HAS GENETICS HIT A BRICK WALL?
BY DAN LEAPMAN
BY DAN LEAPMAN
GRAPHIC/VICTORIA SIU
"ONE DAY you're going to be able to walk into a doctor's office and have a computer analyze a tissue sample, identify the pathogen that ails you and then instantly prescribe a treatment best suited to your specific illness and individual genetic make-up.” -Paul Horn, Senior VP of IBM, 2001
The Guardian described the completion of the The Human Genome Project (1990-2003) as “Biology’s Holy Grail” [1]. The public and scientific community believed they had uncovered the blueprint-- the biological programming -- that generates genetic disorders and all the traits that make us who we are.
Naturally, the excitement shifted from characterizing the human genome to designing preventative and specialized care. As Paul Horn suggested 17 years ago, wouldn’t it be possible to predict your genetic disposition for certain disorders, and take steps to prevent them?
Fourteen years after the human genetic code was declared sequenced with 99.99% accuracy, we would expect to be able to control our environment and behavior, or even modify our own genetic makeup to change our hereditary destiny. These ambitions have applications in both disease prevention and genetic healthcare.
While burgeoning technologies exist, the Human Genome Project still hasn’t achieved the goals it was projected to complete, such as clinical genome sequencing and genetically-tailored doctor visits. Huge gaps in our expectations have yet to be filled. Understanding the challenges that genetics has faced explains not only why these expectations came to be but also helps us predict the future of the field.
Has the study of genetics hit a brick wall, or will the field break through into extraordinary achievements?
High Expectations
Perhaps some of the perceived “holes” that we currently see in genetics were due to excess enthusiasm that was not congruent with actual advancements in the field. Whether advancements in mapping, sequencing, and DNA replication before 1990 were enough to merit the scope of the Genome Project, the success of its mission to map the entire human genome, and its $3 billion public investment, is up to individual discretion.
As James Watson was the main source of enthusiasm for the Genome Project and genetics in general, we strive to understand his intentions for the field through the lens of his contributions and status in science.
In 1953, Watson worked alongside Francis Crick to create a model of DNA that both matched Rosalind Franklin’s x-ray crystallography data and explained all of its properties. Watson was offered a position at Harvard University in 1956 and a Nobel Prize in 19622. Modern Library named his autobiography the Double Helix one of the 100 Best Nonfiction Books of the 20th Century [3].
Watson was the world’s most popular geneticist, the head of the NIH, and the director of the Human Genome Project [4]. It is no wonder why he might angle the NIH and the operations of many of the best laboratories in the world toward genetics, whether supported by hard evidence or not. Due to Watson, our inflated expectations for genetics may be partially responsible for the field’s shortcomings.
Disaster Strikes
The Human Genome Project did complete many individual scientific feats over its course. However, to understand the apparent shortcomings of the field, we must understand the medical challenges that genetics has faced.
In 1984, at the age of 3, Jesse Gelsinger was diagnosed with ornithine transcarbamylase (OTC) deficiency, a disorder where one’s genes do not have the complete sequence that codes for OTC, a necessary enzyme produced by the liver [5]. The year 1994 marked a surge of articles that supposed that viral vectors could be used for gene therapy [6].
The idea was that if a person lacked a certain gene, a virus could infect the target cells and, like viruses do, implant its own DNA. If the virus carried the gene that the person lacked, the individual’s genetic code would effectively gain that gene [7]. By 1999, viral vector therapy would come into fruition, and Gelsinger would be the first human trial. A long awaited 15 years after his first diagnosis, under the oversight of the University of Pennsylvania, his liver was injected with a crippled adenovirus that carried the gene necessary to produce the OTC enzyme, and the virus began to enter his cells[8].
Two days later, Gelsinger was dead. According to a death report, the virus spread beyond Jesse’s liver to other organs, and his body reacted with an inflammatory response that brought his fever to 104.5 and put him in a coma. The ventilator could not oxygenate his blood via his fluid-filled lungs [9].
The subsequent lawsuits (whose settlements totalled $517,496 from UPenn and $514,622 from Children's National Medical Center in Washington, D.C) caused hesitation among the scientific community regarding gene therapy9. Whereas the government had reviewed 331 gene-therapy trials by August of 1999 [10], by the coming January, the FDA had cancelled all trials at the University of Pennsylvania and had begun investigations on 69 others [11]. There was great skepticism among scientists about the viability of gene manipulation as a medical technique, and some hesitation among medical doctors to put gene therapy into practice. It seemed as though the Gelsinger case was a death sentence for genetics. Would genetic medical therapies ever see the light of day?
Advancements in Genetic Technology
While the study of genetics has had a certainly tumultuous past, the pursuit of genetic technologies has been all but fruitless. There have certainly been major advancements resulting from research succeeding the Human Genome Project.
