Week 4: Learning goals and objectives
In Week 4 you will be learning about the…
- Role of (public health) genetic epidemiology in the effort to improve global health;
- How genomic research is translated into benefits for human health in southern Ethiopia.;
- The importance of newborn screening to the prevention of disease before clinical features appear;
- Some of the ethical and legal challenges to the use of Newborn Screening (NBS);
- How prenatal screening might be considered to be a first step to “designer babies;”
- Biological, ethical, legal and social issues raised by Pre-implantation Genetic Diagnosis (PGD) and prenatal testing.
Your objectives are to…
- Explain what is meant by the words “genetic testing” as applied specifically to “cytogenetic analysis” and “molecular genetic testing.”
- Discuss why it is possible that the benefits of newborn screening may be overstated.
- Understand why “Podoconiosis” is a good example of the application of genomic science to address a “considerable public health problem” in Ethiopia.
- Consider the pros and cons of developing some sort of federal oversight of reproductive genetic testing.
- Give some examples of the kinds of ethical questions that might emerge by the testing of embryos.
- Choose under what circumstances you would consider opting for a prenatal test on an embryo/fetus and explain your reason(s).
- Identify some of the social and moral questions about making changes in human DNA that can be passed down from one generation to the next (e.g., “mitochondrial replacement” therapy).
- Why might “Whole Genome Sequencing” be considered as “The Ultimate Genetic Test”?
As the basic science of population health, genetic epidemiology—the study of the role of genetic factors in determining health and disease in families and in populations, and the interplay of such genetic factors with environmental factors—will have an increasingly important role in addressing the gaps in the translation of genomic information, especially in the conduct of population-based research aimed at improving health and preventing disease.
As illuminated by the clips from the 1997 film “GATTACA,” the important role human genomic epidemiology will continue to play in the continuum from gene discovery to the development and applications of genomic information for diagnosing, predicting, treating, and preventing disease, will be crucial to the evidence-based integration of human genomics into the practice of medicine and public health in the 21st century.
Translating genomic research into benefits for human health requires large numbers of population-based biological samples. Check out a breakthrough case-in-point, the first study of a non-communicable disease to have used genome-wide association (GWAS) for an African population. The “Podo Project” demonstrates the global reach of genomics research into the lives of people in parts of the world where endemic diseases very often go unchecked. (Note: You can learn more about GWAS in the Resources section below)
Residual bloodspots from state newborn screening programs are one potential source of specimens for these studies. Guthrie cards (Guthrie filter paper collection kits) have been used for decades to collect blood for newborn screening programs in the United States, Australia, New Zealand, Japan, and for most countries in Europe and South America.
Dr. Robert Guthrie introduced the first newborn screening test (NBS) in the United States for phenylketonuria (PKU) in the early ’60s and the use of the Guthrie card to collect the heel stick blood for newborn screening is now standard.
For example, the U.S. has been using Guthrie cards for this purpose since the early 1960’s. Blood is usually collected through a heel prick 24 to 48 hours after birth and is placed on the cards, which may be archived after screening. Genetic information from Guthrie cards is a valuable resource. It opens doors to examine risk factors and potentially diagnose diseases before the clinical features are present.
One such disease might be a “Cerebral Palsy“-like condition, which is usually not diagnosed until a child is nearly two. NBS information could also be used to lessen the ravages of a spectrum of pediatric cancers which are known to be present at birth but which don’t present until later in childhood.
Blood samples are collected as part of a mandatory (state-wide) public health program aimed at benefiting individual newborns; Additions and removals from the panel are typically reviewed by a panel of experts. Four criteria generally relied upon when making decisions for early newborn screening programs are:
- having an acceptable treatment protocol in place that changes the outcome for patients diagnosed early with the disease;
- an understanding of the condition’s natural history;
- an understanding about who will be treated as a patient;
- a NBS screening test that is reliable for both affected and unaffected patients and is acceptable to the public.
