Apple Has Plans for Your DNA

 

The iPhone could become a new tool in genetic studies. Why It Matters Gene research is held back by medical privacy rules and limited data sharing. Of all the rumors ever to swirl around the world’s most valuable company, this may be the first that could involve spitting in a plastic cup. Apple is collaborating with U.S. researchers to help launch apps that would offer some iPhone owners the chance to get their DNA tested, many of them for the first time, according to people familiar with the plans. The apps are based on ResearchKit, a software platform Apple introduced in March that helps hospitals or scientists run medical studies on iPhones by collecting data from the devices’ sensors or through surveys. The first five ResearchKit apps, including one called mPower that tracks symptoms of Parkinson’s disease, quickly recruited thousands of participants in a few days, demonstrating the reach of Apple’s platform. “Apple launched ResearchKit and got a fantastic response. The obvious next thing is to collect DNA,” says Gholson Lyon, a geneticist at Cold Spring Harbor Laboratory, who isn’t involved with the studies. Nudging iPhone owners to submit DNA samples to researchers would thrust Apple’s devices into the center of a widening battle for genetic information. Universities, large technology companies like Google (see “Google Wants to Store Your Genome”), direct-to-consumer labs, and even the U.S. government (see “U.S. to Develop DNA Study of One Million People”) are all trying to amass mega-databases of gene information to uncover clues about the causes of disease (see “Internet of DNA”). In two initial studies planned, Apple isn’t going to directly collect or test DNA itself. That will be done by academic partners. The data would be maintained by scientists in a computing cloud, but certain findings could appear directly on consumers’ iPhones as well. Eventually, it’s even possible consumers might swipe to share “my genes” as easily as they do their location. An Apple spokeswoman declined to comment. But one person with knowledge of the plans said the company’s eventual aim is to “enable the individual to show and share” DNA information with different recipients, including organizers of scientific studies. This person, like others with knowledge of the research, spoke on condition of anonymity because of the company’s insistence on secrecy. One of these people said the DNA-app studies could still be cancelled, but another said Apple wants the apps ready for the company’s worldwide developers’ conference, to be held in June in San Francisco. Sophisticated data Starting last year, Apple began taking steps to make its devices indispensable for “digital health.” Its latest version of the iOS operating system includes an app called Health, which has fields for more than 70 types of health data—everything from your weight to how many milligrams of manganese you eat (as yet, there’s no field for your genome). Apple also entered a partnership with IBM to develop health apps for nurses and hospitals, as well as to mine medical data. Now Apple is closely involved in shaping initial studies that will collect DNA. One, planned by the University of California, San Francisco, would study causes of premature birth by combining gene tests with other data collected on the phones of expectant mothers. A different study would be led by Mount Sinai Hospital in New York. Atul Butte, leader of the UCSF study and head of the Institute for Computational Health Sciences, said he could not comment on Apple’s involvement. “The first five [ResearchKit] studies have been great and are showing how fast Apple can recruit. I and many others are looking at types of trials that are more sophisticated,” Butte says. Noting that the genetic causes of premature birth aren’t well understood, he says, “I look forward to the day when we can get more sophisticated data than activity, like DNA or clinical data.” To join one of the studies, a person would agree to have a gene test carried out—for instance, by returning a “spit kit” to a laboratory approved by Apple. The first such labs are said to be the advanced gene-sequencing centers operated by UCSF and Mount Sinai. The planned DNA studies would look at 100 or fewer medically important disease genes (known as a “gene panel”), not a person’s entire genome. These targeted tests, if done at large scale, would not cost more than a few hundred dollars each. Like the ResearchKit apps