HMS professor of genetics George Church has been working toward an affordable genome for 30 years. With next-generation sequencing platforms coming of age, he is finally close to that goal. He is ramping up the Personal Genome Project (PGP)—an effort to sequence the genomes of 100,000 individuals—against the backdrop of plummeting platform costs.
On Oct. 6, a California company called Complete Genomics (with Church as an adviser and collaborator) announced that it could sequence a complete human genome for just $5,000. Church plans to sequence only a portion of the PGP participants’ genomes, so the price tag should be lower for each volunteer. He is focusing on the protein-coding regions, or exons, which are thought to contain most of the information relevant to human disease.
Using an exon-capture method developed by former HMS postdoc Jay Shendure and HMS lecturer Gregory Porreca (see Focus, Oct. 26, 2007), Church has already started to sequence the genomes of 10 volunteers, dubbed the PGP-10. On Oct. 20, these individuals received their first batch of data, which (in most cases) included more than 10 percent of the protein-coding regions of the genome.
“As someone who actually deals with patients who have genetic disorders, I can tell you that it makes sense to target the protein-coding regions,” said clinical geneticist Joseph Thakuria, medical director of the PGP and an attending physician at Massachusetts General Hospital. “In the overwhelming majority of cases, the pathogenic mutation resides in an exon.”
Thakuria sifted through the first batch of PGP-10 data and pulled out sequences associated with disease in the scientific literature. He also scanned Affymetrix data from each participant, identifying single nucleotide polymorphisms of interest. He shared the findings—which included few surprises—with the PGP-10 during individual consultations.
Following these meetings, nine of the 10 volunteers decided to release their data to the public through the PGP website. Due to technical problems, one volunteer did not receive his exon information. He will decide whether or not to release the data after reviewing it.
The PGP website is accessible to anyone with an Internet connection. “It’s truly an open source model,” said Church. He and colleagues are now selecting the next batch of volunteers.
Last April, Harvard University’s Institutional Review Board gave Church permission to scale his project to 100,000 people from a screen of 350,000 potential participants. As the database grows, it will serve as a powerful resource for researchers probing the genetic basis of diseases and other traits. Researchers will also have access to a biobank of reprogrammed fibroblasts from PGP participants. Each volunteer will provide a skin biopsy that will serve as a source of adult stem cells for future experiments.
Personal Genome Project FAQs
What is the PGP?
Through the Personal Genome Project (PGP), Harvard Medical School professor of genetics George Church plans to sequence the genomes of 100,000 individuals. It will initially focus on the protein-coding regions of the genome, which are thought to contain the most interpretable and strongest information relevant to traits. In addition to providing DNA, PGP participants will supply detailed medical and non-medical data, enabling researchers to mine project data for links between particular DNA sequences and traits.
Who are the PGP-10?
The first ten participants in the PGP, called the PGP-10, were selected based on their knowledge of and experience with genetics research. Church and Harvard University’s Institutional Review Board wanted to ensure that they understood the potential risks associated with publishing their genomic sequences. The PGP-10 comprises an eclectic group ranging from language and cognition researcher Steven Pinker to IT and health care startup investor Esther Dyson. For a complete list, visit: http://www.personalgenomes.org/pgp10.html
The Human Genome Project cost the government $2.7 billion. How does Church plan to pay for the project? DNA sequencing costs have plummeted since the completion of the Human Genome Project in 2003. Church has been working toward an affordable genome for 30 years. The Church lab and other groups have developed "next-generation sequencers" that read millions to billions of pieces of DNA in an array simultaneously instead of processing each piece separately. They’ve generated additional cost savings by altering the equipment and process to use less of each reagent.
On Oct. 6, a California company called Complete Genomics (with Church as an advisor/collaborator) announced that it could sequence a complete human genome for just $5,000. One can sequence the 1 percent of the genome coding for proteins for far less, though barriers remain to getting down to 1 percent of $5000.
Participants will be encouraged to subsidize their own participation in the project by paying an enrollment fee of $1000. Financial assistance can be requested by those unable to pay the full fee. Enrollment fees will be used to help defray the costs of research.
What are the goals of the PGP?
The goal of the PGP is to make personal genome sequencing more affordable, accessible, and useful for humankind. In support of this goal, PGP staff will:
- Develop a broad vision for how personal genomes may be used to improve the understanding and management of human health and disease.
- Provide educational and informational resources for improving general understanding of personal genomics and its potential.
- Recruit individuals interested in obtaining and openly sharing their genome sequences, related health and physical information, and reporting their experiences as a participant of the project on an ongoing basis.
- Develop technologies to improve the accessibility of personal genome sequencing.