One of these advancements is screening tests for newborns. The CDC describes the procedure as “using a few drops of blood from the newborn's heel, [to test] for certain genetic, endocrine, and metabolic disorders..[including] hearing loss and critical congenital heart defects (CCHDs)” [12]. The American Association for Clinical Chemistry repeatedly emphasizes that the importance of screening tests is that they can determine disorders that cause enzyme deficiencies and other disorders not visible through traditional medical examination techniques, saving babies every day [13].
BRCA1 testing represents another accomplishment extending from the Human Genome Project. The BRCA1 gene produces an enzyme that suppresses tumor growth and repairs damaged DNA, and the procedure can identify if you have a mutation in that gene. Mutations in that gene are associated with predispositions to common cancers such as breast (both male and female), ovarian, prostate, and more [14]. Based on this finding, the scientific community has gained insight into the genetic basis of the formation of tumors. Perhaps more importantly, however, BRCA1 testing is a key preventative care measure, as individuals identified to possess mutations in the gene have an opportunity to regulate their lifestyle factors and environment to reduce their current and future risk for cancer.
Despite the setbacks that genetics has faced, studying genetics has undoubtedly generated life-saving technologies, and expanded the frontier of human knowledge.
Future
Despite issues that genetics has encountered, scientists in the field continue to improve in their ability to treat and prevent genetic disorders. Looking back, we must be aware of instances where our institutions fail us, and stop anticipating a “holy grail” in any discipline of scientific research. The reality is that science is a slow, exponential process that includes both successes and failures. This is the basis of the scientific method. The more hurdles that we hit, the more opportunity we have to change our viewpoints, pursue viable alternatives, and grow beyond expectations.
References
The Guardian described the completion of the The Human Genome Project (1990-2003) as “Biology’s Holy Grail” [1]. The public and scientific community believed they had uncovered the blueprint-- the biological programming -- that generates genetic disorders and all the traits that make us who we are.
Naturally, the excitement shifted from characterizing the human genome to designing preventative and specialized care. As Paul Horn suggested 17 years ago, wouldn’t it be possible to predict your genetic disposition for certain disorders, and take steps to prevent them?
Fourteen years after the human genetic code was declared sequenced with 99.99% accuracy, we would expect to be able to control our environment and behavior, or even modify our own genetic makeup to change our hereditary destiny. These ambitions have applications in both disease prevention and genetic healthcare.
While burgeoning technologies exist, the Human Genome Project still hasn’t achieved the goals it was projected to complete, such as clinical genome sequencing and genetically-tailored doctor visits. Huge gaps in our expectations have yet to be filled. Understanding the challenges that genetics has faced explains not only why these expectations came to be but also helps us predict the future of the field.
Has the study of genetics hit a brick wall, or will the field break through into extraordinary achievements?
High Expectations
Perhaps some of the perceived “holes” that we currently see in genetics were due to excess enthusiasm that was not congruent with actual advancements in the field. Whether advancements in mapping, sequencing, and DNA replication before 1990 were enough to merit the scope of the Genome Project, the success of its mission to map the entire human genome, and its $3 billion public investment, is up to individual discretion.
As James Watson was the main source of enthusiasm for the Genome Project and genetics in general, we strive to understand his intentions for the field through the lens of his contributions and status in science.
In 1953, Watson worked alongside Francis Crick to create a model of DNA that both matched Rosalind Franklin’s x-ray crystallography data and explained all of its properties. Watson was offered a position at Harvard University in 1956 and a Nobel Prize in 19622. Modern Library named his autobiography the Double Helix one of the 100 Best Nonfiction Books of the 20th Century [3].
Watson was the world’s most popular geneticist, the head of the NIH, and the director of the Human Genome Project [4]. It is no wonder why he might angle the NIH and the operations of many of the best laboratories in the world toward genetics, whether supported by hard evidence or not. Due to Watson, our inflated expectations for genetics may be partially responsible for the field’s shortcomings.
Disaster Strikes
The Human Genome Project did complete many individual scientific feats over its course. However, to understand the apparent shortcomings of the field, we must understand the medical challenges that genetics has faced.
In 1984, at the age of 3, Jesse Gelsinger was diagnosed with ornithine transcarbamylase (OTC) deficiency, a disorder where one’s genes do not have the complete sequence that codes for OTC, a necessary enzyme produced by the liver [5]. The year 1994 marked a surge of articles that supposed that viral vectors could be used for gene therapy [6].
The idea was that if a person lacked a certain gene, a virus could infect the target cells and, like viruses do, implant its own DNA. If the virus carried the gene that the person lacked, the individual’s genetic code would effectively gain that gene [7]. By 1999, viral vector therapy would come into fruition, and Gelsinger would be the first human trial. A long awaited 15 years after his first diagnosis, under the oversight of the University of Pennsylvania, his liver was injected with a crippled adenovirus that carried the gene necessary to produce the OTC enzyme, and the virus began to enter his cells[8].
Two days later, Gelsinger was dead. According to a death report, the virus spread beyond Jesse’s liver to other organs, and his body reacted with an inflammatory response that brought his fever to 104.5 and put him in a coma. The ventilator could not oxygenate his blood via his fluid-filled lungs [9].
