Cancer Genome Sequenced

Scientists have sequenced the whole genome of a cancer cell for the first time. By comparing the DNA sequence of cancerous cells taken from a patient, who died of leukemia in her fifties, with the DNA collected from her healthy tissue, the scientists identified 10 mutations found only in the cancer cells. The mutations appear to affect cancer cell growth, as well as response to chemotherapy drugs.

The experiment, which involved sequencing two complete human genomes, would have been unfeasible just a year ago due to the expense of genome sequencing. But cheap new sequencing technologies are changing the paradigm of genomics research. The project cost about $1 million, compared with the $300 million of the Human Genome Project.

The new study is different than other recent genomics studies of cancer, which focused on candidate genes rather than searching the entire 20,000 genes of the human genome. (See "Cancer Redefined.") It is also the first female genome to be sequenced.

According to an article in the New York Times,

"This is the first of many of these whole cancer genomes to be sequenced," said Richard K. Wilson, director of Washington University's Genome Sequencing Center and the senior author of the study. "They'll give us a whole bunch of clues about what's going on in the DNA when cancer starts to bloom."

Dr. Wilson said he hoped that in 5 to 20 years, DNA sequencing for cancer patients would consist of dropping a spot of blood onto a chip that slides into a desktop computer and getting back a report that suggests which drugs will work best for each person.

... Indeed, 8 of the 10 mutations his group found in the leukemia patient had never been linked to the disease before and would not have been found with the more traditional, "usual suspects" approach.

Some of the patient's mutated genes appeared to promote cancer growth. One probably made the cancer drug-resistant by enabling the tumor cells to pump chemotherapy drugs right out of the cell before they could do their work. The other mutated genes seemed to be tumor suppressors, the body's natural defense against dangerous genetic mistakes.

"Their job is surveillance," Dr. Wilson said. "If cells start to do something out of control, these genes are there to shut it down. When we find three or four suppressors inactivated, it's almost like tumor has systematically started to knock out that surveillance mechanism. That makes it tougher to kill. It gets a little freaky. This is unscientific, but we say, gee, it looks like the tumor has a mind of its own, it knows what genes it has to take out to be successful. It's amazing."

It will take more research to determine exactly what the mutations do. Researchers would also like to know the order in which they occurred, and whether there was one that finally tipped the balance towards cancer.

"When this patient came to the cancer center and had a bone marrow biopsy, she already had 10 mutations," Dr. Wilson said. "You'd love to know, if you had taken a bone marrow sample a year before, what would you have seen?"

Tests of 187 other patients with acute myelogenous leukemia found that none had the eight new mutations found in the first patient.

That finding suggests that many genetic detours can lead to the same awful destination, and that many more genomes must be studied, but it does not mean that every patient will need his or her own individual drug, Dr. Wilson said.

"Ultimately, one signal tells the cell to grow, grow, grow," he said. "There has to be something in common. It's that commonality we'll find that will tell us what treatment will be the most powerful."

Genetic Privacy: An Outdated Concern?

George Church, a participant and leader of the Personal Genome Project at Harvard Medical School, undergoes a skin biopsy. Scientists will develop cell lines from Church's skin cells, which will be distributed to scientists around the world for research. Credit: Personal Genome Project.

The vote was unanimous. Every one of the PGP-10--the first 10 volunteers for the Personal Genome Project--decided to make the genomic information he or she has received so far public, along with his or her medical and other trait information. (For background on the project, check out yesterday's "Genomes on Display.") The group revealed its decisions at a press conference at Harvard Medical School on Monday afternoon.

None of the information that the participants have learned is likely to be life shattering. Harvard psychologist Steven Pinker, for example, learned that, according to the study's results, he has some susceptibility to irregular menstrual periods and to being born prematurely. "I'm not too concerned about that," he said at the press conference. Clearly, neither of these variations is important for Pinker's health, although theoretically, this information might be of interest to future Pinker generations who inherit them.

