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The Human Genome Gets Fully Sequenced: A Simplistic Take on Century Long Effort

Posted in Big Data, Bio Instrumentation in Experimental Life Sciences Research, BioIT: BioInformatics, BioIT: BioInformatics, NGS, Clinical & Translational, Pharmaceutical R&D Informatics, Clinical Genomics, Cancer Informatics, Biological Networks, Gene Regulation and Evolution, Disease Biology, Genome Biology, Next Generation Sequencing (NGS), Nobel Prize Winners, Single-cell sequencing, Variation in human protein-coding regions, tagged AAAS, Craig Venter, DNA Sequencing, genetic variants, Human Genome Project, Jennifer Doudna, junk DNA, telomere consortium on June 14, 2022| Leave a Comment »

The Human Genome Gets Fully Sequenced: A Simplistic Take on Century Long Effort

 

Curator: Stephen J. Williams, PhD

Article ID #295: The Human Genome Gets Fully Sequenced: A Simplistic Take on Century Long Effort. Published on 6/14/2022

WordCloud Image Produced by Adam Tubman

Ever since the hard work by Rosalind Franklin to deduce structures of DNA and the coincidental work by Francis Crick and James Watson who modeled the basic building blocks of DNA, DNA has been considered as the basic unit of heredity and life, with the “Central Dogma” (DNA to RNA to Protein) at its core.  These were the discoveries in the early twentieth century, and helped drive the transformational shift of biological experimentation, from protein isolation and characterization to cloning protein-encoding genes to characterizing how the genes are expressed temporally, spatially, and contextually.

Rosalind Franklin, who’s crystolagraphic data led to determination of DNA structure. Shown as 1953 Time cover as Time person of the Year

Dr Francis Crick and James Watson in front of their model structure of DNA

 

 

 

 

 

 

 

 

 

Up to this point (1970s-mid 80s) , it was felt that genetic information was rather static, and the goal was still to understand and characterize protein structure and function while an understanding of the underlying genetic information was more important for efforts like linkage analysis of genetic defects and tools for the rapidly developing field of molecular biology.  But the development of the aforementioned molecular biology tools including DNA cloning, sequencing and synthesis, gave scientists the idea that a whole recording of the human genome might be possible and worth the effort.

How the Human Genome Project  Expanded our View of Genes Genetic Material and Biological Processes

 

 

From the Human Genome Project Information Archive

Source:  https://web.ornl.gov/sci/techresources/Human_Genome/project/hgp.shtml

History of the Human Genome Project

The Human Genome Project (HGP) refers to the international 13-year effort, formally begun in October 1990 and completed in 2003, to discover all the estimated 20,000-25,000 human genes and make them accessible for further biological study. Another project goal was to determine the complete sequence of the 3 billion DNA subunits (bases in the human genome). As part of the HGP, parallel studies were carried out on selected model organisms such as the bacterium E. coli and the mouse to help develop the technology and interpret human gene function. The DOE Human Genome Program and the NIH National Human Genome Research Institute (NHGRI) together sponsored the U.S. Human Genome Project.

 

Please see the following for goals, timelines, and funding for this project

 

History of the Project

• HGP Goals and Corresponding Completion Dates
• Budget History of the U.S. Human Genome Project
• Timeline: Major Events in the Human Genome Project

It is interesting to note that multiple government legislation is credited for the funding of such a massive project including

Project Enabling Legislation

• The Atomic Energy Act of 1946 (P.L. 79-585) provided the initial charter for a comprehensive program of research and development related to the utilization of fissionable and radioactive materials for medical, biological, and health purposes.
• The Atomic Energy Act of 1954 (P.L. 83-706) further authorized the AEC “to conduct research on the biologic effects of ionizing radiation.”
• The Energy Reorganization Act of 1974 (P.L. 93-438) provided that responsibilities of the Energy Research and Development Administration (ERDA) shall include “engaging in and supporting environmental, biomedical, physical, and safety research related to the development of energy resources and utilization technologies.”
• The Federal Non-nuclear Energy Research and Development Act of 1974 (P.L. 93-577) authorized ERDA to conduct a comprehensive non-nuclear energy research, development, and demonstration program to include the environmental and social consequences of the various technologies.
• The DOE Organization Act of 1977 (P.L. 95-91) mandated the Department “to assure incorporation of national environmental protection goals in the formulation and implementation of energy programs; and to advance the goal of restoring, protecting, and enhancing environmental quality, and assuring public health and safety,” and to conduct “a comprehensive program of research and development on the environmental effects of energy technology and program.”

