130 posts · 82,961 views
A mathematician by training, I discovered genetics in 2006 and never turned back. This blog was born to share all the fascinating things I learn about genes and DNA through my current research on viral genetics and HIV.
EE Giorgi
130 posts
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- December 12, 2011
- 07:16 PM
- 3,192 views
Another gene therapy success story
Last October I reported an incredible story in which researchers used an HIV chimeric virus to cure leukemia. Here's another success story. Hemophilia B is a blood clotting disorder caused by spontaneous mutations in the Factor IX gene, leading to a deficiency of Factor IX, an enzyme essential in blood coagulation. The gene is expressed mostly in the liver, where the enzyme is produced and then sent into circulation in the blood. Less than 1% of normal levels of Factor IX lead to severe hemophil........ Read more »
Nathwani, A., Tuddenham, E., Rangarajan, S., Rosales, C., McIntosh, J., Linch, D., Chowdary, P., Riddell, A., Pie, A., Harrington, C.... (2011) Adenovirus-Associated Virus Vector–Mediated Gene Transfer in Hemophilia B. New England Journal of Medicine, 2147483647. DOI: 10.1056/NEJMoa1108046
- December 13, 2011
- 02:10 PM
- 3,158 views
Not all vectors are created equal
As I was reading the paper I discussed yesterday, I realized there was a part I didn't fully understand and I needed to research more. I received some great comments on that post that pointed me in the right direction.A gene delivery vector is an engineered virus modified so that it contains the genes needed for therapy. Once inside the cell, the genetic material needs to reach the nucleus where it has to recruit a complementary DNA strand in order for the gene to be expressed. Conceptually, it ........ Read more »
McCarty, D. (2008) Self-complementary AAV Vectors; Advances and Applications. Molecular Therapy, 16(10), 1648-1656. DOI: 10.1038/mt.2008.171
- December 15, 2011
- 08:43 AM
- 3,127 views
So mice can be vaccinated against HIV. What about humans, though?
I hope I can get away with yet another paper on gene therapy this week. You may actually have already heard about this one: it came out at the end of November and it had quite some resonance because the researchers claimed to have establish lasting immunogenicity to HIV in mice‚ using, again gene therapy. I have already discussed the potential use of gene therapy to cure HIV. In fact, the only human to ever be "cured" of HIV was a leukemia patient who, after receiving a genetically modified ve........ Read more »
Balazs, A., Chen, J., Hong, C., Rao, D., Yang, L., & Baltimore, D. (2011) Antibody-based protection against HIV infection by vectored immunoprophylaxis. Nature. DOI: 10.1038/nature10660
- September 18, 2011
- 09:33 AM
- 1,177 views
Is an HIV vaccine finally possible? Unraveling the secrets of broadly neutralizing antibodies
Last month I talked about the daunting challenge that HIV has presented for the past thirty years. HIV is so variable that as soon as the immune system builds a defense against it, the virus comes up with a new variant that allows it to escape. The only way to defeat such an elusive enemy is with immune responses able to recognize a broad range of HIV subtypes and variants. Unfortunately, antibodies with these characteristics are produced by a minority of patients and only years into the infecti........ Read more »
Wu, X., Zhou, T., Zhu, J., Zhang, B., Georgiev, I., Wang, C., Chen, X., Longo, N., Louder, M., McKee, K.... (2011) Focused Evolution of HIV-1 Neutralizing Antibodies Revealed by Structures and Deep Sequencing. Science, 333(6049), 1593-1602. DOI: 10.1126/science.1207532
Scheid, J., Mouquet, H., Ueberheide, B., Diskin, R., Klein, F., Oliveira, T., Pietzsch, J., Fenyo, D., Abadir, A., Velinzon, K.... (2011) Sequence and Structural Convergence of Broad and Potent HIV Antibodies That Mimic CD4 Binding. Science, 333(6049), 1633-1637. DOI: 10.1126/science.1207227
- November 29, 2011
- 08:41 AM
- 1,139 views
Sample size, P-values, and publication bias: the positive aspects of negative thinking
If you follow the science blogging community, you may have noticed a lot of talking about sample size in the past couple of weeks. So I did my share of mulling things over and this is what I came up with.1- The study in question had a small sample size but reported a significant p-value (<0.05). Such study is NOT underpowered. An underpowered study is a study that does not have a sufficiently large sample size to allow detection of a significant result. A significant result is by definition a........ Read more »
Dirnagl, U., & Lauritzen, M. (2010) Fighting publication bias: introducing the Negative Results section. Journal of Cerebral Blood Flow , 30(7), 1263-1264. DOI: 10.1038/jcbfm.2010.51
- October 4, 2011
- 06:51 AM
- 1,108 views
Gene therapy makes sense. And antisense, too!