The subsequent lawsuits (whose settlements totalled $517,496 from UPenn and $514,622 from Children's National Medical Center in Washington, D.C) caused hesitation among the scientific community regarding gene therapy9. Whereas the government had reviewed 331 gene-therapy trials by August of 1999 [10], by the coming January, the FDA had cancelled all trials at the University of Pennsylvania and had begun investigations on 69 others [11]. There was great skepticism among scientists about the viability of gene manipulation as a medical technique, and some hesitation among medical doctors to put gene therapy into practice. It seemed as though the Gelsinger case was a death sentence for genetics. Would genetic medical therapies ever see the light of day?
Advancements in Genetic Technology
While the study of genetics has had a certainly tumultuous past, the pursuit of genetic technologies has been all but fruitless. There have certainly been major advancements resulting from research succeeding the Human Genome Project.
One of these advancements is screening tests for newborns. The CDC describes the procedure as “using a few drops of blood from the newborn's heel, [to test] for certain genetic, endocrine, and metabolic disorders..[including] hearing loss and critical congenital heart defects (CCHDs)” [12]. The American Association for Clinical Chemistry repeatedly emphasizes that the importance of screening tests is that they can determine disorders that cause enzyme deficiencies and other disorders not visible through traditional medical examination techniques, saving babies every day [13].
BRCA1 testing represents another accomplishment extending from the Human Genome Project. The BRCA1 gene produces an enzyme that suppresses tumor growth and repairs damaged DNA, and the procedure can identify if you have a mutation in that gene. Mutations in that gene are associated with predispositions to common cancers such as breast (both male and female), ovarian, prostate, and more [14]. Based on this finding, the scientific community has gained insight into the genetic basis of the formation of tumors. Perhaps more importantly, however, BRCA1 testing is a key preventative care measure, as individuals identified to possess mutations in the gene have an opportunity to regulate their lifestyle factors and environment to reduce their current and future risk for cancer.
Despite the setbacks that genetics has faced, studying genetics has undoubtedly generated life-saving technologies, and expanded the frontier of human knowledge.
Future
Despite issues that genetics has encountered, scientists in the field continue to improve in their ability to treat and prevent genetic disorders. Looking back, we must be aware of instances where our institutions fail us, and stop anticipating a “holy grail” in any discipline of scientific research. The reality is that science is a slow, exponential process that includes both successes and failures. This is the basis of the scientific method. The more hurdles that we hit, the more opportunity we have to change our viewpoints, pursue viable alternatives, and grow beyond expectations.
References
- Meek, J., & Ellison, M. (2000). On the path of biology's holy grail. Retrieved October 08, 2016, from https://www.theguardian.com/science/2000/jun/05/genetics.uknews1
- James Watson - Biographical - Nobel Prize. (2014). Retrieved October 20, 2016, from http://www.nobelprize.org/nobel_prizes/medicine/laureates/1962/watson-bio.html
- 100 Best Nonfiction « Modern Library. (n.d.). Retrieved October 20, 2016, from http://www.modernlibrary.com/top-100/100-best-nonfiction/
- Collins, F. (2015, April 25). DNA’s Double Anniversary | NIH Director's Blog. Retrieved October 20, 2016, from https://directorsblog.nih.gov/2013/04/25/dnas-double-anniversary/
- Gelsinger, P. (2000). Jesse’s intent. Guinea Pig Zero, 8, 7-17.
- Flotte, T. R., & Carter, B. J. (1995). Adeno-associated virus vectors for gene therapy. Gene therapy, 2(6), 357-362.
- Hawley, R. G., Lieu, F. H., Fong, A. Z., & Hawley, T. S. (1994). Versatile retroviral vectors for potential use in gene therapy. Gene therapy, 1(2), 136-138.
Chicago - Marshall, E. (2000). Gene therapy on trial. Science, 288(5468), 951-957
- Couzin, J., & Kaiser, J. (2005). As Gelsinger case ends, gene therapy suffers another blow. Science, 307(5712), 1028-1028.
- Stolberg, S. G. (1999, November 28). The Biotech Death of Jesse Gelsinger - The New York Times. Retrieved October 22, 2016, from http://www.nytimes.com/1999/11/28/magazine/the-biotech-death-of-jesse-gelsinger.html
- Somia, N., & Verma, I. M. (2000). Gene therapy: trials and tribulations. Nature Reviews Genetics, 1(2), 91-99.
- Home | Newborn Screening | NCBDDD | CDC. (2016, February 23). Retrieved October 20, 2016, from http://www.cdc.gov/ncbddd/newbornscreening/index.html
- Screening Tests for Newborns. (n.d.). Retrieved October 14, 2016, from https://labtestsonline.org/understanding/wellness/a-newborn-1/a-newborn-2/
- BRCA1 and BRCA2: Cancer Risk and Genetic Testing Fact ... (2015, April 1). Retrieved October 20, 2016, from https://www.cancer.gov/about-cancer/causes-prevention/genetics/brca-fact-sheet