A Tipping Point on Human Germline Modification?

Posted by Jessica Cussins on March 19th, 2015

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In a March 5 expose in MIT Technology Review titled "Engineering the Perfect Baby," Antonio Regalado reported on just how close some scientists are to using the precision gene editing technique CRISPR to modify nuclear DNA within human gametes or embryos. A week later, an article in Nature alluded to rumors that this has already been done, and that papers reporting on it will be published shortly.

This startling news has prompted statements about human germline modification from three different groups of scientists so far: one published in Nature, one in Science, and one released by the International Society for Stem Cell Research. All discourage clinical applications and call for public dialogue and debate to acknowledge the profound societal, policy, ethical and safety implications raised by efforts to control the genes we pass on to future generations – a welcome sign from within the scientific community. But the statements offer a range of different paths forward.

A Center for Genetics and Society press statement released this morning supports the call for a moratorium on human germline gene editing. CGS opposes efforts to create genetically altered human beings, and has long advocated that the United States join the 40+ other countries that already prohibit this.

The proposal for the strongest moratorium came from scientists writing in Nature under the clear headline "Don’t edit the human germ line." Their commentary, posted on March 12, calls for "a voluntary moratorium in the scientific community" to discourage human germline modification and to raise public awareness of the critical difference between gene editing in somatic cells and in germ cells. The authors include scientists and executives associated with the gene-editing company Sangamo BioSciences and with the Alliance for Regenerative Medicine, an advocacy organization of stem cell companies and institutes, whose executive committee approved the statement.

The authors emphasize a key distinction between altering somatic (non-reproductive) and germline cells. While somatic gene therapies hold real medical promise for treating a range of diseases, the medical rationale for using germline alterations on gametes or embryos is unconvincing. As the authors of the Nature commentary put it, “Heritable human genetic modifications pose serious risks, and the therapeutic benefits are tenuous.”

(Unfortunately, the authors seem less concerned about “mitochondrial DNA transfer,” which is an example of a distinct, but nonetheless profound, form of germline alteration that poses an accompanying array of inherent challenges. Is there a justifiable reason to condemn every form of germline alteration but this one? Does this really qualify as a “truly compelling case” when safer alternatives exist?)

The second commentary, published today by Science, is authored by a group of prominent bioethicists and scientific figures. As suggested by its title, “A prudent path forward for genomic engineering and germline gene modification,” its tone is more permissive than that of the Nature statement, and in fact it encourages moving ahead with germline gene editing research. It does, however, “strongly discourage…any attempts at germline genome modification for clinical applications in humans, while societal, environmental, and ethical implications of such activity are discussed among scientific and governmental organizations.”

A statement from the International Society for Stem Cell Research, also released today, takes a similar line, calling for “a moratorium on attempts to apply nuclear genome editing of the human germ line in clinical practice.” It notes that

consensus is lacking on what, if any, therapeutic applications of germ line genome modification might be permissible. For example, some argue that the ability to eradicate disease justifies attempts at therapeutic editing of the human germ line, while others emphasize the difficulty of drawing clear distinctions between applications in human disease and attempts at human enhancement.

News articles about these developments have appeared in Nature (1, 2), Science, The New York Times, MIT Technology Review and The Independent. Stem cell biologist Paul Knoepfler has been tracking them on his blog. According to a poll he conducted over the past week, readers across the globe support a moratorium on gene editing of human germ cells.

Science’s Gretchen Vogel sums up the broad calls for restraint here, noting that while these technical possibilities were mostly hypothetical at the infamous 1975 Asilomar conference, we now have to face their reality. Vogel quotes George Church asking: “What is the scenario that we’re actually worried about? That it won’t work well enough? Or that it will work too well?” The fact that both scenarios are deeply troubling marks human germline modification as one of the world’s most dangerous and consequential technologies.

