Chinese Scientists to Pioneer First Human CRISPR Clinical Trial

  • Chinese Team Begins First CRISPR-Based Anticancer Immunotherapy Clinical Study
  • US Consortium’s CRISPR Clinical Study OK’d by NIH Panel
  • Survey Indicates More Worry than Enthusiasm for Gene-Editing in Babies
Taken from jeantet.ch

Taken from jeantet.ch

Regular readers of my blog will recall a number of previous postings on gene editing using CRISPR-Cas9 (aka CRISPR), which has rapidly become the hottest trend in nucleic acid-based biotechnology and medical research. That opinion is partly based on the fact that this relatively new technology has already amassed thousands of publications, including 1,250 in 2015 alone! Additional evidence follows from the numerous start-up and established biopharma companies pursuing CRISPR-based therapeutics, which is “the biggest biotech discovery of the century” according to one report.

Now, even more exciting developments for CRISPR are on the horizon. Chinese researchers are poised for the first human clinical trial using CRISPR, and an analogous study in the US awaiting FDA approval. Both of these trials involve forms of cancer immunotherapy, which is a very hot field in itself, and is briefly introduced in the next section.

Cancer Immunotherapy

Cancer immunotherapy is the use of the immune system to treat cancer either actively, passively, or by a combination of these approaches, which exploit the fact that cancer cells often have macromolecules on their surface that can be detected by the immune system (aka tumor-associated antigens, TAAs). Active immunotherapy directs the immune system to attack tumor cells by targeting TAAs, whereas passive immunotherapies enhance existing anti-tumor responses and include the use of monoclonal antibodies, lymphocytes and cytokines.

Numerous antibody therapies have been approved by the FDA and other regulatory authorities worldwide. In contrast, active immunotherapies, which usually involve the removal of immune cells from the blood or from a tumor for reintroduction to the patient, have lagged in such approvals. In fact, the only US-approved cell-based therapy is Dendreon’s Provenge®, for the treatment of prostate cancer. A recent series of NY Times articles highlights some powerful examples of cancer immunotherapy, especially from the perspective of interviews with patients and their physicians.

Taken from howitworksdaily.com

Taken from howitworksdaily.com

For the purpose of this blog, I’ll add that adoptive T-cell therapy is a form of passive immunization by the transfusion of T-cells, which are found in blood and tissue and usually activate when they find “foreign” pathogens. These pathogens can be either infected cells, or antigen presenting cells present in tumor tissue, where they are known as tumor infiltrating lymphocytes. Although these cells can attack the tumor, the environment within the tumor is highly immunosuppressive, preventing immune-mediated tumor death.

As depicted below, T-cells specific to a tumor antigen can be removed from a tumor sample or filtered from blood. Subsequent activation and culturing is performed ex vivo, with the resultant cells being reinfused. Importantly, activation can take place through genetic engineering, such as gene editing by CRISPR.

Cancer specific T-cells can be obtained by fragmentation and isolation of tumor infiltrating lymphocytes, or by genetically engineering cells from peripheral blood. The cells are activated and grown prior to transfusion into the recipient (tumor bearer). Taken from Wikipedia.org

Cancer specific T-cells can be obtained by fragmentation and isolation of tumor infiltrating lymphocytes, or by genetically engineering cells from peripheral blood. The cells are activated and grown prior to transfusion into the recipient (tumor bearer). Taken from Wikipedia.org

CRISPR Goes Clinical in China

As I write this post, Chinese scientists at Sichuan University’s West China Hospital in Chengdu will reportedly become the first in the world to inject people with cells modified using the CRISPR gene-editing method. This landmark trial will involve patients with metastatic non-small cell lung cancer who have not responded to chemotherapy, radiation therapy and/or other treatments.

The team will extract T cells from the blood of the trial participants and then use CRISPR to knock out a gene encoding a protein called PD-1 that normally regulates the T cell’s immune response to prevent it from attacking healthy cells. As depicted below, this so-called checkpoint has been targeted by small molecule inhibitors (anti PD-1), but with somewhat limited success so far—notably including failure of a would-be billion-dollar drug (Opdivo®) recently reported by Bristol-Myers Squibb. Nevertheless, the presently envisaged PD-1 gene-edited cells will be amplified in the lab and re-introduced into the patient’s bloodstream to circulate and, hopefully, attack the cancer.