Genes code proteins. When a gene carries a defective mutation, it will either stop coding the protein or it will code a defective one. This is, unfortunately, the basis of many genetic diseases. In principle, if we could substitute the defective gene with a healthy one, the problem would be solved. That's what gene therapy boils down to. In fact, there are ways to deliver the genes to the affected cells. For example, you can take a virus that targets the cells where the defective gene is express........ Read more »
Suto, R., Tominaga, K., Mizuguchi, H., Sasaki, E., Higuchi, K., Kim, S., Iwao, H., & Arakawa, T. (2004) Dominant-negative mutant of c-Jun gene transfer: a novel therapeutic strategy for colorectal cancer. Gene Therapy, 11(2), 187-193. DOI: 10.1038/sj.gt.3302158
Morgan RA, Dudley ME, Wunderlich JR, Hughes MS, Yang JC, Sherry RM, Royal RE, Topalian SL, Kammula US, Restifo NP.... (2006) Cancer regression in patients after transfer of genetically engineered lymphocytes. Science (New York, N.Y.), 314(5796), 126-9. PMID: 16946036
Zhang Y, Zhu C, & Pardridge WM. (2002) Antisense gene therapy of brain cancer with an artificial virus gene delivery system. Molecular therapy : the journal of the American Society of Gene Therapy, 6(1), 67-72. PMID: 12095305
Yatabe, N., Kyo, S., Kondo, S., Kanaya, T., Wang, Z., Maida, Y., Takakura, M., Nakamura, M., Tanaka, M., & Inoue, M. (2002) 2-5A antisense therapy directed against human telomerase RNA inhibits telomerase activity and induces apoptosis without telomere impairment in cervical cancer cells. Cancer Gene Therapy, 9(7), 624-630. DOI: 10.1038/sj.cgt.7700479
- September 15, 2011
- 12:22 PM
- 1,071 views
All you need is love... and the right alleles
It's been called the "love hormone" because studies have shown that it is released during labor and breastfeeding. Children soothed by their mothers produce it, and, apparently, it has a role in easing social interactions. Oxytocin is a hormone secreted by the pituitary gland. It is a neurotransmitter, which basically means that it helps send signals from the brain to the receiving cells.OXTR is the oxytocin gene receptor, in other words, this gene codes the protein that sits on t........ Read more »
Saphire-Bernstein, S., Way, B., Kim, H., Sherman, D., & Taylor, S. (2011) Oxytocin receptor gene (OXTR) is related to psychological resources. Proceedings of the National Academy of Sciences, 108(37), 15118-15122. DOI: 10.1073/pnas.1113137108
- September 11, 2011
- 11:46 AM
- 1,018 views
How did that pesky virus end up in our DNA?
