Author:Zalewski, Zachary A.

PREFACE INTRODUCTION I. ON TARGETED GENOME EDITING: TOWARDS MASTERING (AND POSSIBLY REDESIGNING) THE BLUEPRINT OF LIFE; A "BRIEF" HISTORY OF CRISPR-CAS9 DEVELOPMENT II. THE CRISPR-CAS9 GOLD RUSH: DEVELOPMENTS AT HOME AND ABROAD A. The People's Republic of China B. The United Kingdom C. Sweden III. THE STATE OF THE DEBATE IN THE UNITED STATES: FUNDING, STATUTES, AND REGULATIONS A. The Major Hurdle to Funding TGE Experimentation on Human Embryos: The Dickey-Wicker Amendment & NIH Interpretative Guidance B. Federal Funding of Scientific Research: Why it Matters and How it is Done 1. The HGP Corollary: Big Science Works Best when Supported with Big Dollars (In this Case, Government Dollars) 2. The Present Regulatory Framework is Insufficient to Accommodate TGE Research on Human Embryos a. From Grant Application to Bench: Initial and Ongoing Review and Oversight b. Additional Oversight through the FDA and DAC INTERLUDE: THE SOVIET UNION WINS ROUND TWO OF THE SPACE RACE IV. RECOMMENDATIONS A. Reinterpreting or Reevaluating Dickey-Wicker B. NIH Guidance Should Interpret Dickey-Wicker to Permit TGE That Uses Nonviable Human Embryos C. Congress Should Amend Dickey-Wicker to Limit the Prohibition of Federal Funds to 'Viable' or 'Diploid' Human Embryos D. Proposed ad hoc Committee Solution CONCLUSION EPILOGUE PREFACE

"As to the Soviet satellite, we congratulate Soviet scientists upon putting a satellite into orbit."

--Dwight D. Eisenhower, Oct. 9, 1957 (1)

On October 4, 1957, the Union of Soviet Socialist Republics became the first world power to successfully put a human-made satellite into Earth's orbit. (2) The Sputnik I satellite was modest by today's standards: it was less than two feet in diameter, weighed less than 200 pounds, (3) and was only capable of emitting pulsed radio signals. (4) By many accounts, it was little more than a large beach ball floating around and around the Earth. (5) Nevertheless, the propaganda value of the Soviet achievement in the burgeoning Cold War was significant and unmistakable. (6) The Space Race had begun, and the Soviets had won the first leg of it. The American response was swift. On January 31, 1958-119 days after the Sputnik I launch--Explorer-I successfully launched and entered Earth's orbit.7 It was the result of a multidisciplinary collaboration between civilian and military scientists, consisting of Dr. William H. Pickering and the Jet Propulsion Laboratory at the California Institute of Technology, Dr. James Van Allen (8) of the University of Iowa, and Dr. Wernher von Braun's United States Army Redstone Arsenal team. (9) The United States Congress also acted swiftly: on July 29, 1958, President Eisenhower signed into law the National Aeronautics and Space Act, (10) establishing, among other things, the National Aeronautics and Space Council, (11) and the civilian National Aeronautics and Space Administration ("NASA"). (12) Its 1958 budget was $89 million, 0.1 percent of the Federal Budget. But by the height of the Space Race in 1966, NASA's budget totaled nearly $6 billion, or 4.41 percent of the Federal Budget. (13) The Race to master Outer Space had begun and, although the United States was behind, it was running to win.


"One test result is worth one thousand expert opinions." --Wernher von Braun (14)

One of the many fascinating and potentially revolutionary developments in the field of biomedical research in recent years has been the development of molecular tools that enable scientists to engage in Targeted Genomic Editing ("TGE"). TGE empowers scientists to efficiently and precisely modify or delete a gene of interest or to add new genetic sequences to a target of interest. (15) Recently, through the combined efforts of many United States and international researchers, a system known as CRISPR-Cas9 has emerged as both a relatively inexpensive and more precise method of TGE than any previously recognized in the field. (16) With the discovery of CRISPR-Cas9, the potential for TGE-mediated gene therapies has never been greater. It is likely that, with time and effort, TGE may revolutionize medicine as we know it, giving new hope to both current patients and carriers of heritable genetic disorders. TGE could also result in "human enhancement." (17) The very idea that we could "exert control over human heredity with this technique" (18) raises questions as to whether tinkering with the blueprint of life is even a good idea to begin with. But only those who have mastered the technology will know the full breadth of its scope. Are we capable of mastering the "Inner Space" of our cells? If we can, should we do so? If this nation is not the first to know if we can, will we be able to decide whether we should?