Taken from smartpatients.com

Taken from smartpatients.com

Potential Concerns of CRISPR Clinical Trials

While the Chinese trial may be groundbreaking, it is not without risk. There is concern that the edited T-cells could attack normal tissue as it’s well documented that CRISPR can result in gene edits at the wrong place in the genome. To help mediate this risk, the T-cells will be validated by biotechnology company MedGenCell—a collaborator on the trial—to ensure that the correct gene is knocked out before the cells are re-introduced into patients.  Since the primary purpose of this phase one trial is to determine if the approach is safe, participants will be closely monitored for side effects, and researchers will pay close attention to biological markers in the blood.

Some may say that this type of trial in humans is premature, but China has always tried to be a leader in CRISPR research. Carl June, a clinical researcher in immunotherapy at the University of Pennsylvania in Philadelphia explains, ‘China places a high priority on biomedical research.’ And Tetsuya Ishii, a bioethicist in Japan, is quoted in Nature magazine as saying that ‘When it comes to gene editing, China goes first.”

Initial CRISPR Clinical Trial in USA Awaiting Review Board and FDA Approvals

While the Chinese team seems positioned to be the first to conduct a CRISPR clinical trial, the US isn’t far behind. As reported earlier this summer, the Recombinant DNA Research Advisory Committee (RAC) at the NIH has approved an analogous—but genetically more complex—proposal to use CRISPR-edited T cells for cancer immunotherapy. The RAC reviews all proposals for human trials involving modified DNA that are conducted in the United States, and the investigators now have to convince review boards at their own institutions, and the FDA, to allow the trial. This will hopefully be done by the end of 2016.

The proposed trial is a collaborative effort involving the University of Pennsylvania, M.D. Anderson Cancer Center in Texas, and the University of California, San Francisco. This trial will be funded by a $250-million immunotherapy foundation formed in April 2016 by former Facebook president Sean Parker. According to a news item in Nature, The University of Pennsylvania will produce the edited cells, and will recruit and treat patients alongside the collaborating medical centers in Texas and California.

In this study, researchers will perform three CRISPR edits with T cells from patients with several types of cancers: 1. a gene for a protein engineered to detect and target cancer cells will be inserted, 2. a natural T-cell protein that could interfere with this process will be removed and 3. the gene for a protein that identifies the T cells as immune cells and prevents the cancer cells from disabling them will be removed. The researchers will then infuse the edited cells back into the patient.

Both of the studies being performed by the Chinese and US teams are very exciting to me. I will be paying close attention to the progress of these studies over the next few months and hope to report back to you with some very interesting and ground breaking results.

Survey Indicates Public Concern in the US About Gene Editing in Babies

A Pew Research Center pole focusing on concerns about gene editing was recently reported in Nature. The poll surveyed more than 4,700 people in the United States and the results indicate that more people are concerned than enthusiastic about gene editing.

The quadrants below (from 0-100%) show responses to the question, “How worried or enthusiastic do you feel about gene editing to reduce disease risk in babies?”

Taken from nature.com

Taken from nature.com

While these findings speak for themselves, I hasten to add that this same pole also asked “Have you heard or read about this topic?” The following replies (in quadrants from 0-100%) indicate that a substantial percentage of respondents who have not at all read about gene editing nevertheless expressed either worry or enthusiasm for gene editing. Ditto for those who read a little about gene editing.

babies

It would seem, then, that we should take this poll with a grain (or two) of salt as it apparently includes a substantial amount of uninformed opinion. This is not too surprising given the complex nature of gene editing and it’s relatively new position in research. We can see from the results of this poll that a significant amount of education may be needed to garner increased public support for gene editing. Hopefully, the results of the studies highlighted above will begin to pave this road.

Hope for the Best but Expect Complications

This section heading, which summarizes my parting comments about the advent of CRISPR-enabled clinical trials, is based upon my having participated in several decades of research on nucleic acid-based concepts for radically different approaches to traditional small-molecule therapeutics. First was the idea of using chemically modified antisense oligonucleotides to block gene expression, which encountered non-specificity issues, low potency, delivery, and a host of other issues that took two decades to sort through. Then there was the idea of using chemically modified short-interfering RNA (siRNA) for modulating gene expression via RNA interference (RNAi). This, too, encountered similar problems in reaching the clinic. Ditto for anti-microRNAs (antagomirs).

I’m hoping that CRISPR-based therapies meet with success far faster—and prove to be affordable to society. I won’t, however, be surprised if progress is slow—and quite expensive.

Are you excited about potential CRISPR-based therapies? Do you have concerns about their safety and efficacy? Do you believe the general public is ready to accept gene editing therapies? Please share your thoughts as your comments are always welcome.

DIY CRISPR Kit – Door to Democratization or Disaster?