John Halamka, CIO for Harvard Medical School, carries a mutation for hereditary motor and sensory neuropathy with optic atrophy, a childhood neurological disease. But since Halamka survived childhood unscathed, and only three other people in the world have been shown to carry that particular mutation, it's hard to know what impact, if any, it has had on his health. (George Church, who heads the project, also noted that given the preliminary nature of the data released on Monday, the finding might be an error.)

Before the PGP-10 revealed its decisions to the world, the group spent the day discussing some of the issues that the unique project raises--especially the issue of privacy. The plan for the PGP is to make all aspects as open as possible, from the technology that is developed to the medical and genetic information of the participants. The rationale is that it is difficult to promise research subjects anonymity when the data being collected includes genetic information--the ultimate personal identifier--so it's better to make everything open from the get-go.

"We are at the beginning of a revolution in health care: huge numbers of us will have our genomes sequenced for medical, forensic, or military purposes, and the notion that information can be kept private is nuts," said Stan Lapidus, CEO of Helicos Biosciences. "Part of the PGP is to understand how our lives are affected. I have a hunch it will be not a lot."

Entrepreneur Ester Dyson said that she wanted to bring genomic information into the realm of the mundane. "I want to show people this information is not inherently dangerous," she said. "Information when misused is always dangerous, but it's more dangerous when people attribute something mystical to it."

Still, if they change their minds, the participants will be able to block or redact any information--as much as that can be done. Pinker, for example, said that he isn't sure if he wants to know whether he carries a genetic variant that dramatically increases his risk of Alzheimer's disease. But because of the way that DNA is inherited, it's possible to determine whether someone likely carries the variation by the code of neighboring DNA. In addition, Church and his collaborators are creating and distributing cell lines made from participants' skin cells, which means that their DNA could be sequenced by anyone studying the cell lines.

Google Founder's Blog Delves into Personal Health

Credit: Google

In his new personal blog, started yesterday, famed Google founder and multibillionaire Sergey Brin delves immediately into a deeply personal subject: his genetic risk for Parkinson's disease. Brin, whose mother suffers from Parkinson's, learned that he carries a mutation linked to increased risk of the disease after being screened by 23andMe, a personal-genomics startup cofounded by his wife, Anne Wojcicki.

23andMe's brand of direct-to-consumer testing has garnered criticism from the genomics community for going on the market before scientists have had a chance to assess whether such tests can actually help, or would possibly hinder, an individual's health. (If someone finds out that she is at greater risk for type 2 diabetes, for example, she may adopt a fatalistic attitude, eating junk food and not exercising.) Critics are also concerned that the general public won't be able to understand the subtleties of the test: 23andMe's service identifies genetic variations that may increase an individual's risk of disease, but that does not mean that the carrier will ever get it. (A review in our current issue argues against this point of view.)

While Brin doesn't discuss why he decided to go public with his results, perhaps he wants to use his role as an Internet celebrity and, in some sense, experimental test subject to better educate the public. His post nicely outlines the limitations of personal-genomics testing and discusses what an individual can do once he learns his own risks, even for a disease like Parkinson's, with few proven preventative interventions. Better public understanding of these issues is going to be crucial as personal genomics makes its way into medical care, be it through companies like 23andMe or other venues. (Cynical readers, of course, might see an alternative motive: an attempt to drum up interest in his wife's company's service, in which Google has invested.)

From Brin's post:

...The exact implications of this are not entirely clear. Early studies tend to have small samples with various selection biases. Nonetheless it is clear that I have a markedly higher chance of developing Parkinson's in my lifetime than the average person. In fact, it is somewhere between 20% to 80% depending on the study and how you measure. At the same time, research into LRRK2 looks intriguing (both for LRRK2 carriers and potentially for others).

This leaves me in a rather unique position. I know early in my life something I am substantially predisposed to. I now have the opportunity to adjust my life to reduce those odds (e.g. there is evidence that exercise may be protective against Parkinson's). I also have the opportunity to perform and support research into this disease long before it may affect me. And, regardless of my own health it can help my family members as well as others.

