In 1990, the international science community undertook a massive task: The Human Genome Project was started with the goal of mapping the complete sequence of the human genome. After 13 years, the project was successful and by 2003, it enabled mapping of the sequence of the human genome’s almost three billion base pairs. It was a phenomenal feat of research and its impact on the medical and biological fields has been incalculable. We, as a race, now hold an “instruction manual” for making the human body. The full map is made freely accessible to all, for public or private use, by the National Center for Biotechnology Information (NIH, 2008). Since completion of the project, the applications of this knowledge have been numerous.
The International HapMap Catalog
The HapMap Catalog project was started in 2002 – a full year before completion of the Human Genome Project (HGP). Using a sequence provided by the HGP, the HapMap Catalog was the successful attempt to speed up the discovery of genes related to common illness, by cataloging common genetic variations in humans. The DNA sequence of any two people is 99.5% identical; the variations are where potential disease lies. The first HapMap was completed in 2005. Between 2005 and 2012, scientists were able to identify a vast number of associations between specific regions of the genome and disease (yourgenome.org, 2016). The Catalog has led to a more robust understanding of diseases such as: type 2 diabetes, ADHD, early-onset myocardial infarction, asthma, bipolar disorder, schizophrenia, psoriasis, lung cancer, addiction, and many more (Manolio & Collins, 2009).
The ENCODE Project
In 2003, the National Human Genome Research Institute (NHGRI) launched the ENCODE project. The purpose of ENCODE, or the Encyclopedia of DNA Elements, was to identify and describe all of the functional parts of the genome in order to answer the question, “How does the genome work?” Over 1,800 different studies were completed and in 2012, the first “operating manual” for the human genome was produced. Scientists in the ENCODE project identified the genes that carry the code for protein construction and over 9,000 genes with important effects in our cells. Scientists also found that over 80 percent of the human genome sequence controls aspects of biological function (yourgenome.org, 2016).
The Pan-Cancer Atlas
In 2012, the Pan-Cancer Initiative was launched with the purpose of studying cancer on a molecular level. This initiative culminated in the release of the Pan-Cancer Atlas in April 2018. The Cancer Genome Atlas Consortium (TCGA), a collaboration supported by the National Cancer Institute (NCI) and the NHGRI, analyzed over 11,000 tumors from 33 of the most prevalent forms of cancer to create an in-depth understanding of how, where, and why tumors develop in humans. The Pan-Cancer Atlas is a great resource for the development of new treatments and precision medicine. Scientists were able to reclassify tumor types based on molecular similarity. It was found that tumors are influenced by their cell of origin, but not completely. Initially, tumors were treated by different means depending upon cell of origin. With new knowledge and new molecular sub-classification of tumors, drugs can be created specifically to deal with small differences in the molecular construction of similar tumors (Hoadley et al, 2018).
Scientists have come closer to figuring out how and why tumors develop. The Pan-Cancer Atlas reveals how genetics and body mutation collaborate in cancer progression. The relationship of the tumor to its microenvironment was also studied. Understanding of the development and movement of cancerous cells can help develop new treatments and immunotherapies, help understand recidivism, and help understand the occurrence of cancers across ancestral groups (Ding et al, 2018).
Most intriguing in the development of the Pan-Cancer Atlas, scientists were able to find and document vulnerabilities in tumor signaling pathways that can aid in developing personalized treatments and therapies (Sanchez-Vega, 2018). It is hoped that with treatment, the found vulnerabilities can be leveraged to stop cancer cell growth and spread.
Newborn Screening
Currently, every human is genetically tested at birth for the presence of certain diseases. With just a few drops of blood taken from the heel of the infant, doctors can tell if it will develop conditions in the future. Early detection and treatment can help mitigate effects of the condition as the child grows (NIH, 2018). Individual states determine the diseases babies are screened for – for example: Michigan babies are tested for 57 genetic diseases including cystic fibrosis, critical congenital heart disease, sickle cell anemia, beta-thalassemia, tri-functional protein deficiency, congenital adrenal hyperplasia, and maple syrup urine disease (babysfirsttest.org, 2018).
It is important to clarify that, at this point in time, newborns are screened only for diseases required by their birth state. At this time, babies do not undergo complete genetic screening; many believe, however, that complete universal genome sequencing is inevitable. Some say that this potential future development is a good thing; others disagree and believe that the economic and psycho-social impacts (the cost of predicting one’s life plan based on uncertain results) of the practice should be considered (Johnston et al, 2018). There are potential fiscal costs to universal genome sequencing, as well. In 2008, the Genetic Information Non-Discrimination Act was passed to protect consumers from unfair health insurance costs due to information found in screening. This act, however, does not include life insurance, disability, or long-term care insurance (Zhang, 2017).
Future Applications
Scientists at the Broad Institute and Harvard University have developed a tool that makes disease detection more precise. The researchers are currently building a website that will allow users to upload genetic data and then receive a probability score for heart disease, breast cancer, chronic inflammatory bowel disease, atrial fibrillation, and type 2 diabetes (Kolata, 2018).
