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Posts Tagged ‘Cold Spring Harbor Laboratory’


Cold Spring Harbor Conference Meetings

Larry H. Bernstein, MD, FCAP, Curator

LPBI

Cold Spring Harbor Meetings

  1. “MicroRNAs in aging” from the Molecular Basis of Aging and Disease meeting CSHL ASIA 9/17/2015

CSHL Keynote; Dr. Frank Slack, Harvard Medical School

by CSHL Leading Strand

https://i.ytimg.com/vi_webp/YuRUBBSOZxw/mqdefault.webp

  1. Dorcus Cummings Lecture “The Genetic Legacy of Neanderthals” from the 80th Symposium: 21st Century Genetics – Genes at Work 5/30/15

CSHL Keynote, Dr Svante Paabo, Max-Planck-Institute

by CSHL Leading Strand

https://i.ytimg.com/vi_webp/GS8CT92rL4A/mqdefault.webp

  1. “Neuron-glia metabolic coupling—Relevance for neuronal plasticity and functional brain imaging” from the New Insights into Glia Function and Dysfunction meeting, Suzhou China

CSHL Keynote Series; Dr. Pierre J Magistretti, University of Lausanne

by CSHL Leading Strand

https://i.ytimg.com/vi_webp/eaWiElwsof0/mqdefault.webp

  1. 2015 Cold Spring Harbor Symposium
    21st Century Genetics:

CSHL 2015 Symposium Interview Series with Emmanuelle Charpentier

by CSHL Leading Strand

https://i.ytimg.com/vi_webp/H5Xaa1T4GB0/mqdefault.webp

  1. 2015 Cold Spring Harbor Symposium
    21st Century Genetics:

 13:33

CSHL 2015 Symposium Interview Series with Joanna Wysocka

by CSHL Leading Strand

https://i.ytimg.com/vi_webp/MDOL2SaI5-M/mqdefault.webp

  1. 2015 Cold Spring Harbor Symposium
    21st Century Genetics:

CSHL 2015 Symposium Interview Series wth Wolf Reik

by CSHL Leading Strand

https://i.ytimg.com/vi_webp/hROna-Wyz7Y/mqdefault.webp

  1. 2015 Cold Spring Harbor Symposium
    21st Century Genetics:

CSHL 2015 Symposium Interview Series with Susan Lindquist

by CSHL Leading Strand
https://i.ytimg.com/vi_webp/OC3l1UI9CZg/mqdefault.webp

  1. 2015 Cold Spring Harbor Symposium
    21st Century Genetics:

CSHL 2015 Symposium Interview Series with Richard Young

by CSHL Leading Strand

https://i.ytimg.com/vi_webp/z7jNOeo4DNU/mqdefault.webp

  1. 2015 Cold Spring Harbor Symposium
    21st Century Genetics:

CSHL 2015 Symposium Interviews with Svante Pääbo

by CSHL Leading Strand

https://i.ytimg.com/vi_webp/qMkKWovOYkY/mqdefault.webp

  1. 2015 Cold Spring Harbor Symposium
    21st Century Genetics:

CSHL 2015 Interview Series with Anne Ferguson-Smith

by CSHL Leading Strand

https://i.ytimg.com/vi_webp/trwQ71bAW7o/mqdefault.webp

  1. 2015 Cold Spring Harbor Symposium
    21st Century Genetics:

CSHL 2015 Symposium Interview Series with Jennifer Doundna

by CSHL Leading Strand

https://i.ytimg.com/vi_webp/xwXBmsGOp-M/mqdefault.webp

  1. 2015 Cold Spring Harbor Symposium
    21st Century Genetics:

CSHL 2015 Symposium Interview Series with Job Dekker

by CSHL Leading Strand

https://i.ytimg.com/vi_webp/d6sYIfxu9bI/mqdefault.webp

  1. 2015 Cold Spring Harbor Symposium
    21st Century Genetics:

CSHL 2015 Symposium Interview Series with Julius Brennecke

by CSHL Leading Strand

https://i.ytimg.com/vi_webp/4e9LpoxqnuA/mqdefault.webp

  1. “Mendelian randomization: Harnessing genocopy/phenocopy to identify modifiable causes of disease” from the Biology of Genomes meeting 5/8/2015

CSHL Keynote; Dr George Davey Smith, University of Bristol

by CSHL Leading Strand

https://i.ytimg.com/vi_webp/PvHKBCYwMnY/mqdefault.webp

  1. 2015 Cold Spring Harbor Symposium
    21st Century Genetics:

CSHL 2015 Symposium Interview Series with Titia de Lange

by CSHL Leading Strand

https://i.ytimg.com/vi_webp/YOGLD2Iz02k/mqdefault.webp

  1. “Ubiquitin and Autophagy Networks” from the The Ubiquitin Family meeting April 24, 2015

CSHL Keynote; Dr Ivan Dikic, Goethe University Medical School

by CSHL Leading Strand

https://i.ytimg.com/vi_webp/UsKZiZWPr8w/mqdefault.webp

  1. “How biology optimizes both specificity and efficiency—Single molecule studies of ubiquitylation” from the Cellular Dynamics & Models meeting 3/4/2015

CSHL Keynote; Dr. Marc Kirschner, Harvard Medical School

by CSHL Leading Strand

https://i.ytimg.com/vi_webp/xhRhkYxroT4/mqdefault.webp

  1. The Glymphatic System” from the Blood Brain Barrier meeting 12/12/2014

CSHL Keynote, Dr. Maiken Nedergaard, University of Rochester Medical Center

by CSHL Leading Strand

https://i.ytimg.com/vi_webp/S-JXgPUmd3A/mqdefault.webp

  1. Pushing the scale of genetic engineering” from the Synthetic Biology meeting in Suzhou China, CSHL-Asia 12/2/2014

CSHL Keynote Series, Dr. Christopher Voight, Massachusetts Institute of Technology

by CSHL Leading Strand

https://i.ytimg.com/vi_webp/tRXS7xMvep0/mqdefault.webp

Quantitative Biology

2012 Cold Spring Harbor Asia Conference on Synthetic Biology

Hongyu Zhao*

http://dx.doi.org/10.1007/s40484-013-0010-6

Keynote speeches

In the first keynote speech, Birger Lindberg Møller presented a lecture on “Plant power: the ultimate way to go green”. Plant can produce bioactive defense compounds when attacked by insects and microbes. Several of these compounds are used in the treatment of human diseases including cancer. They use the “share-your-parts” principle of synthetic biology to

promote the production of bioactive compounds that are difficult or impossible to synthesize using chemical methods. The second keynote speaker, Lars K. Nielsen presented “Metabolic and regulatory models for synthetic biology design”. He reviewed the status of rational in-silico strain design, providing a cost effective way of constructing metabolic pathways for making biocompounds. The last keynote speaker Sven Panke provided promises and ambition on technical advances as well as on a conceptual rethinking of how we design biocatalysts. He illustrated principles of designing biocatalysts with examples from his own work on nanoand pico-liter reactor design for screening purposes, on real-time mass spectrometry for pathway analysis and optimization, and protein switching for orthogonal in vitro pathways.

Prokaryotic genome engineering

Yu-Sin Jang (KAIST, Korea) reported that the direct butanol-forming pathway is a better channel for optimization of butanol production. An interesting topic was shared by Akio Kawahara-Kobayash (Tokyo Institute of Technology, Japan). At earlier stages in the evolution of the universal genetic code, fewer than 20 amino acids were considered for use. They made artificial genetic codes involving a reduced alphabet to provide not only new insights into primordial genetic codes, but also an essential protein engineering tool for the assessment of the early stages of protein evolution and for the improvement of pharmaceuticals. To meet the demands of industrial production, microbes should maintain a maximized and fixed carbon flux towards target metabolites regardless of fluctuations in intracellular or extracellular environments.

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From Molecular Biology to Translational Medicine: How Far Have We Come, and Where Does It Lead Us?

The Initiation and Growth of Molecular Biology and Genomics, Part I

Curator: Larry H Bernstein, MD, FCAP

Introduction and purpose

This material will cover the initiation phase of molecular biology, Part I; to be followed by the Human Genome Project, Part II; and concludes with Ubiquitin, it’s Role in Signaling and Regulatory Control, Part III.
This article is first a continuation of a previous discussion on the role of genomics in discovery of therapeutic targets titled Directions for genomics in personalized medicine https://pharmaceuticalintelligence.com/2013/01/27/directions-for-genomics-in-personalized-medicine/

The previous article focused on key drivers of cellular proliferation, stepwise mutational changes coinciding with cancer progression, and potential therapeutic targets for reversal of the process. It also covers the race to delineation of the Human Genome, discovery methods and fundamental genomic patterns that are ancient in both animal and plant speciation.

This article reviews the web-like connections between early and later discoveries, as significant finding has led to novel hypotheses and many more findings over the last 75 years. This largely post WWII revolution has driven our understanding of biological and medical processes at an exponential pace owing to successive discoveries of chemical structure, the basic building blocks of DNA and proteins, of nucleotide and protein-protein interactions, protein folding, allostericity, genomic structure, DNA replication, nuclear polyribosome interaction, and metabolic control. In addition, the emergence of methods for copying, removal and insertion, and improvements in structural analysis as well as developments in applied mathematics have transformed the research framework.

In the Beginning

During the Second World War we had the discoveries of physics and the emergence out of the Manhattan Project of radioactive nuclear probes from E.O. Lawrence University of California Berkeley Laboratory. The use of radioactive isotopes led to the development of biochemistry and isolation of nucleotides, nucleosides, enzymes, and filling in of details of pathways for photosynthesis, for biosynthesis, and for catabolism.
Perhaps a good start of the journey is a student of Neils Bohr named Max Delbruck (September 4, 1906 – March 9, 1981), who won the Nobel prize for discovering that bacteria become resistant to viruses (phages) as a result of genetic mutations, founded a new discipline called Molecular Biology, lifting the experimental work in Physiology to a systematic experimentation in biology with the rigor of Physics using radiation and virus probes on selected cells. In 1937 he turned to research on the genetics of Drosophila melanogaster at Caltech, and two years later he coauthored a paper, “The growth of bacteriophage”, reporting that the viruses replicate in one step, not exponentially. In 1942, he and Salvador Luria of Indiana University demonstrated that bacterial resistance to virus infection is mediated by random mutation. This research, known as the Luria-Delbrück experiment, notably applied mathematics to make quantitative predictions, and earned them the 1969 Nobel Prize in Physiology or Medicine, shared with Alfred Hershey. His inferences on genes’ susceptibility to mutation was relied on by physicist Erwin Schrödinger in his 1944 book, What Is Life?, which conjectured genes were an “aperiodic crystal” storing code-script and influenced Francis Crick and James D. Watson in their 1953 identification of cellular DNA’s molecular structure as a double helix.

