK
From the magazine issue dated Jul 13, 2009
It's June 2018. Sally picks up a handheld device and holds it to her finger. With a tiny pinprick, it draws off a fraction of a droplet of blood, makes 2,000 different measurements and sends the data wirelessly to a distant computer for analysis. A few minutes later, Sally gets the results via e-mail, and a copy goes to her physician. All of Sally's organs are fine, and her physician advises her to do another home medical checkup in six months.
This is what the not-so-distant future of medicine will look like. Over the next two decades, medicine will change from its current reactive mode, in which doctors wait for people to get sick, to a mode that is far more preventive and rational. I like to call it P4 medicine—predictive, personalized, preventive and participatory. What's driving this change are powerful new measurement technologies and the so-called systems approach to medicine. Whereas medical researchers in the past studied disease by analyzing the effects of one gene at a time, the systems approach will give them the ability to analyze all your genes at once. The average doctor's office visit today might involve blood work and a few measurements, such as blood pressure and temperature; in the near future physicians will collect billions of bytes of information about each individual—genes, blood proteins, cells and historical data. They will use this data to assess whether your cell's biological information-handling circuits have become perturbed by disease, whether from defective genes, exposure to bad things in the environment or both.
Several emerging technologies are making this holistic, molecular approach to disease possible. Nano-size devices will measure thousands of blood elements, and DNA sequencers will decode individual human genomes rapidly, accurately and inexpensively. New computers will sort through huge amounts of data gathered annually on each individual and boil down this information to clear results about health and disease.
Medicine will begin to get more predictive and personalized (the first two aspects of P4 medicine) over the next five to 10 years. First, doctors will be able to sequence the genome of each patient, which together with other data will yield useful predictions about his or her future health; it will be able to tell you, for example, that you have a 30 percent chance of developing ovarian cancer before age 30. Second, a biannual assessment of your blood will make it possible to get an update on the current state of your health for each of your 50 or so organ systems. These steps will place the focus of medicine on individual patients and on assessing the impact that genes and their interactions with the environment have in determining health or disease.
In preventive medicine (the third P), researchers will use systems medicine to develop drugs that help prevent disease. If, say, you have a 50 percent chance of developing prostate cancer by the time you're 50, you may be able to start taking a drug when you're 30 that would reduce substantially reduce that probability. In the next 10 to 20 years the focus of health care will shift from dealing with disease to maintaining wellness.
Participatory medicine acknowledges the unparalleled opportunities that patients will have to take control of their health care. To participate effectively, though, they will have to be educated as to the basic principles of P4 medicine. New companies that can analyze human genome variation, like 23andMe and Navigenics, are already planning to provide patients with genetic information that may be useful in modifying their behavior to avoid future health problems. In the future, patients will need not just genetic data but insight into how the environment is turning genes on and off to cause disease—just as smoking often causes lung cancer and exposure to sunlight can cause skin cancer.
P4 medicine will have a big impact on many industries, including pharmaceuticals, food and insurance, as well as health care. The interesting question is whether preexisting businesses and entrenched bureaucracies will be able to respond to these winds of change, or whether a host of new companies will emerge to replace them—focused precisely on these new opportunities.
Research will also have to change. Because most important diseases such as diabetes, cancer, heart disease, obesity and Alzheimer's are so complex, the traditional approaches to studying them have had only marginal results. Powerful new systems approaches, individual measurements and computational technologies will transform our ability to deal with complexity and fashion new drugs and approaches for therapy and prevention.
Medical education will also need to be transformed. Although today's medical students will be practicing P4 medicine within the next five to 20 years, their training is still focused on a classification of disease based on observation of relatively few measurements of health parameters. Tomorrow's physicians will need to be familiar with the complexity of the human biological system as never before, and they'll have to be handy with computer-based tools. Physicians will need to deal with patients who have an enormous amount of information at their disposal. And doctors will need to deal with maintaining wellness more than with disease.
The digitization of medicine—that is, our ability to extract and store disease-relevant information from DNA and molecules in the blood of each individual—together with the revolutionary changes in diagnosis, therapy and prevention will allow those of us in the developed world to export P4 medicine to the developing world and thus transform the quality of its health care. The new P4 medicine will eventually lead to a universal democratization of health care, bringing to billions the fundamental right of health, unimaginable even a few years ago.
Hood invented the genome sequencing technology that led to the decoding of the human genome in 2001. He is a pioneer of systems biology and medicine and founder of the Institute for System Biology in Seattle, Washington.
http://www.newsweek.com/id/204227
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Biology’s Odd Couple
By Lily Huang NEWSWEEK
From the magazine issue dated Jul 13, 2009
About 10 years ago, biology entered betting season. An upstart scientist named J. Craig Venter jolted the genetics establishment by launching his own gene-sequencing outfit, funded by commercial investment, and setting off toward biology's holy grail—the human genome—on his own. It was Venter versus the old guard—old because of where they got their money (governments and trusts) and the sequencing technique they wanted to hold onto. Venter won that race, and not because he got there first. By combining the freedom of academic inquiry and commercial capital, he came up with a new way of doing science so effective that it forced the old institutions to either ramp up or play second fiddle.
With Venter's momentum, biology has continued to surge into new territory, but now he's not alone in pushing the pace. In fact, with his staff of hundreds at the J. Craig Venter Institute, he is looking dangerously like the establishment he raced past almost a decade ago. Another maverick in the stable, Harvard biologist George Church, is a titan in the academic world, tackling the major challenges of genomic-age biology with an ingenuity distinct from Venter's. Both are building on the foundation of DNA sequencing, trying to drive down the cost of decoding individual genomes and—the more radical enterprise—using their digital control of cells and DNA to design new organisms. Between them, Venter and Church direct or influence a major portion of work in both sequencing and synthetic biology, including three different commercial efforts to develop bacteria that could produce the next generation of biofuels.