released so far, the studies would be approved by Apple and by an institutional review board, a type of oversight body that advises researchers on studies involving volunteers. The ResearchKit program has been spearheaded by Stephen Friend, a onetime pharmaceutical company executive and now the head of Sage Bionetworks, a nonprofit that advocates for open scientific research. Friend’s vision for a data “commons” in which study subjects are active participants in scientific research was enthusiastically embraced by Apple starting in 2013. Friend, whom Apple describes as a medical technology advisor, declined an interview request through an assistant. Silicon Valley companies are intent on using apps and mobile devices to overrun what Friend has called the “medical-industrial complex.” The problem is that hospitals and research groups are notorious for hoarding data, in many cases because they are legally bound to do so by state and federal privacy regulations. But no law stops individuals from sharing information about themselves. Thus one reason to “empower patients,” as rhetoric has it, is that if people collect their own data, or are given control of it, it could quickly find wide use in consumer apps and technologies, as well as in science. One study that could get a boost from the iPhone is the Resilience Project, a joint undertaking by Sage and Mount Sinai to discover why some people are healthy even though their genes say they should have serious inherited diseases like cystic fibrosis. That project has already scoured DNA data previously collected from more than 500,000 people, and as of last year it had identified about 20 such unusual cases. But the Resilience Project was having difficulty contacting those people because their DNA had been collected anonymously. By contrast, recruiting people through iPhone apps could make ongoing contact easy. Hard to handle By playing this role in gene studies, Apple would join a short list of companies trying to excite people about what they might do with their own genetic information. Among them are the genealogy company Ancestry.com, the Open Humans Project, and 23andMe, a direct-to-consumer testing company that has collected DNA profiles of more than 900,000 people who bought its $99 spit kits. That is one of the largest DNA data banks anywhere, but it took 23andMe nine years of constant media attention, such as appearance on Oprah, to reach those numbers. By comparison, Apple sold 60 million iPhones in just the first three months of this year, contributing to a total of about 750 million overall. That means DNA studies on the ResearchKit platform could, theoretically, have rapid and immense reach. But DNA data remains tricky to handle, and in some cases what people can be told about it is regulated by the U.S. Food & Drug Administration. One study launched this year by the University of Michigan, Genes for Good, uses a Facebook app to recruit subjects and carry out detailed surveys about their health and habits. In that study, participants will be sent a spit kit and will later gain access to DNA information via a file they can download to their desktops. So far about 4,200 people have signed up, says Gonçalo Abecasis, the geneticist running the research. Abecasis says that the project will tell people something about their ancestry but won’t try to make health predictions. “There is tension in figuring out what is okay as part of our research study and what would be okay in terms of health care,” he says. “You can imagine that a lot of people have a good idea how to interpret the DNA … but what is appropriate to disclose isn’t clear.” One issue facing Apple is whether consumers are even interested in their DNA. So far, most people still have no real use for genetic data, and common systems for interpreting it are lacking as well. “In 10 years it could be incredibly significant,” says Lyon, the Cold Spring Harbor geneticist. “But the question is, do they have a killer app to interact with their [DNA] quickly and easily.” Some people have ideas. Imagine you could swipe your genes at a drugstore while filling a prescription, getting a warning if you’re predicted to have a reaction to the drug. Or perhaps an app could calculate exactly how closely related you are to anyone else. But Lyon believes that right now the story is mostly about helping researchers. “They need people to donate their DNA,” he says. “One incentive is to have it on their phone where they can play with it.”