It should also be emphasized that the project was not JUST funded through NIH but also Department of Energy

Project Sponsors

• The U.S. Department of Energy funded its Human Genome Program through their Office of Biological and Environmental Research. (genome@science.doe.gov).
• The U.S. National Institutes of Health funded its program through the National Human Genome Research Institute (NHGRI).

For a great read on Dr. Craig Ventnor with interviews with the scientist see Dr. Larry Bernstein’s excellent post The Human Genome Project

 

By 2003 we had gained much information about the structure of DNA, genes, exons, introns and allowed us to gain more insights into the diversity of genetic material and the underlying protein coding genes as well as many of the gene-expression regulatory elements.  However there was much uninvestigated material dispersed between genes, the then called “junk DNA” and, up to 2003 not much was known about the function of this ‘junk DNA’.  In addition there were two other problems:

• The reference DNA used was actually from one person (Craig Ventor who was the lead initiator of the project)
• Multiple gaps in the DNA sequence existed, and needed to be filled in

It is important to note that a tremendous amount of diversity of protein has been realized from both transcriptomic and proteomic studies.  Although about 20 to 25,000 coding genes exist the human proteome contains about 600,000 proteoforms (due to alternative splicing, posttranslational modifications etc.)

This expansion of the proteoform via alternate splicing into isoforms, gene duplication to paralogs has been shown to have major effects on, for example, cellular signaling pathways (1)

However just recently it has been reported that the FULL human genome has been sequenced and is complete and verified.  This was the focus of a recent issue in the journal Science.

Source: https://www.science.org/doi/10.1126/science.abj6987

Abstract

Since its initial release in 2000, the human reference genome has covered only the euchromatic fraction of the genome, leaving important heterochromatic regions unfinished. Addressing the remaining 8% of the genome, the Telomere-to-Telomere (T2T) Consortium presents a complete 3.055 billion–base pair sequence of a human genome, T2T-CHM13, that includes gapless assemblies for all chromosomes except Y, corrects errors in the prior references, and introduces nearly 200 million base pairs of sequence containing 1956 gene predictions, 99 of which are predicted to be protein coding. The completed regions include all centromeric satellite arrays, recent segmental duplications, and the short arms of all five acrocentric chromosomes, unlocking these complex regions of the genome to variational and functional studies.

 

The current human reference genome was released by the Genome Reference Consortium (GRC) in 2013 and most recently patched in 2019 (GRCh38.p13) (1). This reference traces its origin to the publicly funded Human Genome Project (2) and has been continually improved over the past two decades. Unlike the competing Celera effort (3) and most modern sequencing projects based on “shotgun” sequence assembly (4), the GRC assembly was constructed from sequenced bacterial artificial chromosomes (BACs) that were ordered and oriented along the human genome by means of radiation hybrid, genetic linkage, and fingerprint maps. However, limitations of BAC cloning led to an underrepresentation of repetitive sequences, and the opportunistic assembly of BACs derived from multiple individuals resulted in a mosaic of haplotypes. As a result, several GRC assembly gaps are unsolvable because of incompatible structural polymorphisms on their flanks, and many other repetitive and polymorphic regions were left unfinished or incorrectly assembled (5).

 

Fig. 1. Summary of the complete T2T-CHM13 human genome assembly.
(A) Ideogram of T2T-CHM13v1.1 assembly features. For each chromosome (chr), the following information is provided from bottom to top: gaps and issues in GRCh38 fixed by CHM13 overlaid with the density of genes exclusive to CHM13 in red; segmental duplications (SDs) (42) and centromeric satellites (CenSat) (30); and CHM13 ancestry predictions (EUR, European; SAS, South Asian; EAS, East Asian; AMR, ad-mixed American). Bottom scale is measured in Mbp. (B and C) Additional (nonsyntenic) bases in the CHM13 assembly relative to GRCh38 per chromosome, with the acrocentrics highlighted in black (B) and by sequence type (C). (Note that the CenSat and SD annotations overlap.) RepMask, RepeatMasker. (D) Total nongap bases in UCSC reference genome releases dating back to September 2000 (hg4) and ending with T2T-CHM13 in 2021. Mt/Y/Ns, mitochondria, chrY, and gaps.

Note in Figure 1D the exponential growth in genetic information.

Also very important is the ability to determine all the paralogs, isoforms, areas of potential epigenetic regulation, gene duplications, and transposable elements that exist within the human genome.