In the context of these criteria, a number of ethical, legal, and social challenges to the use of this resource for genomic research, including questions regarding consent, access, privacy, and the identifiability of samples. Addressing these issues, moreover, raises questions about the moral justification for mandatory screening when residual samples are used for research purposes.
For example, the state of Minnesota had been retaining blood spots indefinitely for use in screening research, follow-up care, and other research programs until 2011, when the Minnesota Supreme Court ruled that the Minnesota Department of Health (MDH) was illegally holding blood spots indefinitely. To comply with the court, the state was eventually forced to destroy the blood spots for 1 million children who were born before 2011. Under the current policy, MDH retains normal blood spots (those testing negative) for 71 days before they are destroyed. Samples with abnormal results and the test results for all babies are kept for 24 months before being destroyed. During these retention periods, MDH may only use blood spots for basic program operations, and not for research, public health studies, or to develop new screening tests without the written consent of a parent or guardian.
A new bill, the Newborn Screening Program Modifications bill (SF 2047), which passed by a 41-22 vote on April 24, 2014, would reinstate the ability of the state to retain these spots indefinitely again, and to use them and test results in research related to newborn screening and to develop new tests, although parents would be able to choose if they do not want their child’s samples and results stored. (See: Minnesota newborn screening controversy)
The new bill has strong support of screening advocacy groups, but it has drawn fire from the Minnesota “Citizen’s Council for Health Freedom” whose members are “deeply concerned” that it will undercut genetic privacy and take choice from parents and give it to the state. “Our genetic information is ours and if we give consent, the research can happen,” said Twila Brase, the Council’s president, whose nonprofit group lobbies for patients and physicians rights. “Until there is consent for the storage and the use of our genetic information, no research should happen. (See: Privacy debate surrounds use of newborns’ blood samples)
As the Minnesota case demonstrates, the public health and research purposes of bloodspot collection will be impossible to separate, and additionally, serve to underscore the need for improved education about newborn screening and some form of parental permission (informed consent?) for the use of samples.
Additionally, the research use of bloodspots warrants the expansion of the ethical frameworks used to rationalize screening to include benefits to children and populations. Studies also reveal a lack of guidance for health departments and argue for the development of policy recommendations for the storage and use of bloodspots to help programs address the rights of families and promote the potential social goods generated through public health research.
Of all our natural rights, none is guarded more zealously than the right of personal privacy, especially when it involves private matters of personal health. Yet, as medical technology advances and public health costs demand action, the boundary between privacy rights and the “common good” is increasingly strained.
Genomics – the study of genes and their roles in disease – offers enormous potential for bettering public health and reducing health care costs. Those are worthy ends, but they require genetically screening a significant number of individuals for predisposition to disease. Using the coercive power of government to enforce genetic screening and research rubs against the unalienable right of personal privacy.
Minnesota has been leading the challenging legislative effort to lay out the details of those concerns. There has been only limited national guidance on the best candidate conditions for newborn screening since the National Academy of Sciences report of 1975 and the United States Congress Office of Technology Assessment report of 1988 despite rapid developments since then in genetics, in screening technologies, and in some treatments.
The American College of Medical Genetics issued a publication giving a recommendation for a national newborn screening panel several years ago. The HRSA Secretary’s Advisory Committee on Heritable Disorders in Newborns and Children now serves as the reviewer and approver for new disorders on the newborn screening panel. To make the issue of newborn screening au courant, in 2013 The American Academy of Pediatrics (AAP) issued new guidance on the genetic testing of children:
“Genetic testing and screening of minors is widespread, and testing is done routinely on virtually all newborns. In the American Academy of Pediatrics (AAP) policy statement, “Ethical and Policy Issues in Genetic Testing and Screening of Children,” in the March 2013 issue of Pediatrics (published online Thursday, Feb. 21), the AAP and the American College of Medical Genetics (ACMG) issue recommendations on updated technologies and new uses of genetic testing and screening.