There's reason to believe that Church has a decent chance of unseating Venter as biology's next wunderkind. The field of genomics is only at the beginning of its growth spurt—sequencing, it turns out, was just phase one. Far from producing answers, the sequenced genome has instead led scientists into a thicket of questions: What exactly do combinations of genetic code produce in an organism over a lifetime? If we can read the script, can we also write it? Leading science out of the genomic wilderness arguably calls for a vision more deeply imaginative than the task of the Human Genome Project, which was clearly framed and, at heart, a code-reading slog. Radical invention—the kind of out-of-left-field inspiration that makes a thinker either brilliant or totally unrealistic—is the strength of Church, as opposed to Venter, who is more of an aggregator, a connector of existing ideas and methods. The script of this new biology is largely unwritten, and just because Venter turned the first page doesn't mean that in the end his vision will prevail. "Sometimes," Church says, "it's best to be second."
The quest for ideas farther afield may be one reason Venter joined the Harvard faculty this spring—his first academic post since 1982. (Venter declined to be interviewed for this article.) He and Church are even members of the same research initiative, called Origins of Life, where they're investigating life in its most basic genetic and molecular forms. Venter's participation is a sign of just how widely applicable the high-concept work of the university could be. More than ever, over the uncarved terrain of the new biology, Venter and Church are blurring the distinction between the academic and the commercial. Steven Shapin, a Harvard historian of science, says that at this point we must "stop categorizing—and just look at what these people are doing." On top of all the daring science, Venter and Church are also conducting a "sociology experiment": "They're making up their own social roles," Shapin says, "making up themselves." All the while, Church insists that he and Venter are "not right on top of each other" but are "part of the same ecosystem," fulfilling different roles. Then again, Shapin points out, "the lion and the wildebeest are in the same ecosystem." The question is, who's the lion?
If you were to speak of George Church as an underdog to any of his university peers, you would probably get a laugh: with more than a dozen graduate students and 18 postdoctoral researchers, he runs one of the biggest labs in the richest university in the world. Next to Venter's institute, though, his still feels like a scrappy outfit in the corner. But he likes it this way: "Sometimes—not always—the smaller operation is more nimble," he says. Church's group has produced prototypes for some of the second-generation DNA-sequencing machines, which he hopes will help bring down the cost of sequencing genomes to the point where your genes can be consulted as routinely as X-rays.
At the moment, both Venter and Church are working to construct rudimentary organisms. The promise of this technology is difficult to exaggerate. By altering the chemistry of organisms, manipulating genomes and even constructing parts of cells, they can engineer tools out of living things. Both Church and Venter think of cells as machinery. Announcing his latest breakthrough in March with the synthesis of ribosomes, the all-important protein generators of the cell, Church used a hot-rod analogy: "It's like the hood is off and you can tinker directly." Venter has described his own work with reengineering cells in terms of a PC: "We can boot up a chromosome … boot up a cell."
As Church and Venter lay the groundwork for a new way of understanding and using biology, their respective approaches reveal their essential differences. Venter's great stride toward designing life forms was in transplanting the genome of one bacterium into another—two different species of the genus Mycoplasma. The transplanted genome took over its new cells and turned them into cells of its own species. Preceding Church at the Harvard lectern in March at an Origins of Life symposium, Venter described this as creating "software that makes its own hardware"—but in truth both software and hardware were already present and living; he came up with a different combination, and got it to do something completely novel. Church, in making ribosomes, has surmounted a different kind of barrier. The ribosome is regarded as the living cell's most irreducible part, and something common to every kind of cell—those that make up bacteria as well as plants and humans. The physicist Freeman Dyson has spoken of the ribosome as the key to the origin of life; two years ago, at an intimate gathering of some of the world's most imaginative scientists on a Connecticut farm, Dyson told Church, Venter and the three other researchers present that "the invention of the ribosome is the central mystery" of how living things ever came to be. Church has now managed to take a ribosome apart and build it up again, which means he can make something even more primitive—until, with a simple collection of atoms, he jump-starts a living organism of his own making. "I'm not quite ready to say that we have connected all the dots," he says, but it's now conceivable that "you can get from chemicals to RNAs, to smallish ribosomes, to full ribosomes, and then to a cell."
Right now, for both scientists, the bacterial equivalent of a hot rod is an organism that can consume carbon dioxide and make engine fuel. Last year Venter told newsweek that Synthetic Genomics, the commercial counterpart of his nonprofit research institute, was one or two years away from producing its first fuels. Church, though, had already founded a startup, LS9, in 2005 to develop a commercial product. The idea behind both ventures is to exploit the ability of natural bacteria to turn sugar into fatty acids, which is only a few chemical steps removed from diesel fuel.
At this stage, both Church and Venter welcome a crowded playing field, with different startups testing a variety of approaches, but this race, more than that for the human genome, has a far more tangible prize for whoever is first—or maybe, if they succeed better, second. "There will be convergence on whatever works," Church says. "Until there's actually somebody making a lot of money, there's not going to be convergence." In the meantime, Church cheerfully points out that Venter is manipulating the wrong kind of bacterium. While he and others are using E. coli, Venter has stuck with Mycoplasma, which has very few genes to manipulate but grows far more slowly and has a sensitive membrane, so that it is likely to come apart on contact with the fuel it's meant to produce. "He's like Captain Ahab," says Church of Venter. "The Mycoplasma is his white whale. He decided that small is beautiful and he's going to synthesize it. Partly because he wasn't prepared to change the technology enough so he could synthesize something bigger."
Church is, foremost, an inventor in the purest sense, someone who would make something completely new to perform a function that no one even thought might be helpful. His chief preoccupation in graduate school was making an automated DNA sequencer that could process vast amounts of data as quickly as possible. In 1979, even people in his own lab didn't see why you would ever want something like that. "That was really ridiculously out of touch with where the market was," Church admits now, but his eyes smile. Years later, Leroy Hood, at Caltech, made the prototype that became the ABI 3700, the first-generation automated sequencer that inspired Venter to crash through the gates of the genome. Hood disparaged that early model as the equivalent of a Ford Model A, but Venter couldn't wait; he pushed on with it, worked out the inevitable bugs and, by running 300 imperfect machines instead of 230 perfect ones, ground out the human genome. Church, though, was already working ahead.
Venter's genius lies in using invented technologies and techniques to produce unexpected breakthroughs. The ABI 3700s, those Model A's, nevertheless became famous because of what he got them to do. The shotgun sequencing technique didn't originate from him, but he showed the range of its utility, first by sequencing whole genomes, and then by taking genetic snapshots of the ocean and the earth's soil by sequencing samples of living things. When he saw how the ABI machine worked, he realized that all the parts needed for a new genomic age were now in place: a collection of complementary DNA plasmids; a company that purified those plasmids, so they could be sequenced; an automated sequencer; and a public database where sequences of genes could be stored. The connections Venter saw between these four groups gave way to his vision.