Cellular defense against fatal associations between proteins and DNA

 

Formaldehyde (COH2), generated in cells or derived from the environment, can crosslink DNA to proteins, which interferes with DNA replication. The newly identified repair protein Wss1 chops down the protein component of DNA-protein crosslinks, thereby enabling cells to complete replication.

DNA -- the carrier of genetic information -- is constantly threatened by damage originating from exogenous and endogenous sources. Very special DNA lesions are DNA-protein crosslinks -- proteins covalently linked to DNA. So far hardly anything was known about repair mechanisms specifically targeting DNA-protein crosslinks. Stefan Jentsch's team at the Max Planck Institute of Biochemistry in Martinsried, Germany, now discovered a protease that is able to chop down the protein component of DNA-protein crosslinks, thereby enabling organisms to copy their genetic information even if crosslinks arise.

 The results of this study have major implications for the understanding of genome integrity and cancer development.

The DNA in each cell is highly vulnerable to various types of damage.

A special class of damage is caused by reactive compounds, such as formaldehyde, which are produced as byproducts of cellular reactions and cause the crosslinking (a formation of a covalent linkage) of proteins to DNA. Importantly, these so-called DNA-protein crosslinks are also caused by several anti-cancer drugs and are extremely toxic as they interfere with essential processes such as DNA replication.

Cells need to unwind and separate the DNA double helix in order to copy its genetic information prior to the next round of cell division. DPCs inhibit this process by blocking the way of the unwinding enzyme replicative helicase, thus preventing replication and consequently cell division.

In the laboratory of Stefan Jentsch at the Max-Planck-Institute of Biochemistry, scientists now identified the protease Wss1 as a new safeguarding factor that chops down the protein components of DNA-protein crosslinks and thereby enables cells to duplicate their genome. Julian Stingele, a PhD student in the laboratory, found that cells lacking Wss1 are particularly sensitive to formaldehyde, extremely vulnerable to DNA-protein crosslinks and suffer from genomic instability. Notably, Wss1 has the unique property to cleave proteins only in the presence of DNA, suggesting that the enzyme is well tailored for its task to remove crosslinks from the genome and thus preserve genome stability.

Because the repair of DNA lesions is essential to prevent cancer formation, it is of crucial importance to understand the underlying cellular mechanisms. The newly identified DNA-protein crosslink-repair pathway is particularly important for rapidly dividing cells. Given the fact that cancer cells divide much faster than the majority of human cells, Wss1 might be an attractive future drug target for cancer therapy.

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Story Source:

The above story is based on materials provided by Max-Planck-Gesellschaft. Note: Materials may be edited for content and length.

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Journal Reference:

1. Julian Stingele, Michael S. Schwarz, Nicolas Bloemeke, Peter G. Wolf, Stefan Jentsch. A DNA-Dependent Protease Involved in DNA-Protein Crosslink Repair. Cell, 2014; DOI: 10.1016/j.cell.2014.04.053

Sweet genes: New way found by which metabolism is linked to the regulation of DNA

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A research team at the Faculty of Medicine & Dentistry at the University of Alberta have discovered a new way by which metabolism is linked to the regulation of DNA, the basis of our genetic code. The findings may have important implications for the understanding of many common diseases, including cancer.

The DNA wraps around specialized proteins called histones in the cell's nucleus. Normally, histones keep the DNA tightly packaged, preventing the expression of genes and the replication of DNA, which are required for cell growth and division. In order for these critical functions to take place, histones need to be modified with the attachment of an acetyl-group, donated by a critical molecule called acetyl-CoA. This attachment relaxes the DNA, allowing for DNA replication and gene expression. This mechanism is called "epigenetic regulation of DNA" and is important for normal functions (like the growth of an embryo or brain functions) or in common diseases like heart failure or cancer. Until now, how the nucleus generates acetyl-CoA for histone acetylation had remained elusive.

The research team, lead by postdoctoral fellow Gopinath Sutendra and professor Evangelos Michelakis in the Department of Medicine, discovered that an enzyme thought to reside only within mitochondria, called Pyruvate Dehydrogenase Complex (PDC), can actually find its way into the nucleus and do what it is designed to do in the mitochondria: generate acetyl-CoA. When in mitochondria, PDC uses the carbohydrates from our diet to generate acetyl-CoA for energy production. When in the nucleus, PDC can produce acetyl-CoA for histone acetylation.

"Although this jumping of an enzyme from one organelle into another in the cell is not unheard off, our results were quite surprising," Sutendra says. "We wanted to measure acetyl-CoA levels and PDC in the mitochondria because that's where we thought they were. But accidentally we had the nuclei isolated at the same time and we saw PDC in the nucleus. So we asked, 'what is PDC doing there?' And that started it all."