Analyses and resources

A number of companion studies were carried out to characterize the complete sequence of a human genome, including comprehensive analyses of centromeric satellites (30), segmental duplications (42), transcriptional (49) and epigenetic profiles (29), mobile elements (49), and variant calls (25). Up to 99% of the complete CHM13 genome can be confidently mapped with long-read sequencing, opening these regions of the genome to functional and variational analysis (23) (fig. S38 and table S14). We have produced a rich collection of annotations and omics datasets for CHM13—including RNA sequencing (RNA-seq) (30), Iso-seq (21), precision run-on sequencing (PRO-seq) (49), cleavage under targets and release using nuclease (CUT&RUN) (30), and ONT methylation (29) experiments—and have made these datasets available via a centralized University of California, Santa Cruz (UCSC), Assembly Hub genome browser (54).

 

To highlight the utility of these genetic and epigenetic resources mapped to a complete human genome, we provide the example of a segmentally duplicated region of the chromosome 4q subtelomere that is associated with facioscapulohumeral muscular dystrophy (FSHD) (55). This region includes FSHD region gene 1 (FRG1), FSHD region gene 2 (FRG2), and an intervening D4Z4 macrosatellite repeat containing the double homeobox 4 (DUX4) gene that has been implicated in the etiology of FSHD (56). Numerous duplications of this region throughout the genome have complicated past genetic analyses of FSHD.

The T2T-CHM13 assembly reveals 23 paralogs of FRG1 spread across all acrocentric chromosomes as well as chromosomes 9 and 20 (Fig. 5A). This gene appears to have undergone recent amplification in the great apes (57), and approximate locations of FRG1 paralogs were previously identified by FISH (58). However, only nine FRG1 paralogs are found in GRCh38, hampering sequence-based analysis.

Future of the human reference genome

The T2T-CHM13 assembly adds five full chromosome arms and more additional sequence than any genome reference release in the past 20 years (Fig. 1D). This 8% of the genome has not been overlooked because of a lack of importance but rather because of technological limitations. High-accuracy long-read sequencing has finally removed this technological barrier, enabling comprehensive studies of genomic variation across the entire human genome, which we expect to drive future discovery in human genomic health and disease. Such studies will necessarily require a complete and accurate human reference genome.

CHM13 lacks a Y chromosome, and homozygous Y-bearing CHMs are nonviable, so a different sample type will be required to complete this last remaining chromosome. However, given its haploid nature, it should be possible to assemble the Y chromosome from a male sample using the same methods described here and supplement the T2T-CHM13 reference assembly with a Y chromosome as needed.

Extending beyond the human reference genome, large-scale resequencing projects have revealed genomic variation across human populations. Our reanalyses of the 1KGP (25) and SGDP (42) datasets have already shown the advantages of T2T-CHM13, even for short-read analyses. However, these studies give only a glimpse of the extensive structural variation that lies within the most repetitive regions of the genome assembled here. Long-read resequencing studies are now needed to comprehensively survey polymorphic variation and reveal any phenotypic associations within these regions.

Although CHM13 represents a complete human haplotype, it does not capture the full diversity of human genetic variation. To address this bias, the Human Pangenome Reference Consortium (59) has joined with the T2T Consortium to build a collection of high-quality reference haplotypes from a diverse set of samples. Ideally, all genomes could be assembled at the quality achieved here, but automated T2T assembly of diploid genomes presents a difficult challenge that will require continued development. Until this goal is realized, and any human genome can be completely sequenced without error, the T2T-CHM13 assembly represents a more complete, representative, and accurate reference than GRCh38.

 

This paper was the focus of a Time article and their basis for making the lead authors part of their Time 100 people of the year.

From TIME

The Human Genome Is Finally Fully Sequenced

Source: https://time.com/6163452/human-genome-fully-sequenced/

 

The first human genome was mapped in 2001 as part of the Human Genome Project, but researchers knew it was neither complete nor completely accurate. Now, scientists have produced the most completely sequenced human genome to date, filling in gaps and correcting mistakes in the previous version.

The sequence is the most complete reference genome for any mammal so far. The findings from six new papers describing the genome, which were published in Science, should lead to a deeper understanding of human evolution and potentially reveal new targets for addressing a host of diseases.

A more precise human genome

“The Human Genome Project relied on DNA obtained through blood draws; that was the technology at the time,” says Adam Phillippy, head of genome informatics at the National Institutes of Health’s National Human Genome Research Institute (NHGRI) and senior author of one of the new papers. “The techniques at the time introduced errors and gaps that have persisted all of these years. It’s nice now to fill in those gaps and correct those mistakes.”

“We always knew there were parts missing, but I don’t think any of us appreciated how extensive they were, or how interesting,” says Michael Schatz, professor of computer science and biology at Johns Hopkins University and another senior author of the same paper.

