Tag Archives: genomics

Deconstructing Schizophrenia

Genetic and biomedical researchers have made yet another tremendous breakthrough from analyzing the human genome. This time a group of scientists, from Harvard Medical School, Boston Children’s Hospital and the Broad Institute, have identified key genetic markers and biological pathways that underlie schizophrenia.

In the US alone the psychiatric disorder affects around 2 million people. Symptoms of schizophrenia usually include hallucinations, delusional thinking and paranoia. While there are a number of drugs used to treat its symptoms, and psychotherapy to address milder forms, nothing as yet has been able to address its underlying cause(s). Hence the excitement.

From NYT:

Scientists reported on Wednesday that they had taken a significant step toward understanding the cause of schizophrenia, in a landmark study that provides the first rigorously tested insight into the biology behind any common psychiatric disorder.

More than two million Americans have a diagnosis of schizophrenia, which is characterized by delusional thinking and hallucinations. The drugs available to treat it blunt some of its symptoms but do not touch the underlying cause.

The finding, published in the journal Nature, will not lead to new treatments soon, experts said, nor to widely available testing for individual risk. But the results provide researchers with their first biological handle on an ancient disorder whose cause has confounded modern science for generations. The finding also helps explain some other mysteries, including why the disorder often begins in adolescence or young adulthood.

“They did a phenomenal job,” said David B. Goldstein, a professor of genetics at Columbia University who has been critical of previous large-scale projects focused on the genetics of psychiatric disorders. “This paper gives us a foothold, something we can work on, and that’s what we’ve been looking for now, for a long, long time.”

The researchers pieced together the steps by which genes can increase a person’s risk of developing schizophrenia. That risk, they found, is tied to a natural process called synaptic pruning, in which the brain sheds weak or redundant connections between neurons as it matures. During adolescence and early adulthood, this activity takes place primarily in the section of the brain where thinking and planning skills are centered, known as the prefrontal cortex. People who carry genes that accelerate or intensify that pruning are at higher risk of developing schizophrenia than those who do not, the new study suggests.

Some researchers had suspected that the pruning must somehow go awry in people with schizophrenia, because previous studies showed that their prefrontal areas tended to have a diminished number of neural connections, compared with those of unaffected people. The new paper not only strongly supports that this is the case, but also describes how the pruning probably goes wrong and why, and identifies the genes responsible: People with schizophrenia have a gene variant that apparently facilitates aggressive “tagging” of connections for pruning, in effect accelerating the process.

The research team began by focusing on a location on the human genome, the MHC, which was most strongly associated with schizophrenia in previous genetic studies. On a bar graph — called a Manhattan plot because it looks like a cluster of skyscrapers — the MHC looms highest.

Using advanced statistical methods, the team found that the MHC locus contained four common variants of a gene called C4, and that those variants produced two kinds of proteins, C4-A and C4-B.

The team analyzed the genomes of more than 64,000 people and found that people with schizophrenia were more likely to have the overactive forms of C4-A than control subjects. “C4-A seemed to be the gene driving risk for schizophrenia,” Dr. McCarroll said, “but we had to be sure.”

Read the entire article here.

A New Mobile App or Genomic Understanding?


Silicon Valley has been a tremendous incubator for some of most our recent inventions: the first integrated transistor chip, which led to Intel; the first true personal computer, which led to Apple. Yet, this esteemed venture capital (VC) community now seems to need a self-medication of innovation. Aren’t we all getting a little jaded from yet another “new, great mobile app” — worth in the tens of billions (but having no revenue model) — courtesy of a bright and young group of 20-somethings?

It is indeed gratifying to see innovators, young and old, rewarded for their creativity and perseverance. Yet, we should be encouraging more of our pioneers to look beyond the next cool smartphone invention. Perhaps our technological and industrial luminaries and their retinues of futurists could do us all a favor if they channeled more of their speculative funds at longer-term and more significant endeavors: cost-effective desalination; cheaper medications; understanding and curing our insidious diseases; antibiotic replacements; more effective recycling; cleaner power; cheaper and stronger infrastructure; more effective education. These are all difficult problems. But therein lies the reward.

Clearly some pioneering businesses are investing in these areas. But isn’t it time we insisted that the majority of our private and public intellectual capital (and financial) should be invested in truly meaningful ways. Here’s an example from Iceland — with their national human genome project.

From ars technica:

An Icelandic genetics firm has sequenced the genomes of 2,636 of its countrymen and women, finding genetic markers for a variety of diseases, as well as a new timeline for the paternal ancestor of all humans.

Iceland is, in many ways, perfectly suited to being a genetic case study. It has a small population with limited genetic diversity, a result of the population descending from a small number of settlers—between 8 and 20 thousand, who arrived just 1100 years ago. It also has an unusually well-documented genealogical history, with information sometimes stretching all the way back to the initial settlement of the country. Combined with excellent medical records, it’s a veritable treasure trove for genetic researchers.