Watson-Crick Double Helix Model

A new understanding of heredity and hereditary disease was possible once it was determined that DNA consists of two chains twisted around each other, or double helixes, of alternating phosphate and sugar groups, and that the two chains are held together by hydrogen bonds between pairs of organic bases—adenine (A) with thymine (T), and guanine (G) with cytosine (C). Modern biotechnology also has its basis in the structural knowledge of DNA—in this case the scientist’s ability to modify the DNA of host cells that will then produce a desired product, for example, insulin.
The background for the work of the four scientists was formed by several scientific breakthroughs:

  1. the progress made by X-ray crystallographers in studying organic macromolecules;
  2. the growing evidence supplied by geneticists that it was DNA, not protein, in chromosomes that was responsible for heredity;
  3. Erwin Chargaff’s experimental finding that there are equal numbers of A and T bases and of G and C bases in DNA;
  4. and Linus Pauling’s discovery that the molecules of some proteins have helical shapes.

In 1962 James Watson (b. 1928), Francis Crick (1916–2004), and Maurice Wilkins (1916–2004) jointly received the Nobel Prize in physiology or medicine for their 1953 determination of the structure of deoxyribonucleic acid (DNA), performed with a knowledge of Chargaff’s ratios of the bases in DNA and having  access to the X-ray crystallography of Maurice Wilkins and Rosalind Franklin at King’s College London. Because the Nobel Prize can be awarded only to the living, Wilkins’s colleague Rosalind Franklin (1920–1958), who died of cancer at the age of 37, could not be honored.
Of the four DNA researchers, only Rosalind Franklin had any degrees in chemistry. Franklin completed her degree in 1941 in the middle of World War II and undertook graduate work at Cambridge with Ronald Norrish, a future Nobel Prize winner. She returning to Cambridge after a year of war service, presented her work and received the PhD in physical chemistry. Franklin then learned the  X-ray crystallography in Paris and rapidly became a respected authority in this field. Returning to returned to England to King’s College London in 1951, her charge was to upgrade the X-ray crystallographic laboratory there for work with DNA.

bt2304  Rosalind Franklin, crystallographer

Cold Spring Harbor Laboratory

I digress to the beginnings of the Cold Spring Harbor Laboratory. A significant part of the Laboratory’s life revolved around education with its three-week-long Phage Course, taught first in 1945 by Max Delbruck, the German-born, theoretical-physicist-turned-biologist. James D Watson first came to Cold Spring Harbor Laboratory with his thesis advisor, Salvador Luria, in the summer of 1948. Over its more than 25-year history, the Phage Course was the training ground for many notable scientists. The Laboratory’s annual scientific Symposium, has provided a unique highly interactive education about the exciting field of “molecular” biology. The 1953 symposium featured Watson coming from England to give the first public presentation of the DNA double helix. When he became the Laboratory’s director in 1968 he was determined to make the Laboratory an important center for advancing molecular biology, and he focused his energy on bringing large donations to the enterprise CSHNL. It became a magnate for future discovery at which James D. Watson became the  Director in 1968, and later the Chancellor. This contribution has as great an importance as his Nobel Prize discovery.

Biochemistry and Molecular Probes comes into View

Moreover, at the same time, the experience of Nathan Kaplan and Martin Kamen at Berkeley working with radioactive probes was the beginning of an establishment of Lawrence-Livermore Laboratories role in metabolic studies, as reported in the previous paper. A collaboration between Sid Collowick, NO Kaplan and Elizabeth Neufeld at the McCollum Pratt Institute led to the transferase reaction between the two main pyridine nucleotides.  Neufeld received a PhD a few years later from the University of California, Berkeley, under William Zev Hassid for research on nucleotides and complex carbohydrates, and did postdoctoral studies on non-protein sulfhydryl compounds in mitosis. Her later work at the NIAMDG on mucopolysaccharidoses. The Lysosomal Storage Diseases opened a new chapter on human genetic diseases when she found that the defects in Hurler and Hunter syndromes were due to decreased degradation of the mucopolysaccharides. When an assay became available for α-L-iduronidase in 1972, Neufeld was able to show that the corrective factor for Hurler syndrome that accelerates degradation of stored sulfated mucopolysaccharides was α-L-iduronidase.

______________________________________________________

The Hurler Corrective Factor. Purification and Some Properties (Barton, R. W., and Neufeld, E. F. (1971) J. Biol. Chem. 246, 7773–7779)
The Sanfilippo A Corrective Factor. Purification and Mode of Action (Kresse, H., and Neufeld, E. F. (1972) J. Biol. Chem. 247, 2164–2170)
_______________________________________________________

I mention this for two reasons:
[1] We see a huge impetus for nucleic acids and nucleotides research growing in the 1950’s with a post WWII emergence of work on biological structure.
[2] At the same time, the importance of enzymes in cellular metabolic processes runs parallel to that of the genetic code.

In 1959 Arthur Kornberg was a recipient of the Nobel prize for Physiology or Medicine based on his discovery of “the mechanisms in the biological synthesis of deoxyribonucleic acid” (DNA polymerase) together with Dr. Severo Ochoa of New York University. In the next 20 years Stanford University Department of Biochemistry became a top rated graduate program in biochemistry. Today, the Pfeffer Lab is distinguished for research into how human cells put receptors in the right place through Rab GTPases that regulate all aspects of receptor trafficking. Steve Elledge (1984-1989) at Harvard University is one of  its graduates from the 1980s.

Transcription –RNA and the ribosome

In 2006, Roger Kornberg was awarded the Nobel Prize in Chemistry for identifying the role of RNA polymerase II and other proteins in transcribing DNA. He says that the process is something akin to a machine. “It has moving parts which function in synchrony, in appropriate sequence and in synchrony with one another”. The Kornbergs were the tenth family with closely-related Nobel laureates.  The 2009 Nobel Prize in Chemistry was awarded to Venki Ramakrishnan, Tom Steitz, and Ada Yonath for crystallographic studies of the ribosome. The atomic resolution structures of the ribosomal subunits provide an extraordinary context for understanding one of the most fundamental aspects of cellular function: protein synthesis. Research on protein synthesis began with studies of microsomes, and three papers were published on the atomic resolution structures of the 50S and 30S the atomic resolution of structures of ribosomal subnits in 2000. Perhaps the most remarkable and inexplicable feature of ribosome structure is that two-thirds of the mass is composed of large RNA molecules, the 5S, 16S, and 23S ribosomal RNAs, and the remaining third is distributed among ~50 relatively small and innocuous proteins. The first step on the road to solving the ribosome structure was determining the primary structure of the 16S and 23S RNAs in Harry Noller’s laboratory. The sequences were rapidly followed by secondary structure models for the folding of the two ribosomal RNAs, in collaboration with Carl Woese, bringing the ribosome structure into two dimensions. The RNA secondary structures are characterized by an elaborate series of helices and loops of unknown structure, but other than the insights offered by the structure of transfer RNA (tRNA), there was no way to think about folding these structures into three dimensions. The first three-dimensional images of the ribosome emerged from Jim Lake’s reconstructions from electron microscopy (EM) (Lake, 1976).

Ada Yonath reported the first crystals of the 50S ribosomal subunit in 1980, a crucial step that would require almost 20 years to bring to fruition (Yonath et al., 1980). Yonath’s group introduced the innovative use of ribosomes from extremophilic organisms. Peter Moore and Don Engelman applied neutron scattering techniques to determine the relative positions of ribosomal proteins in the 30S ribosomal subunit at the same time. Elegant chemical footprinting studies from the Noller laboratory provided a basis for intertwining the RNA among the ribosomal proteins, but there was still insufficient information to produce a high resolution structure, but Venki Ramakrishnan, in Peter Moore’s laboratory did it with deuterated ribosome reconstitutions. Then the Yale group was ramping up its work on the H. marismortui crystals of the 50S subunit. Peter Moore had recruited long-time colleague Tom Steitz to work on this problem and Steitz was about to complete the final event in the pentathlon of Crick’s dogma, having solved critical structures of DNA polymerases, the glutaminyl tRNA-tRNA synthetase complex, HIV reverse transcriptase, and T7 RNA polymerase. In 1999 Steitz, Ramakrishnan, and Yonath all presented electron density maps of subunits at approximately 5 Å resolution, and the Noller group presented 10 Å electron density maps of the Thermus 70S ribosome. Peter Moore aptly paraphrased Churchill, telling attendees that this was not the end, but the end of the beginning. Almost every nucleotide in the RNA is involved in multiple stabilizing interactions that form the monolithic tertiary structure at the heart of the ribosome.
Williamson J. The ribosome at atomic resolution. Cell 2009; 139:1041-1043.    http://dx.doi.org/10.1016/j.cell.2009.11.028/      http://www.sciencedirect.com/science/article/pii/S0092867409014536

This opened the door to new therapies.  For example, in 2010 it was reported that Numerous human genes display dual coding within alternatively spliced regions, which give rise to distinct protein products that include segments translated in more than one reading frame. To resolve the ensuing protein structural puzzle, we identified human genes with alternative splice variants comprising a dual coding region at least 75 nucleotides in length and analyzed the structural status of the protein segments they encode. The inspection of their amino acid composition and predictions by the IUPred and PONDR® VSL2 algorithms suggest a high propensity for structural disorder in dual-coding regions.
Kovacs E, Tompa P, liliom K, and Kalmar L. Dual coding in alternative reading frames correlates with intrinsic protein disorder. PNAS 2010.   http://www.jstor.org/stable/25664997   http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2851785
http://www.pnas.org/content/107/12/5429.full.pdf