I feel fortunate to be in this position. Until the fountain of youth is discovered, all of us will have some conditions in our old age only we don't know what they will be. I have a better guess than almost anyone else for what ills may be mine -- and I have decades to prepare for it.

In an article that I wrote for Tech Review two years ago on the study linking this genetic variation to Parkinson's disease in Ashkenazi Jews, scientists speculated on future clinical testing. (Brin is of Jewish descent.)

While gene testing for diseases that have no known cure, such as Parkinson's, is controversial, Laurie J. Ozelius, a molecular geneticist at Albert Einstein College of Medicine of Yeshiva University in the Bronx, who was involved in the research, says testing still could have some advantages. "People who come to the doctor [with symptoms of Parkinson's] already have a lot of degeneration. Now we can look at [earlier] stages of the disease," she says. "If we find treatments that slow the disease, it's better to identify a gene carrier so we can start the treatment earlier."

Susan B. Bressman, senior investigator of the report and a neurologist at Einstein, says that having a group with a known risk for Parkinson's will aid in future studies of the disorder. Because not everyone with the mutation will go on to develop the disease, scientists can try to identify the genetic or environmental factors that put some people at greater risk. Scientists could also test potential neuroprotective drugs in this group much more efficiently than in a general population.

23andMe Sharply Cuts Cost of Genome Analysis

For about the cost of a Sony PlayStation 3, you can now order a genome-wide scan of your DNA. 23andMe, a California-based personal-genomics startup, backed in part by Google, announced a dramatic cut in price today (from $999 to $399) for its genome analysis service. Customers who order the service send in a spit sample and receive a genetic analysis that includes predictions of their risk of developing various diseases, evaluations of other traits, and ancestry information; customers can even opt to compare their genomes with those of others. The company's two main competitors, Navigenics and Decode, offer similar services for $1,000 to $2,500.

According to an article from the Associated Press,

[Company founder Linda] Avey says one inspiration for the company's new pricing came from the iPod and iPhone, which sold for a similar amount in their early incarnations. The company hopes that consumers will start to see personal gene scans as similarly accessible technology with both serious medical value and gee-whiz appeal.

A press release from 23andMe says the price cut is enabled by improvements in genome analysis technology. The company uses gene microarrays made by Illumina, which have also been quickly dropping in price.

However, others speculate that 23andMe's price cut was fueled by an attempt to remedy lower-than-expected sales. Perhaps tellingly, the company has not yet revealed how many customers have subscribed to its service.

Another personal-genomics startup in Cambridge, MA, Knome, also expects to announce price cuts soon. Knome's service sequences and analyzes the entire genome, rather than specific areas, as 23andMe's does. As a consequence, it currently costs $350,000.

Personal-Genomics Companies Get California License

After sending cease-and-desist letters to a number of companies offering personal-genomics services directly to consumers, the state of California appears to have made peace with at least two of them--Navigenics and 23andMe. Both received licenses this week allowing them to continue to do business in California.

The letters, sent in June by the California Department of Public Health, outlined two main state regulations: laboratories performing tests must be clinically licensed, and a physician's order is required for all clinical tests. (For more on the state's action, see "Genetic Testing for Consumers Scrutinized.")

According to an article published Tuesday in the New York Times,

The companies had argued that they were not offering medical testing but rather personal genetic information services, and that consumers had a right to information from their own DNA. The companies also said they did not need a license because the actual testing of the DNA samples was being done by outside laboratories that did have licenses.

But the two companies do their own interpretation of the raw genetic data. Now, after reviewing the procedures used by the companies, the state is satisfied that the companies' interpretation is based on the scientific literature, Ms. Billingsley [a senior official in the California public health department] said.

Ms. Billingsley said the companies also satisfied the requirement for a doctor to be involved. Navigenics already was paying a physician to review customer orders and now it appears that 23andMe might be doing something similar.

It's not yet clear what this latest development portends for future regulatory debates, especially at the federal level; few federal regulations for these types of tests exist. As their popularity grows, scientists, regulators, and entrepreneurs will need to grapple with the central question of how to define this new breed of medical information, which falls short of being a diagnostic tool and, unlike risk factors such as cholesterol level and blood pressure, is deeply personal and ultimately immutable.