The researchers at genetics firm deCODE compared the complete genomes of participants with historical and medical records, publishing their findings in a series of four papers in Nature Genetics last Wednesday. The wealth of data allowed them to track down genetic mutations that are related to a number of diseases, some of them rare. Although few diseases are caused by a single genetic mutation, a combination of mutations can increase the risk for certain diseases. Having access to a large genetic sample with corresponding medical data can help to pinpoint certain risk-increasing mutations.

Among their headline findings was the identification of the gene ABCA7 as a risk factor for Alzheimer’s disease. Although previous research had established that a gene in this region was involved in Alzheimer’s, this result delivers a new level of precision. The researchers replicated their results in further groups in Europe and the United States.

Also identified was a genetic mutation that causes early-onset atrial fibrillation, a heart condition causing an irregular and often very fast heart rate. It’s the most common cardiac arrhythmia condition, and it’s considered early-onset if it’s diagnosed before the age of 60. The researchers found eight Icelanders diagnosed with the condition, all carrying a mutation in the same gene, MYL4.

The studies also turned up a gene with an unusual pattern of inheritance. It causes increased levels of thyroid stimulation when it’s passed down from the mother, but decreased levels when inherited from the father.

Genetic research in mice often involves “knocking out” or switching off a particular gene to explore the effects. However, mouse genetics aren’t a perfect approximation of human genetics. Obviously, doing this in humans presents all sorts of ethical problems, but a population such as Iceland provides the perfect natural laboratory to explore how knockouts affect human health.

The data showed that eight percent of people in Iceland have the equivalent of a knockout, one gene that isn’t working. This provides an opportunity to look at the data in a different way: rather than only looking for people with a particular diagnosis and finding out what they have in common genetically, the researchers can look for people who have genetic knockouts, and then examine their medical records to see how their missing genes affect their health. It’s then possible to start piecing together the story of how certain genes affect physiology.

Finally, the researchers used the data to explore human history, using Y chromosome data from 753 Icelandic males. Based on knowledge about mutation rates, Y chromosomes can be used to trace the male lineage of human groups, establishing dates of events like migrations. This technique has also been used to work out when the common ancestor of all humans was alive. The maternal ancestor, known as “Mitochondrial Eve,” is thought to have lived 170,000 to 180,000 years ago, while the paternal ancestor had previously been estimated to have lived around 338,000 years ago.

The Icelandic data allowed the researchers to calculate what they suggest is a more accurate mutation rate, placing the father of all humans at around 239,000 years ago. This is the estimate with the greatest likelihood, but the full range falls between 174,000 and 321,000 years ago. This estimate places the paternal ancestor closer in time to the maternal ancestor.

Read the entire story here.

Image: Gígjökull, an outlet glacier extending from Eyjafjallajökull, Iceland. Courtesy of Andreas Tille / Wikipedia.

Biological Transporter

Molecular-biology entrepreneur and genomics engineering pioneer, Craig Venter, is at it again. In his new book, Life at the Speed of Light: From the Double Helix to the Dawn of Digital Life, Venter explains his grand ideas and the coming era of discovery.

From ars technica:

J Craig Venter has been a molecular-biology pioneer for two decades. After developing expressed sequence tags in the 90s, he led the private effort to map the human genome, publishing the results in 2001. In 2010, the J Craig Venter Institute manufactured the entire genome of a bacterium, creating the first synthetic organism.

Now Venter, author of Life at the Speed of Light: From the Double Helix to the Dawn of Digital Life, explains the coming era of discovery.

Wired: In Life at the Speed of Light, you argue that humankind is entering a new phase of evolution. How so?

J Craig Venter: As the industrial age is drawing to a close, I think that we’re witnessing the dawn of the era of biological design. DNA, as digitized information, is accumulating in computer databases. Thanks to genetic engineering, and now the field of synthetic biology, we can manipulate DNA to an unprecedented extent, just as we can edit software in a computer. We can also transmit it as an electromagnetic wave at or near the speed of light and, via a “biological teleporter,” use it to recreate proteins, viruses, and living cells at another location, changing forever how we view life.

So you view DNA as the software of life?

All the information needed to make a living, self-replicating cell is locked up within the spirals of DNA’s double helix. As we read and interpret that software of life, we should be able to completely understand how cells work, then change and improve them by writing new cellular software.

The software defines the manufacture of proteins that can be viewed as its hardware, the robots and chemical machines that run a cell. The software is vital because the cell’s hardware wears out. Cells will die in minutes to days if they lack their genetic-information system. They will not evolve, they will not replicate, and they will not live.

Of all the experiments you have done over the past two decades involving the reading and manipulation of the software of life, which are the most important?

