Advertisements
Feeds:
Posts
Comments

Archive for the ‘stem cell biology and patient-specific’ Category


Reporter and Curator: Dr. Sudipta Saha, Ph.D.

 

Leigh syndrome is one of the hundreds of so-called mitochondrial diseases, which are caused by defects in the mitochondria that produce 90 percent of the body’s energy. These disorders are rare; about 1,000 to 4,000 babies in the United States are born with one every year. But they are devastating and can result in grave impairment of nearly any bodily system. They are largely untreatable, uniformly incurable and very difficult to screen.

 

Leigh syndrome is a terrible disease. It emerges shortly after birth and claims one major organ after another. Movement becomes difficult, and then impossible. A tracheotomy and feeding tube are often necessary by toddlerhood, and as the disease progresses, lungs frequently have to be suctioned manually. Most children with the condition die by the age of 5 or 6.

 

Scientists have devised a procedure called mitochondrial replacement therapy (M.R.T.) that involves transplanting the nucleus of an affected egg (mitochondrial diseases are passed down from the mother’s side) into an unaffected one whose nucleus has been removed. The procedure is sometimes called “three-parent in vitro fertilization”. Mitochondria contain a minuscule amount of DNA, any resulting embryo would have mitochondrial DNA from the donor egg and nuclear DNA from each of its parents.

 

After decades of careful study in cell and animal research M.R.T. is now finally being tested in human clinical trials by doctors in Britain (no births confirmed yet officially). In the United States, however, this procedure is effectively illegal. M.R.T. does not involve altering any genetic code. Defective mitochondria are swapped out for healthy ones.

 

Mitochondrial DNA governs only a handful of basic cellular functions. It is separate from nuclear DNA, which helps determine individual traits like physical appearance, intelligence and personality. That means M.R.T. cannot be used to produce the genetically enhanced “designer babies” and thus should be allowed in humans. But, there is no way to know how safe or effective M.R.T. is until doctors and scientists test it in humans.

 

References:

 

 

https://pharmaceuticalintelligence.com/2016/10/07/the-three-parent-technique-to-avoid-mitochondrial-disease-in-embryo/

 

 

 

 

Advertisements

Read Full Post »

Immunoediting can be a constant defense in the cancer landscape


Reporter and Curator: Dr. Sudipta Saha, Ph.D.

 

There are many considerations in the cancer immunoediting landscape of defense and regulation in the cancer hallmark biology. The cancer hallmark biology in concert with key controls of the HLA compatibility affinity mechanisms are pivotal in architecting a unique patient-centric therapeutic application. Selection of random immune products including neoantigens, antigens, antibodies and other vital immune elements creates a high level of uncertainty and risk of undesirable immune reactions. Immunoediting is a constant process. The human innate and adaptive forces can either trigger favorable or unfavorable immunoediting features. Cancer is a multi-disease entity. There are multi-factorial initiators in a certain disease process. Namely, environmental exposures, viral and / or microbiome exposure disequilibrium, direct harm to DNA, poor immune adaptability, inherent risk and an individual’s own vibration rhythm in life.

 

When a human single cell is crippled (Deranged DNA) with mixed up molecular behavior that is the initiator of the problem. A once normal cell now transitioned into full threatening molecular time bomb. In the modeling and creation of a tumor it all begins with the singular molecular crisis and crippling of a normal human cell. At this point it is either chop suey (mixed bit responses) or a productive defensive and regulation response and posture of the immune system. Mixed bits of normal DNA, cancer-laden DNA, circulating tumor DNA, circulating normal cells, circulating tumor cells, circulating immune defense cells, circulating immune inflammatory cells forming a moiety of normal and a moiety of mess. The challenge is to scavenge the mess and amplify the normal.

 

Immunoediting is a primary push-button feature that is definitely required to be hit when it comes to initiating immune defenses against cancer and an adaptation in favor of regression. As mentioned before that the tumor microenvironment is a “mixed bit” moiety, which includes elements of the immune system that can defend against circulating cancer cells and tumor growth. Personalized (Precision-Based) cancer vaccines must become the primary form of treatment in this case. Current treatment regimens in conventional therapy destroy immune defenses and regulation and create more serious complications observed in tumor progression, metastasis and survival. Commonly resistance to chemotherapeutic agents is observed. These personalized treatments will be developed in concert with cancer hallmark analytics and immunocentrics affinity and selection mapping. This mapping will demonstrate molecular pathway interface and HLA compatibility and adaptation with patientcentricity.