Previously on Biopolitical Times:

“High IQ Eggs Wanted” – ads appeal to ego and altruism, offer $10,000

Posted by Lisa C. Ikemoto, Biopolitical Times guest contributor on March 19th, 2015

This ad appeared as a “suggested post” on a law student’s Facebook News Feed page. Sponsored by A Perfect Match, a southern California company that “specializes in the recruitment of intelligent, college-aged egg donors,” it includes appealing taglines: “Gift of life,” “$10,000 or more,” “Change lives . . . earn money!”

The law student said the ad made her feel “like a hen.”

The fertility industry asserts that women gift their eggs for others’ use and receive payment for the time and effort of doing so. Thus, we call them “egg donors.” In fact, the egg donation process carefully calibrates the ratio of altruism and financial need that motivates women to provide eggs for other’s use.

Medical sociologist Jennifer Haylett’s work in fertility centers reveals that staff screen out applicants who place too much emphasis on financial motive. Rene Almeling’s research shows that fertility clinics nudge egg providers to construct altruistic explanations. And yet, what intended parents and agencies pay for are ascribed traits.

The ABCs of egg donation are SAT, IQ, and college ranking. High scores and enrollment at prestigious universities are central to the egg market. Certainly, other traits matter, as well. Youth, good health, race, ethnicity, religion, good looks, height, and athleticism are among the characteristics used to solicit, profile, and select women. Women not enrolled in college are sometimes chosen as third-party egg providers. But what agencies prize are college students.

Third-party eggs form the basis of a luxury market governed by the rules of supply and demand. For example, demand for eggs from Asian women exceeds supply. Thus, prices offered to Asian women for their eggs sometimes exceed the prices offered to women of other races. However, it is the elitist criteria – near-perfect SAT scores and a place at a top-ten university – that consistently command the higher prices.

Paying women to provide high IQ eggs resembles a mix of awarding scholarships and executing futures contracts. Universities, egg agencies, and intended parents offer “$10,000 or more” to applicants who meet the elite criteria. Like commodities traders, they are speculating. Agency ads invite speculation in high scores as predictors of future success. It is probably true that if and when conception with third-party eggs results in birth, parents care more about the happiness and well-being than the IQs of their children. But at the outset, so-called traits like test scores matter. They matter most because of the ways in which SAT, IQ and college ranking are used to sort and price women who want “to change lives and earn money.”

The “High IQ Eggs Wanted” ad omits any notice of health risks arising from ovarian stimulation and egg retrieval. California law requires that ads include specific notice language that includes the statement, “There may be risks associated with human egg donation.” The law exempts members of the American Society for Reproductive Medicine (ASRM) who certify compliance with ASRM guidelines. By its own admission, A Perfect Match, Inc. exceeds the ASRM guidelines that restrict payment to women to $5,000 to $10,000, and is therefore subject to the notice requirement.

The California law also requires disclosure to women, before any contract is signed, of “specific information on the known risks of egg donation.” Disclosure does not address risks arising from the conflict of interest that pervades egg retrieval from egg donors – most physicians who perform the procedure are paid to maximize the fertility chances of another.

However, disclosure is important. Known risks focus on short-term, physical risks. They range from mild to severe effects of the drugs used to suppress ovulation, stimulate production of multiple eggs, and then release the eggs simultaneously. Severe ovarian hyperstimulation syndrome (OHSS) may be the scariest risk. Researchers have identified risk factors for OHSS,and ironically, agencies select for two of these factors – youth and low body mass index. It is suspected that conflict of interest prompts use of a third factor – high doses of ovarian stimulation drugs to maximize egg production.

There are unknowns, as well, including long-term effects of the drug most often used for ovarian suppression. Apparently, that’s the acceptable cost of making the gift of life.

Lisa Ikemoto, J.D., LL.M., is Professor at the University of California, Davis School of Law, where she teaches bioethics, health care law, public health law, reproductive rights, law & policy, and marital property, and a Fellow at the Center for Genetics and Society.

Universal Newborn Genome Sequencing and Generation Alpha

Posted by Ricki Lewis, Biopolitical Times guest contributor on March 16th, 2015

I have been struggling with why the idea – and likely coming reality – of universal newborn genome sequencing disturbs me. It’s finally crystallized: the practice could create a genetic underclass.