Both the AAP and ACMG agree that the best interest of the child should be the principle factor on whether to offer testing and screening. Both the AAP and ACMG support mandatory genetic screening for all newborns. Parents or guardians should have the right to refuse newborn screening after being informed about the significant benefits and improbable risks.
Most genetic testing beyond the newborn period is done on children with intellectual disabilities, autism spectrum disorders or multiple anomalies for diagnostic purposes. Genetic testing of older children may increase as data and knowledge expand. The recommendations on predictive testing are now divided into conditions that occur in childhood and those that occur in adulthood.
For children at risk of childhood-onset conditions, testing is permitted with parental consent, and when feasible, the child’s assent. Testing for adult-onset conditions is discouraged, but exceptions can be made with appropriate counseling and the consent of the parent and child. Given the rapid advances in genetics and genomics, pediatricians and other health care providers need to stay informed and updated on best practices.”
Prenatal and Universal Genetic Testing
At age 25, a woman’s odds of having a baby with the disorder known as Down Syndrome are 1 in 1,200. Those odds climb to 1 in about 350 by the age of 35 and to 1 in about 49 by age 44. Until recently, only pregnant women 35 and older were routinely tested with an invasive procedure known as amniocentesis, to see if their fetuses had the extra chromosome that causes the condition. Older women have a higher risk of conceiving a child with birth defects. But it is women under 35 who give birth to the majority of children with Down syndrome, simply because there are so many more women under 35 having babies.
Because amniocentesis carries a small risk of miscarriage, it has not been routinely offered to younger women. Women under 35, then, who carried a fetus with Down Syndrome were likely to find out only at birth. People with Down syndrome suffer from mild to moderate mental retardation, are at high risk for congenital heart defects and a variety of other medical problems, and have an average life expectancy of 49. As adults, some hold jobs, but many have difficulty living independently.
Currently about 6,000 Downs babies are born in the United States each year. Now, a new, safer screening procedure is being offered to all pregnant women, regardless of age. It involves a first-trimester sonogram and two blood tests. Because about 90 percent of pregnant women who are given a Down syndrome diagnosis choose to have an abortion, the greater availability of the test may lead to sharply fewer Down syndrome births. (See: More accurate test)
The new testing procedure comes as a relief to many prospective parents, who feel ill equipped or unwilling to cope with a child who has medical and cognitive disabilities. It may be time to start preparing ourselves for the medical and social ramifications of this burgeoning technology, known as NIPD (non-invasive prenatal genetic diagnosis, or cell-free DNA tests, CfDNA).
The CfDNA test relies on DNA fragments shed by the placenta that, in nearly all pregnancies, are equivalent to fetal DNA. These short fragments of DNA, along with fragments from the pregnant woman, float in the woman’s bloodstream. This mixture of fragments can be extracted and analyzed for extra material from specific chromosomes.
Noninvasive testing of fetal DNA in the mother’s blood can accurately—and early in pregnancy (7th – 9th week)–detect various syndromes (Down, Edwards, Patau) all of which can cause serious developmental and medical issues, and will soon become a standard of care for all women, and presages a time when information about a fetus extends well beyond a handful of known fetal conditions to any human trait that has a major genetic component.
These tests are likely to become commercially available within the next five years. When they do, it is estimated that the number of fetal genetic tests annually in the United States will jump from the current 100,000 to about 3 million.
With NIPD comes the technical ability to analyze thousands of genetic markers with as little as 10 milliliters of mom’s blood. But some disability-rights advocates, and especially parents of children with Down syndrome — even many who support abortion rights — find the increase in testing alarming. They say the benefits of having a child with disabilities are poorly understood; for many, the experience has provided unexpected joys. They argue that there is a benefit to society’s having a range of human diversity. And a dwindling population of people with Down syndrome (it currently numbers about 350,000) could mean less social support, reduced funds for medical research and a lonelier world for those born with the condition.