In 2012, it was shown that drug-bound ribosomes can synthesize a distinct subset of cellular polypeptides. The structure of a protein defines its ability to thread through the antibiotic-obstructed tunnel. Synthesis of certain polypeptides that initially bypass translational arrest can be stopped at later stages of elongation while translation of some proteins goes to completion. (Kannan K, Vasquez-Laslop N, and Mankin AS. Selective Protein Synthesis by Ribosomes with a Drug-Obstructed Exit Tunnel. Cell 2012; 151; 508-520.) http://dx.doi.org/10.1016/j.cell.2012.09.018     http://www.sciencedirect.com/science/article/pii/S0092867412011257

Mobility of genetic elements

Barbara McClintock received the Nobel Prize for Medicine for the discovery of the mobility of genetic elements, work that been done in that period. When transposons were demonstrated in bacteria, yeast and other organisms, Barbara rose to a stratospheric level in the general esteem of the scientific world, but she was uncomfortable about the honors. It was sufficient to have her work understood and acknowledged. Prof. Howard Green said of her, “There are scientists whose discoveries greatly transcend their personalities and their humanity. But those in the future who will know of Barbara only her discoveries will know only her shadow”.
“In Memoriam – Barbara McClintock”. Nobelprize.org. 5 Feb 2013   http://www.nobelprize.org/nobel_prizes/medicine/laureates/1983/mcclintock-article.html/

She introduced her Nobel Lecture in 1983 with the following observation: “An experiment conducted in the mid-nineteen forties prepared me to expect unusual responses of a genome to challenges for which the genome is unprepared to meet in an orderly, programmed manner. In most known instances of this kind, the types of response were not predictable in advance of initial observations of them. It was necessary to subject the genome repeatedly to the same challenge in order to observe and appreciate the nature of the changes it induces…a highly programmed sequence of events within the cell that serves to cushion the effects of the shock. Some sensing mechanism must be present in these instances to alert the cell to imminent danger, and to set in motion the orderly sequence of events that will mitigate this danger”. She goes on to consider “early studies that revealed programmed responses to threats that are initiated within the genome itself, as well as others similarly initiated, that lead to new and irreversible genomic modifications. These latter responses, now known to occur in many organisms, are significant for appreciating how a genome may reorganize itself when faced with a difficulty for which it is unprepared”.

An experiment with Zea conducted in the summer of 1944 alerted her to the mobility of specific components of genomes involved the entrance of a newly ruptured end of a chromosome into a telophase nucleus. This experiment commenced with the growing of approximately 450 plants in the summer of 1944, each of which had started its development with a zygote that had received from each parent a chromosome with a newly ruptured end of one of its arms. The design of the experiment required that each plant be self-pollinated to isolate from the self-pollinated progeny new mutants that were expected to appear, and confine them to locations within the ruptured arm of a chromosome. Each mutant was expected to reveal the phenotype produced by a minute homozygous deficiency. Their modes of origin could be projected from the known behavior of broken ends of chromosomes in successive mitoses. Forty kernels from each self-pollinated ear were sown in a seedling bench in the greenhouse during the winter of 1944-45.

Some seedling mutants of the type expected overshadowed by segregants exhibiting bizarre phenotypes. These were variegated for type and degree of expression of a gene. Those variegated expressions given by genes associated with chlorophyll development were startingly conspicuous. Within any one progeny chlorophyll intensities, and their pattern of distribution in the seedling leaves, were alike. Between progenies, however, both the type and the pattern differed widely.

The effect of X-rays on chromosomes

Initial studies of broken ends of chromosomes began in the summer of 1931. By 1931, means of studying the beads on a string hypothesis was provided by newly developed methods of examining the ten chromosomes of the maize complement in microsporocytes in meiosis. The ten bivalent chromosomes are elongated in comparison to their metaphase lengths. Each chromosome

  • is identifiable by its relative length,
  • by the location of its centromere, which is readily observed at the pachytene stage, and
  • by the individuality of the chromomeres strung along the length of each chromosome.

At that time maize provided the best material for locating known genes along a chromosome arm, and also for precisely determining the break points in chromosomes that had undergone various types of rearrangement, such as translocations, inversions, etc.
The recessive phenotypes in the examined plants arose from loss of a segment of a chromosome that carried the wild-type allele, and X-rays were responsible for inducing these deficiencies. A conclusion of basic significance could be drawn from these observations:

  1. broken ends of chromosomes will fuse, 2-by-2, and
  2. any broken end with any other broken end.

This principle has been amply proved in a series of experiments conducted over the years. In all such instances the break must sever both strands of the DNA double helix. This is a “double-strand break” in modern terminology. That two such broken ends entering a telophase nucleus will find each other and fuse, regardless of the initial distance that separates them, soon became apparent.

During the summer of 1931 she had seen plants in the maize field that showed variegation patterns resembling the one described for Nicotiana.  Dr. McClintock was interested in selecting the variegated plants to determine the presence of a ring chromosome in each, and in the summer of 1932 with Dr. Stadler’s generous cooperation from Missouri, she had the opportunity to examine such plants. Each plant had a ring chromosome, but It was the behavior of this ring that proved to be significant. It revealed several basic phenomena. The following was noted:

In the majority of mitoses

  • replication of the ring chromosome produced two chromatids completely free from each other
  • could separate without difficulty in the following anaphase.
  • sister strand exchanges do occur between replicated or replicating chromatids
  • the frequency of such events increases with increase in the size of the ring.
  • these exchanges produce a double-size ring with two centromeres.
  • Mechanical rupture occurs in each of the two chromatid bridges formed at anaphase by passage of the two centromeres on the double-size ring to opposite poles of the mitotic spindle.
  • The location of a break can be at any one position along any one bridge.
  • The broken ends entering a telophase nucleus then fuse.
  • The size and content of each newly constructed ring depend on the position of the rupture that had occurred in each bridge.
  1. The conclusion was that cells sense the presence in their nuclei of ruptured ends of chromosomes
  2. then activate a mechanism that will bring together and then unite these ends
  3. this will occur regardless of the initial distance in a telophase nucleus that separated the ruptured ends.

The ability of a cell to

  • sense these broken ends,
  • to direct them toward each other, and
  • then to unite them so that the union of the two DNA strands is correctly oriented,
  • is a particularly revealing example of the sensitivity of cells to all that is going on within them.

Evidence from gave unequivocal support for the conclusion that broken ends will find each other and fuse. The challenge is met by a programmed response. This may be necessary, as

  1. both accidental breaks and
  2. programmed breaks may be frequent.
  3. If not repaired, such breaks could lead to genomic deficiencies having serious consequences.

A cell capable of repairing a ruptured end of a chromosome must sense the presence of this end in its nucleus. This sensing

  • activates a mechanism that is required for replacing the ruptured end with a functional telomere.
  • that such a mechanism must exist was revealed by a mutant that arose in the stocks.
  • this mutant would not allow the repair mechanism to operate in the cells of the plant.

Entrance of a newly ruptured end of a chromosome into the zygote is followed by the chromatid type of breakage-fusion-bridge cycle throughout mitoses in the developing plant.
This suggested that the repair mechanism in the maize strains is repressed in cells producing

  • the male and female gametophytes and
  • also in the endosperm,
  • but is activated in the embryo.

The extent of trauma perceived by cells

  • whose nuclei receive a single newly ruptured end of a chromosome that the cell cannot repair,
  • and the speed with which this trauma is registered, was not appreciated until the winter of 1944-45.

By 1947 it was learned that the bizarre variegated phenotypes that segregated in many of the self-pollinated progenies grown on the seedling bench in the fall and winter of 1944-45, were due to the action of transposable elements. It seemed clear that

  • these elements must have been present in the genome,
  • and in a silent state previous to an event that activated one or another of them.

She concluded that some traumatic event was responsible for these activations. The unique event in the history of these plants relates to their origin. Both parents of the plants grown in 1944 had contributed a chromosome with a newly ruptured end to the zygote that gave rise to each of these plants.
Detection of silent elements is now made possible with the aid of DNA cloning method. Silent AC (Activator) elements, as well as modified derivatives of them, have already been detected in several strains of maize. When other transposable elements are cloned it will be possible to compare their structural and numerical differences among various strains of maize. In any one strain of maize the number of silent but potentially transposable elements, as well as other repetitious DNAs, may be observed to change, and most probably in response to challenges not yet recognized.
Telomeres are especially adapted to replicate free ends of chromosomes. When no telomere is present, attempts to replicate this uncapped end may be responsible for the apparent “fusions” of the replicated chromatids at the position of the previous break as well as for perpetuating the chromatid type of breakage-fusion-bridge cycle in successive mitoses.
In conclusion, a genome may react to conditions for which it is unprepared, but to which it responds in a totally unexpected manner. Among these is

  • the extraordinary response of the maize genome to entrance of a single ruptured end of a chromosome into a telophase nucleus.
  • It was this event that was responsible for activations of potentially transposable elements that are carried in a silent state in the maize genome.
  • The mobility of these activated elements allows them to enter different gene loci and to take over control of action of the gene wherever one may enter.

Because the broken end of a chromosome entering a telophase nucleus can initiate activations of a number of different potentially transposable elements,

  • the modifications these elements induce in the genome may be explored readily.

In addition to

modifying gene action, these elements can

  • restructure the genome at various levels,
  • from small changes involving a few nucleotides,
  • to gross modifications involving large segments of chromosomes, such as
  1. duplications,
  2. deficiencies,
  3. inversions,
  4. and other reorganizations.

In the future attention undoubtedly will be centered on the genome, and with greater appreciation of its significance as a highly sensitive organ of the cell,

  • monitoring genomic activities and correcting common errors,
  • sensing the unusual and unexpected events,
  • and responding to them,
  • often by restructuring the genome.

We know about the elements available for such restructuring. We know nothing, however, about

  • how the cell senses danger and instigates responses to it that often are truly remarkable.

Source: 1983 Nobel Lecture. Barbara McClintock. THE SIGNIFICANCE OF RESPONSES OF THE GENOME TO CHALLENGE.