I do think the synthetic cell is my most important contribution. But if I were to select a single study, paper, or experimental result that has really influenced my understanding of life more than any other, I would choose one that my team published in 2007, in a paper with the title Genome Transplantation in Bacteria: Changing One Species to Another. The research that led to this paper in the journal Science not only shaped my view of the fundamentals of life but also laid the groundwork to create the first synthetic cell. Genome transplantation not only provided a way to carry out a striking transformation, converting one species into another, but would also help prove that DNA is the software of life.

What has happened since your announcement in 2010 that you created a synthetic cell, JCVI-syn1.0?

At the time, I said that the synthetic cell would give us a better understanding of the fundamentals of biology and how life works, help develop techniques and tools for vaccine and pharmaceutical development, enable development of biofuels and biochemicals, and help to create clean water, sources of food, textiles, bioremediation. Three years on that vision is being borne out.

Your book contains a dramatic account of the slog and setbacks that led to the creation of this first synthetic organism. What was your lowest point?

When we started out creating JCVI-syn1.0 in the lab, we had selected M. genitalium because of its extremely small genome. That decision we would come to really regret: in the laboratory, M. genitalium grows slowly. So whereas E. coli divides into daughter cells every 20 minutes, M. genitalium requires 12 hours to make a copy of itself. With logarithmic growth, it’s the difference between having an experimental result in 24 hours versus several weeks. It felt like we were working really hard to get nowhere at all. I changed the target to the M. mycoides genome. It’s twice as large as that of genitalium, but it grows much faster. In the end, that move made all the difference.

Some of your peers were blown away by the synthetic cell; others called it a technical tour de force. But there were also those who were underwhelmed because it was not “life from scratch.”

They haven’t thought much about what they are actually trying to say when they talk about “life from scratch.” How about baking a cake “from scratch”? You could buy one and then ice it at home. Or buy a cake mix, to which you add only eggs, water and oil. Or combining the individual ingredients, such as baking powder, sugar, salt, eggs, milk, shortening and so on. But I doubt that anyone would mean formulating his own baking powder by combining sodium, hydrogen, carbon, and oxygen to produce sodium bicarbonate, or producing homemade corn starch. If we apply the same strictures to creating life “from scratch,” it could mean producing all the necessary molecules, proteins, lipids, organelles, DNA, and so forth from basic chemicals or perhaps even from the fundamental elements carbon, hydrogen, oxygen, nitrogen, phosphate, iron, and so on.

There’s a parallel effort to create virtual life, which you go into in the book. How sophisticated are these models of cells in silico?

In the past year we have really seen how virtual cells can help us understand the real things. This work dates back to 1996 when Masaru Tomita and his students at the Laboratory for Bioinformatics at Keio started investigating the molecular biology of Mycoplasma genitalium—which we had sequenced in 1995—and by the end of that year had established the E-Cell Project. The most recent work on Mycoplasma genitalium has been done in America, by the systems biologist Markus W Covert, at Stanford University. His team used our genome data to create a virtual version of the bacterium that came remarkably close to its real-life counterpart.

You’ve discussed the ethics of synthetic organisms for a long time—where is the ethical argument today?

The Janus-like nature of innovation—its responsible use and so on—was evident at the very birth of human ingenuity, when humankind first discovered how to make fire on demand. (Do I use it burn down a rival’s settlement, or to keep warm?) Every few months, another meeting is held to discuss how powerful technology cuts both ways. It is crucial that we invest in underpinning technologies, science, education, and policy in order to ensure the safe and efficient development of synthetic biology. Opportunities for public debate and discussion on this topic must be sponsored, and the lay public must engage. But it is important not to lose sight of the amazing opportunities that this research presents. Synthetic biology can help address key challenges facing the planet and its population. Research in synthetic biology may lead to new things such as programmed cells that self-assemble at the sites of disease to repair damage.

What worries you more: bioterror or bioerror?

I am probably more concerned about an accidental slip. Synthetic biology increasingly relies on the skills of scientists who have little experience in biology, such as mathematicians and electrical engineers. The democratization of knowledge and the rise of “open-source biology;” the availability of kitchen-sink versions of key laboratory tools, such as the DNA-copying method PCR, make it easier for anyone—including those outside the usual networks of government, commercial, and university laboratories and the culture of responsible training and biosecurity—to play with the software of life.

Following the precautionary principle, should we abandon synthetic biology?

My greatest fear is not the abuse of technology, but that we will not use it at all, and turn our backs to an amazing opportunity at a time when we are over-populating our planet and changing environments forever.

You’re bullish about where this is headed.

I am—and a lot of that comes from seeing the next generation of synthetic biologists. We can get a view of what the future holds from a series of contests that culminate in a yearly event in Cambridge, Massachusetts—the International Genetically Engineered Machine (iGEM) competition. High-school and college students shuffle a standard set of DNA subroutines into something new. It gives me hope for the future.