There is a price, though, to precipitous application: though Venter sequenced the first diploid human genome (his own, completed in 2007) for far less than the $3 billion originally projected by the federal budget, it was still on the order of $70 million—for one genome. Church, using his own second-generation sequencing instruments just two years later, has now sequenced 95 percent of his genome, while running a tab of about $5,000. He simultaneously sequenced the genomes of nine other people, too, to launch the Personal Genome Project, an open database of genomes matched with each individual's phenotypic traits and medical history. The aim is to amass a statistically significant pool of data that would begin to show the complex connections between a person's genes and the traits and diseases that actually manifest in one's life. The project now has more than 13,000 volunteers for sequencing, and Church hopes to collect 100,000. None of this would have been possible with first-generation sequencing technology, and, says Church, "I didn't really want to do it until the price was right."
When asked, at the Connecticut retreat, how their work was different, Church replied, "Craig is more productive." To which Venter graciously added, "I use George's techniques." As they build the new biology, they have moved closer and closer into each other's orbit, perhaps the better to see, in the work of the other, how the future is shaping up. And though their work gets at the core of living things—in ways that may give humans control over the very process that created life—they are capable of an almost comical diffidence. This isn't "playing God": "You're certainly not creating a universe," said Church at the discussion table in Connecticut. "You're constructing things."
"You're only so big," Venter added.
"Pretty small," agreed Church. "Pretty small."
© 2009
http://www.newsweek.com/id/204235
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Life’s Complexities
The genome's bounty is further off than expected, but it may yet yield deeper and wider insights.
Fred Guterl
From the magazine issue dated Jul 13, 2009
If a person's genes are his destiny, why do Sunney Xie's twin daughters have different personalities, and even different fingerprints? The girls share identical genes and nearly identical upbringings, and yet somehow, as they developed through toddlerhood, their biological paths diverged. Biologists have been pondering the relative influence of nature and nurture since long before Crick and Watson discovered the basic structure of DNA in 1953, but is it possible, after all these years, that they've been missing a third influence? Xie, a biologist at Harvard, has for the past three years performed experiments in his Cambridge, Massachusetts, lab aimed squarely at this question, and he thinks he's found the overlooked factor. It is pure chance.
The idea that randomness may play a role in the life of the cell is still largely conjectural, but it is typical of the kind of intellectual ferment in the life sciences of late. It's been nine years since Craig Venter and others decoded the human genome, the panoply of genes that govern the workings of each and every human cell, and declared that the "book of life" had been revealed. Since then, biologists have found that the genome is only the beginning to life's complexities. Only slightly more than 1 percent of the genome consists of genes that produce proteins, which do the day-to-day job of running the cell's operations. Scientists are pretty sure the other 99 percent plays a big role, but what that might be is still being sorted out. Although biologists have known since the 1980s that only a few diseases are caused by a single gene, some are now thought to arise from varying subsets of tens of thousands of genes. And as if the genome weren't complex enough, the way these genes are packaged in the cell may have as much to do with development and disease than the genes themselves. This phenomenon, called "epigenetics," may even account for traits that are passed down from one generation to the next—in other words, inheritance without DNA.
These developments mean that the full bounty of the genomics revolution is going to take longer than most people thought 10 years ago. But there's reason to believe that the route out of the present confusion will lead to deeper and wider insights, as the stories in this special report on the life sciences show. For one thing, significant practical breakthroughs are already brewing in the labs. Epigenetics has already led to some startling leads in the war on cancer and other diseases, and drugs for some forms of leukemia, for instance, are already in the pipeline. Scientists have figured out how to take adult stem cells from the skin and other organs and reprogram them genetically, the first step toward turning them into replacement tissue tailor-made to the patient's immune system. The realization that the cell is a complex entity that is greater than the sum of its parts has forced doctors on the forefront of medical research to consider their patients as biological "systems." This awareness is now transforming the way medicine is practiced and taught, as Dr. Leroy Hood points out in an essay.
Medicine isn't the only field that's set to benefit from the new genomics, as our report shows. A better understanding of the biological underpinnings of plants is giving scientists ways of improving the yields and nutritional content of crops without having to tinker directly with the genetic makeup of plants. It's also opened the door to the possibility of meddling with the biosphere itself by introducing genetically modified creatures, such as mosquitoes with immunity to the malaria parasite, into the wild. Research along these lines is causing something of a furor in environment circles, as health officials look to technology to improve global health.
Randomness hasn't yet emerged into the mainstream of biology, but its recent appearance in scholarly journals adds a certain symmetry to science. Probabilities played a role in the huge upheaval in physics in the early 20th century. In 1926 Erwin Schrödinger declared that an atom isn't anything like a tiny solar system, and that electrons, unlike planets, are best described in terms of the likelihood of their appearing at any one place and time. The idea raised Albert Einstein's hackles: "God doesn't play dice with the universe," he objected. But it made the equations come out better, and equations are hard to argue with, especially when they produce nuclear weapons and iPods. If it turns out that God also rolls the dice each time a stretch of DNA does its work, it could mean that biology needs a new mathematics that takes probabilities into account, just as physics did after Schrödinger. To say that biology stands today where physics stood in 1926—on the verge of rewriting its equations—is pure conjecture, but it's got the feel of truth.
URL: http://www.newsweek.com/id/204236© 2009
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Beyond the Book of Life
By Stephen S. Hall NEWSWEEK
From the magazine issue dated Jul 13, 2009
Roll over, Mendel. Watson and Crick? They are so your old man's version of DNA. And that big multibillion-dollar hullabaloo called the Human Genome Project? To some scientists, it's beginning to look like an expensive genetic floor pad for a much more intricate—and dynamic—tapestry of life that lies on top of it.
There's a revolution sweeping biology today—begrudged by a few, but accepted by more and more biologists—that is changing scientific thinking about the way genes work, the way diseases arise and the way some of the most dreadful among them, including cancer, might be diagnosed and treated. This revolution is called epigenetics, and it is not only beginning to explain some of the biological mysteries that deepened with the Human Genome Project. Because of a series of accidental events, it is already prolonging the lives of human patients with deadly diseases.