In 2009 the Nobel Prize in Physiology or Medicine was awarded to Elizabeth Blackburn, Carol Greider and Jack Szoztak for the discovery of Telomerase. This recognition came less than a decade after the completion of the Human Genome Project previously discussed. Prof. Blackburn acknowledges a strong influence coming from the work of Barbara McClintock. The discovery is tied to the pond organism Tetrahymena thermophila, and studies of yeast cells. Blackburn was drawn to science after reading the biography of Marie Curie by her daughter, Irina, as a child. She recalls that her Master’s mentor while studying the metabolism of glutamine in the rat liver, thought that every experiment should have the beauty and simplicity of a Mozart sonata. She did her PhD at the distinguished Laboratory for Molecular Biology at Cambridge, the epicenter of molecular biology sequencing the regions of bacteriophage phiX 174, a single stranded DNA bacteriophage. Using Fred Sanger’s methods to piece together RNA sequences she showed the first sequence of a 48 nucleotide fragment to her mathematical-gifted Cambridge cousin, who pointed out repeats of DNA sequence patterns! She worked on the sequencing of the DNA at the terminal regions of  the short “minichromosomes” of the ciliated protozoan Tetrahymena thermophile at Yale in 1975. She continued her research begun at Yale at UCSF funded by the NIH based on an intriguing audiogram showing telomeric DNA in Tetrahymena.
I describe the work as follows:

  • Prof. Blackburn incorporated 32P isotope labelled deoxynucleoside residues into the rDNA molecules for DNA repair enzymatic reactions and found that
  • the end regions were selectively labeled by combinations of 32P isotope radiolabled nucleoside triphosphate, and by mid-year she had an audiogram of the depurination products.
  • The audiogram showed sequences of 4 cytosine residues flanked by either an adenosine or a guanosine residue.
  • In 1976 she had deduced a sequence consisting of a tandem array of CCCAA repeats, and subsequently separated the products on a denaturing gel electrophoresis that appeared as tiger stripes extending up the gel.
  • The size of each band was 6 bases more than the band below it.

Telomere must have a telomerase!

The discovery of the telomerase enzyme activity was done by the Prize co-awardee, Carol Greider. They were trying to decipher the structure right at the termini of telomeres of both cliliated protozoans and yeast plasmids. The view that in mammalian telomeres there is a long protruding G-rich strand does not take into account the clear evidence for the short C strand repeat oligonucleotides that she discovered. This was found for both the Tetrahymena rDNA minichromosome molecules and linear plasmids purified from yeast.
In contrast to nucleosomal regions of chromosomes, special regions of DNA, for example

  • promoters that must bind transcription initiation factors that control transcription, have proteins other than the histones on them.
  • The telomeric repeat tract turned out to be such a non-nucleosomal region.

They  found that by clipping up chromatin using an enzyme that cuts the linker between neighboring nucleosomes,

  • it cut up the bulk of the DNA into nucleosome-sized pieces
  • but left the telomeric DNA tract as a single protected chunk.

The resulting complex of the telomeric DNA tract plus its bound cargo of protective proteins behaved very differently, from nucleosomal chromatin, and concluded that it had no histones or nucleosomes.

Any evidence for a protein on the bulk of the rDNA molecule ends, such as their behavior in gel electrophoresis and the appearance of the rDNA molecules under the electron microscope, was conspicuously lacking. This was reassuring that there was no covalently attached protein at the very ends of this minichoromosome. Despite considerable work, she was unable to determine what protein(s) would co-purify with the telomeric repeat tract DNA of Tetrahymena. It was yeast genetics and approaches done by others that turned out to provide the next great leaps forward in understanding telomeric proteins. Carol Greider, her colleague, noticed the need to scale up the telomerase activity preparations and they used a very large glass column for preparative gel filtration chromatography.

Jack W Szostak at the Howard Hughes Medical Institue at Harvard shared in the 2009 Nobel Prize. He became interested in molecular biology taking a course on the frontiers of Molecular Biology and reading about the experiments of Meselson-Stahl barely a decade earlier, and learned how the genetic code had been unraveled. The fact that one could deduce, from measurements of the radioactivity in fractions from a centrifuge tube, the molecular details of DNA replication, transcription and translation was astonishing. A highlight of his time at McGill was the open-book, open-discussion final exam in this class, in which the questions required the intense collaboration of groups of students.

At Cornell, Ithaca, he collaborated with  John Stiles and they came up with a specific idea to chemically synthesize a DNA oligonucleotide of sufficient length that it would hybridize to a single sequence within the yeast genome, and then to use it as an mRNA and gene specific probe. At the time, there was only one short segment of the yeast genome for which the DNA sequence was known,

  • the region coding for the N-terminus of the iso-1 cytochrome c protein,

intensively studied by Fred Sherman
The Sherman lab, in a tour de force of genetics and protein chemistry, had isolated

  • double-frameshift mutants in which the N-terminal region of the protein was translated from out-of-frame codons.
  • Protein sequencing of the wild type and frame-shifted mutants allowed them to deduce 44 nucleotides of DNA sequence.

If they could prepare a synthetic oligonucleotide that was complementary to the coding sequence, they could use it to detect the cytochrome-c mRNA and gene. At the time, essentially all experiments on mRNA were done on total cellular mRNA. Ray Wu was already well known for determining the sequence of the sticky ends of phage lambda, the first ever DNA to be sequenced, and his lab was deeply involved in the study of enzymes that could be used to manipulate and sequence DNA more effectively, but would not take on a project from another laboratory. So John went to nearby Rochester to do postdoctoral work with Sherman, and he was able to transfer to Ray Wu’s laboratory. In order to carry out his work, Ray Wu sent him to Saran Narang’s lab in Ottawa, and he received training there under Keichi Itakura, who synthesized the Insulin gene. A few months later, he received several milligrams of our long sought 15-mer. In collaboration with John Stiles and Fred Sherman, who sent us RNA and DNA samples from appropriate yeast strains, they were able to use the labeled 15-mer as a probe to detect the cyc1 mRNA, and later the gene itself. He notes that one of the delights of the world of science is that it is filled with people of good will who are more than happy to assist a student or colleague by teaching a technique or discussing a problem. He remained in Ray’s lab after completion of the PhD upon the arrival of Rodney Rothstein from Sherman’s lab in Rochester, who introduced him to yeast genetics, and he was prepared for the next decade of work on yeast.

  • first in recombination studies, and
  • later in telomere studies and other aspects of yeast biology.

His studies of recombination in yeast were enabled by the discovery, in Gerry Fink’s lab at Cornell, of a way to introduce foreign DNA into yeast. These pioneering studies of yeast transformation showed that circular plasmid DNA molecules could on occasion become integrated into yeast chromosomal DNA by homologous recombination.

  • His studies of unequal sister chromatid exchange in rDNA locus resulted in his first publication in the field of recombination.

The idea that you could increase transformation frequency by cutting the input DNA was pleasingly counterintuitive and led us to continue our exploration of this phenomenon. He gained an appointment to the Sidney-Farber Cancer Institute due to the interest of Prof. Ruth Sager, who gathered together a great group of young investigators. In work spearheaded by his first graduate student, Terry Orr-Weaver, on

  • double-strand breaks in DNA
  • and their repair by recombination (and continuing interaction with Rod Rothstein),
  • they were attracted to what kinds of reactions occur at the DNA ends.

It was at a Gordon Conference that he was excited hearing a talk by Elizabeth Blackburn on her work on telomeres in Tetrahymena.

  • This led to a collaboration testing the ability of Tetrahymena telomers to function in yeast.
  • He performed the experiments himself, and experienced the thrill of being the first to know that our wild idea had worked.
  • It was clear from that point on that a door had been opened and that they were going to be able to learn a lot about telomere function from studies in yeast.
  • Within a short time he was able to clone bona fide yeast telomeres, and (in a continuation of the collaboration with Liz Blackburn’s lab)
  • they obtained the critical sequence information that led (them) to propose the existence of the key enzyme, telomerase.

A fanciful depiction evoking both telomere dynamics and telomere researchers, done by the artist Julie Newdoll in 2008, elicits the idea of a telomere as an ancient Sumarian temple-like hive, tended by a swarm of ancient Sumarian Bee-goddesses against a background of clay tablets inscribed with DNA sequencing gel-like bands.
Dr. Blackburn recalls owing much to Barbara McClintock for her scientific findings, but also, Barbara McClintock also gave her advice in a conversation with her in 1977, during which

  • she had unexpected findings with the rDNA end sequences.
  • Dr. McClintock urged her to trust in intuition about the scientific research results.

This advice was surprising then because intuitive thinking was not something that she accepted to be a valid aspect of being a biology researcher.
MLA style: “Elizabeth H. Blackburn – Biographical”. Nobelprize.org. 5 Feb 2013. http://www.nobelprize.org/nobel_prizes/medicine/laureates/2009/blackburn.html

Summary:

In this Part I of a series of 3, I have described the

  • emergence of Molecular Biology and
  • closely allied work on the mechanism of Cell Replication and
  • the dependence of metabolic processes on proteins and enzymatic conversions through a surge of
  • post WWII research that gave birth to centers for basic science research in biology and medicine in both US and in England, which was preceded by work in prewar Germany. This is to be followed by further developments related to the Human Genome Project.
  • Transcription initiation (Photo credit: Wikipedia)
  • Schematic relationship between biochemistry, genetics, and molecular biology (Photo credit: Wikipedia)
  • Central dogma of molecular biology (Photo credit: Wikipedia)

 

Transcription initiation

Transcription initiation (Photo credit: Wikipedia)

Schematic relationship between biochemistry, g...

Schematic relationship between biochemistry, genetics, and molecular biology (Photo credit: Wikipedia)

Central dogma of molecular biology

Central dogma of molecular biology (Photo credit: Wikipedia)

 

 

 

                        Nucleotides_1.svg

 

 

 

Related References on the Open Access On;ine Scientific Journal

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English: Nobel laureate Dr. James D. Watson, C...

English: Nobel laureate Dr. James D. Watson, Chancellor, Cold Spring Harbor Laboratory. These images are freely available and may be used without special permission. (Photo credit: Wikipedia)

Novel Cancer Hypothesis Suggests Antioxidants Are Harmful

Reporter:

Larry H Bernstein, MD, FCAP

Hypothesis – following on James Watson

A new hypothesis that focuses on reactive oxygen species (ROS) proposes that antioxidant levels within cancer cells are a problem and are responsible for resistance to treatment.

