We are living in a period of great change for the medicalsciences. Technological advances in DNA sequencing and information technologywill, for the first time, make it possible for an individual to not only havetheir genome sequenced for less than $1,000, but also to have that informationmade available to their physician through cloud-based storage and softwaretools. The democratization of DNA sequencing, data storage and analysispromises to have a positive impact on the diagnosis and treatment of a myriadof genetically based human diseases, some of which will be detected and treatedearly through newborn screenings. These advancements will also have profoundeffects on continued medical research by further deepening our understanding ofbiology.
Sequencing a patient's DNA must include a method to storethe information within a robust and secure environment, either at ahospital/medical system, or in a cloud-based storage system. Once approvedusers access this data, software tools will perform sophisticated analyses,including comparisons to private or publicly available data on other patients'DNA sequences, clinical presentations and drug responsiveness. The end productof this will be a simplified report that summarizes the key findings from the sequencingtest and provides recommendations for treatment based on outcomes data from apool of patients.
Many of the patients with the same disease will share agroup of common DNA variations, and measurement of them will become the basisfor diagnostic tests. These new diagnostics will be used to inform any numberof decisions, including differential diagnosis, treatment selection (medicalversus surgical) and drug/dosage selection.
Treatment decisions made by patients and physicians who areguided by DNA variation information will be a major advance for the medicalsciences. But what about the DNA variation for which no information isavailable? For example, a variation in the open reading frame of a gene with noknown function could be found to be predicative of disease severity, but in theabsence of understanding the function of the protein, no effective treatmenttargeting it would be created. Such poorly annotated DNA variants willrepresent the vast majority of findings enabled through next-generationsequencing.
Rapid, informative and inexpensive DNA variation annotationrepresents the future for much of medical research, and will continue to serveas the basis for significant technology development in academic and industrysettings. Associations between DNA variants and protein function, pathwayhomeostasis, cell growth and viability, or organism growth and health can bemost easily identified when the differences between normal and variant genesare identified in cells or animals where all other variables are identical.
Manipulation of chromosomal DNA sequence through a moleculartechnique known as "gene editing" will allow for this type comparison. Theediting process can begin with inexpensive and highly accurate DNA synthesis,followed by the creation of full-length genes. These synthetic genes,containing either the normal or the variant DNA sequence of interest, can thenbe introduced into cells. With appropriate molecular engineering technologies,the synthetic DNA can replace the existing DNA sequence in each of the twochromosomes of the cell.
Alternatively, the recent revolution in gene-editingtechnology allows for direct replacement of one DNA sequence for another atspecific regions within each chromosome without requiring the synthesis offull-length genes. This technology promises to transform biological research,as gene editing will no longer be expensive or inefficient. Creating cells withidentical genomes, except for the region which has been edited, will removemany of the non-informative differences commonly seen between cells that arenot as closely related—differences that are often incorrectly attributed to theimpact of the genetic variation instead of other DNA sequence differences inthe cells that have not been detected.
Ultimately, information on DNA variants discovered throughnext-generation sequencing experiments will need to have more than cell culturedata if the genetic variants are to be used for clinical decision making. Forthis, in-vivo studies are paramount.This can be accomplished by introducing specific DNA variation into one or bothcopies of a gene within an animal to compare its growth and health to a matchedcontrol. There are two major avenues for this approach.
The first involves developing induced pluripotent stem (iPS)cells from animal disease models containing complex genetic backgrounds thathave been shown to be useful for studying disease pathophysiology and drugefficacy. These iPS cells can begenerated from various cell types, and then used as targets for gene editingusing the technologies discussed above.
Once editing is confirmed through DNA sequence analysis, thecells can be used to derive animals containing the DNA variant in their germline, and ultimately to generate animals that are either homozygous orheterozygous for the variant.
The second avenue is to perform gene editing directly onembryonic stem cells, which are cells derived from non-disease model animals.These edited cells would be used to generate animals that are either homozygousor heterozygous for the variant. In both of these examples, scientists couldascertain the impact of the DNA variation on normal or disease model animalgrowth and health, and thus obtain highly useful biological annotation of thegenetic variant.
Combined, advances in next-generation sequencing, informationtechnology and gene editing will help transform medicine in the 21st century. DNAvariants that are well annotated will contribute to the first wave of thistransformation. This will be followed by the exponential growth of newlyannotated DNA variants, which will lead to even more advances. It can beanticipated that the interpretation of an individual's genome sequence willbecome more actionable with time, a reality that will change the question aboutpersonal sequence information from "where do you go from here?" to "what isyour decision?"
Mark Stevenson ispresident and chief operating officer of Life Technologies. He has more than 20years of international executive management experience. Stevenson received hisB.S. in chemistry from the University of Reading and an M.B.A. from HenleyManagement School, both in the United Kingdom.
