“designer babies” or “genetically modified humans.”

Perspective
Brave New Genome

Eric S. Lander, Ph.D.

June 3, 2015DOI: 10.1056/NEJMp1506446



Fifty years ago, microbiologists sparked the recombinant-DNA revolution with the discovery that bacteria have innate immune systems based on restriction enzymes. These enzymes bind and cut invading viral genomes at specific short sequences, and scientists rapidly repurposed them to cut and paste DNA in vitro — transforming biologic science and giving rise to the biotechnology industry.

Ten years ago, microbiologists discovered that bacteria also harbor adaptive immune systems, and subsequent progress has been breathtakingly rapid.1 Between 2005 and 2009, microbial genetic studies conducted by the laboratories of Mojica, Jansen, Koonin, Horvath, van der Oost, Sontheimer, Marraffini, and others revealed that bacteria have a programmable mechanism that directs nucleases, such as Cas9, to bind and cut invading DNA that matches “guide RNAs” encoded in specific bacterial genome regions containing clustered regularly interspaced short palindromic repeats (CRISPR). In 2010 and 2011, Moineau and Charpentier defined the critical components of the CRISPR-Cas9 system, and Siksnys showed that it could be reconstituted in new bacterial species. Biochemical studies in 2012, by Charpentier and Doudna and by Siksnys, confirmed these results in vitro. In 2013, Zhang and Church each described how to repurpose the CRISPR-Cas9 system to work in mammalian cells, creating a general-purpose tool for editing the genome in living human cells. Over the past 2 years, thousands of laboratories around the world have begun to use CRISPR-Cas9 in research.

Genome editing also holds great therapeutic promise. To treat human immunodeficiency virus (HIV) infection, physicians might edit a patient's immune cells to delete the CCR5 gene, conferring the resistance to HIV carried by the 1% of the U.S. population lacking functional copies of this gene. To treat progressive blindness caused by dominant forms of retinitis pigmentosa, they might inactivate the mutant allele in retinal cells. To prevent myocardial infarctions that kill patients with homozygous familial hypercholesterolemia, they might edit liver cells to restore a functional copy of the gene encoding low-density lipoprotein receptors. Editing of blood stem cells might cure sickle cell anemia and hemophilia.

These goals will require overcoming serious technical challenges (such as avoiding “off-target” edits elsewhere in the genome, which might give rise to cancer), but they pose no unique ethical issues because they affect only a patient's own somatic cells.

However, the technology also raises a more troubling possibility: creating children carrying permanent, heritable changes to the human germline DNA. The press has dubbed such brave new progeny “designer babies” or “genetically modified humans.”

When scientists realized in the mid-1970s that recombinant DNA posed potential hazards, they called for a voluntary moratorium on experiments and organized a now-famous gathering in Asilomar, California, to develop biosafety principles for handling recombinant organisms, setting the field on its successful course. Now, several groups have urged a moratorium on human germline editing,2,3 and the National Academy of Sciences has announced a fall 2015 meeting, which it plans to coordinate with academies from other countries, to begin an international conversation on the topic.

The task now is to develop a clear framework for evaluating human germline editing. Here, I offer a starting point, focusing on four key issues. (When considering these issues, readers should note that the Broad Institute, which I head, has filed patents on some of this technology, as detailed in my disclosure statement.)

The first is technical: whether genome editing can be performed with sufficient precision to permit scientists to responsibly contemplate creating genetically modified babies. Currently, the technology is far from ready: Liang and colleagues recently applied genome editing to human tripronuclear zygotes (abnormal products of in vitro fertilization [IVF] that are incapable of developing in vivo) and documented problems including incomplete editing, inaccurate editing, and off-target mutations.4 Even with improved accuracy, the process is unlikely to be risk-free.

The second issue is whether there are compelling medical needs that outweigh the risks — both from inaccurate editing and from unanticipated effects of the intended edits. Various potential applications must be considered.

The most common argument for germline editing concerns preventing devastating monogenic diseases, such as Huntington's disease. Though avoiding the roughly 3600 rare monogenic disorders caused by known disease genes is a compelling goal, the rationale for embryo editing largely evaporates under careful scrutiny. Genome editing would require making IVF embryos, using preimplantation genetic diagnosis (PGD) to identify those that would have the disease, repairing the gene, and implanting the embryo. Yet it would be easier and safer simply to use PGD to identify and implant the embryos that aren't at risk: the proportion is high in the typical cases of a parent heterozygous for a dominant disease (50%) or two parents who are carriers for a recessive disease (75%). To reduce the incidence of monogenic disease, what's needed most is not embryo editing, but routine genetic testing so that the many couples who don't know they are at risk can avail themselves of PGD.