References:

 

https://www.linkedin.com/pulse/immunoediting-cancer-landscape-john-catanzaro/

 

https://www.cell.com/cell/fulltext/S0092-8674(16)31609-9

 

https://www.researchgate.net/publication/309432057_Circulating_tumor_cell_clusters_What_we_know_and_what_we_expect_Review

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4190561/

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5840207/

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5593672/

 

https://www.frontiersin.org/articles/10.3389/fimmu.2018.00414/full

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5593672/

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4190561/

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4388310/

 

https://www.linkedin.com/pulse/cancer-hallmark-analytics-omics-data-pathway-studio-review-catanzaro/

 

Read Full Post »


Stem Cells Differentiated into Insulin-Producing Cells in Mice

Reported: Irina Robu, PhD

Dr. Douglas Melton team from Harvard University funded in part by NIH’s National Institute of Diabetes and Digestive and Kidney Diseases set out to transform stem cells into beta cells that have the potential to replace damaged beta cells. While scientists have been able to change stem cells into insulin-producing cells, these cells don’t have markers that indicate they are beta cells, and they aren’t responsive to glucose.

Since diabetes is a disorder of elevated blood sugars where the body does not harvest enough insulin to meet where the body does not harvest enough insulin to respond properly to the insulin being made. When blood glucose levels rise, beta cells in the pancreas normally make the hormone insulin. Insulin triggers cells throughout the body to take up sugar from the blood. In type 2 diabetes, the most common form, tissues in the body lose their sensitivity to insulin, and pancreatic beta cells can’t make enough insulin to keep glucose levels in check. In type 1 diabetes, the body’s own immune system attacks and destroys beta cells. High blood glucose levels can lead to heart disease, blindness, and other health problems over time.

One approach to treat diabetes is to replace destroyed beta cells. Transplanted human pancreatic cells from deceased donors have been successfully used to treat people with type 1 diabetes. But this method is restricted by the accessibility of donor cells and the side effects of immunosuppression. The other approach is to develop functioning beta cells from stem cells which have the potential to transform into many different cell types. These cells can grow indefinitely in the laboratory and can differentiate, into any cell type found in the body.
In this experiment, the researchers grew a human embryonic stem cell line and 2 human-induced pluripotent stem cell lines in a culture system that allowed them to produce large numbers of cells. The researchers tested more than 150 combinations of over 70 compounds to figure out a method to produce functional human beta cells from the cultured stem cells which when added in exact combinations over a period of several weeks, they transformed human pluripotent stem cells into beta cells that functioned similarly to normal adult beta cells.

The cultured beta cells had specific markers that were found on normal beta cells which displayed changes in calcium levels when exposed to glucose and packaged insulin into granules. However, when transplanted into mice these cells secreted insulin in response to glucose. However, when the cells were transplanted into diabetic mice, abnormally high blood glucose levels lowered. More work is needed to develop these cells for clinical use. However, at this point they can serve as a useful screening tool for diabetes drugs.

SOURCE
http://www.frontlinegenomics.com/news/26168/stem-cells-turned-into-insulin-producing-cells-in-mice/

 

 

Read Full Post »


The Puzzle of Stem Cells and Cancer Stem Cells: The MIT Stem Cell Initiative

Reporter: Irina Robu, PhD

The MIT Stem Cell Initiative is looking to research fundamental biological questions about normal adult stem cells and their malignant counterparts, cancer stem cells. The MIT Stem Cell Initiative is applying new technologies and approaches in pursuit of this goal. In particular, the MIT Stem Cell Initiative has focused on the breast and colon, as these tissues are quite different from each other, yet each constitutes a major portion of cancer occurrence. The program purposes are to

(a) identify the stem cells and cancer stem cells in various tissues and tumor types,

(b) control how these cells change during aging or with disease progression and

(c) determine the similarities and differences between

  • normal cells, and
  • cancer stem cells,

with the goal of finding weaknesses in cancer stem cells that can be feasible and exact targets for treatment.

In due course, the ability to identify, purify, and establish several populations of stem cells and cancer stem cells could aid researchers to understand the biology of these cells, and learn how to exploit them more efficiently in regenerative medicine applications and target them in cancer.

Normal adult stem cells are undifferentiated cells within a tissue that divide to produce two daughter cells and divide periodically to replenish or repair the tissue. One of the two daughter cells remain in the stem cell state and the other adopts a partially differentiated state, then goes on to divide and differentiate further to harvest multiple cell types that form that tissue. The division process is through a precise process to ensure that tissues are restricted to the appropriate size and cell content.

Cancer stem cells perform the same division but, rather than differentiating, the additional cells produced by the second daughter cell amass to form the bulk of the tumor.

  • Cancer stem cells can regrow the tumor, and
  • are frequently resistant to chemotherapy.

This exclusive ability of normal and cancer stem cells to both self-renew and form a tissue or tumor is referred to by researchers as “stemness,” and has important implications for biomedical applications.

As a result, cancer stem cells are thought to be responsible for

  • tumor recurrence after remission, and also for the
  • formation of metastases, which account for the majority of cancer-associated deaths.

Accordingly, an anti-cancer stem cell therapy that can target and kill cancer stem cells is one of the holy grail of cancer treatment as means to suppress both tumor recurrence and metastatic disease. One of the important tasks to studying normal and cancer stem cells, and to ultimately harnessing that knowledge is developing the ability to identify, purify, and propagate these cells. Accordingly, the main goal in stem cell and cancer stem cell research is discovering ways to distinguish them, preferably by identifying unique surface markers that can be used to cleanse stem cell and cancer stem cell populations and enable their study.