The work is the result of the Telomere to Telomere consortium, which is supported by NHGRI and involves genetic and computational biology experts from dozens of institutes around the world. The group focused on filling in the 8% of the human genome that remained a genetic black hole from the first draft sequence. Since then, geneticists have been trying to add those missing portions bit by bit. The latest group of studies identifies about an entire chromosome’s worth of new sequences, representing 200 million more base pairs (the letters making up the genome) and 1,956 new genes.

 

NOTE: In 2001 many scientists postulated there were as much as 100,000 coding human genes however now we understand there are about 20,000 to 25,000 human coding genes.  This does not however take into account the multiple diversity obtained from alternate splicing, gene duplications, SNPs, and chromosomal rearrangements.

Scientists were also able to sequence the long stretches of DNA that contained repeated sequences, which genetic experts originally thought were similar to copying errors and dismissed as so-called “junk DNA”. These repeated sequences, however, may play roles in certain human diseases. “Just because a sequence is repetitive doesn’t mean it’s junk,” says Eichler. He points out that critical genes are embedded in these repeated regions—genes that contribute to machinery that creates proteins, genes that dictate how cells divide and split their DNA evenly into their two daughter cells, and human-specific genes that might distinguish the human species from our closest evolutionary relatives, the primates. In one of the papers, for example, researchers found that primates have different numbers of copies of these repeated regions than humans, and that they appear in different parts of the genome.

“These are some of the most important functions that are essential to live, and for making us human,” says Eichler. “Clearly, if you get rid of these genes, you don’t live. That’s not junk to me.”

Deciphering what these repeated sections mean, if anything, and how the sequences of previously unsequenced regions like the centromeres will translate to new therapies or better understanding of human disease, is just starting, says Deanna Church, a vice president at Inscripta, a genome engineering company who wrote a commentary accompanying the scientific articles. Having the full sequence of a human genome is different from decoding it; she notes that currently, of people with suspected genetic disorders whose genomes are sequenced, about half can be traced to specific changes in their DNA. That means much of what the human genome does still remains a mystery.

The investigators in the Telomere to Telomere Consortium made the Time 100 People of the Year.

Michael Schatz, Karen Miga, Evan Eichler, and Adam Phillippy

Illustration by Brian Lutz for Time (Source Photos: Will Kirk—Johns Hopkins University; Nick Gonzales—UC Santa Cruz; Patrick Kehoe; National Human Genome Research Institute)

BY JENNIFER DOUDNA

MAY 23, 2022 6:08 AM EDT

Ever since the draft of the human genome became available in 2001, there has been a nagging question about the genome’s “dark matter”—the parts of the map that were missed the first time through, and what they contained. Now, thanks to Adam Phillippy, Karen Miga, Evan Eichler, Michael Schatz, and the entire Telomere-to-Telomere Consortium (T2T) of scientists that they led, we can see the full map of the human genomic landscape—and there’s much to explore.

In the scientific community, there wasn’t a consensus that mapping these missing parts was necessary. Some in the field felt there was already plenty to do using the data in hand. In addition, overcoming the technical challenges to getting the missing information wasn’t possible until recently. But the more we learn about the genome, the more we understand that every piece of the puzzle is meaningful.

I admire the

T2T group’s willingness to grapple with the technical demands of this project and their persistence in expanding the genome map into uncharted territory. The complete human genome sequence is an invaluable resource that may provide new insights into the origin of diseases and how we can treat them. It also offers the most complete look yet at the genetic script underlying the very nature of who we are as human beings.

Doudna is a biochemist and winner of the 2020 Nobel Prize in Chemistry

Source: https://time.com/collection/100-most-influential-people-2022/6177818/evan-eichler-karen-miga-adam-phillippy-michael-schatz/

Other articles on the Human Genome Project and Junk DNA in this Open Access Scientific Journal Include:

 

International Award for Human Genome Project

 

Cracking the Genome – Inside the Race to Unlock Human DNA – quotes in newspapers

 

The Human Genome Project

 

Junk DNA and Breast Cancer

 

A Perspective on Personalized Medicine

 

 

 

 

 

 

 

Additional References

 

1. P. Scalia, A. Giordano, C. Martini, S. J. Williams, Isoform- and Paralog-Switching in IR-Signaling: When Diabetes Opens the Gates to Cancer. Biomolecules 10, (Nov 30, 2020).