Over the past several years, and largely without much public notice, physicians have reported success using epigenetic therapies against cancers of the blood and have even made progress against intractable solid-tumor malignancies like lung cancer. The story is still preliminary and unfolding (dozens of clinical trials using epigenetic drugs are currently underway), but Dr. Margaret Foti, chief executive officer of the American Association for Cancer Research, recently noted that epigenetics is already resulting in "significant improvements" in cancer diagnosis and therapy. "It's really coming into its own now," she said. Leaping on the bandwagon, the National Institutes of Health made epigenetics the focus of one of its cutting-edge "Roadmap" initiatives announced last fall.
"I think we were all brought up to think the genome was it," says C. David Allis, a scientist at Rockefeller University whose research in the 1990s helped catalyze the current interest in epigenetics. "But even when the genome was a done deal, some people thought, 'Is that the whole story?' It's really been a watershed in understanding that there is something beyond the genome."
The emergence of epigenetics represents a fundamental rethinking of how molecular biology works. Scientists have learned that while DNA remains the basic text of life, the script is often controlled by stage directions embedded in a layer of biochemicals that, roughly speaking, sit on top of the DNA. These modifications, called epimutations, can turn genes on and off, often at inappropriate times. In other words, epigenetics has introduced the startling idea that it's not just the book of life (in the form of DNA) that's important, but how the book is packaged.
At one level, this higher order of control makes perfect sense. Biologists have long known that developing organisms—humans included—need a full complement of genes at the moment of fertilization, but that many genes subsequently get turned on and off as the embryo develops. In humans, this is a lifelong process. There are genes for a fetal version of hemoglobin, for example, and then an adult version that kicks in after birth; through epigenetic control, the fetal genes are permanently turned off at a certain stage of development, and the adult genes are permanently activated. As each one of us developed from a fertilized egg, stem cells in the early embryo matured into brain cells, liver cells and indeed several hundred specialized cells and tissues; at each step of that maturation process, our DNA was modified. When we entered puberty, quiescent genes were suddenly activated. And as we age, the dings of earlier life experiences seem to shape the activity of our DNA. Many if not most of those changes are epigenetic in nature, where the DNA itself remains unchanged, but the packaging has been dramatically perturbed; animal experiments suggest that environmental factors, from childhood diet and maternal care to stress, can play epigenetic havoc with our basic DNA hardware.
The interest in epigenetics has assumed critical mass in the past 10 years for several reasons. The Human Genome Project, often touted as "biology's moonshot," provided the basic text of life, in the form of the complete human sequence of DNA, but scientists have had a hard time linking specific genetic causes to many common illnesses. The role of "misspelled" DNA (in the form of both classic mutations and genetic variation, first teased out in the 19th century by the monk Gregor Mendel) has turned out to explain, in the words of a recent New England Journal of Medicinecommentator, "only a small fraction of disease." "We were all raised on the Watson and Crick concept of DNA-driven inheritance," Allis says. "It turns out that epigenetics may be even more responsible for gene expression and disease than DNA alone, especially in more advanced multicellular organisms." In the 1990s, meanwhile, scientists like Allis reported basic but breathtaking discoveries that showed how several groups of enzymes, common to every cell, could create epimutations without ever changing the DNA script.
Basic research has shown that enzymes can tamper with genetic information in at least two distinct ways. In some cases, the on-off switch of a gene can be smothered when an enzyme attaches chemicals to the DNA; known as DNA methy-lation, this process essentially silences a gene that should be on. In other cases, a separate class of enzyme improperly disrupts the normal cellular packaging of DNA. Typically, the gossamer thread of DNA is wound around a spool of protein called histone; when this second class of enzymes strips away part of the packaging, the DNA becomes so tightly wound up that it can't loosen up enough to be read by the cell. In effect, the slip jacket for specific genes is so tight that it's impossible to crack open the spine and get a glimpse of the genetic text. Conversely, sometimes genes that should remain permanently interred in a tomb of histone suddenly come back to life, like some cellular version of Night of the Living Dead.
In the past five years, the evidence has become "absolutely rock solid" to cancer researchers that epigenetic changes play a fundamental role in cancer, according to Robert A. Weinberg, an elder statesman of cancer biology at the Whitehead Institute in Cambridge, Mass. DNA methylation, he adds, "may ultimately be far more important than gene mutation in shutting down tumor suppressor genes," one of the cell's main mechanisms to short-circuit an incipient cancer.
Each epigenetic change seems to leave a chemical flag, or "mark," on the DNA, and hence researchers are intensely cataloging these marks into "epigenomes" as a possible clue to diagnosis, prognosis and perhaps even prevention of disease. Unlike genetic markers, which reveal small "typographic" variations in the spelling of genes, epigenetic markers indicate places where entire genes have been silenced or activated. Paula Vertino of the Emory University School of Medicine, for example, has identified patches of DNA that seem especially prone to be inappropriately silenced or activated in breast and lung cancer; researchers at Johns Hopkins have used epigenetic markers in brain-cancer cells to predict which patients are likelier to benefit from chemotherapy. Recent laboratory findings suggest that deciphering the layers of genetic control modifying DNA has implications not just for cancer, but also for chronic diseases associated with aging, like heart disease and diabetes; for mental disorders like autism and depression; for stem-cell biology; and even for our notions of what constitutes an inherited disease. Everything is up for grabs.
"There's only one genome," says Wolf Reik, professor of epigenetics at the University of Cambridge in England, "but hundreds of epigenomes." And unlike string theory in physics, for example, epigenetics is neither an exotic intellectual idea nor a theory awaiting verificationby future data. The biology is real, and the practical effects have already reached the bedside.
In the 1990s, Stephen Baylin of Johns Hopkins University led the effort showing that epigenetic changes in DNA were associated with cancer; in fact, disruptions in tumor suppressor genes, which normally protect cells against cancer, are more often due to epigenetic silencing than outright mutation. In May, Baylin and Peter Jones of the University of Southern California received a three-year, $9.1 million grant to launch accelerated testing of epigenetic therapy in patients with lung, colon and breast cancer, with interim results promised within a year. The Hopkins group has presented preliminary results at recent meetings showing that a combination of two epigenetic drugs produced several responses (including one complete remission) in patients with advanced lung cancer. "The trials are still ongoing, and we don't know what percentage of patients will respond, if it will be 10 or 20 percent," says Baylin. "But we have had very robust responses, of both primary tumors and metastases, in non-small-cell lung cancer." "That's just extraordinary," says Foti of AACR, noting the poor prognosis for patients with these advanced cancers.