The theory destroys any reason for taking antioxidative nutritional supplements, because they “more likely cause than prevent cancer,” according to Nobel laureate James Watson, PhD, from Cold Spring Harbor Laboratory, New York.

Dr. Watson, who shared the Nobel prize for unraveling the structure of DNA, regards this theory as being “among my most important work since the double helix, notes a press release from his institution, where he has been director since 1968.

The theory was published online January 8 in Open Biology.

Dr. Watson explains that

the vast majority of agents used to directly kill cancer cells, including

  • ionizing radiation,
  • most chemotherapeutic agents, and
  • some targeted therapies,

work by generating — either directly or indirectly — ROS that block key steps in the cell cycle.

This generation of ROS creates a hypoxic environment in which cancers cells undergo a transformation from epithelial to mesenchymal cells (EMT).

These transformed cells almost inevitably possess very high amounts of antioxidants, which effectively block the effects of anticancer treatments, Dr. Watson notes. Once a cancer becomes resistant to chemotherapy, it usually is equally resistant to ionizing radiation, he points out.

In addition, these transformed EMT cancer cells generate free-floating mesenchymal cells, which have the flexibility and movement that allows them to

  • metastasize to other body locations (brain, liver, lung).
  • “Only when they have moved do most cancers become life-threatening,” Dr. Watson notes.

Interestingly, the widely used antidiabetic drug metformin has been shown to preferentially kill mesenchymal stem cells. “In a still much unappreciated article published 3 years ago,

  • ” metformin added to chemotherapy
  • “induced prolonged remission if not real cures” in mouse models of cancer

(Cancer Res. 2009;69:7507-7511), Dr. Watson writes.

He notes that clinical trials are currently looking to see if adding

  • metformin to chemotherapy provides clinical benefits
  • diabetics who have been using metformin regularly have a reduced incidence of many cancers.

Resistance to Therapy From Antioxidants in Cancer Cells

Dr. Watson proposes that anticancer therapies work by generating ROS, which cause apoptosis.

However, as cancer cells evolve, they produce antioxidant proteins that block this effect, such as

  • glutathione,
  • superoxide dismutase,
  • catalase, and
  • thioredoxin.

The fact that cancer cells largely driven by RAS and Myc are among the most difficult of cancers to treat

  • could be due to their high levels of ROS-destroying antioxidants, Dr. Watson argues.
  • High antioxidative levels might also explain the effective incurability of pancreatic cancer, he adds.

If this theory is correct, then drugs that lower antioxidant levels within cancer cells would be therapeutic.

In fact, the ROS-generating agent arsenic trioxide has been shown to reduce levels of glutathione and thioredoxin. Arsenic trioxide is

  • currently being used to treat promyeloblastic leukemia, but this theory
  • suggests that the drug could be useful in many major cancers.

Nutritional Antioxidants Could Be Harmful

One far-reaching implication of this theory is that antioxidants as nutritional supplements, including

  • beta-carotene,
  • vitamins A, C, and E, and
  • selenium, could be harmful in cancer.

For years, such supplements have been widely hyped for cancer prevention and/or treatment, as has

  • encouragement to eat colorful fruit and berries, which contain antioxidants.

The time has come to seriously ask whether antioxidant use more likely causes than prevents cancer.

However, Dr. Watson warns that recent data strongly hint that much of the untreatability of late-stage cancer might be the result of “its possession of too many antioxidants, [so]

  • the time has come to seriously ask whether antioxidant use more likely causes than prevents cancer.”

Many nutritional intervention trials have shown no obvious effectiveness in preventing gastrointestinal cancer or in lengthening mortality, he writes. “In fact, they seem to slightly shorten the lives of those who take them.”

Hence, he concludes, “blueberries best be eaten because they taste good, not because their consumption will lead to less cancer.”

Very Complex Process

Maurie Markman, MD, national director for medical oncology at the Cancer Treatment Centers of America, who writes the Medscape Markman on Oncology blog, was asked to comment on the theory.

“The importance of the critical relationship between oxidating activity and antioxidants in the normal functioning of cells has been recognized by many investigators, and it is not surprising that this process would be quite relevant in cancer. However,

  • it must be emphasized that this is a very complex process and the balance between these powerful influences at the cellular level is certain to be very carefully controlled.
  • it should be noted that antioxidants are components of our normal diets.
  • it is most unlikely that a simple approach to somehow removing antioxidants from the body will be a useful strategy in cancer management,”

Open Biol. 2013;2:120144. Full text

Comment: Dr. Larry H. Bernstein

Pathology has a tradition going back to Rokitanski and Rudolph Virchow.  The complexity of this issue is that there is a concomitant metabolic abnormality. and a series of step-by-step changes in the cell related to a change from aerobic to anaerobic glycolysis in the presence of oxygen, noted by Otto Warburg, which is accompanied by mutations, which combined lead to cellular prolieration and cell migration.  When you reach the stage of metastasis to distant sites, the process most likely is irreversible.

The proposal that the epithelial cells become mesenchymal is not tenable in the case of most epithelial tumors, at least in the sense that they are not sarcomas.  The problem is that the intercellular adhesion breaks down, and the underlying stroma also is malignant.  If that is what is inferred, it is a new twist.

________________________________________________________________________________________________________________________________________________________________

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Personalized medicine gearing up to tackle cancer    ritusaxena

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_________________________________________________________________________________________________________________________________________________________________

Blackberries are a source of polyphenol antiox...

Blackberries are a source of polyphenol antioxidants (Photo credit: Wikipedia)

Reactive oxygen species and detoxifying system...

Reactive oxygen species and detoxifying system (French) (Photo credit: Wikipedia)

English: Major cellular sources of ROS in livi...

English: Major cellular sources of ROS in living cells. Novo and Parola Fibrogenesis & Tissue Repair 2008 1:5 doi:10.1186/1755-1536-1-5 (Photo credit: Wikipedia)

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Reporter: Aviva Lev-Ari, PhD, RN

 

ABOUT CGC

The Consumer Genetics Conference covers the key issues facing clinical genetics, personalized medicine, molecular diagnostics, and consumer-targeted DNA applications. It provides a unique outlet where all voices can be heard: pro & con, physician & consumer, research & clinical, academic & corporate, financial & regulatory. CGC is more than just another personalized medicine conference. Since the inaugural meeting in 2009, CGC has been the place where consumer companies learn genomics, and where genomics companies learn how to approach consumers. This year’s event is highlighted by keynote presentations from:

– Kenneth Chahine, Ph.D., J.D., ancestry.com
– Jay Flatley, President and CEO, Illumina
– Lee Silver, Ph.D., Princeton University

Spanning three days, the conference will focus on:
– Day 1: Technology
– Day 2: Business + Translation
– Day 3: Application

And 40+ Cutting-Edge Presentations on:
– Personal Genomics
– Third-Generation Sequencing
– Molecular Diagnostics
– Investment & Funding Opportunities
– Genome Interpretation
– The Future of Personalized Medicine
– Big Data
– Prenatal/Neonatal & Disease Diagnostics
– Empowering Patients
– Nutrition, Food Genetics & Cosmetics

SPEAKERS

Confirmed speakers to date include:

Sandy Aronson, Executive Director of IT, Partners HealthCare Center for Personalized Genetic Medicine (PCPGM)

Arindam Bhattacharjee, Ph.D., CEO and Founder, Parabase Genomics

Diana Bianchi, M.D., Executive Director, Mother Infant Research Institute; Vice Chair for Research, Department of Pediatrics, Floating Hospital for Children, Tufts Medical Center

Cinnamon Bloss, Ph.D., Assistant Professor and Director, Social Sciences and Bioethics, Scripps Translational Science Institute

Alexis Borisy, Partner, Third Rock Ventures

John Boyce, President and CEO, GnuBio

Mike Cariaso, Founder, SNPedia; Author of Promethease

Kenneth Chahine, Ph.D., J.D., Senior Vice President and General Manager, DNA, ancestry.com

Michael Christman, CEO, Coriell Institute for Medical Research

Cindy Crowninshield, RD, LDN, Licensed Registered Dietitian, Body Therapeutics & Sodexo; Founder, Eat2BeWell & Eat4YourGenes; Conference Director, Cambridge Healthtech Institute

Kevin Davies, Ph.D., Editor-in-Chief, Bio-IT World

Chris Dwan, Principal Investigator and Director, Professional Services, BioTeam

Jay Flatley, President & CEO, Illumina

Andrew C. Fish, Executive Director, AdvaMedDx

Dennis Gilbert, Ph.D., Founder, President and CEO, VitaPath Genetics

Rosalynn Gill, Ph.D., Vice President, Clinical Affairs, Boston Heart Diagnostics

Steve Gullans, Managing Director, Excel Venture Management

Don Hardison, President & CEO, Good Start Genetics, Inc.

Richard Kellner, Founder and President, Genome Health Solutions, Inc.

Robert Klein, Ph.D., Chief Business Development Officer, Complete Genomics

Isaac S. Kohane, M.D., Ph.D., Henderson Professor of Health Sciences and Technology, Children’s Hospital and Harvard Medical School; Director, Countway Library of Medicine; Director, i2b2 National Center for Biomedical Computing; Co-Director, HMS Center for Biomedical Informatics

Stan Lapidus, President, CEO and Founder, SynapDx

Gholson Lyon, M.D., Ph.D., Assistant Professor in Human Genetics, Cold Spring Harbor Laboratory; Research Scientist, Utah Foundation for Biomedical Research

Daniel MacArthur, Ph.D., Assistant Professor, Massachusetts General Hospital; Co-founder, Genomes Unzipped

Craig Martin, Chief Executive Officer, Feinstein Kean Healthcare

James McCullough, CEO and Founder, Exosome Diagnostics

Kevin McKernan, CSO, Courtagen Life Sciences

Neil A. Miller, Director of Informatics, Center for Pediatric Genomic Medicine, Children’s Mercy Hospital

Paul Morrison, Ph.D., Laboratory Director, Molecular Biology Core Facilities, Dana-Farber Cancer Institute

Geert-Jan Mulder, M.D., General Partner, Forbion Capital

Steve Murphy, M.D., Managing Partner, Wellspring Total Health

Michael Murray, M.D., Clinical Chief, Genetics Division, Brigham and Women’s Hospital; Instructor, Harvard Medical School, The Harvard Clinical and Translational Science Center

Brian T. Naughton, Ph.D., Founding Scientist, 23andMe

Nathan Pearson, Ph.D., Director of Research, Knome, Inc.