New technologies are permitting the researchers to make significant headway in these investigations, progress that was not possible just a few years ago. Explicitly, they are using

  • a mixture of specially cultured cells,
  • highly controllable mouse models of cancer, and s
  • ingle-cell RNA sequencing and
  • computational analysis techniques that are extremely matched to extracting an excessive deal of information from the moderately small number of stem cells.

SOURCE

http://news.mit.edu/2018/mit-initiative-delves-into-stem-cell-biology-1015

Read Full Post »


LIVE 2018 The 21st Gabay Award to LORENZ STUDER, Memorial Sloan Kettering Cancer Center, contributions in stem cell biology and patient-specific, cell-based therapy

REAL TIME Reporter: Aviva Lev-Ari, PhD, RN

AWARD LECTURE

Tue., Oct. 9, 2018
4:00 PM
Shapiro Campus Center Theater
Brandeis University

CURRENT WINNER

lorenzstuder.jpgLORENZ STUDER

MACARTHUR FELLOWS PROGRAM

Lorenz Studer

Stem Cell Biologist | Class of 2015

Pioneering a new method for large-scale generation of dopaminergic neurons that could provide one of the first treatments for Parkinson’s disease and prove the broader feasibility of stem cell–based therapies for other neurological disorders.

https://www.macfound.org/fellows/947/

118 publications on PubMed

https://www.ncbi.nlm.nih.gov/pubmed/?term=LORENZ+STUDER

 

PRESIDING

Dagmar Ringe Professor of Biochemistry, Chemistry and Rosenstiel Basic Medical Sciences Research Center

WELCOME

Lisa Lynch Provost and Maurice B. Hexter Professor of Social and Economic Policy Brandeis University

 

RESPONSE Lorenz Studer, MD Director, Center for Stem Cell Biology Memorial Sloan Kettering Cancer Center Member, Developmental Biology Program Memorial Sloan Kettering Cancer Center

Fully defined protocol for all ectodermal lineage

  • Nervous system: Forebrain, Midbrain, Spinal cord:
  • CNS lineage to PNS Lineage
  • Excitatory cortical neurons
  • cortical interneurons Astrocytes
  • microglia
  • Age-reset disease – late-onset during reprogramming – Is age reversible?
  • Loss of age-related markers
  • iPSC-derived cells yield stage cell upon differentiation
  • In vitro differentiation techniques: 2D Directed Differentiation 3D- Organoids
  • Graded MORPHOGEN SIGNALING
  • DOXYCYLINE: ISHH-ORGANIZER – 5 discrete forebrain regions
  • Building Human brain cells in 2D and in 3D
  • Organized cells –>>>  directed organoids –>> Organized Organoids
  • Parkinson, 1817 – Essay on Shaky Palsy (Niagrostaterial pathway)
  • Genetics and related dysfunction: affecting PD
  • Charckot, 1889
  • PD – new approach following drugs and deep brain stimulation failure in advanced disease: Fetal tissue transplant trials: Fetal Grafting
  • graft-induced dyskinesia
  • Long term, 15 years positive effects
  • Stem-cell-based regenerative therapy could transform PD therapy
  • 1995  Fetal DA neuron grafting for PD in Switzerland
  • 1998 – midbrain stem cell derived DA neuron
  • 200-2003 – Stem cell in brain implantation in WashDC
  • 2011 – Behavioral assays that are restored in mice
  • Optogenetics: manipulating – Light on the brain – control animal’s neurons
  • MOA of Graft function
  • Dopamine neurons – Stratium area of the human brain
  • From bench to bedside – WNT boost enhances EN1 expression
  • Neuron melanin induction
  • Manufacturing and QA testing: GMP – Off the shelf Allogenic Product
  • 1,000 human dose equivalents
  • cryopreserve
  • MSK-DA01 is highly enriched for mDA neuron precursors without detectable hESC Contaminants
  • FDA feedback and final steps to IND – PRE-IND MEETING: 2014, 2016
  • GLP STUDIES:
  • TUMORIGENICITY, BIODISTRIBUTION AND TOXISITY
  • HISTOLOGY OF FINAL PRODUCT
  • CLINICAL TRIAL DESIGN – STEM-PD – MSK and Weill Cornell Medicine
  • HLA expression is absent in edited iPSC with expression of HLA-E to block NK clearance
  • FUTURE: CRISPR
  • ATLaS-PD – assessing the longitudinal Symptoms/signs to moderate of severe stage
  • Development of a new PD therapy from Pluripotent Stem Cells
  • BlueRock Therapeutics – MSK-PD – Start up – $240Million funding
  • Stem cell based dopamine therapy for PD
  • Immunosuppression for 12 months
  • defined levodopa response > 45% improvement
  • Conclusions
  • Cell banks for clinical trials
  • NY state Stem cell science consortia

http://www.brandeis.edu/rosenstiel/images/pdfs/gabbay21program.pdf

Read Full Post »