A new framework is being developed to identify the presence and cause of Autism Spectrum Disorders (Chen et al, 2018).
A new test is being developed using DNA to detect whether a heart transplant will be rejected (Burke, 2018).
The HGP led to great discoveries, perhaps none greater than the practice of genome editing. This technology enables a scientist to change an organism’s DNA. In other words, scientists can now add, remove or alter genetic material at specific locations in the genome. Genome editing can have great implications in the prevention and treatment of human disease. Current research is entirely informational in nature. Scientists have been experimenting using cells and animal models and it is still being determined whether genome editing is safe and effective for humans.
Multiple approaches to genome editing have been developed, but the most promising is CRISPR-Cas9. CRISPR-Cas9 is short for “clustered regularly interspaced short palindromic repeats and associated protein 9”. CRISPR was patterned from the naturally occurring genome editing system in bacteria. Bacteria capture snippets of DNA from invading viruses and use those snippets to create DNA segments called CRISPR arrays. If the virus attacks again, the bacteria use the CRISPR array to create an RNA (ribonucleic acid) segment to target the DNA and use Cas9 (or a similar) enzyme to cut it – rendering it inoperative. Scientists have successfully used this method to alter DNA at the cellular level.
In the lab, CRISPR-Cas9 works much the same way. Researchers create a small piece of RNA which is then bonded to a Cas9 enzyme. The RNA and enzyme are then bonded to a target piece of DNA. The Cas9 enzyme cuts the DNA at a specified location and once cut, researchers use the cell’s own machinery to make changes to the DNA strand (NIH, 2018).
CRISPR is being used in labs all around the world and in no time at all, private business has moved in. Currently, three main companies are founded with genome editing and CRISPR as their focus.
In order to move the research further, the National Institute of Health (NIH) is launching a new program entitled Somatic Cell Genome Editing program. This program aims to create new tools to perform safe and effective human gene editing. The tools, when developed, will be presented free to any and all labs throughout the scientific community.
Human genome editing is in our future and not everyone is confident that it will be used in an ethical manner. Currently, germline cell and embryo editing are illegal in most countries, but not all. For example, embryo and germline cell editing is not illegal in the United States. In 2017, a team of scientists in Oregon successfully edited, using CRISPR-Cas9, a human embryo (Connor, 2017).
Regardless of the implications, the HGP was a massive feat of international collaboration and science. We now have an “instruction manual” with its own “operations manual.” How we use this information is up to us. Medically, the goal is to increase the life enjoyment of human beings through the eradication of disease. If we, as a species and scientific community, attain this goal, the Human Genome Project will go down as one of the greatest accomplishments in history.
REFERENCES
Babysfirsttest.org. (2018). Baby’s first test. Genetic Alliance. Retrieved from https://www.babysfirsttest.org/newborn-screening/states/michigan
Burke, E. (2018). Improving the detection of heart transplant rejection with DNA sequencing. Genome.gov. Retrieved from https://goo.gl/1bGLe9
Chen, S., Fragoza, R., Klei, L., Liu, Y., Wang, J., Roeder, K., Yu, H. (2018). An interactome perturbation framework prioritizes damaging missense mutations for developmental disorders. Nature Genetics, 50, 1032-1040.
Connor, S. (2017). First human embryos edited in U.S. MIT Technology Review. Retrieved from https://goo.gl/7kvj1G
Ding, L., Bailey, M., Porta-Pardo, E., Thorsson, V., Colaprico, A., Bertrand, D., Getz, G. (2018). Perspective on oncogenic processes at the end of the beginning of cancer genomics. Cell, 173(2), 305-320.
Hoadley, K., Yau, C., Hinoue, T., Wolf, D., Lazar, A., Drill, E., Laird, P. (2018). Cell-of-origin patterns dominate the molecular classification of 10,000 tumors from 33 types of cancer. Cell, 173(2), 291-304.
Johnston, J., Lantos, J., Goldenberg, A., Chen, F., Parens, E., & Koenig, B. (2018). Sequencing newborns: A call for nuanced use of genomic technologies. The Hastings Center Report. Retrieved from https://goo.gl/gcYn4X
Kolata, G. (2018). Clues to your health are hidden at 6.6 million spots in your DNA. New York Times. Retrieved from nytimes.com
Manolio, T., & Collins, F. (2009). The hapmap and genome-wide association studies in diagnosis and therapy. Annu Rev Med, 60, 443-456.
NIH. (2018). Retrieved from genome.gov
Sanchez-Vega, F., Mina, M., Armenia, J., Chatila, W., Luna, A., La, K., Schultz, N. (2018). Oncogenic signaling pathways in the cancer genome atlas. Cell, 173(2), 321-337.
Yourgenome.org. (2016). How is the completed human genome sequence being used? Retrieved from yourgenome.org
Zhang, S. (2017). The loopholes in the law prohibiting genetic discrimination. The Atlantic. Retrieved from https://goo.gl/AdmJvS