For more on regulation of direct-to-consumer genetic testing, check out the review "Personal Genomics: Access Denied?" in the September issue of Technology Review.

1,000 Genomes

In a testament to the steady plummet in sequencing costs, today the National Human Genome Research Institute (NHGRI) announced a massive international collaboration to sequence the genomes of 1,000 people from around the world.

According to the NHGRI statement,

"The 1000 Genomes Project will examine the human genome at a level of detail that no one has done before," said Richard Durbin, Ph.D., of the Wellcome Trust Sanger Institute, who is co-chair of the consortium. "Such a project would have been unthinkable only two years ago. Today, thanks to amazing strides in sequencing technology, bioinformatics and population genomics, it is now within our grasp. So we are moving forward to build a tool that will greatly expand and further accelerate efforts to find more of the genetic factors involved in human health and disease."

The findings should give added power to the recent wave of studies identifying specific genetic risk factors for common health problems, such as diabetes, heart disease, lupus, and others. (See "Genes for Several Common Diseases Found.")

According to NHGRI director Francis Collins,

"This new project will increase the sensitivity of disease discovery efforts across the genome five-fold and within gene regions at least 10-fold. Our existing databases do a reasonably good job of cataloging variations found in at least 10 percent of a population. By harnessing the power of new sequencing technologies and novel computational methods, we hope to give biomedical researchers a genome-wide map of variation down to the 1 percent level. This will change the way we carry out studies of genetic disease."

Like previous international sequencing projects, the data will be made available for analysis in free public databases. Once scientists identify part of the genome associated with a particular disease, they will be able to look up that area of the genome in the database to find a list of gene variants in that region.

The project will be a huge technological feat; to date, only three human genomes have been sequenced.

From NHGRI:

The project depends on large-scale implementation of several new sequencing platforms. Using standard DNA sequencing technologies, the effort would likely cost more than $500 million. However, leaders of the 1000 Genomes Project expect the costs to be far lower--in the range of $30 million to $50 million--because of the project's pioneering efforts to use new sequencing technologies in the most efficient and cost-effective manner.

In the first phase of the 1000 Genomes Project, lasting about a year, researchers will conduct three pilots. The results of the pilots will be used to decide how to most efficiently and cost effectively produce the project's detailed map of human genetic variation.

The first pilot will involve sequencing the genomes of two nuclear families (both parents and an adult child) at deep coverage that averages 20 passes of each genome. This will provide a comprehensive dataset from six people that will help the project figure out how to identify variants using the new sequencing platforms, and serve as a basis for comparison for other parts of the effort.

The second pilot will involve sequencing the genomes of 180 people at low coverage that averages two passes of each genome. This will test the ability to use low-coverage data from new sequencing platforms to identify sequence variants and to put them in their genomic context.

The third pilot will involve sequencing the coding regions, called exons, of about 1,000 genes in about 1,000 people. This is aimed at exploring how best to obtain an even more detailed catalog in the approximately 2 percent of the genome that is comprised of protein-coding genes.

During its two-year production phase, the 1000 Genomes Project will deliver sequence data at an average rate of about 8.2 billion bases per day, the equivalent of more than two human genomes every 24 hours. The volume of data--and the interpretation of those data--will pose a major challenge for leading experts in the fields of bioinformatics and statistical genetics.

The 1,000 volunteers will be selected from those who participated in the HapMap project, a map of common genetic variation (see "A New Map for Health"), and will include:

Yoruba in Ibadan, Nigeria; Japanese in Tokyo; Chinese in Beijing; Utah residents with ancestry from northern and western Europe; Luhya in Webuye, Kenya; Maasai in Kinyawa, Kenya; Toscani in Italy; Gujarati Indians in Houston; Chinese in metropolitan Denver; people of Mexican ancestry in Los Angeles; and people of African ancestry in the southwestern United States.