Michael S. Phillips, Ph.D., Canada Research Chair in Translational Pharmacogenomics; Director, Molecular Diagnostic Laboratory, Montreal Heart Institute; Associate Professor, Université de Montréal

John Quackenbush, Ph.D., Professor, Biostatistics and Computational Biology, Cancer Biology Center for Cancer Computational Biology, Dana-Farber Cancer Institute

Martin G. Reese, President and CEO, Omicia

Heidi L. Rehm, Ph.D., FACMG, Chief Laboratory Director, Molecular Medicine, Partners HealthCare Center for Personalized Genetic Medicine (PCPGM); Assistant Professor of Pathology, Harvard Medical School

Oliver Rinner, Ph.D., CEO, BiognoSYS AG

Meredith Salisbury, Senior Consultant, Bioscribe

Marc Salit, Group Leader, Biochemical Science and Multiplexed Biomolecular Science, National Institute of Standards and Technology

Lee Silver, Ph.D., Professor of Molecular Biology and Public Affairs; Faculty Associate, Science, Technology & Environmental Policy Program, Office of Population Research, and the Center for Health and Wellbeing, Woodrow Wilson School, Princeton University

Jamie Streator, Managing Director, Healthcare Investment Banking, Cowen & Company

Joseph V. Thakuria, M.D., MMSc, Attending Physician in Clinical and Biochemical Genetics Medical Genetics, Massachusetts General Hospital; Medical Director, Personal Genome Project; Harvard Catalyst Translational Genetics and Bioinformatics Program, MGH Center for Human Genetics Research

Samuil R. Umansky, M.D., Ph.D., D.Sc., Co-founder, CSO, and President, DiamiR LLC

David A. Weitz, Ph.D., Mallinckrodt Professor of Physics and Applied Physics, Harvard School of Engineering and Applied Sciences

Speaker to be Announced, Barclays

DAY 1: TECHNOLOGY

WEDNESDAY, OCTOBER 3

7:30 am Conference Registration

8:30 Opening Remarks

John Boyce, President and CEO, GnuBIO and Meredith Salisbury, Senior Consultant, Bioscribe

 

OPENING PLENARY SESSION

 

» 8:45 KEYNOTE PRESENTATION

Self-Discovery in the Age of Personal Genomes

Lee Silver, Ph.D., Professor of Molecular Biology and Public Affairs; Faculty Associate, Science, Technology & Environmental Policy Program, Office of Population Research, and the Center for Health and Wellbeing, Woodrow Wilson School, Princeton University

With blinding speed, the biomedical research enterprise is advancing the technology to read personal genomes with greater accuracy, in less time, and at less expense.Meanwhile, consumer genetics has blossomed from infancy to adolescence with an array of innovative consumer-facing products. This unanticipated cottage industry is struggling with growing pains in a mix of conflicted regulators, restless innovators, and demanding consumers. Genetic information, like all information, “wants to be free,” but the commercialization environment is not yet optimized for personal freedom.

 

9:40 The Era of Clinical Sequencing and Personalized Medicine

Michael Christman, CEO, Coriell Institute for Medical Research

Advances in understanding genomic variation and associated clinical phenotypes continue to increase while the cost of full genome sequencing rapidly declines. Having access to your genomic information will become increasingly important as physicians are progressively receptive to incorporating genomics into routine clinical practice. When you need a new prescription, it will be necessary for your physician to quickly and securely access your genetic data to understand drug efficacy prior to dosing. Who will patients and medical professionals trust to store and interpret the data? Coriell is positioned to significantly contribute to the research needed to accelerate the adoption and routine use of genomics in medicine.

 

10:20 FEATURED PRESENTATION

Stan Lapidus, President, CEO and Founder, SynapDx

 

10:50 Coffee Break

 

BIG DATA/ANALYSIS

11:20 IT Infrastructure Required to Manage Patient Genetic Test Results

Sandy Aronson, Executive Director of IT, Partners HealthCare Center for Personalized Genetic Medicine (PCPGM)

There are many challenges associated with getting the maximum value out of a genetic test. This talk will focus on information technology infrastructure that can help.

11:50 Issues in Genomics at Scale

Chris Dwan, Principal Investigator and Director, Professional Services, BioTeam

2012 marks, in many respects, the beginning of the second decade of high-throughput DNA sequencing. Robust, well understood solutions exist for many of the major technical challenges involved in operating a high-throughput genomics facility. Petabyte scale data storage, well suited to research computing in this space, provides a clean example. Certainly it still requires careful planning and thorough engineering to deploy such infrastructure. However, we can now purchase robust systems from multiple vendors rather than having to stitch together solutions in-house. Perhaps more importantly, we can rely on the experience of a community of peers who have been through the exercise before. By contrast, the legal, regulatory, ethical, and privacy concerns in this space have only begun to be explored. As we plan for the coming years, we must certainly plan for technical uncertainty. Technologists find themselves in the role of guessing at the future. As translational medicine, clinical genome sequencing, and other practices become the norm, we must assume extreme and occasionally capricious changes to the social ecosystem. This talk will explore these issues in the context of nearly a decade supporting research computing and genomics for a broad variety of institutions.

12:20 pm Sponsored Presentation (Opportunity Available)

12:50 Luncheon Presentation (Sponsorship Opportunity Available)
or Lunch on Your Own

 

MOLECULAR DIAGNOSTICS

2:05 Panel Discussion
Panelists will first give a brief presentation and then convene for a panel discussion.

Michael S. Phillips, Ph.D., Canada Research Chair in Translational Pharmacogenomics; Director, Molecular Diagnostic Laboratory, Montreal Heart Institute; Associate Professor, Université de Montréal (Moderator)

Molecular Diagnostics and the Patient/Consumer

Andrew C. Fish, Executive Director, AdvaMedDx

This presentation will envision a future in which molecular diagnostics are widely utilized not only for decision making by health professionals, but also for the development and use of a wide range of consumer products that include genetic tests themselves. The speaker will discuss various policy implications of this convergence of patient and consumer interests driven by the expanding availability of molecular diagnostics.

Bridging the Gap between Genetic Risk and Blood Diagnostics by Personalized Health Monitoring

Oliver Rinner, Ph.D., CEO, Biognosys AG

Biognosys has developed a solution to quantify and track protein levels over time from a drop of blood. With a novel mass spectrometric technology, we can record protein signals from 1000s of proteins in a single instrument run and store such digital protein maps in a digital bio-bank that can be screened in silico for known and novel biomarkers. We will provide this technology as personalized health monitoring to patients and consumers that seek actionable information about their state of health.

Measuring Disease Treatment and Progression at the Molecular Level without Biopsy

James McCullough, CEO and Founder, Exosome Diagnostics

Exosome has developed a solution that has the ability to measure, at the molecular level without biopsy, the dynamic nature of both treatment and disease progression. The company has developed a means of isolating exosomes: exosomes are shed into all biofluids, including blood, urine, and CSF, forming a stable source of intact, disease-specific nucleic acids. From these, the company is able to develop predictive gene expression profiles to achieve high sensitivity for rare gene transcripts and the expression of genes responsible for cancers and other diseases. This technology obviates the need for biopsy, and provides a means for detection at a much earlier stage of treatment.

3:20 Refreshment Break

3:50 Sponsored Presentation (Opportunity Available)

 

SEQUENCING

4:20 Panel Discussion

Like a double helix, the future growth of consumer genetics is intimately entwined with technology advances in next-generation sequencing. While the industry excitedly awaits the commercial debut of potentially disruptive nanopore sequencing platforms, existing platforms continue to roll out new enhancements and sequencing strategies that bring us within striking distance of clinical-grade whole genome sequencing. This panel discussion brings together leaders from existing and emerging sequencing providers to present and debate a range of questions including the pros and cons of targeted versus whole-genome sequencing, the emergence of third-generation sequencing platforms, and the challenges of integrating genome sequencing into the clinic.

Paul Morrison, Ph.D., Laboratory Director, Molecular Biology Core Facilities, Dana-Farber Cancer Institute (Moderator)

Panelists:

John Boyce, President and CEO, GnuBIO
Robert Klein, Ph.D., Chief Business Development Officer, Complete Genomics Inc.
Speaker to be Announced, Life Technologies
Speaker to be Announced, Illumina

5:50-6:50 Welcome Reception in the Exhibit Hall with Poster Viewing

 

DAY 2: BUSINESS + TRANSLATION

THURSDAY, OCTOBER 4

7:45 am Morning Coffee

 

TRANSLATIONAL GENOMICS

8:15 Panel Discussion
Panelists will first give a brief presentation and then convene for a panel discussion.

Kevin Davies, Ph.D., Editor-in-Chief, Bio-IT World (Moderator)

All Genomes are Dysfunctional: The Challenges of Interpreting Whole-Genome Data from Healthy Individuals

Daniel MacArthur, Ph.D., Assistant in Genetics, Massachusetts General Hospital; Co-founder, Genomes Unzipped

Recent advances in DNA sequencing technology have made cheap, rapid interrogation of complete genome and exome sequences an almost mundane exercise, and have resulted in significant progress in the discovery of disease-causing sequence changes from the genomes of individuals with rare diseases or cancers. However, such successes do not necessarily translate into an improved ability to use genome-scale data to predict future disease probability for currently healthy individuals. In this presentation I will highlight some of the major technical and analytical challenges associated with developing predictive genomic medicine for the healthy majority.

Consumer Genomics: What do People do with Their Genomes?

Cinnamon Bloss, Ph.D., Assistant Professor and Director, Social Sciences and Bioethics, Scripps Translational Science Institute

Direct-to-consumer personalized genomic testing is controversial, and there are few empirical data to inform the debate regarding use and regulation. The Scripps Genomic Health Initiative is a large longitudinal cohort study of over 2,000 adults who have undergone testing with a commercially available genomic test. Findings from this initiative regarding the psychological, behavioral and clinical impacts of genomic testing on consumers will be presented.

Advances in Noninvasive Prenatal Genetic Testing: Does this Mean “Designer” Babies for All?