If the amount of clinical testing seems surprising, it's probably because the medical part of the epigenetics story is unfolding in reverse: doctors had the drugs long before they had a theory suggesting how to use them properly. Indeed, several of the drugs now being tested against cancer have been around for decades, but in the past were used in the wrong way for the wrong reason. Azacitidine, for example, was first discovered in Czechoslovakia in the 1960s as a traditional chemotherapy drug, and doctors used it to kill cancer cells the old-fashioned way: giving as much as patients could tolerate. Jones, a South African by birth who now heads the Norris Comprehensive Cancer Center at USC, discovered in the 1980s that the drug had another mode of action: it could turn genes back on by stripping away the "duct tape" of DNA methylation that muffled genes. This suggested a different kind of attack on cancer—not by killing cancer cells outright, but by reversing the epigenetic changes that make a cell cancerous in the first place.
In the 1980s, as a young oncology fellow at Mount Sinai School of Medicine in New York, Lewis Silverman proposed testing azacitidine as an epigenetic drug—that is, at lower doses than is typical for traditional chemotherapy, where it still might be effective reversing silenced genes. Silverman has since shown that low doses of the drug reduce the symptoms of a type of leukemia and allows patients to live longer. The Food and Drug Administration approved azacitidine in May 2004; the drug is now marketed as Vidaza.
A different class of epigenetic drug has emerged from work at Harvard, Columbia and Memorial Sloan-Kettering Cancer Center in New York. In addition to the silencing effect of methylation, genes can be turned on and off by enzymes that tighten or loosen the packaging of DNA. Paul Marks and Ronald Breslow at Columbia created a small molecule, called vorinostat, that blocks the action of the enzymes that tamper with DNA's packaging, thus turning inactivated genes back on. That drug was approved by the FDA in 2006 for a rare form of lymphoma and is now being tested against a number of other cancers; Merck markets the drug as Zolinza. Part of the current clinical excitement is that there are already hints that combinations of these and second-generation drugs may be more effective at reversing the epigenetic changes in cancer cells.
Researchers remain guarded in their optimism. Issa concedes that the first-generation epigenetic drugs have not included a home run like Gleevec, the molecular treatment for chronic myeloid leukemia that produces dramatic and lasting remissions. And it is not unusual for deleterious side effects to become more apparent as drugs are used more widely—a particular concern in the case of drugs that have the potential to modify gene expression broadly in normal cells. But people who have witnessed the explosion of promising results in the past year have difficulty suppressing their excitement. "The promise is staggering," says Allis.
The stakes in epigenetics go well beyond clinical therapies, however. There have been hints from laboratory experiments and epidemiological studies that epigenetic changes in one generation—caused, for example, by smoking or diet—can be passed on to children and even grandchildren. Reik, who is also associate director of the Babraham Institute in Cambridge, is investigating how the overlay of epigenetic changes is erased from DNA when mice make their germ cells—how all the epigenetic changes, like some microscopic version of duct tape, get stripped off the DNA that goes into the sperm in males and eggs in females. "People are now beginning to realize that there are probably things that don't get wiped out or erased in the germ cells," he says, "so these are so-called epimutations that can be passed on from parents to children and to grandchildren—not genetic changes passed on, like Mendel, but an epimutation.
"We don't know how common this might be," Reik adds, choosing his words carefully, "but it's potentially quite revolutionary. It's not only challenging Mendel, but potentially challenging even Darwin. We are very careful when we talk about these things."
© 2009 If the amount of clinical testing seems surprising, it's probably because the medical part of the epigenetics story is unfolding in reverse: doctors had the drugs long before they had a theory suggesting how to use them properly. Indeed, several of the drugs now being tested against cancer have been around for decades, but in the past were used in the wrong way for the wrong reason. Azacitidine, for example, was first discovered in Czechoslovakia in the 1960s as a traditional chemotherapy drug, and doctors used it to kill cancer cells the old-fashioned way: giving as much as patients could tolerate. Jones, a South African by birth who now heads the Norris Comprehensive Cancer Center at USC, discovered in the 1980s that the drug had another mode of action: it could turn genes back on by stripping away the "duct tape" of DNA methylation that muffled genes. This suggested a different kind of attack on cancer—not by killing cancer cells outright, but by reversing the epigenetic changes that make a cell cancerous in the first place.
In the 1980s, as a young oncology fellow at Mount Sinai School of Medicine in New York, Lewis Silverman proposed testing azacitidine as an epigenetic drug—that is, at lower doses than is typical for traditional chemotherapy, where it still might be effective reversing silenced genes. Silverman has since shown that low doses of the drug reduce the symptoms of a type of leukemia and allows patients to live longer. The Food and Drug Administration approved azacitidine in May 2004; the drug is now marketed as Vidaza.
A different class of epigenetic drug has emerged from work at Harvard, Columbia and Memorial Sloan-Kettering Cancer Center in New York. In addition to the silencing effect of methylation, genes can be turned on and off by enzymes that tighten or loosen the packaging of DNA. Paul Marks and Ronald Breslow at Columbia created a small molecule, called vorinostat, that blocks the action of the enzymes that tamper with DNA's packaging, thus turning inactivated genes back on. That drug was approved by the FDA in 2006 for a rare form of lymphoma and is now being tested against a number of other cancers; Merck markets the drug as Zolinza. Part of the current clinical excitement is that there are already hints that combinations of these and second-generation drugs may be more effective at reversing the epigenetic changes in cancer cells.
Researchers remain guarded in their optimism. Issa concedes that the first-generation epigenetic drugs have not included a home run like Gleevec, the molecular treatment for chronic myeloid leukemia that produces dramatic and lasting remissions. And it is not unusual for deleterious side effects to become more apparent as drugs are used more widely—a particular concern in the case of drugs that have the potential to modify gene expression broadly in normal cells. But people who have witnessed the explosion of promising results in the past year have difficulty suppressing their excitement. "The promise is staggering," says Allis.