The race to explore and, eventually, master this "Inner Space" has already begun. On October 28, 2016, a team of researchers in China initiated the first clinical trial to administer cells containing genes edited with the "revolutionary CRISPR-Cas9 technique." (19) In response to this, Dr. Carl June of the University of Pennsylvania remarked that this would "trigger a biomedical 'Sputnik 2.0'... between China and the United States." (20) Clinical researchers in the United States expect to begin CRISPR-Cas9 human trials within the next year, (21) three years behind their Chinese counterparts. (22) This lag is owed, in part, to the "few[er] regulatory hurdles [in China] to testing it on humans." (23) After the tragic death in 1999 of Jesse Gelsinger, (24) a profound "chilling effect on the field" (25) of gene therapy occurred, (26) but clinical researchers have been gradually returning to the prospect of modifying genes in humans to ameliorate disease. For example, on November 13, 2017, California clinicians treated Brian Madeux with an infusion of "billions of copies of a corrective gene and a genetic tool to cut his DNA in a precise spot." (27) Brian suffers from Hunter syndrome, an inherited condition resulting from a mutation in a gene (28) for an enzyme (29) that cells need to break down large sugar molecules. (30) Because of Hunter syndrome, Brian has had to undergo twenty-six operations--approximately one surgery for each 1.6 years of life. (31) This trial, using a more tried TGE tool in Zinc Finger Nucleases ("ZFNs") (32), has given Brian and others renewed hope that their disease state may not be one of permanence. (33)

TGE, as a molecular tool, may be employed in a variety of organisms, including humans. Two routes of directing therapies exist for TGE: one, in gene transfers aimed to treat patients living with myriad genetic disorders, or two, to modify the human germline: that is, the sex cells (sperm and egg) which form an embryo during the process of fertilization. (34) In bridging the gap between the laboratory bench and the patient's bedside, researchers must be empowered to study closely the utility of TGE in a human context, including on human embryos. Unfortunately, current federal law and regulation of federal funding of scientific research precludes TGE utilizing human embryos, an effective barrier to innovation. (35) The Dickey-Wicker Amendment, incorporated into annual Congressional appropriations bills since 1996, prohibits appropriated funding from being used to conduct research in which human embryos are destroyed. (36) The National Institutes of Health ("NIH") distributes federal funding of biomedical research with more than 80 percent of its $32.3 billion annual budget going to research universities and institutions. (37) NIH Guidelines presently comply with established law, noting that the agency "... will not at present entertain proposals for germ line alteration." (38) By contrast, at least three international governments34. the People's Republic of China, (39) the United Kingdom, (40) and Sweden (41)--have tentatively embraced the idea by funding research projects that include CRISPR-Cas9 experimentation on human embryos, and at the same time pushing the United States even further behind in this 'Inner Space Race.'

If we consider ourselves to be--and if we are intent on remaining-the preeminent intellectual superpower of the world, we must embrace a national policy that, at least, opens the door to contemplating federally-funded embryonic research with respect to TGE, and accelerates research and development in this area. It is in both the national interest--and the public interest--to allocate the requisite resources to develop this technology and its likely successors. If we fail to do so, we risk: (1) falling behind more ambitious nations who seek to know, as an unambiguous matter of government policy, the metes and bounds of TGE; (2) being dictated to by those nations about what should and should not be done once the technology has been mastered; and (3) prospectively forfeiting subsequent intellectual property rights, including the right to exclude, likely to result from the fruits of the scientific exercise. (42) Our national interest demands that such reasonable action be taken as to both enable and empower our scientific community to more effectively chart this potential "final frontier" of Inner Space.

This Note advocates for the federal government funding of TGE experimentation on human embryos, and recommends additional funding to accelerate scientific development and inquiry. It also reconsiders the question of prohibiting the federal funding of embryonic experimentation in a controlled research environment, while suggesting ways of overcoming the short- and medium-term ethical questions certain to arise. Part I will provide a brief scientific and historical background of TGE, emphasizing CRISPR-Cas9. Part II will discuss recent and ongoing developments at home and abroad and demonstrate the risk of an emerging knowledge gap in this field. Part III will discuss where the debate stands in this country, and examine the barriers to research in this field. Finally, Part IV will outline a number of...

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