Genome editing would add substantial value only when all embryos would be affected — for example, when one parent is homozygous for a dominant disorder or both parents are homozygous for a recessive disorder. But such situations are vanishingly rare for most monogenic diseases. For dominant Huntington's disease, for example, the total number of homozygous patients in the medical literature is measured in dozens. For most recessive disorders, cases are so infrequent (1 per 10,000 to 1 per million) that marriages between two affected persons will hardly ever occur unless the two are brought together by the disorder itself. The most common situation would probably be two parents with recessive deafness due to the same gene (among the many that can cause inherited deafness) who wish to have a hearing child.

Another potential application is reducing the risk of common diseases, such as heart disease, cancer, diabetes, and multiple sclerosis. The heritable influence on disease risk is polygenic, shaped by variants in dozens to hundreds of genes. Common variants tend to make only modest contributions (for example, reducing risk from 10% to 9.5%); rare variants sometimes have larger effects, including a few for which heterozygosity provides significant protection against disease.

Some observers might propose reshaping the human gene pool by endowing all children with many naturally occurring “protective” variants. However, genetic variants that decrease risk for some diseases can increase risk for others. (For example, the CCR5 mutations that protect against HIV also elevate the risk for West Nile virus, and multiple genes have variants with opposing effects on risk for type 1 diabetes and Crohn's disease.) The full medical effect of most variants is poorly characterized, let alone the combined effects of many variants. Safety studies would be needed to assess effects across various genetic backgrounds and environmental exposures. The situation is particularly dicey for rare protective heterozygous variants: most have never been seen in the homozygous state in humans and might have deleterious effects. Yet heterozygous parents would routinely produce homozygous children (one quarter of the total) — unless humans forswore natural reproduction in favor of IVF.

Currently, the best arguments might be for eliminating the ε4 variant at the APOE gene (which increases risk for Alzheimer's disease and cardiovascular disease) and bestowing null alleles at the PCSK9 gene (which reduces the risk of myocardial infarction). Still, our knowledge is incomplete. For example, APOE ε4 has also been reported to be associated with better episodic and working memory in young adults.

Some scientists might ask: Why limit ourselves to naturally occurring genetic variants? Why not use synthetic biology to write new cellular circuits that, for example, cause cells to commit suicide if they start down the road toward cancer? But such efforts would be reckless, at least for now. We remain terrible at predicting the consequences of even simple genetic modifications in mice. One cautionary tale among many is a genetic modification of the tp53 gene that protected mice against cancer while unexpectedly causing premature aging.5 We would also need to anticipate the potential interactions among the diverse genetic circuits that creative scientists will cast into the gene pool. Mistakes would be inevitable, and there would be no way to recall novel genes from the human population.

A more distant frontier would be to reshape nonmedical traits. Height may prove challenging (the hundreds of natural variants have tiny effects), but hair and eye color may be pliable. Disruption of the MC1R gene is associated with bright red hair, although it also heightens the risk of melanoma. Sports-minded parents might want to introduce the overactive erythropoietin gene that conferred high oxygen-carrying ability on a seven-time Olympic medalist in cross-country skiing. Nonnatural genetic modifications hold even bolder prospects — and risks.

The third key issue is who has the right to decide. Some people will argue that parents should have unfettered autonomy — that modifying one's progeny is akin to using PGD to avoid genetic diseases or choosing sperm donors on the basis of intellectual or athletic prowess. Yet parental autonomy must be weighed against the interests of future generations who cannot consent to the genetic modifications their flesh will be heir to.

The final issue concerns morality — what's right and wrong and how we ought to live as a society. Although scientists may be reluctant to debate ethics, we have a responsibility to do so and insights to offer. How would routine genome editing change our world? Would we come to regard our children as manufactured products? Would marketers shape genetic fashions? Would the “best” genomes go to the most privileged? If we cross this threshold, it's hard to see how we could ever return.

The recombinant-DNA moratorium of the 1970s was a temporary pause to establish safety rules for laboratory research. Today's debate concerns not research (which should proceed) but clinical applications to human beings that result in permanent changes to the human gene pool.

Genetic modification of human embryos is not a new idea. At least among Western governments, there has been a long-standing consensus that manipulating the human germline is a line that should not be crossed. Some European countries have outlawed genetic modification of embryos. The United States lacks a legislative ban, but the Food and Drug Administration — whose approval is needed for introducing substances, including DNA, into embryos — has said it will not permit genetic modification, and the National Institutes of Health (NIH) Recombinant DNA Advisory Committee will not currently approve such work at institutions receiving NIH funding (www.nih.gov/about/director/04292015_statement_gene_editing_technologies.htm). In many other countries, the situation remains unresolved.