 

 

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The Nobel Prize in Chemistry 2020: Emmanuelle Charpentier & Jennifer A. Doudna

Posted in Award Nominations, Cell Biology, CRISPR alternative for editing genes without cutting, CRISPR applied to Human Germ Line, CRISPR/Cas9 & Gene Editing, DNA repair, Gene Therapy & Gene Editing Development, Genetics & Innovations in Treatment, Genetics & Pharmaceutical, Genome Biology, Interviews with Key Opinion Leaders (KOLs), Molecular Genetics & Pharmaceutical, Nobel Prize Winners, Stem Cells for Regenerative Medicine, tagged CRISPR –Cas9 system for genetic engineering, CRISPR Biology • Genome Editing • Gene Drives • DNA Repair • Model and Industrial Organisms • Technology Development • Stem Cells/Cancer • Genome-Wide Screens, CRISPR-based gene editing, CRISPR-Cas9, CRISPR/Cas and base editing, gene editing, gene editing technology platform, Jennifer Doudna, nobel leureates, Nobel Prize, Nobel Prize in Chemistry, Stanford University on October 8, 2020| Leave a Comment »

The Nobel Prize in Chemistry 2020: Emmanuelle Charpentier & Jennifer A. Doudna

Reporters: Stephen J. Williams, Ph.D. and Aviva Lev-Ari, PhD, RN

WordCloud Image Produced by Adam Tubman

The Royal Swedish Academy of Sciences has decided to award the Nobel Prize in Chemistry 2020 to

Emmanuelle Charpentier
Max Planck Unit for the Science of Pathogens, Berlin, Germany

Jennifer A. Doudna
University of California, Berkeley, USA

“for the development of a method for genome editing”

https://www.nobelprize.org/prizes/chemistry/2020/popular-information/#:~:text=Emmanuelle%20Charpentier%20and%20Jennifer%20Doudna,microorganisms%20with%20extremely%20high%20precision.

Genetic scissors: a tool for rewriting the code of life

Emmanuelle Charpentier and Jennifer A. Doudna have discovered one of gene technology’s sharpest tools: the CRISPR/Cas9 genetic scissors. Using these, researchers can change the DNA of animals, plants and microorganisms with extremely high precision. This technology has had a revolutionary impact on the life sciences, is contributing to new cancer therapies and may make the dream of curing inherited diseases come true.

Researchers need to modify genes in cells if they are to find out about life’s inner workings. This used to be time-consuming, difficult and sometimes impossible work. Using the CRISPR/Cas9 genetic scissors, it is now possible to change the code of life over the course of a few weeks.

“There is enormous power in this genetic tool, which affects us all. It has not only revolutionised basic science, but also resulted in innovative crops and will lead to ground-breaking new medical treatments,” says Claes Gustafsson, chair of the Nobel Committee for Chemistry.

As so often in science, the discovery of these genetic scissors was unexpected. During Emmanuelle Charpentier’s studies of Streptococcus pyogenes, one of the bacteria that cause the most harm to humanity, she discovered a previously unknown molecule, tracrRNA. Her work showed that tracrRNA is part of bacteria’s ancient immune system, CRISPR/Cas, that disarms viruses by cleaving their DNA.

Charpentier published her discovery in 2011. The same year, she initiated a collaboration with Jennifer Doudna, an experienced biochemist with vast knowledge of RNA. Together, they succeeded in recreating the bacteria’s genetic scissors in a test tube and simplifying the scissors’ molecular components so they were easier to use.

In an epoch-making experiment, they then reprogrammed the genetic scissors. In their natural form, the scissors recognise DNA from viruses, but Charpentier and Doudna proved that they could be controlled so that they can cut any DNA molecule at a predetermined site. Where the DNA is cut it is then easy to rewrite the code of life.

Since Charpentier and Doudna discovered the CRISPR/Cas9 genetic scissors in 2012 their use has exploded. This tool has contributed to many important discoveries in basic research, and plant researchers have been able to develop crops that withstand mould, pests and drought. In medicine, clinical trials of new cancer therapies are underway, and the dream of being able to cure inherited diseases is about to come true. These genetic scissors have taken the life sciences into a new epoch and, in many ways, are bringing the greatest benefit to humankind.

Illustrations

The illustrations are free to use for non-commercial purposes. Attribute ”© Johan Jarnestad/The Royal Swedish Academy of Sciences”

Illustration: Using the genetic scissors (pdf)
Illustration: Streptococcus’ natural immune system against viruses:CRISPR/Cas9 pdf)
Illustration: CRISPR/Cas9 genetic scissors (pdf)

Read more about this year’s prize

Popular information: Genetic scissors: a tool for rewriting the code of life (pdf)
Scientific Background: A tool for genome editing (pdf)

Emmanuelle Charpentier, born 1968 in Juvisy-sur-Orge, France. Ph.D. 1995 from Institut Pasteur, Paris, France. Director of the Max Planck Unit for the Science of Pathogens, Berlin, Germany.