Last time we talked about the different types of genetic and epigenetic chimeras. We learned what a chimeric virus is, and that retroviruses need to get integrated into the host's DNA in order to replicate. They basically inject their RNA into the cell, the RNA gets transformed into DNA, the viral DNA enters the cell's nucleus and once in the the nucleus it's integrated into the cell's DNA.This process has been going on for as long as viruses have existed. And viruses have existed for a long tim........ Read more »
Emerman M, & Malik HS. (2010) Paleovirology--modern consequences of ancient viruses. PLoS biology, 8(2). PMID: 20161719
Dunlap KA, Palmarini M, Varela M, Burghardt RC, Hayashi K, Farmer JL, & Spencer TE. (2006) Endogenous retroviruses regulate periimplantation placental growth and differentiation. Proceedings of the National Academy of Sciences of the United States of America, 103(39), 14390-5. PMID: 16980413
Dupressoir A, & Heidmann T. (2011) [Syncytins - retroviral envelope genes captured for the benefit of placental development]. Medecine sciences : M/S, 27(2), 163-9. PMID: 21382324
- December 5, 2011
- 09:12 AM
- 1,005 views
Timing the AIDS pandemic and why it made history (part I)
This week I would like to discuss two Science papers that have marked a milestone in HIV research. In order to place them in the right context, I need to start with a brief historical digression. If you're interested in the history of the discovery of the AIDS disease, I highly recommend watching the movie And the Band Played On. It's very well done and realistically portrays how the medical investigation was conducted. For the purpose of my discussion here, though, I will start from the movemen........ Read more »
Hahn, B., Shaw, G. M., De Cock, K. M, Sharp, P. M. (2000) AIDS as a Zoonosis: Scientific and Public Health Implications. Science, 287(5453), 607-614. DOI: 10.1126/science.287.5453.607
- October 19, 2011
- 09:11 AM
- 998 views
MHC molecules, mating, sniffing, and birthcontrol: believe me, there's a link!
Today we talk about… mating! Whoa -- did you just see that spike in the stats page? Haha, okay, but first you have to sit through the usual genetic lesson. Here it goes: we start talking about the major histocompatibility complex, or MHC.I've mentioned many times in my previous posts that in order to trigger an immune response you have to make sure that the immune system recognizes the antigen, or "foreign" object. Antigens are made of proteins that, once inside the cell, are chopped into bits........ Read more »
Wedekind C, Seebeck T, Bettens F, & Paepke AJ. (1995) MHC-dependent mate preferences in humans. Proceedings. Biological sciences / The Royal Society, 260(1359), 245-9. PMID: 7630893
Roberts SC, Gosling LM, Carter V, & Petrie M. (2008) MHC-correlated odour preferences in humans and the use of oral contraceptives. Proceedings. Biological sciences / The Royal Society, 275(1652), 2715-22. PMID: 18700206
- October 12, 2011
- 10:51 PM
- 997 views
Are vaccines the future of cancer treatment?
The September issue of the Cancer Journal is dedicated to cancer vaccines and how they may hold the key for cancer treatment and prevention. This is not to be confused with vaccines against cancer-causing viruses, like HPV. In that case the vaccine elicits antibody responses against the virus. In the context of cancer, though, a vaccine would use the immune system's own weapons in order to destroy tumor cells. An example is the vaccine to treat advanced prostate cancer that was approved by the F........ Read more »
Dhodapkar MV, & Dhodapkar KM. (2011) Vaccines targeting cancer stem cells: are they within reach?. Cancer journal (Sudbury, Mass.), 17(5), 397-402. PMID: 21952290
Perez SA, von Hofe E, Kallinteris NL, Gritzapis AD, Peoples GE, Papamichail M, & Baxevanis CN. (2010) A new era in anticancer peptide vaccines. Cancer, 116(9), 2071-80. PMID: 20187092
- December 22, 2011
- 08:22 AM
- 938 views
Guest post: How to camouflage a virus and why it's important
Last week I covered a couple of recent gene therapy studies and discussed the different types of vectors used in order to make these therapies more efficient. One of the obstacles that hinders the efficiency of gene therapy is the immune system: if the patient has previously developed immunity against the viral vector, the virus will be quickly cleared out of the system without being able to deliver the genes. Therefore, the question is: how can we prevent the immune system from attacking the vi........ Read more »