Diana Bianchi, M.D., Executive Director, Mother Infant Research Institute; Vice Chair for Research, Department of Pediatrics, Floating Hospital for Children, Tufts Medical Center

Noninvasive prenatal testing for Down syndrome and other chromosome disorders using massively parallel DNA sequencing techniques is now available on a clinical basis in the US. With expected advances in sequencing techniques it will soon be possible to take a blood sample from a pregnant woman and determine if her fetus has a chromosome abnormality or a single gene disorder. How much information do prospective couples want and how do these technical advances affect well-established algorithms for prenatal care?

Translating Genomics into Clinical Care

Heidi L. Rehm, Ph.D., FACMG, Chief Laboratory Director, Molecular Medicine, Partners HealthCare Center for Personalized Genetic Medicine (PCPGM); Assistant Professor of Pathology, Harvard Medical School

This talk will focus on approaches to integrate clinical sequencing into genomic medicine. It will cover next generation sequencing test development from disease panels to whole genomes and the interpretation and reporting of genetic variants identified in patients.

Impact of Genomic Sequencing on Public Health and Preventive Medicine

Joseph V. Thakuria, M.D., MMSc, Attending Physician in Clinical and Biochemical Genetics and Medical Director, Personal Genome Project, Massachusetts General Hospital Center for Human Genetics Research

Early findings in the Personal Genome Project (established by George Church) suggest significant impact for public health and preventive medicine. Solutions to accelerate clinical adoption and address large molecular data challenges will be explored.

9:30 FEATURED PRESENTATION
Genome-in-a-Bottle: Reference Materials and Methods for Confidence in Whole Genome Sequencing

Marc Salit, Group Leader, Biochemical Science and Multiplexed Biomolecular Science, National Institute of Standards and Technology

Genome-in-a-Bottle: Reference Materials and Methods for Confidence in Whole Genome Sequencing Clinical application of ultra high throughput sequencing (UHTS) or “Next Generation Sequencing” for hereditary genetic diseases and oncology is rapidly emerging.  At present, there are no widely accepted genomic standards or quantitative performance metrics for confidence in variant calling. These are needed to achieve the confidence in measurement results expected for sound, reproducible research and regulated applications in the clinic.  NIST has convened the “Genome-in-a-Bottle Consortium” to develop the reference materials, reference methods, and reference data needed to assess confidence in human whole genome variant calls. A principal motivation for this consortium is to develop an infrastructure of widely accepted reference materials and accompanying performance metrics to provide a strong scientific foundation for the development of regulations and professional standards for clinical sequencing.

10:00 Coffee Break in the Exhibit Hall with Poster Viewing

 

VENTURE CAPITAL & INVESTMENT BANKING

10:30 Panel Discussion

This “Funding to IPO Panel” consists of some of the top venture capitalists and investment bankers in therapeutics, diagnostics, and consumer genetics. This series of presentations and follow-on panel, will take attendees through the financial cycle – from funding to IPO, with VC’s and bankers highlighting the corporate criteria most important to them, and the metrics by which they make their decisions.
Panelists:

Geert-Jan Mulder, M.D., General Partner, Forbion Capital

Alexis Borisy, Partner, Third Rock Ventures

Steve Gullans, Managing Director, Excel Venture Management

Jamie Streator, Managing Director, Healthcare Investment Banking, Cowen & Company

Speaker to be Announced, Barclays

12:15 pm Luncheon Presentation (Sponsorship Opportunity Available)
or Lunch on Your Own

 

GENOME DATA: THE PHYSICIAN’S PERSPECTIVE

1:45 Panel Discussion

While making the effort to deploy genomics and sequence data in preventative and clinical care is a noble cause, it is also one that requires pragmatic solutions. This panel discussion will address practical issues related to the day-to-day use of genomic technologies in the clinic — from hospital to private practice to academia.

Steve Murphy, M.D., Managing Partner, Wellspring Total Health (Moderator)
Panelists:

Michael Murray, M.D., Clinical Chief, Genetics Division, Brigham and Women’s Hospital; Instructor, Harvard Medical School, The Harvard Clinical and Translational Science Center

Isaac Samuel Kohane, M.D., Ph.D., Henderson Professor of Health Sciences and Technology, Children’s Hospital and Harvard Medical School; Director, Countway Library of Medicine; Director, i2b2 National Center for Biomedical Computing; Co-Director, HMS Center for Biomedical Informatics

3:00 Refreshment Break in the Exhibit Hall with Poster Viewing

 

GENOME INTERPRETATION

3:30 Omicia: Interpreting Genomes for Clinical Relevance

Martin G. Reese, President and CEO, Omicia

Automatic annotation of variants and integration of disparate data sources is just the first step in the eventual adoption of genomes into clinical practice. The next step is reducing this complexity into the very few, actionable clinically relevant findings. We will show how we integrate such methods within an automated, comprehensive and easy-to-use platform for the interpretation of individual genome data. This system allows for prioritizing variants with respect to its potential clinical impact and is preloaded with clinical gene sets and proprietary annotations to enhance discovery and reporting of personal genes and variants. Furthermore, it is extensible and allows the integration of the user’s proprietary gene and variants sets. We will show several exome and genome analyses.

3:50 Personalized Genomic Interpretation with SNPedia and Promethease

Mike Cariaso, Founder, SNPedia; Author of Promethease

With whole genome prices falling and microarray genotyping accessible to ordinary people over the internet, the challenge is no longer in acquiring the raw data, but in interpreting and using it. In this talk, I will outline a freely available database of literature, organized by the relevant DNA position and phenotypic effects. A complementary analysis program reads raw genomic data and produces a hyperlinked and searchable report of known associations. It can also perform special processing of family trios (child, mother, father), make predictions about offspring, and identify shared ancestry.

4:10 GenoSpace: Creating an Information Ecosystem for 21st Century Genomic Medicine

John Quackenbush, Ph.D., Professor, Biostatistics and Computational Biology, Cancer Biology Center for Cancer Computational Biology, Dana-Farber Cancer Institute

New sequencing technologies are driving the cost of genomic data generation to unprecedented lows, making sequencing available as a potentially valuable clinical and diagnostic tool. The challenge is solving “the last 100 yards” problem–delivering the data to those who need to access it in a manner in which they can use it effectively. GenoSpace has developed technology to connect the diverse consumers and producers of genomic data, creating an ecosystem in which we have the potential to advance genomic medicine.

 

VISIONS FOR PERSONALIZED MEDICINE

 

» 4:30 KEYNOTE PRESENTATION

The Big Picture: Visions for Personalized Medicine

Jay Flatley, President and CEO, Illumina

 

Illumnia logo small5:30 Social Event and Party

 

DAY 3: APPLICATIONS

FRIDAY, OCTOBER 5

8:00 am Morning Coffee

» 8:30 KEYNOTE PRESENTATION 

An Inside Look at How AncestryDNA Uses Population Genetics to Enrich Its Online Family History Experience

Kenneth Chahine, Ph.D., J.D., Senior Vice President & General Manager, DNA, ancestry.com

Ancestry.com is the world’s largest online resource for family history with an extensive collection of over 10 billion historical records that are digitized, indexed and made available online over the past 13 years. In May 2012, AncestryDNA launched a direct-to-consumer genealogical DNA test that delivers two results to customers. The first result predicts identity-by-descent and allows the customer to find genetic relatives within the AncestryDNA customer database. The second determines the customer’s admixture to provide a predicted genetic ethnicity using a state-of-the-art algorithm. The AncestryDNA team leverages pedigrees, documents, geographical information and its extensive biobank of worldwide DNA samples to conduct innovative research in population genetics and translates the complexities of genetic science into a simple, understandable, and meaningful user experience.

 

9:15 Past, Present and Future of Consumer Genetics, a Pioneer’s Perspective

Rosalynn Gill, Ph.D., Vice President, Clinical Affairs, Boston Heart Diagnostics

The first consumer genetics company, Sciona, founded by Rosaylnn Gill, launched its services in April 2001 in the UK in what was either a breakthrough in innovation or an act of incredible naiveté. Twelve years later, many lessons have been learned, but the jury is still out on the appropriate regulatory framework, the necessary industry standards and what constitutes a sustainable business model.

9:45 Sponsored Presentation (Opportunity Available)

10:15 Coffee Break in the Exhibit Hall with Poster Viewing

 

PRENATAL/NEONATAL DIAGNOSTICS 

10:45 Panel Discussion

Panelists will first give a brief presentation and then convene for a panel discussion.

Meredith Salisbury, Senior Consultant, Bioscribe (Moderator)

Neonatal Genomic Medicine

Neil A. Miller, Director of Informatics, Center for Pediatric Genomic Medicine, Children’s Mercy Hospital

The causal gene is known for more than 3,500 monogenic diseases. Many of these can present in the neonatal period, causing up to 30% of neonatal intensive care unit admissions. In the last six months, we have started to offer very rapid diagnostic testing for these diseases at Children’s Mercy Hospital based on genome sequencing. The emerging indications and utility of neonatal genomic medicine will be discussed.

Screening Neonates by Targeted Next-Generation DNA Sequencing

Arindam Bhattacharjee, Ph.D., CEO and Founder, Parabase Genomics

We are developing a neonatal genome sequencing test that will allow screening and diagnosis of primarily newborns and infants affected with a disease or condition allowing prompt treatment. The current approach of DNA based genetic screening for symptomatic and high-risk is not focused around neonates, and so healthcare providers and parents are unable to understand the cause and treatment of the condition in absence of clear symptoms. Our test is unique in that it simultaneously screens and/or diagnoses hundreds of these conditions at once from a single sample, providing more comprehensive information to families and their physicians. It is yet affordable, and provides access to the high-resolution sequence data.

Using NGS Sequencing to Improve the Standard of Care for Routine Genetic Carrier Screening

Don Hardison, President & CEO, Good Start Genetics, Inc.