Jennifer A. Doudna, born 1964 in Washington, D.C, USA. Ph.D. 1989 from Harvard Medical School, Boston, USA. Professor at the University of California, Berkeley, USA and Investigator, Howard Hughes Medical Institute.

 

Other Articles on the Nobel Prize in this Open Access Journal Include:

2020 Nobel Prize for Physiology and Medicine for Hepatitis C Discovery goes to British scientist Michael Houghton and US researchers Harvey Alter and Charles Rice

CONTAGIOUS – About Viruses, Pandemics and Nobel Prizes at the Nobel Prize Museum, Stockholm, Sweden 

AACR Congratulates Dr. William G. Kaelin Jr., Sir Peter J. Ratcliffe, and Dr. Gregg L. Semenza on 2019 Nobel Prize in Physiology or Medicine

2018 Nobel Prize in Physiology or Medicine for contributions to Cancer Immunotherapy to James P. Allison, Ph.D., of the University of Texas, M.D. Anderson Cancer Center, Houston, Texas. Dr. Allison shares the prize with Tasuku Honjo, M.D., Ph.D., of Kyoto University Institute, Japan

2017 Nobel prize in chemistry given to Jacques Dubochet, Joachim Frank, and Richard Henderson  for developing cryo-electron microscopy

2016 Nobel Prize in Chemistry awarded for development of molecular machines, the world’s smallest mechanical devices, the winners: Jean-Pierre Sauvage, J. Fraser Stoddart and Bernard L. Feringa

Correspondence on Leadership in Genomics and other Gene Curations: Dr. Williams with Dr. Lev-Ari

Programming life: An interview with Jennifer Doudna by Michael Chui, a partner of the McKinsey Global Institute

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Ribozymes and RNA Machines – Work of Jennifer A. Doudna

Posted in Genome Biology, Interviews with Scientific Leaders, tagged Biochemistry & Molecular Biology, Craig Mello, DNA, genetic disorder, Huntington's disease, In vitro fertilisation, Jennifer Doudna, National Academy of Sciences, RNA, Sickle Cell disease, UC Berkeley, University of California Berkeley, Yale University on April 15, 2013| Leave a Comment »

Ribozymes and RNA Machines –  Work of Jennifer A. Doudna

Reporter: Aviva Lev-Ari, PhD, RN

WordCloud Image Produced by Adam Tubman

Article 21.1.1- Ribozymes and RNA Machines – Work of Jennifer A. Doudna

UPDATED 3/27/2014

New DNA-editing technology spawns bold UC initiative

http://newscenter.berkeley.edu/2014/03/18/new-dna-editing-technology-spawns-bold-uc-initiative/

Crispr Goes Global

http://vcresearch.berkeley.edu/news/profile/doudna_jennifer

UPDATED 3/5/2014

Double Nicking by RNA-Guided CRISPR Cas9 for Enhanced Genome Editing Specificity

http://www.cell.com/retrieve/pii/S0092867413010155

One-Step Generation of Mice Carrying Mutations in Multiple Genes by CRISPR/Cas-Mediated Genome Engineering

http://www.cell.com/retrieve/pii/S0092867413004674

RNA-Guided Human Genome Engineering via Cas9

http://www.sciencemag.org/content/suppl/2013/01/03/science.1232033.DC1

SOURCE

From: Expert CRISPR/Cas9 Publications <Expert_CRISPRCas9_Publications@mail.vresp.com>
Date: Tue, 04 Mar 2014 17:03:01 +0000
To: <avivalev-ari@alum.berkeley.edu>
Subject: CRISPR-mediated gene editing resources

UPDATED on 11/10/2013

Exclusive: ‘Jaw-dropping’ breakthrough hailed as landmark in fight against hereditary diseases as Crispr technique heralds genetic revolution

Development to revolutionise study and treatment of a range of diseases from cancer, incurable viruses such as HIV to inherited genetic disorders such as sickle-cell anaemia and Huntington’s disease

STEVE CONNOR 

SCIENCE EDITOR

Thursday 07 November 2013

A breakthrough in genetics – described as “jaw-dropping” by one Nobel scientist – has created intense excitement among DNA experts around the world who believe the discovery will transform their ability to edit the genomes of all living organisms, including humans.

Click image above to enlarge graphic

The development has been hailed as a milestone in medical science because it promises to revolutionise the study and treatment of a range of diseases, from cancer and incurable viruses to inherited genetic disorders such as sickle-cell anaemia and Down syndrome.