On the day that genome sequencing of all newborns begins, a cohort of individuals about whom a tremendous amount of personal information exists will be instantly created. At the same time, the practice will establish a shrinking cohort of most of the rest of us who do not know our genome information.

A century from now, possibly everyone will have access to her or his genome data. But until then, how can we prepare to handle the avalanche of information of what I’d call, if I were a science fiction writer, “generation Alpha?”

My idea of the Alphas is inspired by the 1992 dystopian novel The Children of Men, by P.D. James. In 1994, all human sperm suddenly die, and 1995 becomes Year Omega. After that, populations plummet in the face of global infertility, with the last remaining people, the Omegas, struggling towards inevitable extinction.

What will happen in our world as the Alphas age? For now, mining sequenced genomes is experimental and seeks to end the “diagnostic odysseys” endured by patients, typically children with rare or one-of-a-kind diseases . But just as opening a magazine can reveal much more than the article one is looking for, a genome sequence provides hundreds of thousands of gene variants that might mean something about a person’s health. And so the American College of Medical Genetics and Genomics lists 56 “actionable” secondary (“incidental”) conditions, a minimal menu of conditions which doctors can prevent or treat. The list is always growing.

Thousands of newborns have already had their genomes sequenced, and the actual deciphering takes under a day – a lot better than the decade it took for the first human genomes. But our understanding of our genomes, of how genotype becomes phenotype, lags behind the ability to decipher the overlapping strings of A, C, T and G. The value of an “annotated” genome to “raw sequence” is like comparing the meaning of the novel To Kill a Mockingbird to the book cut up into a pile of tiny pieces. When it comes to genomes, meaning and context are everything.

The era of looking for what we already know, the “round up the usual suspects” approach to gene identification and disease diagnosis, will gradually end as more human genome sequences and their interpretations are stored in clouds. Our algorithms will ultimately identify all possible gene variants and all possible combinations of and interactions among them – and what they mean at the whole-body level, the phenotype.

My concern is not those “usual suspects,” the well-studied mutations known for decades to cause inherited illness: cystic fibrosis, sickle cell disease, Huntington disease. I fear the fuzzier genetic information. Genome-wide association studies, for example, identify suites of gene variants that signal a good chance that an illness will happen, but not with the power of a clinical diagnosis. The media often trumpet such findings with a false sense of certainty. (Note on terminology: “gene variant” is a broader, more politically correct term without the negative connotation of “mutation,” which classically means “change in a gene” from the most common form [“wild type”] in a particular population.)  

What I fear most isn’t the use of genome information in predicting disease, but in identifying the harder-to-follow, multifactorial traits that are molded by genes and the environment: intelligence, personality, temperament and talents. Each gene contributes a small amount and to a differing degree to characteristics that aren’t as neatly predictable as the single-gene, Mendelian disorders like cystic fibrosis.

Will the idea of genetic determinism – that we are our genes – strengthen as the stockpile of genomic information swells through the population, beginning with the youngest? Will the practice become the ultimate example of paternalism, because newborns weren’t asked? As they age, can they choose not to know? Will that even be imaginable, as today it is difficult to envision a time without the Internet? Choosing not to know will be especially difficult if others have access to genome information. And who should those others be?

Annotated genome sequences could guide pediatricians in troubleshooting problems, providing a powerful new tool in preventive medicine. At the first birthday, a microbiome analysis might be added to identify children with tendencies towards certain conditions, or with underdeveloped immune systems due to too much cleanliness.

Beyond infancy, will availability of genome information fuel stratification as DNA information better predicts who is most likely to benefit from a scarce medical resource, and only the young have that information? Years from now, will I be denied a treatment unless I have my genome sequenced to show that I’m just as likely to benefit as a 20-year-old whose genome has been in the electronic medical record since birth?

In a few years, will posh preschools scan applicants’ genome information to select pupils? Will teachers use it to create compatible playgroups, or to identify bullies like the Tom Cruise film Minority Report punished future criminals? Will standardized test scores be compared to DNA data to deduce whether students are working up to their potential? Will employers look for genomic red flags, the way they stalk Facebook now for visual evidence of stupidity? I’ve already written about the fallacy of DNA-based dating. 