More broadly, some see technology that allows for the filtering out of people with Down syndrome as a first step toward “designer babies” that are genetically selected to fit aesthetic and cultural values. As prenatal tests become available for a range of genetic imperfections, there is a growing debate over where to draw the line. For a few hundred dollars extra, some parents are now requesting that an amniocentesis, or a similar procedure that can take place earlier in a pregnancy, be analyzed not only for Down syndrome but also for about 100 genetic aberrations that have been linked to physical and cognitive disorders.
These deletions or duplications of DNA were previously hard or impossible to detect. Yet, because not as much is known about them, they are also less definitive than Down syndrome. One observation made by disability-rights advocates is that a couple’s choice to terminate a pregnancy once they learn of a genetic anomaly has a lot to do with the way the doctor conveys the news to them. Most doctors have little or no training on how to relay a prenatal diagnosis of Down syndrome, let alone the myriad of other conditions that can now be tested for.
Often, they presume that a couple will want to abort. To counteract that impulse, some parent groups are offering training, or asking doctors to suggest that couples who learn of their fetus’ condition take time to talk to parents of children with the same condition, to learn more about what it is like to raise them before making a decision. This will be crucial when newborn whole genome/exome sequencing goes mainstream. (See: Exome Sequencing and Genome sequencing for newborns)
Pre-implantation Genetic Diagnosis (and Germinal Cell Manipulation)—Where to draw the line?
For many years, parents have been using a procedure known as Preimplantation Genetic Diagnosis, or PGD, to screen embryos for genes certain to cause childhood diseases that are severe and largely untreatable. The procedure has also been used to avoid passing on Huntington’s disease. Now, a growing number of couples are using PGD to detect predispositions to diseases that may or may not develop later in life, may be treatable, and, by the time a child grows up, may even be curable.
Increasingly, prospective parents who carry risk-genes like BRCA1 or another gene that raises the risk of colon cancer are considering PGD. For many people, the prospect of cancer is scary enough to warrant the often-arduous process. Yet it is also possible to test embryos for a form of deafness, or a predisposition to arthritis, asthma or obesity. Some clinics test for gender. The growing use of the technology raises more questions about where to draw the line.
To perform PGD, a couple who could otherwise conceive naturally instead undergoes the same in vitro fertilization process that is used to assist infertile couples. Several eggs are extracted from the mother and fertilized with the father’s sperm in a petri dish. Then, when the resulting embryos are three days old, doctors remove a single cell from each and analyze its DNA. Only the embryos without the defective gene are considered candidates to implant in the mother’s uterus. The others are discarded. The process of embryo screening is physically taxing for the woman and can cost $20,000 or more.
Perhaps not surprisingly, discussions about the procedure can also cause rifts within families. It raises the specter of eugenics in the most personal terms.
In that latter regard, developing a technique meant to prevent a devastating illness and ultimately using it to try to make so-called “designer babies,” kids who are more intelligent or have other qualities that the parents find desirable, is a “bright line” that many believed would never be crossed.
However, on February 2, 2015, Britain became the first –and only country to date—to legislatively allow scientists to alter the human germ line (Oocytes) designed to prevent the occurrence of “Mitochondrial Disease,” an incurable, and fatal, disease in children. In the process, the descriptor “Three parent babies” was added to the world’s reproductive lexicon.
Others warn parents considering PGD and/or germinal cell manipulation that no good can come of thumbing their noses at fate. An embryo selected to avoid cancer, they argue, could turn out to have autism or a cleft lip or some other physical or cognitive problem.
When a child conceived through normal means is born with an anomaly of some kind, a parent simply accepts it. When that child is “chosen” through various manipulative techniques there is some perceived additional responsibility attached. Yet for couples who have seen close family members die of an inherited form of some terrible disease, for example, the fear of passing on the risk to a child can outweigh any squeamishness about “playing God” with the help of genetic technology. Apart from the likelihood of preventing disease, some believe it is is acceptable, if not desirable, to use such technologies to select for physical traits, as well, when that becomes possible.