The stakes in epigenetics go well beyond clinical therapies, however. There have been hints from laboratory experiments and epidemiological studies that epigenetic changes in one generation—caused, for example, by smoking or diet—can be passed on to children and even grandchildren. Reik, who is also associate director of the Babraham Institute in Cambridge, is investigating how the overlay of epigenetic changes is erased from DNA when mice make their germ cells—how all the epigenetic changes, like some microscopic version of duct tape, get stripped off the DNA that goes into the sperm in males and eggs in females. "People are now beginning to realize that there are probably things that don't get wiped out or erased in the germ cells," he says, "so these are so-called epimutations that can be passed on from parents to children and to grandchildren—not genetic changes passed on, like Mendel, but an epimutation.
"We don't know how common this might be," Reik adds, choosing his words carefully, "but it's potentially quite revolutionary. It's not only challenging Mendel, but potentially challenging even Darwin. We are very careful when we talk about these things."
If the amount of clinical testing seems surprising, it's probably because the medical part of the epigenetics story is unfolding in reverse: doctors had the drugs long before they had a theory suggesting how to use them properly. Indeed, several of the drugs now being tested against cancer have been around for decades, but in the past were used in the wrong way for the wrong reason. Azacitidine, for example, was first discovered in Czechoslovakia in the 1960s as a traditional chemotherapy drug, and doctors used it to kill cancer cells the old-fashioned way: giving as much as patients could tolerate. Jones, a South African by birth who now heads the Norris Comprehensive Cancer Center at USC, discovered in the 1980s that the drug had another mode of action: it could turn genes back on by stripping away the "duct tape" of DNA methylation that muffled genes. This suggested a different kind of attack on cancer—not by killing cancer cells outright, but by reversing the epigenetic changes that make a cell cancerous in the first place.
In the 1980s, as a young oncology fellow at Mount Sinai School of Medicine in New York, Lewis Silverman proposed testing azacitidine as an epigenetic drug—that is, at lower doses than is typical for traditional chemotherapy, where it still might be effective reversing silenced genes. Silverman has since shown that low doses of the drug reduce the symptoms of a type of leukemia and allows patients to live longer. The Food and Drug Administration approved azacitidine in May 2004; the drug is now marketed as Vidaza.
A different class of epigenetic drug has emerged from work at Harvard, Columbia and Memorial Sloan-Kettering Cancer Center in New York. In addition to the silencing effect of methylation, genes can be turned on and off by enzymes that tighten or loosen the packaging of DNA. Paul Marks and Ronald Breslow at Columbia created a small molecule, called vorinostat, that blocks the action of the enzymes that tamper with DNA's packaging, thus turning inactivated genes back on. That drug was approved by the FDA in 2006 for a rare form of lymphoma and is now being tested against a number of other cancers; Merck markets the drug as Zolinza. Part of the current clinical excitement is that there are already hints that combinations of these and second-generation drugs may be more effective at reversing the epigenetic changes in cancer cells.
Researchers remain guarded in their optimism. Issa concedes that the first-generation epigenetic drugs have not included a home run like Gleevec, the molecular treatment for chronic myeloid leukemia that produces dramatic and lasting remissions. And it is not unusual for deleterious side effects to become more apparent as drugs are used more widely—a particular concern in the case of drugs that have the potential to modify gene expression broadly in normal cells. But people who have witnessed the explosion of promising results in the past year have difficulty suppressing their excitement. "The promise is staggering," says Allis.
The stakes in epigenetics go well beyond clinical therapies, however. There have been hints from laboratory experiments and epidemiological studies that epigenetic changes in one generation—caused, for example, by smoking or diet—can be passed on to children and even grandchildren. Reik, who is also associate director of the Babraham Institute in Cambridge, is investigating how the overlay of epigenetic changes is erased from DNA when mice make their germ cells—how all the epigenetic changes, like some microscopic version of duct tape, get stripped off the DNA that goes into the sperm in males and eggs in females. "People are now beginning to realize that there are probably things that don't get wiped out or erased in the germ cells," he says, "so these are so-called epimutations that can be passed on from parents to children and to grandchildren—not genetic changes passed on, like Mendel, but an epimutation.
"We don't know how common this might be," Reik adds, choosing his words carefully, "but it's potentially quite revolutionary. It's not only challenging Mendel, but potentially challenging even Darwin. We are very careful when we talk about these things."
http://www.newsweek.com/id/204233
-----------
A Doctor’s Vision of the Future of Medicine
By Leroy Hood NEWSWEEK
From the magazine issue dated Jul 13, 2009
It's June 2018. Sally picks up a handheld device and holds it to her finger. With a tiny pinprick, it draws off a fraction of a droplet of blood, makes 2,000 different measurements and sends the data wirelessly to a distant computer for analysis. A few minutes later, Sally gets the results via e-mail, and a copy goes to her physician. All of Sally's organs are fine, and her physician advises her to do another home medical checkup in six months.
This is what the not-so-distant future of medicine will look like. Over the next two decades, medicine will change from its current reactive mode, in which doctors wait for people to get sick, to a mode that is far more preventive and rational. I like to call it P4 medicine—predictive, personalized, preventive and participatory. What's driving this change are powerful new measurement technologies and the so-called systems approach to medicine. Whereas medical researchers in the past studied disease by analyzing the effects of one gene at a time, the systems approach will give them the ability to analyze all your genes at once. The average doctor's office visit today might involve blood work and a few measurements, such as blood pressure and temperature; in the near future physicians will collect billions of bytes of information about each individual—genes, blood proteins, cells and historical data. They will use this data to assess whether your cell's biological information-handling circuits have become perturbed by disease, whether from defective genes, exposure to bad things in the environment or both.
Several emerging technologies are making this holistic, molecular approach to disease possible. Nano-size devices will measure thousands of blood elements, and DNA sequencers will decode individual human genomes rapidly, accurately and inexpensively. New computers will sort through huge amounts of data gathered annually on each individual and boil down this information to clear results about health and disease.