I’m not sure where all this is heading, but it is coming. Newborn genome sequencing could happen within 5 to 10 years, experts have told me. At a conference April 8-10 at Children’s Mercy in Kansas City, several research groups already doing this work will address population-wide newborn genome sequencing. That’s a great start to what will certainly be an intriguing and important conversation.

Ricki Lewis is a science writer with a PhD in genetics. She is author of The Forever Fix: Gene Therapy and the Boy Who Saved It (St. Martin’s Press), the college textbook Human Genetics: Concepts and Applications (McGraw-Hill Education), and co-author of two human anatomy and physiology textbooks. She has also published a short human genetics book, an essay collection, a novel about stem cells, and more than 3,000 articles. She writes the DNA Science blog at Public Library of Science and contributes regularly to Medscape Medical News. Ricki is a genetic counselor at CareNet Medical Group in Schenectady, NY, and teaches “Genethics” online for the Alden March Bioethics Institute of Albany Medical College. She lives near Schenectady, New York with husband Larry and many felines.

California and your DNA: Is it a healthy relationship?

Posted by Jessica Cussins on March 16th, 2015

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98% of all babies born in the United States have a tiny prick of their blood screened for a few serious diseases within the first few days of their lives. This test has been hugely successful at catching and beginning early treatment for inherited diseases such as sickle cell anemia and severe combined immunodeficiency.

Pressure is now mounting on multiple fronts to take advantage of this wellspring of potential genetic information. In the past, some states, most notably Texas, have gotten in trouble for their willingness to give it up for uses with which many parents are uncomfortable.

Now, attention has turned to California. In an article in U-T San Diego, the Council for Responsible Genetics’ Jeremy Gruber points out that while 19 states store these samples for more than two years, only California and a few other states keep them permanently and rent them out to researchers for a fee.

While the state’s Department of Public Health asserts that the samples are anonymous, we’ve been learning over and over again that DNA is rarely truly anonymous.

For example, the UK Department of Health finally acknowledged in correspondence with The Guardian that the genomic information in the 100,000 Genome Project will not actually be anonymous, but “pseudonymised” – though they have continued use of the former term publicly because apparently “the term ‘pseudonymisation’ is not widely understood.”

In the US, each state is rapidly building its criminal DNA database, in some cases using DNA from people never convicted of a crime. In an article in The Sacramento Bee, Jeremy B. White reports on growing concern about outside pressure to find new ways to access genetic data, by whatever means necessary. Jennifer Lynch, a senior staff attorney at the Electronic Frontier Foundation (EFF), asked “are we going to get to the point where law enforcement says, ‘Well, we have this giant repository with the information of everyone born in California in the last 30 years, and that’s a huge treasure trove’?”

It’s not an entirely abstract concern. Earlier this month, the Supreme Court sided in favor of letting a conviction stand that had been made using DNA collected from an interrogation-room chair.

In a brief to the Court, the EFF warned that "allowing police the limitless ability to collect and search genetic material will usher in a future where DNA may be collected from any person at any time, entered into and checked against DNA databases, and used to conduct pervasive surveillance."

Even if newborn DNA is never explicitly shared with police enforcement, Assemblyman Mike Gatto, D-Los Angeles believes “it’s only a matter of time before there’s a high-profile hack.” Gatto has created a bill (AB 170) to help parents regain agency over the fate of these samples. The bill would enable parents to choose to have their babies’ sample destroyed immediately after its intended use.

But the bill wouldn’t necessarily do enough if parents aren’t properly informed. Gruber has found that the majority of people don’t see any written materials explaining what will happen with their newborn’s sample, and that in California, consent to long-term storage and third-party use is simply assumed unless parents take the initiative and put their dissent in writing. He points out that newborn screening and storage tend to be exempt from state genetic privacy laws, so improved transparency will be critical to preventing misuse.

Previously on Biopolitical Times:

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