The discussions that will begin in the fall may solidify a broad international consensus that germline editing should be banned — with the possible exception of correcting severe monogenic disease genes, in the few cases in which there is no alternative. For my own part, I see much wisdom in such a position, at least for the foreseeable future. A ban could always be reversed if we become technically proficient, scientifically knowledgeable, and morally wise enough and if we can make a compelling case. But authorizing scientists to make permanent changes to the DNA of our species is a decision that should require broad societal understanding and consent.

It has been only about a decade since we first read the human genome. We should exercise great caution before we begin to rewrite it.

ASCO 2015 immune checkpoint blockade in cancer

Advances in Immune Checkpoint Blockade Headlining Plenary

Allison Shelley May 31, 2015



CHICAGO — Investigators from around the world will take the American Society of Clinical Oncology meeting's biggest stage this afternoon to present the latest in cutting-edge cancer research.
Dr Alan Venook

Alan Venook, MD, from the University of California, San Francisco will chair the plenary, along with Peter Paul Yu, MD, from Palo Alto Medical Foundation in California.

Discussions on immune checkpoint blockade in cancer will kick off the session with James Patrick Allison, PhD, the science of oncology award lecturer from the University of Texas M.D. Anderson Cancer Center in Houston, presenting new insights, opportunities, and prospects for a cure.

Jedd Wolchok, MD, from the Memorial Sloan Kettering Cancer Center in New York City, will present CheckMate, a comparison of immune checkpoint inhibitors in melanoma.

"We're very encouraged that the initial observations about the efficacy of this combination held up in this large phase 3 trial," Dr. Wolchok said in an early-morning statement to reporters. "Our study also suggests that patients with a specific tumor marker appear to benefit the most from the combination treatment, whereas other patients may do just as well with nivolumab alone."

Childhood Cancer Survivor Report

Gregory Armstrong, MD, from St. Jude Children's Research Hospital will present a report from the Childhood Cancer Survivor Study showing a reduction in late mortality among 5-year survivors of childhood cancer.

"Fifty years ago, only one in five children would survive cancer, and today, over 80% are alive 5 years after diagnosis," Dr. Armstrong told reporters. "Yet these survivors still grow up with increased risk of dying from late effects, like heart disease and second cancers. Now, we've not only helped more children survive their primary cancer, but we've also extended their overall lifespan by reducing the overall toxicity of treatment."

Optimal Timing of Surgery in Oral Cancer

Anil D'Cruz, MBBS, from the Tata Memorial Centre in Mumbai, India, will present results from a randomized controlled phase 3 study showing that preventive neck lymph node surgery resulted in a 37% reduction in risk for death compared with surgery after relapse.

"Our study is the first to conclusively prove that more lives can be saved with elective neck dissection," Dr. D'Cruz told reporters.

Adding neck surgery to initial treatment is worthwhile, he said, and these results help establish preventive surgery as the standard of care in this disease, he suggested.

New data on whole-brain radiation will also be presented at plenary.

Shift in Whole-Brain Radiation Practice

A phase 3 randomized trial shows that the risks for adjuvant whole-brain radiation therapy outweigh benefits for patients with limited brain metastases.

"We used to offer whole-brain radiation early on, but we now know that the toxicities of this therapy are worse for the patient than cancer growth or recurrences in the brain," senior investigator Jan Buckner, MD, from the Mayo Clinic in Rochester, Minnesota said in a statement. "We expect that practice will shift to reserve the use of whole-brain radiation therapy for salvage treatment and end-stage palliative care," she explained.

Precision Medicine Oncology NCI-MATCH trial

Largest-Ever Precision Medicine Oncology Trial Ready for Launch
Anita T. Shaffer @Shaffer1
Published Online: Monday, June 1, 2015

A landmark clinical trial that will channel patients into treatment arms based on molecular abnormalities rather than cancer types aims to test the efficacy of more than 20 drugs simultaneously in an ambitious National Cancer Institute (NCI) plan to further propel oncology drug discovery into the precision medicine era.

Starting in July, the NCI-MATCH trial will seek to recruit 1000 adults 18 years of age or older with progressive advanced solid tumors and lymphomas that are either refractory to standard therapy or for which there is no standard therapy. Participants will be assigned to small phase II trials based on molecular tumor profiling of specimens from biopsies conducted at the time of study entry.

The trial is “a critical and leading part” of the nation’s precision medicine initiative, Clifford A. Hudis, MD, FACP, said during a 2015 ASCO Annual Meeting press briefing where NCI-MATCH and other innovative research projects were detailed.