You’ve been working to convert DNA into a digital signal that can be transmitted to a unit which then rebuilds an organism.

At Synthetic Genomics, Inc [which Venter founded with his long-term collaborator, the Nobel laureate Ham Smith], we can feed digital DNA code into a program that works out how to re-synthesize the sequence in the lab. This automates the process of designing overlapping pieces of DNA base-pairs, called oligonucleotides, adding watermarks, and then feeding them into the synthesizer. The synthesizer makes the oligonucleotides, which are pooled and assembled using what we call our Gibson-assembly robot (named after my talented colleague Dan Gibson). NASA has funded us to carry out experiments at its test site in the Mojave Desert. We will be using the JCVI mobile lab, which is equipped with soil-sampling, DNA-isolation and DNA sequencing equipment, to test the steps for autonomously isolating microbes from soil, sequencing their DNA and then transmitting the information to the cloud with what we call a “digitized-life-sending unit”. The receiving unit, where the transmitted DNA information can be downloaded and reproduced anew, has a number of names at present, including “digital biological converter,” “biological teleporter,” and—the preference of former US Wired editor-in-chief and CEO of 3D Robotics, Chris Anderson—”life replicator”.

Read the entire article here.

Image: J Craig Venter. Courtesy of Wikipedia.

Britain’s Genomics NHS

The United Kingdom is plotting a visionary strategy that will put its treasured National Health Service (NHS) at the heart of the new revolution in genomics-based medical care.

From Technology Review:

By sequencing the genomes of 100,000 patients and integrating the resulting data into medical care, the U.K. could become the first country to introduce genome sequencing into its mainstream health system. The U.K. government hopes that the investment will improve patient outcomes while also building a genomic medicine industry. But the project will test the practical challenges of integrating and safeguarding genomic data within an expansive health service.

Officials breathed life into the ambitious sequencing project in June when they announced the formation of Genomics England, a company set up to execute the £100 million project. The goal is to “transform how the NHS uses genomic medicine,” says the company’s chief scientist, Mark Caulfield.

Those changes will take many shapes. First, by providing whole-genome sequencing and analysis for National Health Service patients with rare diseases, Genomics England could help families understand the origin of these conditions and help doctors better treat them. Second, the company will sequence the genomes of cancer patients and their tumors, which could help doctors identify the best drugs to treat the disease. Finally, say leaders of the 100,000 genomes project, the efforts could uncover the basis for bacterial and viral resistance to medicines.

“We hope that the legacy at the end of 2017, when we conclude the 100,000 whole-genome sequences, will be a transformed capacity and capability in the NHS to use this data,” says Caulfield.

In the last few years, the cost and time required to sequence DNA have plummeted (see “Bases to Bytes”), making the technology more feasible to use as part of clinical care. Governments around the world are investing in large-scale projects to identify the best way to harness genome technology in a medical setting. For example, the Faroe Islands, a sovereign state within the Kingdom of Denmark, is offering sequencing to all of its citizens to understand the basis of genetic diseases prevalent in the isolated population. The U.S. has funded several large grants to study how to best use medical genomic data, and in 2011 it announced an effort to sequence thousands of veterans’ genomes. In 1999, the Chinese government helped establish the Beijing Genomics Institute, which would later become the world’s most prolific genome institute, providing sequences for projects based in China and abroad (see “Inside China’s Genome Factory”).

But the U.K. project stands out for the large number of genomes planned and the integration of the data into a national health-care system that serves more than 60 million people. The initial program will focus on rare inherited diseases, cancer, and infectious pathogens. Initially, the greatest potential will be in giving families long-sought-after answers as to why a rare disorder afflicts them or their children, and “in 10 or 20 years, there may be treatments sprung from it,” says Caulfield.

In addition to exploring how to best handle and use genomic data, the projects taking place in 2014 will give Genomics England time to explore different sequencing technologies offered by commercial providers. The San Diego-based sequencing company Illumina will provide sequencing at existing facilities in England, but Caulfeld emphasizes that the project will want to use the sequencing services of multiple commercial providers. “We are keen to encourage competitiveness in this marketplace as a route to bring down the price for everybody.”

To help control costs for the lofty project, and to foster investment in genomic medicine in the U.K., Genomics England will ask commercial providers to set up sequencing centers in England. “Part of this program is to generate wealth, and that means U.K. jobs,” he says. “We want the sequencing providers to invest in the U.K.” The sequencing centers will be ready by 2015, when the project kicks off in earnest. “Then we will be sequencing 30,000 whole-genome sequences a year,” says Caulfield.

Read the entire article here.

Image: Argonne’s Midwest Center for Structural Genomics deposits 1,000th protein structure. Courtesy of Wikipedia.