  • Gene Editing with CRISPR is All the “Buzz”
  • Low-Cost CRISPR Kit Being Sold to DIY “Biohackers”
  • What is the Balance Between Democratization and Preventing Disaster?

The dictionary definition of democratization is the transition to a more democratic political regime. Since democracy emphasizes the role of individuals in society, democratization is generally perceived to be good. This political concept of democratization is being increasingly morphed, if you will, to describe the transition of science and technology from trained specialists in traditional labs to any individual, anywhere—including someone’s kitchen table.

Taken from oocities.org

Taken from oocities.org

Lest you get the impression I’m an elitist, and not in favor of fostering better understanding—and appreciation—of science by non-scientists everywhere, I definitely am not. I want the value of science to be widely appreciated. Even if I weren’t of that opinion, democratization of science and technology is already evident in this exemplary cartoon indicating how DNA is now familiar to virtually everyone. But I digress…

Taken from diy-bio.com

From diy-bio.com

It is evident that molecular biology has also undergone democratization based on emergence of so-called “do it yourself” (DIY) advocates of biology (DIY-BIO), which on the surface seems like a good thing. But, as I’ll expand upon below, DIY-BIO has morphed in a way which has elevated concerns that a well-intentioned DIY aficionado anywhere can now access genetically powerful CRISPR reagents that might inadvertently unleash a harmful home-made organism.

CRISPR Basics

First off, I should note that gene editing by CRISPR—thankfully short for “clustered regularly-interspaced short palindromic repeats”—actually involves another component named Cas9—short for CRISPR associated protein 9. Cas9 is an enzyme that recognizes single guide RNA (sgRNA) hybridized to one strand of specifically targeted DNA via the 5’end of sgRNA, as depicted in green in the mechanism below. The remaining sgRNA has a double-stranded “stem” (black, red) and loop (purple) internal structure, and a 3’ end with several stem-loop structures (red).

Taken from jeantet.ch

Taken from jeantet.ch

The scissors indicate Cas9 cutting both strands of DNA, which thus allows for insertion of so-called donor DNA and, consequently, enabling a variety of genetic manipulations in plants, bacteria, human or animal cells. Chemically synthesized sgRNA that target any gene of interest can be readily designed for purchase, along with Cas9 in the form of biosynthetic Cas9 mRNA encoding this necessary protein component.

CRISPR’s importance as an emerging, useful tool for gene editing is evident from the number of publications in PubMed that have approximately doubled each year since the seminal to give an estimated 2,500 publications indexed to CRISPR as a search term. Unfortunately (but perhaps not surprisingly given the billion-dollar implications), there is an ongoing dispute over inventorship involving the Broad Institute (see Feng Zhang patent), the University of California, and the University of Vienna.

Biohacker Promotes DIY CRISPR Kit

Josiah Zayner (Taken from http://www.ifyoudontknownowyaknow.com)

Josiah Zayner (Taken from http://www.ifyoudontknownowyaknow.com)

As mentioned in the introduction, self-proclaimed “biohackers” who are avid fans and practitioners of DIY molecular biology, have been busily “doing their thing” for some time now without much cautionary publicity. That’s changing, however, as a result of the advent of CRISPR together with relatively easy access to its sgRNA and Cas9 reagents. One case in point involves Josiah Zayner, who has a PhD from the Department of Biochemistry and Molecular Biophysics at the University of Chicago and now lives in the San Francisco Bay Area.

Zayner’s online biographical sketch states that he is “very active in Biohacking and DIY Science and run[s] an online Biohacking supply store The ODIN.” By visiting the website for The ODIN, which reportedly raised $65,000 by crowdfunding online via Indiegogo, you’ll find various items for conducting molecular biology experiments, along with an “about” page stating that “smaller groups of people, small labs or even DIY Scientists on their own can do amazing things if they have access to resources that are normally only available to large heavily funded labs and companies.”

While this seems all fine and good is some ways, the item offered by The ODIN that has led to controversy is the first-ever DIY kit for CRISPR. This, according to an article in The Mercury News, “raises the specter—deeply troubling to some experts—of a day when dangerous gene editing is conducted far from the eyes of government regulators, posing risk to the environment or human health”.

The article goes on to quote one expert who said The ODIN kit is sold for manipulating yeast and could never be used to alter human genes, while another expert cautioned that the kit can teach basic principles to do so with appropriate modifications. Another problem is inadvertent conversion of yeast into a harmful microorganism that might be accidentally spread.