Pulicherla, N., & Asokan, A. (2011) Peptide affinity reagents for AAV capsid recognition and purification. Gene Therapy, 18(10), 1020-1024. DOI: 10.1038/gt.2011.46
- November 17, 2011
- 09:53 AM
- 932 views
The immortality paradox
My friend Tim Bowen posed a really interesting question. Tim is a retired Los Angeles Police Officer, a writer, and a fantastic story teller. If you don't believe me, check out his book (Kindle edition available from Amazon), a collection of stories from when he was an LAPD street cop. A forewarning, though: don't read it in public places unless you don't mind people staring at you. Before you know it, you'll burst out laughing and everybody will be wondering what you've been adding to your brea........ Read more »
Jaskelioff, M., Muller, F., Paik, J., Thomas, E., Jiang, S., Adams, A., Sahin, E., Kost-Alimova, M., Protopopov, A., Cadiñanos, J.... (2010) Telomerase reactivation reverses tissue degeneration in aged telomerase-deficient mice. Nature, 469(7328), 102-106. DOI: 10.1038/nature09603
- September 30, 2011
- 08:02 PM
- 921 views
Deep sequencing and forensic science: how to improve DNA fingerprinting
(In case you missed it, this originally appeared last Thursday as a guest blog on the Writer's Forensics Blog.)There are roughly three billion pairs of nucleotides in human DNA, and the vast majority is identical across individuals. When we talk about “genetic fingerprinting,” we really mean, “looking for a needle in a hay stack.” Luckily, for the most part, we all differ at the same loci. Over the years, the techniques used for DNA typing have improved greatly, diminishing both costs an........ Read more »
Margulies M, Egholm M, Altman WE, Attiya S, Bader JS, Bemben LA, Berka J, Braverman MS, Chen YJ, Chen Z.... (2005) Genome sequencing in microfabricated high-density picolitre reactors. Nature, 437(7057), 376-80. PMID: 16056220
Fordyce SL, Ávila-Arcos MC, Rockenbauer E, Børsting C, Frank-Hansen R, Petersen FT, Willerslev E, Hansen AJ, Morling N, & Gilbert MT. (2011) High-throughput sequencing of core STR loci for forensic genetic investigations using the Roche Genome Sequencer FLX platform. BioTechniques, 51(2), 127-33. PMID: 21806557
- December 18, 2011
- 10:07 AM
- 904 views
Enough with OXTR associations. Here's what I really want to know.
Another OXTR paper came out in PNAS, the third since September. Apparently people are finding more and more association between a common OXTR polymorphism, rs53576, and various behaviors: "One SNP in the third intron of OXTR has emerged as a particularly promising candidate in recent studies on human social behavior: rs53576 (G/A). In recent studies, the A allele of rs53576 has been associated with reduced maternal sensitivity to child behavior, lower empathy, reduced reward dependence, lower op........ Read more »
Chen, F., Kumsta, R., von Dawans, B., Monakhov, M., Ebstein, R., & Heinrichs, M. (2011) Common oxytocin receptor gene (OXTR) polymorphism and social support interact to reduce stress in humans. Proceedings of the National Academy of Sciences, 108(50), 19937-19942. DOI: 10.1073/pnas.1113079108
- January 17, 2012
- 09:06 AM
- 899 views
Introns, exons, and stop codons: how antisense oligonucleotides can fix frameshift mutations
DMD is the largest gene in nature, covering roughly 2.4 mega bases of the X chromosome. It encodes the dystrophin protein, a component of the protein complex that connects the cytoskeleton to the extra-cellular matrix. DMD is a very complex gene. Its RNA transcripts are differentially spliced, which means that the gene produces different transcripts, encoding a large set of protein isoforms. A refresher: every gene is composed of coding parts, called exons, interspersed with non-coding bits, cal........ Read more »
Goemans, N., Tulinius, M., van den Akker, J., Burm, B., Ekhart, P., Heuvelmans, N., Holling, T., Janson, A., Platenburg, G., Sipkens, J.... (2011) Systemic Administration of PRO051 in Duchenne's Muscular Dystrophy. New England Journal of Medicine, 364(16), 1513-1522. DOI: 10.1056/NEJMoa1011367
- October 16, 2011
- 09:12 AM
- 874 views
A chimeric virus to cure leukemia? Yes, we can!