“In oncology, we’ve embraced this idea for years,” said Hudis, a past president of ASCO who is a breast cancer specialist at Memorial Sloan Kettering Cancer Center. “The initiatives that we’re discussing today reflect not a new initiative but an expansion of an ongoing dream that we have been pursuing.”

“This is the largest and most rigorous precision oncology trial that’s every been attempted,” said James H. Doroshow, MD, the NCI’s deputy director.

The NCI has made an internal commitment to fully fund the study independent of the discussions now under way in Congress over the $215 million appropriation that the Obama administration has proposed for the precision medicine initiatives in cancer and other diseases, according to Doroshow.

Doroshow said it probably would cost $30 million to $40 million for the first stages of NCI-MATCH and that the budget could expand by 15% to 20% as more drugs are added to the list of agents tested and additional substudies are conducted. The NCI will pay for biopsies and laboratory sequencing tests, officials indicated.

The project will launch with an initial list of 10 substudies in which both previously approved drugs and investigational agents will be evaluated. Barbara A. Conley, MD, NCI study co-chair, said plans call for the trial to ramp up to more than 20 treatment arms within months of its launch.

First Batch of Drugs Identified

Here is the list of drugs that Conley identified for the first batch of studies and the molecular targets with which they are paired:
Crizotinib—Separate studies in ALK rearrangements and ROS1 translocations
Dabrafenib and trametinib—BRAF V600E or V600K mutations
Trametinib—BRAF fusions or non-V600E, non-V600K BRAF mutations
Afatinib—Separate studies in EGFR and HER2 activating mutations
AZD9291—EGFR T790M and rare EGFR activating mutations
T-DM1—HER2 amplifications
VS-6063—NF2 loss
Sunitinib—cKIT mutations
The FDA has approved six of the drugs on the list: crizotinib (Xalkori), dabrafenib (Tafinlar), trametinib (Mekinist), afatinib (Gilotrif), T-DM1 (Kadcyla), and sunitinib (Sutent).

AZD9291, a third-generation EGFR inhibitor, is being evaluated under the FDA’s breakthrough therapy program for patients with non–small cell lung cancer (NSCLC) whose tumors harbor the T790M resistance mutation. VS-6063, which also is called defactinib, is a small-molecule FAK inhibitor in phase I/II testing in mesothelioma, NSCLC, and ovarian cancer.

In order to enroll enough patients with mutations that allow a treatment match, organizers anticipate that 3000 patients will have to be screened. The goal is to enroll approximately 30 patients in each study.

An essential facet of the trial is the need to employ accurate assays to identify patients with the appropriate molecular features of their tumor, Conley said. Organizers have set up a network expected to provide molecular profiling results within 14 days or less, she said.

The genomic testing will be performed with the Ion Torrent Personal Genome Machine System’s custom panel of 143 genes, which in turn harbor more than 4000 variants.

For every trial, the primary endpoint will be overall response. Secondary endpoints include 6-month progression-free survival, time to progression, toxicity, and biomarker status.

The NCI-MATCH trial marks the next step in the agency’s efforts to harness the promise of precision medicine in oncology, starting with The Cancer Genome Atlas project to characterize genetic abnormalities in a range of cancer types, Doroshow said.

Doroshow described the planning and ultimately the conduct of NCI-MATCH as a national effort. “It has taken an absolute village to build this trial,” he said. “Hundreds of people supported the launch of the trial so far. Ultimately, it will take thousands of investigators to execute this study.”

The ECOG-ACRIN Cancer Research Group, which was formed three years ago through the merger of two oncology research organizations, is partnering with the NCI to plan and carry out the study at 2400 sites nationwide.

One of the army of investigators who will be involved in NCI-MATCH is Juneko Grilley-Olson, MD, an assistant professor at UNC Lineberger Comprehensive Cancer Center in North Carolina who specializes in thoracic and bone and soft tissue oncology.

She will help lead a substudy involving the investigational PI3K inhibitor GDC-0032, also called taselisib, which is expected to be studied in the second wave of trials that start as NCI-MATCH expands. Patients whose tumors harbor a PIK3CA mutation without a KRAS mutation and without PTEN loss are candidates for the study, Grilley-Olson said in an interview.

Grilley-Olson noted that NCI-MATCH organizers are hoping that at least 25% of the patients who enroll in studies have rare cancers.

“Those are tumors that often don’t have dedicated trials,” she said. “In the PI3 kinase arm we would be looking to enrich it for rarer tumors that have not been as extensively studied. With tumors such as breast cancer or lung cancer we probably wouldn’t learn as much additional information in a 30-patient cohort because they have been studied in trials with hundreds and hundreds of people [in those cancers].”