"We were surprised that, despite the recognized importance of histone acetylation in cell biology and medicine, and despite the efforts by many to develop drugs that regulate histone acetylation, the source of acetyl-CoA in the nucleus had remained unknown," Michelakis says. "Sometimes the answers to important biological questions are just next to you, waiting to be discovered," he adds.

The team found that the translocation of PDC into the nucleus made cancer cells grow faster, an observation that may lead to additional strategies in the war against cancer. Yet, because the findings relate to how our DNA is regulated in general, this work may have far broader implications for many physiologic or pathologic conditions where epigenetic regulation is critical. "We are very excited about this new pathway linking energy production (the process known as metabolism) with gene regulation," the researchers say.

The work is published in the July 3, 2014, issue of the journal Cell. Michelakis is particularly proud of the fact that this is the product of a team that is entirely based at the University of Alberta. Many young researchers in the Department of Medicine like Adam Kinnaird, Peter Dromparis and Roxane Paulin were critical members of the team that also included technicians (Trevor Stenson, Alois Haromy, Kyoko Hashimoto) and researchers from the NanoFAB facility (Nancy Zhang, Eric Flaim)

. The work was funded by the Canadian Institutes for Health Research and the Hecht Foundation (Vancouver, Canada).

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Story Source:

The above story is based on materials provided by University of Alberta Faculty of Medicine & Dentistry. Note: Materials may be edited for content and length.

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Journal Reference:

1. Gopinath Sutendra, Adam Kinnaird, Peter Dromparis, Roxane Paulin, Trevor H. Stenson, Alois Haromy, Kyoko Hashimoto, Nancy Zhang, Eric Flaim, Evangelos D. Michelakis. A Nuclear Pyruvate Dehydrogenase Complex Is Important for the Generation of Acetyl-CoA and Histone Acetylation. Cell, 2014; 158 (1): 84 DOI: 10.1016/j.cell.2014.04.046

A mini-antibody with broad antiviral activity chews up viral DNA and RNA

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3D8 scFv with broad antiviral activity has a unique stereoscopic protection mechanism such as a DNA digestion activity in nucleus and RNA hydrolysis activity in cytoplasm. 3D8 scFv proteins can chew up viral DNA or viral RNA at two different places and stages.

Antibodies and their derivatives can protect plants and animals -- including humans -- against viruses. Members of this class of drugs are usually highly specific against components of a particular virus, and mutations in the virus that change these components can make them ineffective. An article published on June 26th in PLOS Pathogens now reports that a mini antibody called 3D8 scFv can degrade (or chew up) viral DNA and RNA regardless of specific sequences and protect mammalian cells and genetically manipulated mice against different viruses.

Sukchan Lee, from Sungkyunkwan University, Suwon, Korea, and colleagues had previously discovered that 3D8 has both DNase and RNase activity (that is, it can degrade both), and that it can inhibit viruses under certain circumstances. In this study, they genetically manipulated cells and mice to produce 3D8.

They show that when the right amount of 3D8 is produced, the cells and the animals become resistant to two different and normally deadly viruses, namely herpes simplex virus and pseudorabies virus. To protect the animals, it appears critical that the right dose of 3D8 is present in the tissues initially infected by the viruses; once the virus has started to multiply and spread, it seems that 3D8 can no longer contain it efficiently.

When the researchers examined the mechanisms underlying the protective activity, they found that 3D8 fights viruses at two different places and stages of the viral life cycle. In the cell nucleus, it degrades viral DNA to prevent it from getting copied. In the cytoplasm (the area outside of the nucleus), it destroys RNA destined to be used for the production of virus components.

As the researchers discuss, the correct 3D8 dose is critical to destroy only viral DNA and RNA (but not their host genetic material), and additional research is needed to understand the basis for this selective activity. Moreover, to protect the host, 3D8 needs to be present at the time of viral infection and in the right tissues. That said, they conclude that "3D8 scFv is a candidate antiviral protein that can potentially confer resistance to a broad spectrum of animal and plant viruses." They also suggest that "this strategy may facilitate control of...viruses uncharacterized at the molecular level, regardless of their genome type or variations in gene products."