Last week I talked about gene therapy and vaccines targeting tumor cells. Following those posts, a friend of mine (thanks, Alex!) pointed me to a recent case report published in the New England Journal of Medicine, which successfully used gene therapy to treat leukemia [1]. Since you know I like to talk about chimeric viruses and all the wonderful things you can do with them, I was instantly drawn to the paper. Leukemia is a type of cancer that causes an abnormal increase in white blood cells......... Read more »
Porter, D., Levine, B., Kalos, M., Bagg, A., & June, C. (2011) Chimeric Antigen Receptor–Modified T Cells in Chronic Lymphoid Leukemia. New England Journal of Medicine, 365(8), 725-733. DOI: 10.1056/NEJMoa1103849
- December 9, 2011
- 10:04 AM
- 868 views
Understanding the cell nucleus in order to unravel the mystery of epigenetic heritability
The above image is the striking view of the surface of a cell nucleus (in pink). The dark crater represents a hole in the nucleus and offers a peek inside: the granular consistency that you see there are the chromosomes, bundled together in what may appear a random distribution but, in reality, is nothing but random:"In all eukaryotic species analyzed so far, spatial genome arrangements are nonrandom: chromosomes or genomic loci occupy preferential positions with respect to each other and/or to ........ Read more »
Zimmer, C., & Fabre, E. (2011) Principles of chromosomal organization: lessons from yeast. The Journal of Cell Biology, 192(5), 723-733. DOI: 10.1083/jcb.201010058
Berger, S. (2007) The complex language of chromatin regulation during transcription. Nature, 447(7143), 407-412. DOI: 10.1038/nature05915
- January 10, 2012
- 07:00 PM
- 859 views
Having kids wears you out? Same holds for telomeres. In zebra finches.
One of my most popular posts on the blog has been The Immortality Paradox, in which I discuss telomeres, aging, and cancer. Telomeres are the ends of he chromosomes, a bit of non-coding DNA that naturally wears off as cells divide and as we age. Once the telomeres reach a certain critical length the cell stops dividing and eventually dies. As a consequence, telomeres length varies across age groups but, even within the same age group, it varies from individual to individual. So, it becomes natur........ Read more »
Heidinger, B., Blount, J., Boner, W., Griffiths, K., Metcalfe, N., & Monaghan, P. (2012) Telomere length in early life predicts lifespan. Proceedings of the National Academy of Sciences. DOI: 10.1073/pnas.1113306109
- January 6, 2012
- 08:56 AM
- 857 views
The curse of drug-resistant TB strains
Tuberculosis (TB) is a disease caused by a number of strains of mycobacteria. It affects mostly the lungs with chronic, bloody cough and fever. It can remain asymptomatic as a latent infection, though about 10% of these latent infections eventually progress to active disease.The two most common drugs used to treat TB are isoniazid and rifampicin, but unfortunately new mycobacteria strains (called MDR strains, which stands for multi-drug resistant) have emerged that are resistant to both these po........ Read more »
Comas, I., Borrell, S., Roetzer, A., Rose, G., Malla, B., Kato-Maeda, M., Galagan, J., Niemann, S., & Gagneux, S. (2011) Whole-genome sequencing of rifampicin-resistant Mycobacterium tuberculosis strains identifies compensatory mutations in RNA polymerase genes. Nature Genetics, 44(1), 106-110. DOI: 10.1038/ng.1038
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