Medicine will begin to get more predictive and personalized (the first two aspects of P4 medicine) over the next five to 10 years. First, doctors will be able to sequence the genome of each patient, which together with other data will yield useful predictions about his or her future health; it will be able to tell you, for example, that you have a 30 percent chance of developing ovarian cancer before age 30. Second, a biannual assessment of your blood will make it possible to get an update on the current state of your health for each of your 50 or so organ systems. These steps will place the focus of medicine on individual patients and on assessing the impact that genes and their interactions with the environment have in determining health or disease.
In preventive medicine (the third P), researchers will use systems medicine to develop drugs that help prevent disease. If, say, you have a 50 percent chance of developing prostate cancer by the time you're 50, you may be able to start taking a drug when you're 30 that would reduce substantially reduce that probability. In the next 10 to 20 years the focus of health care will shift from dealing with disease to maintaining wellness.
Participatory medicine acknowledges the unparalleled opportunities that patients will have to take control of their health care. To participate effectively, though, they will have to be educated as to the basic principles of P4 medicine. New companies that can analyze human genome variation, like 23andMe and Navigenics, are already planning to provide patients with genetic information that may be useful in modifying their behavior to avoid future health problems. In the future, patients will need not just genetic data but insight into how the environment is turning genes on and off to cause disease—just as smoking often causes lung cancer and exposure to sunlight can cause skin cancer.
P4 medicine will have a big impact on many industries, including pharmaceuticals, food and insurance, as well as health care. The interesting question is whether preexisting businesses and entrenched bureaucracies will be able to respond to these winds of change, or whether a host of new companies will emerge to replace them—focused precisely on these new opportunities.
Research will also have to change. Because most important diseases such as diabetes, cancer, heart disease, obesity and Alzheimer's are so complex, the traditional approaches to studying them have had only marginal results. Powerful new systems approaches, individual measurements and computational technologies will transform our ability to deal with complexity and fashion new drugs and approaches for therapy and prevention.
Medical education will also need to be transformed. Although today's medical students will be practicing P4 medicine within the next five to 20 years, their training is still focused on a classification of disease based on observation of relatively few measurements of health parameters. Tomorrow's physicians will need to be familiar with the complexity of the human biological system as never before, and they'll have to be handy with computer-based tools. Physicians will need to deal with patients who have an enormous amount of information at their disposal. And doctors will need to deal with maintaining wellness more than with disease.
The digitization of medicine—that is, our ability to extract and store disease-relevant information from DNA and molecules in the blood of each individual—together with the revolutionary changes in diagnosis, therapy and prevention will allow those of us in the developed world to export P4 medicine to the developing world and thus transform the quality of its health care. The new P4 medicine will eventually lead to a universal democratization of health care, bringing to billions the fundamental right of health, unimaginable even a few years ago.
Hood invented the genome sequencing technology that led to the decoding of the human genome in 2001. He is a pioneer of systems biology and medicine and founder of the Institute for System Biology in Seattle, Washington.
http://www.newsweek.com/id/204227
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Biology’s Odd Couple
By Lily Huang NEWSWEEK
From the magazine issue dated Jul 13, 2009
About 10 years ago, biology entered betting season. An upstart scientist named J. Craig Venter jolted the genetics establishment by launching his own gene-sequencing outfit, funded by commercial investment, and setting off toward biology's holy grail—the human genome—on his own. It was Venter versus the old guard—old because of where they got their money (governments and trusts) and the sequencing technique they wanted to hold onto. Venter won that race, and not because he got there first. By combining the freedom of academic inquiry and commercial capital, he came up with a new way of doing science so effective that it forced the old institutions to either ramp up or play second fiddle.
With Venter's momentum, biology has continued to surge into new territory, but now he's not alone in pushing the pace. In fact, with his staff of hundreds at the J. Craig Venter Institute, he is looking dangerously like the establishment he raced past almost a decade ago. Another maverick in the stable, Harvard biologist George Church, is a titan in the academic world, tackling the major challenges of genomic-age biology with an ingenuity distinct from Venter's. Both are building on the foundation of DNA sequencing, trying to drive down the cost of decoding individual genomes and—the more radical enterprise—using their digital control of cells and DNA to design new organisms. Between them, Venter and Church direct or influence a major portion of work in both sequencing and synthetic biology, including three different commercial efforts to develop bacteria that could produce the next generation of biofuels.
There's reason to believe that Church has a decent chance of unseating Venter as biology's next wunderkind. The field of genomics is only at the beginning of its growth spurt—sequencing, it turns out, was just phase one. Far from producing answers, the sequenced genome has instead led scientists into a thicket of questions: What exactly do combinations of genetic code produce in an organism over a lifetime? If we can read the script, can we also write it? Leading science out of the genomic wilderness arguably calls for a vision more deeply imaginative than the task of the Human Genome Project, which was clearly framed and, at heart, a code-reading slog. Radical invention—the kind of out-of-left-field inspiration that makes a thinker either brilliant or totally unrealistic—is the strength of Church, as opposed to Venter, who is more of an aggregator, a connector of existing ideas and methods. The script of this new biology is largely unwritten, and just because Venter turned the first page doesn't mean that in the end his vision will prevail. "Sometimes," Church says, "it's best to be second."
The quest for ideas farther afield may be one reason Venter joined the Harvard faculty this spring—his first academic post since 1982. (Venter declined to be interviewed for this article.) He and Church are even members of the same research initiative, called Origins of Life, where they're investigating life in its most basic genetic and molecular forms. Venter's participation is a sign of just how widely applicable the high-concept work of the university could be. More than ever, over the uncarved terrain of the new biology, Venter and Church are blurring the distinction between the academic and the commercial. Steven Shapin, a Harvard historian of science, says that at this point we must "stop categorizing—and just look at what these people are doing." On top of all the daring science, Venter and Church are also conducting a "sociology experiment": "They're making up their own social roles," Shapin says, "making up themselves." All the while, Church insists that he and Venter are "not right on top of each other" but are "part of the same ecosystem," fulfilling different roles. Then again, Shapin points out, "the lion and the wildebeest are in the same ecosystem." The question is, who's the lion?
If you were to speak of George Church as an underdog to any of his university peers, you would probably get a laugh: with more than a dozen graduate students and 18 postdoctoral researchers, he runs one of the biggest labs in the richest university in the world. Next to Venter's institute, though, his still feels like a scrappy outfit in the corner. But he likes it this way: "Sometimes—not always—the smaller operation is more nimble," he says. Church's group has produced prototypes for some of the second-generation DNA-sequencing machines, which he hopes will help bring down the cost of sequencing genomes to the point where your genes can be consulted as routinely as X-rays.