- Foster dialog with research communities, industries, and public and governmental bodies with interests in personal genomics, and related ethical, legal, and social issues (ELSI).
- Develop tools for interpreting genomic information and correlating it with related personal medical and biological information.
What does the PGP mean for personalized medicine?
Participants should not expect direct medical benefits from the PGP, as researchers are still working to link particular sequences with traits. As these associations accumulate in the scientific literature, clinicians can begin using an individual’s genomic sequence to predict the chance he or she will develop a particular disease or condition, fostering personalized medicine.
Church envisions a day when many patients will get their genomes sequenced to assess their personal disease risk, and clinicians will help them manage risk through diet, exercise, pharmaceuticals, etc. The PGP may usher in this age of personal genomics by increasing the pace of discovery in the gene association field.
How can I participate?
On April 15, 2008, Church received permission to scale the PGP to 100,000 people. Harvard University’s Institutional Review Board, which oversees research on human subjects, approved Church’s proposal to test potential participants on their genetic knowledge, rather than using formal genetics training as an enrollment requirement.
Church will begin enrolling new participants after the Oct. 20 event. For a complete guide to enrolling in the PGP, visit: http://www.personalgenomes.org/howitworks.html
What are the benefits of participating?
1) Medical Advancement: A motivating force behind the creation of the Personal Genome Project is to provide individuals with an opportunity to share their personal medical information with the scientific research community for purposes that promote human welfare through the advancement of scientific and medical discovery.
2) Scientific Discovery: The answers to many fundamental questions about our basic biology, our experiences as individuals, and our history as a species will be illuminated by scientists once they have access to large datasets that contain many human genomes tied to other forms of personal information, such as medical history or physical traits.
3) Self-curiosity: Early adopters of genome sequencing might be driven by self-curiosity or the pursuit of personal interests in biology or computing. Professional interests might be another reason for being an early adopter of personal genomics, especially for individuals whose work may be impacted significantly by genomics in the near future, such as certain health care workers, policy-makers, investors, and IT professionals.
What is open consent?
In the post-genomic age, established concepts of research ethics are stretched to their limits, and issues of privacy, confidentiality and consent for research are being re-examined. A genomic sequence is akin to a social security number, making implied promises of anonymity disingenuous in studies involving DNA sequencing. Working with ethicist Jeantine Lunshof, George Church showed that scientific innovation and ethics are still compatible if researchers use an open-consent framework.
Open consent is a process where individuals gain an understanding of relevant information in order to make a thoughtful decision about whether to voluntarily enroll in a research project. PGP staff members, for example, provide detailed information about potential risks and explain that they cannot promise participants anonymity.
What are the risks involved with participating?
The Personal Genome Project aims to reduce the risks associated with personal genome sequencing for individuals and society through the development and promotion of thoughtful research practices and policy. Individuals interested in participating should be comfortable with a variety of worst-case scenarios and known risks. In principle, anyone with sufficient knowledge could take a participant's genome and/or other personal information and use them to:
- Infer paternity or other features of the participant's genealogy.
- Claim statistical evidence that could affect employment or insurance or the ability to obtain financial services for the participant. The Genetic Information Nondiscrimination Act, signed into law May 21, 2008, mitigates some of these risks.
- Claim relatedness to criminals or incriminate relatives.
- Make synthetic DNA corresponding to the participant and plant it at a crime scene
- Reveal propensity for a disease currently lacking effective treatment options
What do participants provide to PGP staff?
After providing detailed information about their traits, PGP participants provide a blood sample, saliva sample, and/or skin cells from an arm or leg. Scientists use these for DNA sequencing and other biological measurements. Researchers will reprogram the skin cells into adult stem cells, which will be stored in a biobank. Any researcher can obtain these cells and coax them to become liver tissue, heart muscle, etc., so that they can perform functional studies.
For more information on the Personal Genome Project, visit www.personalgenomes.org.
Conflict Disclosure: Several DNA-sequencing companies have licensed Church lab patents or software. Church also serves in scientific advisory roles for DNA-sequencing companies and direct-to-consumer genomics. For a full list of Church’s technology-transfer and commercial scientific advisory roles, visit http://arep.med.harvard.edu/gmc/tech.html.
Funding Sources: The PGP has received grants for biomedical research from The Broad Institute of Harvard and MIT. The PGP has received financial support in the form of unrestricted gifts from Google, COUQ Foundation, and Orbimed. Relevant grants for technology development (restricted to non-human-subjects related activities) include those from the Department of Energy (DOE GTL) and the National Institutes of Health (NIH NHGRI CEGS). The PGP has received unrestricted royalty donations via Harvard and George Church from Applied Biosystems, Agencourt, Helicos, Lynx (Solexa / Illumina), and Complete Genomics Inc.