For the first time, scientists are able to engineer any part of the human genome with extreme precision using a revolutionary new technique called Crispr, which has been likened to editing the individual letters on any chosen page of an encyclopedia without creating spelling mistakes. The landmark development means it is now possible to make the most accurate and detailed alterations to any specific position on the DNA of the 23 pairs of human chromosomes without introducing unintended mutations or flaws, scientists said.

The technique is so accurate that scientists believe it will soon be used in gene-therapy trials on humans to treat incurable viruses such as HIV or currently untreatable genetic disorders such as Huntington’s disease. It might also be used controversially to correct gene defects in human IVF embryos, scientists said.

Until now, gene therapy has had largely to rely on highly inaccurate methods of editing the genome, often involving modified viruses that insert DNA at random into the genome – considered too risky for many patients.

The new method, however, transforms genetic engineering because it is simple and easy to edit any desired part of the DNA molecule, right down to the individual chemical building-blocks or nucleotides that make up the genetic alphabet, researchers said.

“Crispr is absolutely huge. It’s incredibly powerful and it has many applications, from agriculture to potential gene therapy in humans,” said Craig Mello of the University of Massachusetts Medical School, who shared the 2006 Nobel Prize for medicine for a previous genetic discovery called RNA interference.

“This is really a triumph of basic science and in many ways it’s better than RNA interference. It’s a tremendous breakthrough with huge implications for molecular genetics. It’s a real game-changer,” Professor Mello told The Independent.

“It’s one of those things that you have to see to believe. I read the scientific papers like everyone else but when I saw it working in my own lab, my jaw dropped. A total novice in my lab got it to work,” Professor Mello said.

In addition to engineering the genes of plants and animals, which could accelerate the development of GM crops and livestock, the Crispr technique dramatically “lowers the threshold” for carrying out “germline” gene therapy on human IVF embryos, Professor Mello added.

The new method of gene therapy makes it simple and easy to edit any desired part of the DNA molecule (Getty Creative) Germline gene therapy on sperm, eggs or embryos to eliminate inherited diseases alters the DNA of all subsequent generations, but fears over its safety, and the prospect of so-called “designer babies”, has led to it being made illegal in Britain and many other countries.

The new gene-editing technique could address many of the safety concerns because it is so accurate. Some scientists now believe it is only a matter of time before IVF doctors suggest that it could be used to eliminate genetic diseases from affected families by changing an embryo’s DNA before implanting it into the womb.

“If this new technique succeeds in allowing perfectly targeted correction of abnormal genes, eliminating safety concerns, then the exciting prospect is that treatments could be developed and applied to the germline, ridding families and all their descendants of devastating inherited disorders,” said Dagan Wells, an IVF scientist at Oxford University.

“It would be difficult to argue against using it if it can be shown to be as safe, reliable and effective as it appears to be. Who would condemn a child to terrible suffering and perhaps an early death when a therapy exists, capable of repairing the problem?” Dr Wells said.

The Crispr process was first identified as a natural immune defence used by bacteria against invading viruses. Last year, however, scientists led by Jennifer Doudna at the University of California, Berkeley, published a seminal study showing that Crispr can be used to target any region of a genome with extreme precision with the aid of a DNA-cutting enzyme called CAS9.

Since then, several teams of scientists showed that the Crispr-CAS9 system used by Professor Doudna could be adapted to work on a range of life forms, from plants and nematode worms to fruit flies and laboratory mice.

Earlier this year, several teams of scientists demonstrated that it can also be used accurately to engineer the DNA of mouse embryos and even human stem cells grown in culture. Geneticists were astounded by how easy, accurate and effective it is at altering the genetic code of any life form – and they immediately realised the therapeutic potential for medicine.

“The efficiency and ease of use is completely unprecedented. I’m jumping out of my skin with excitement,” said George Church, a geneticist at Harvard University who led one of the teams that used Crispr to edit the human genome for the first time.

“The new technology should permit alterations of serious genetic disorders. This could be done, in principle, at any stage of development from sperm and egg cells and IVF embryos up to the irreversible stages of the disease,” Professor Church said.

David Adams, a DNA scientist at the Wellcome Trust Sanger Institute in Cambridge, said that the technique has the potential to transform the way scientists are able to manipulate the genes of all living organisms, especially patients with inherited diseases, cancer or lifelong HIV infection.

“This is the first time we’ve been able to edit the genome efficiently and precisely and at a scale that means individual patient mutations can be corrected,” Dr Adams said.