11:45 Luncheon Presentation (Sponsorship Opportunity Available)
or Lunch on Your Own

 

NUTRITION, FOOD GENETICS & COSMETICS

1:00 The Importance of Genetic Testing-Directed Vitamin Use

Dennis Gilbert, Ph.D., Founder, President and CEO, VitaPath Genetics

VitaPath Genetics, Inc. has developed a platform for genomic-based tests that determine the need for vitamin therapy in medically actionable conditions. Using its platform, VitaPath can develop specific vitamin-remediated risk assays that help manage the use of the $30 billion spent on supplements in the U.S. each year. The first test developed by VitaPath measures genetic risk factors associated with the spina bifida to identify women who would benefit from low-risk, prescription strength folic acid supplementation.

1:20 Using Weight Management Genetic Testing in Nutrition Counseling:
A Dietitian Weighs in on the Matter

Cindy Crowninshield, RD, LDN, Licensed Registered Dietitian, Body Therapeutics & Sodexo; Founder, Eat2BeWell & Eat4YourGenes; Conference Director, Cambridge Healthtech Institute

Between January-July 2012, 15 patients took a weight management genetic test to support their weight loss efforts. An individualized nutrition plan based on their eating and lifestyle habits and test results was created for each person. Data and several case studies will be presented to show how successful these patients were in achieving their weight loss goals. Challenges and opportunities will be discussed. Also presented will be tips and suggestions for genetic testing companies on how they can work best with a private practitioner’s office.

1:40 How Microfluidics is Changing the Landscape of Personalized Cosmetics

David A. Weitz, Ph.D., Mallinckrodt Professor of Physics and Applied Physics, Harvard School of Engineering and Applied Sciences

2:00 Refreshment Break in the Exhibit Hall with Poster Viewing

 

DISEASE DIAGNOSTICS

2:30 Clinical Sequencing and Mitochondrial Disease

Kevin McKernan, CSO, Courtagen Life Sciences

We describe the results from sequencing 64 patients’ Mitochondrial genomes in conjunction with 1,100 nuclear genes. Complementing this data with multiplex ELISA assays to monitor protein levels in the blood can provide additional insight to variants of unknown significance and aid therapeutic decisions.

2:50 A Paradigm Shift: Universal Screening Test

Samuil R. Umansky, M.D., Ph.D., D.Sc., Co-founder, CSO, and President, DiamiR LLC

We will present a fundamentally new approach to the development of a screening test aimed at diseases of various organ systems, organs and tissues. The test is non-invasive and cost efficient. The data we will present demonstrate the potential of our approach for early detection of neurodegenerative diseases, cancer and inflammatory diseases of gastrointestinal and pulmonary systems.

 

THE EMPOWERED PATIENT

3:10 Genomes R Us – How Personalized Medicine is Reshaping the Role of Patients, and Why It Matters

Craig Martin, CEO, Feinstein Kean Healthcare

Much has been said about the advancements in science underlying the genomic revolution. We are beginning now to see the impact at the clinical level, and there’s more to come in the pipeline. But what does this shift in medicine do to change the role of the patient? This presentation provides insights into how best to engage with patient communities to expedite research, commercialization and market impact of innovative technologies, diagnostics and treatments, and to help validate the relative efficacy of such advancements in a value-driven world.

3:40 Consumer Empowerment in Health Care and Personal Genomics: Ethical, Societal and Regulatory Considerations

Gholson Lyon, M.D., Ph.D., Assistant Professor in Human Genetics, Cold Spring Harbor Laboratory; Research Scientist, Utah Foundation for Biomedical Research

The pace of exome and genome sequencing is accelerating with the identification of many new disease-causing mutations in research settings, and it is likely that whole exome or genome sequencing could have a major impact in the clinical arena in the relatively near future. However, the human genomics community is currently facing several challenges, including phenotyping, sample collection, sequencing strategies, bioinformatics analysis, biological validation of variant function, clinical interpretation and validity of variant data, and delivery of genomic information to various constituents. I will review these challenges, with an eye toward consumer genetics.

4:10 It Hurts Less If You Know More: An Empowered Patient’s Diagnostic Odyssey

Richard Kellner, Co-Founder and President, Genome Health Solutions, Inc.

For the early detection, diagnosis and treatment of cancer, there is a wide gap between current “standards of care” and what is possible through the use of advanced genomic technologies. Over the past two years I learned this lesson first hand through personal experiences involving myself, close friends and family members. My story is one of serendipity, frustration and then hope. I learned that, unfortunately, where you live and who you know can greatly influence your quality of care. I also learned that you can overcome these limitations by becoming an “empowered patient” who actively seeks out doctors who are willing to get outside of their comfort zones and practice “participatory medicine,” sometimes at the cutting edge of new precision diagnostics. I will present a new roadmap that both patients and doctors can follow toward a new era of personalized genomic medicine.

 

COMPANIES THAT EMPOWER THE PATIENT

4:40 23andMe’s DTC Exome

Brian T. Naughton, Ph.D., Founding Scientist, 23andMe

In October 2011, 23andMe launched a $999 direct-to-consumer exome product to a limited group of customers.This talk presents findings from this project, including the ubiquitous issue of variants of unknown significance.

5:10 Winding the Asklepian Wand: The Advent of Whole Genomes in Healthcare

Nathan Pearson, Ph.D., Director of Research, Knome, Inc.

With ever cheaper sequencing, richer reference data, and sharper interpretation methods, the clinical use of whole genomes is taking root in pediatrics, oncology, and beyond. Our genomes will ultimately join other cornerstones of clinical care, helping us stay healthier from birth to old age. But that prospect will require fast, robust pipelines that smartly interpret genomes, in the context of good phenotype data, and feed decisive insights back to patients and caregivers. Learn how Knome is making that happen.

5:40 Close of Conference

Source:

http://www.consumergeneticsconference.com/cgc_content.aspx?id=117407&libID=117355

 

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How Genome Sequencing is Revolutionizing Clinical Diagnostics, from the ISMB Conference

Reporter: Aviva Lev-Ari, PhD, RN

 

08WednesdayAug 2012

Written by Filipe J. Ribeiro in Events

Filipe Ribeiro New York Genome CenterFilipe J. Ribeiro is a Bioinformatics Scientist at the New York Genome Center.

Recently, I attended the 20th Annual Conference of Intelligent Systems for Molecular Biology (July 15-17, 2012), organized by the International Society for Computational Biology. The conference focuses on the application of computer science, statistical, and mathematical methods to biological systems. I also attended the High Throughput Sequencing Methods and Applications (HiTSeq) satellite meeting (July 13-14, 2012). There, the speakers addressed the opportunities and challenges presented by the availability of the increasingly large genomic datasets from next-generation sequencing.

Many topics were discussed during the two days of HiTSeq, such as new data-analysis methods for RNA sequencing data, methods for improving de novoassemblies, and sequencing-data compression. What impressed me the most were the keynote addresses given by Dr. Stanley Nelson, from the Jonnson Comprehensive Cancer Center at UCLA, and Dr. Gohlson Lyon, from Cold Spring Harbor Laboratory. Both speakers focused on how whole-exome andwhole-genome sequencing are on the verge of revolutionizing clinical diagnosis of genetic disorders and what challenges need to be addressed before sequencing penetrates the clinic.

Dr. Nelson’s talk centered on the use of exome sequencing in the clinical diagnosis of genetic conditions. He presented a few case studies of young children with various rare developmental delays. Rare conditions can be hard to diagnose, and often times numerous tests need to be performed before a conclusion is reached, if a conclusion is reached at all. Also, some conditions are caused by a variety of different mutations to a single gene. These are harder to detect with conventional targeted genetic testing, which relies on known mutations. With exome sequencing a single test is performed; that one test identifies all coding mutations, known and unknown, simple and complex. Even when there is no smoking gun in the large set of mutations typically found in any single individual, the genotype can be reanalyzed at a later point, in light of new research findings.

However, challenges in genomics-based diagnosis still remain. Dr Nelson reports that in roughly 50 percent of cases studied clinically at UCLA, a known causal mutation is found. In 25 percent of cases, a novel genetic mutation is identified that is potentially causal, and in the remaining 25 percent of cases no conclusion can be drawn. Because of the large number of novel mutations that are present in any single individual’s genome, establishing causality of novel variations is often very hard, and care must be taken when interpreting results in order to avoid false positives. To minimize the risk of misdiagnosis in a clinical setting, it is fundamental to have a board of scientists and clinicians to review the conclusions of sequencing tests to ensure their validity.

Another challenge is what to do with secondary or unrelated findings—for example when a patient comes in with a set of symptoms indicative of one condition, and the genetic test finds a different one that is unrelated and asymptomatic. Some conditions (like Huntington’s disease) have no cure, and the patient might not want to learn about any diagnoses that are not actionable. A great deal of care must be taken both before and after genetic testing takes place so that patients understand the risks and the meaning of results.

On a slightly different note, Dr. Lyon focused on the ethical difficulties of returning research-grade results on genetic disorders to study participants. As an example he presented the case of a family that carries a genetic mutation that is fatal in boys at a very early age. A mutation was identified and shown to be causal in a research setting. The ethical dilemma for the researcher is: if one of the women in the family is pregnant with a boy, should she be informed of her carrier status? Research standards are not at the same level as clinical ones, and research results can at times be wrong.

It is not an easy question. Dr. Lyon’s suggestion is that research-grade whole-genome and whole-exome sequencing of study participants should be conducted under the same CLIA-certified standards as clinical tests, with the goal of returning research results to the study participants. Again, counseling and education of study participants regarding the risks and benefits of genetic testing are critical.

One barrier to the adoption of sequencing in a clinical setting is the fact that insurance companies do not cover the costs of whole genome sequencing as they are not yet convinced of the benefits. But that attitude will hopefully change as sequencing costs keep decreasing, and success stories abound. Soon it will be clear that genome sequencing is cost effective in disease diagnosis, prevention, and treatment. Also, for the most part genome sequencing is done only once in a lifetime, and therefore it is not a repetitive cost. (Cancer is an exception; one might want to sequence the cancer cells to identify which specific mutations are driving the tumor and to what drugs the tumor might respond.)

In summary, both speakers painted a picture of how whole-genome and whole-exome sequencing is quickly proving itself as a revolutionary tool in the clinic. Clearly challenges remain: test interpretation must be done carefully, ideally by a board of both scientists and clinicians, and strict CLIA standards should be in place, even in a research setting. But it is certainly clear that next generation sequencing will play an increasingly significant role in the clinic, and, most importantly, in our health.

 

http://blog.nygenome.org/

 

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