Assisted reproductive technologies (ARTs) offer a spectrum of ways to enable any prospective parents, regardless of age, sexual orientation, or marital status to have genetically or biologically connected children.
Universal Genetic Testing
So, how about preventing genetic disease in your children altogether? With that goal in mind—and espousing values that include human rights, freedom from genetic disease, and universal access–a new California bio-tech company, Counsyl.com tests the saliva of prospective parents for more than 100 Mendelian diseases across all major population groups. How couples who test positive as carriers might use this information to conceive a child without a lethal disease is uncertain, but Pre-implantation Genetic Diagnosis (PGD) is clearly one of the options, along with prenatal testing – not to mention the manipulation of donor gametes.
In China and India, greater access to inexpensive ultrasound testing has produced a dramatic skewing of live-birth sex rations. But how about going directly to the in vivo problem aimed at correcting mutations that cause childhood disease (e.g., Cystic Fibrosis) by editing out the faulty DNA altogether in the newborn (AKA “genetic engineering)? (See: Editing fetal DNA)
And what social and ethical issues will arise if/when newborn screening becomes whole genome sequencing? (See Week 7 for more details)
Resources and Discussion
Watch: The Guthrie Test
Watch: More accurate tests
Listen: Screening Embryos for Disease
Watch: Designer babies
Watch: Exome sequencing
Read: Editing fetal DNA
Some Additional Perspectives To Consider:
Read: Enhancing Humans
Mitochondrial Disease is a group of disorders caused by dysfunctional mitochondria, the organelles that generate energy for the cell. Mitochondria are found in every cell of the human body except red blood cells. Mitochondria convert the energy of food molecules into the Adenosine Tri-Phosphate that powers most cell functions. Mitochondrial diseases are sometimes (about 15% of the time) caused by the mitochondrial DNA that affect mitochondrial function. Mitochondrial diseases take on unique characteristics both because of the way the diseases are often inherited and because mitochondria are so critical to cell function.
Listen: Mitochondrial Replacement Therapy (MRT)
Watch: The Details of MRT
The Case of Progeria HGPS (Hutchinson-Gilford Progeria Syndrome) Progeria is an extremely rare, fatal genetic condition. The word Progeria comes from the Greek progeros meaning ‘prematurely old.’
Questions for Discussion
- Should residual bloodspots be used as a genomic research resource without fundamentally changing newborn screening practices? Why? Why not?
- Twyla Brase, a Minnesota privacy advocate says , “Our genetic information is ours … until there is consent for the use of our genetic information, no research should happen.” Do you agree/disagree with this statement, and Why?
- What would you do when you know a genetic disease runs in your family, and you want to have children?
- Is new emerging technology paving the way to a “new eugenics?” Should universal carrier screening become a routine part of medical care?
- Imagine a world free of genetic diseases, where parents control their offspring’s height, eye color and intelligence The science may be closer than you think. Genes interact in ways that we don’t fully understand and there could be unintended consequences, new diseases that result from our tinkering. But even if the science could be perfected, is it morally wrong? Would it lead to eugenics and a stratified society where only the rich enjoy the benefits of genetic enhancement? Or would the real injustice be depriving our children of every scientifically possible opportunity and even life, itself?
- Should there be a policy to prohibit genetically engineered babies? What do you think? Watch the debate (see resources section above titled “Should we prohibit genetically engineered babies?”) and decide on which side of the (Yes? No?) argument do you most agree, and why?
- Do you agree/not agree with the statement: “People who carry a gene, the presence of which will result in a neurological disease leading to a slow and terrible death, have a moral duty to use preimplantation diagnosis–if they can afford it–to spare the next generation” (i.e., discard affected embryos). Support your position.
- What, if any ethical implications are inherent in the repair of genetic defects in the DNA, i.e., use of the “CRISPR” technique in treating chronic disease?