“There have been other technologies for editing the genome but they all leave a ‘scar’ behind or foreign DNA in the genome. This leaves no scars behind and you can change the individual nucleotides of DNA – the ‘letters’ of the genetic textbook – without any other unwanted changes,” he said.

Timeline: Landmarks in DNA science

Restriction enzymes: allowed scientists to cut the DNA molecule at or near a recognised genetic sequence. The enzymes work well in microbes but are more difficult to target in the more complex genomes of plants and animals. Their discovery in the 1970s opened the way for the age of genetic engineering, from GM crops to GM animals, and led to the 1978 Nobel Prize for medicine.

Polymerase chain reaction (PCR): a technique developed in 1983 by Kary Mullis (below, credit: Getty) in California allowed scientists to amplify the smallest amounts of DNA – down to a single molecule – to virtually unlimited quantities. It quickly became a standard technique, especially in forensic science, where it is used routinely in analysing the smallest tissue samples left at crime scenes. Many historical crimes have since been solved with the help of the PCR test. Mullis won the Nobel Prize for chemistry in 1993.

RNA interference: scientists working on the changing colour of petunia plants first noticed this phenomenon, which was later shown to involve RNA, a molecular cousin to DNA. In 1998, Craig Mello and Andrew Fire in the US demonstrated the phenomenon on nematode worms, showing that small strands of RNA could be used to turn down the activity of genes, rather like a dimmer switch. They shared the 2006 Nobel Prize for physiology or medicine for the discovery.

Zinc fingers: complex proteins called zinc fingers, first used on mice in 1994, can cut DNA at selected sites in the genome, with the help of enzymes. Another DNA-cutting technique called Talens can do something similar. But both are cumbersome to use and difficult to operate in practice – unlike the Crispr technique.

VIEW VIDEO

http://www.independent.co.uk/news/science/indyplus-video-crispr-technique-8925604.html

a video of how the Crispr system derived from bacteria works on human cells to correct genetic defects

SOURCE

http://www.independent.co.uk/news/science/exclusive-jawdropping-breakthrough-hailed-as-landmark-in-fight-against-hereditary-diseases-as-crispr-technique-heralds-genetic-revolution-8925295.html?goback=%2Egde_2106240_member_5804987154979381248#%21

Jennifer A. Doudna

Professor of Chemistry
Professor of Biochemistry & Molecular Biology

email: doudna@berkeley.edu
office: 708A Stanley Hall
phone: 510-643-0225
fax: 510-643-0008

lab: 731 Stanley Hall
lab phone: 510-643-0113
lab fax: 510-643-0080

Research Group URL
Recent Publications

Research Interests

Chemical Biology

Ribozymes and RNA Machines: RNA forms a variety of complex globular structures, some of which function like enzymes or form functional complexes with proteins. There are three major areas of focus in the lab: catalytic RNA, the function of RNA in the signal recognition particle and the mechanism of RNA-mediated internal initiation of protein synthesis. We are interested in understanding and comparing catalytic strategies used by RNA to those of protein enzymes, focusing on self-splicing introns and the self-cleaving RNA from hepatitis delta virus (HDV), a human pathogen. We are also investigating RNA-mediated initiation of protein synthesis, focusing on the internal ribosome entry site (IRES) RNA from Hepatitis C virus. Cryo-EM, x-ray crystallography and biochemical experiments are focused on understanding the structure and mechanism of the IRES and its amazing ability to hijack the mammalian ribosome and associated translation factors. A third area of focus in the lab is the signal recognition particle, which contains a highly conserved RNA required for targeting proteins for export out of cells. Each of these projects seeks to understand the molecular basis for RNA function, using a combination of structural, biophysical and biochemical approaches.

Biography

Medical School, 1989-1991; Post-doctoral fellow, University of Colorado, 1991-1994; Assistant/Associate professor, (1994-1998), Professor, (1999-2001), Yale University. Professor of Biochemistry & Molecular Biology, UC Berkeley, (2002-). Howard Hughes Medical Investigator 1997 to present. Packard Foundation Fellow Award, 1996; NSF Alan T. Waterman Award, 2000. Member, National Academy of Sciences, 2002. Member, American Academy of Arts and Sciences, 2003; American Association for the Advancement of Science Fellow Award, 2008; Member, Institute of Medicine of the National Academies, 2010.

READ MORE

Diagnosing Diseases & Gene Therapy: Precision Genome Editing and Cost-effective microRNA Profiling

http://pharmaceuticalintelligence.com/2013/03/28/diagnosing-diseases-gene-therapy-precision-genome-editing-and-cost-effective-microrna-profiling/

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