At the moment, both Venter and Church are working to construct rudimentary organisms. The promise of this technology is difficult to exaggerate. By altering the chemistry of organisms, manipulating genomes and even constructing parts of cells, they can engineer tools out of living things. Both Church and Venter think of cells as machinery. Announcing his latest breakthrough in March with the synthesis of ribosomes, the all-important protein generators of the cell, Church used a hot-rod analogy: "It's like the hood is off and you can tinker directly." Venter has described his own work with reengineering cells in terms of a PC: "We can boot up a chromosome … boot up a cell."
As Church and Venter lay the groundwork for a new way of understanding and using biology, their respective approaches reveal their essential differences. Venter's great stride toward designing life forms was in transplanting the genome of one bacterium into another—two different species of the genus Mycoplasma. The transplanted genome took over its new cells and turned them into cells of its own species. Preceding Church at the Harvard lectern in March at an Origins of Life symposium, Venter described this as creating "software that makes its own hardware"—but in truth both software and hardware were already present and living; he came up with a different combination, and got it to do something completely novel. Church, in making ribosomes, has surmounted a different kind of barrier. The ribosome is regarded as the living cell's most irreducible part, and something common to every kind of cell—those that make up bacteria as well as plants and humans. The physicist Freeman Dyson has spoken of the ribosome as the key to the origin of life; two years ago, at an intimate gathering of some of the world's most imaginative scientists on a Connecticut farm, Dyson told Church, Venter and the three other researchers present that "the invention of the ribosome is the central mystery" of how living things ever came to be. Church has now managed to take a ribosome apart and build it up again, which means he can make something even more primitive—until, with a simple collection of atoms, he jump-starts a living organism of his own making. "I'm not quite ready to say that we have connected all the dots," he says, but it's now conceivable that "you can get from chemicals to RNAs, to smallish ribosomes, to full ribosomes, and then to a cell."
Right now, for both scientists, the bacterial equivalent of a hot rod is an organism that can consume carbon dioxide and make engine fuel. Last year Venter told newsweek that Synthetic Genomics, the commercial counterpart of his nonprofit research institute, was one or two years away from producing its first fuels. Church, though, had already founded a startup, LS9, in 2005 to develop a commercial product. The idea behind both ventures is to exploit the ability of natural bacteria to turn sugar into fatty acids, which is only a few chemical steps removed from diesel fuel.
At this stage, both Church and Venter welcome a crowded playing field, with different startups testing a variety of approaches, but this race, more than that for the human genome, has a far more tangible prize for whoever is first—or maybe, if they succeed better, second. "There will be convergence on whatever works," Church says. "Until there's actually somebody making a lot of money, there's not going to be convergence." In the meantime, Church cheerfully points out that Venter is manipulating the wrong kind of bacterium. While he and others are using E. coli, Venter has stuck with Mycoplasma, which has very few genes to manipulate but grows far more slowly and has a sensitive membrane, so that it is likely to come apart on contact with the fuel it's meant to produce. "He's like Captain Ahab," says Church of Venter. "The Mycoplasma is his white whale. He decided that small is beautiful and he's going to synthesize it. Partly because he wasn't prepared to change the technology enough so he could synthesize something bigger."
Church is, foremost, an inventor in the purest sense, someone who would make something completely new to perform a function that no one even thought might be helpful. His chief preoccupation in graduate school was making an automated DNA sequencer that could process vast amounts of data as quickly as possible. In 1979, even people in his own lab didn't see why you would ever want something like that. "That was really ridiculously out of touch with where the market was," Church admits now, but his eyes smile. Years later, Leroy Hood, at Caltech, made the prototype that became the ABI 3700, the first-generation automated sequencer that inspired Venter to crash through the gates of the genome. Hood disparaged that early model as the equivalent of a Ford Model A, but Venter couldn't wait; he pushed on with it, worked out the inevitable bugs and, by running 300 imperfect machines instead of 230 perfect ones, ground out the human genome. Church, though, was already working ahead.
Venter's genius lies in using invented technologies and techniques to produce unexpected breakthroughs. The ABI 3700s, those Model A's, nevertheless became famous because of what he got them to do. The shotgun sequencing technique didn't originate from him, but he showed the range of its utility, first by sequencing whole genomes, and then by taking genetic snapshots of the ocean and the earth's soil by sequencing samples of living things. When he saw how the ABI machine worked, he realized that all the parts needed for a new genomic age were now in place: a collection of complementary DNA plasmids; a company that purified those plasmids, so they could be sequenced; an automated sequencer; and a public database where sequences of genes could be stored. The connections Venter saw between these four groups gave way to his vision.
There is a price, though, to precipitous application: though Venter sequenced the first diploid human genome (his own, completed in 2007) for far less than the $3 billion originally projected by the federal budget, it was still on the order of $70 million—for one genome. Church, using his own second-generation sequencing instruments just two years later, has now sequenced 95 percent of his genome, while running a tab of about $5,000. He simultaneously sequenced the genomes of nine other people, too, to launch the Personal Genome Project, an open database of genomes matched with each individual's phenotypic traits and medical history. The aim is to amass a statistically significant pool of data that would begin to show the complex connections between a person's genes and the traits and diseases that actually manifest in one's life. The project now has more than 13,000 volunteers for sequencing, and Church hopes to collect 100,000. None of this would have been possible with first-generation sequencing technology, and, says Church, "I didn't really want to do it until the price was right."
When asked, at the Connecticut retreat, how their work was different, Church replied, "Craig is more productive." To which Venter graciously added, "I use George's techniques." As they build the new biology, they have moved closer and closer into each other's orbit, perhaps the better to see, in the work of the other, how the future is shaping up. And though their work gets at the core of living things—in ways that may give humans control over the very process that created life—they are capable of an almost comical diffidence. This isn't "playing God": "You're certainly not creating a universe," said Church at the discussion table in Connecticut. "You're constructing things."
"You're only so big," Venter added.
"Pretty small," agreed Church. "Pretty small."
© 2009
http://www.newsweek.com/id/204235
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