Taken from mercurynews.com

Taken from mercurynews.com

While I share these concerns, it will be virtually impossible to prevent individuals or small groups intent on nefarious activities using CRISPR technology. On the other hand, I have to admit that I would be very concerned if I were living next door or otherwise nearby Josiah if he is indeed practicing what he’s preaching, so to speak, using CRISPR in his kitchen as pictured right.

CRISPRized Plants, Too

If you think that DIY is a passing fad with few devotees, think again. Aside from the main DIY-BIO website that you can peruse, a recent online article in Fusion talks about a couple of DIY enthusiasts doing things that make the hairs on my neck stand up, as the saying goes. For instance, David Ishee, a 30-year-old Mississippi resident who never attended college, does at-home experiments in his shed using online kits for growing plants, but will now use CRISPR to carry out gene editing.

Ishee reportedly will use software like DeskGen that advertises its “on-demand CRISPR libraries” for gene editing, and is quoted as saying “That gives me a lot of new options. Up until now, all the genetic edits I’ve made have been limited to plasmids and unguided genomic insertions. That limits the kinds of cells I can work with and the types of work I can do.”

So what will Ishee do? The answer is that nobody but he knows. If his genetically edited plants grow and seeds get carried by the wind, they could someday end up in your backyard. What then? Who knows? Could be creepy.

Possibly harmful, irreversible consequences of completely democratized CRISPR are completely unknown. Therein lies the essence of the problem that has many experts quite concerned, as reported in Fusion. I share that concern.

Parting Shot

In closing this brief story about DIY synthetic biology using CRISPR, I must say that I wish journalists writing for newspapers and other media would stick to news that is factual and not interpreted for commentary that is flat out wrong or intentionally provocative. My case in point is the following big font, bold letters headline:

“Finally, your chance to play God!”

This was used by time.com to recycle the aforementioned piece by The Mercury News. Shame on time.com for this misleading and totally wrong exclamation. But I digress…

I would greatly appreciate knowing your thoughts about DIY CRISPR by sharing them here as comments.

Zon on Zon’s Zebrafish

  • Leonard Zon Uses Zebrafish to “Fish” for Candidate Drug Compounds
  • Two Candidate Drugs are in Clinical Trials for Cancer Treatments
  • Zon Interviews L. Zon
Leonard I. Zon, M.D. Taken from pediatrics.mc.vanderbilt.edu.

Leonard I. Zon, M.D. Taken from pediatrics.mc.vanderbilt.edu.

The first time I was asked if I was related to the scientist Leonard Zon, I honestly had to reply that I didn’t know, and out of curiosity later looked up his publications, which were quite numerous for a then newish investigator. His current biosketch expertise includes pioneering research in the new fields of stem cell biology and cancer genetics. Dr. Leonard I. Zon is the Grousbeck Professor of Pediatric Medicine at Harvard Medical School, an Investigator with the Howard Hughes Medical Institute, and Director of the Stem Cell Program at Children’s Hospital Boston—that’s impressive!

I found Leonard Zon’s unusual zebrafish-based research and accomplishments therefrom definitely blogworthy, and the coincidences of both our surnames and involvement in science are kind of an unusual “double-doppelgänger,” if you will. In any case, it’s always a surprise to meet your double, even if only in name and profession.

A few regular readers of my blog will likely smile and think that Zon on Zon’s Zebrafish is yet another instance of my penchant for alliteration. However, reading the following snippets about Leonard Zon’s clever—dare I say zany—use of zebrafish for his research will illustrate why they are unusual, interesting and commercially viable.

On the other hand, I must admit that I too smiled at the thought of this unique opportunity to post an interview of one Zon by another Zon, which reminded me a bit of Zappa Plays Zappa. But I digress…

Zebrafish as a Model for Organogenesis

Leonard Zon currently has nearly 250 research publications listed in PubMed, which is a large number by any measure, but that’s even more impressive when you take into account that his first was in 2002—only 14 years ago. That translates to an average of about 3 publications every 2 months each year!

Zon’s inaugural publication in 2002 was an in-depth review in venerable Science in which the abstract presciently reads in part as follows:

Organs are specialized tissues used for enhanced physiology and environmental adaptation. The cells of the embryo are genetically programmed to establish organ form and function through conserved developmental modules. The zebrafish is a powerful model system that is poised to contribute to our basic understanding of vertebrate organogenesis. This review develops the theme of modules and illustrates how zebrafish have been particularly useful for understanding heart and blood formation.

As will be elaborated below, Zon’s most recent publication in 2016—also in Science—has extended the zebrafish model to now include melanoma. If you’re asking yourself, why use zebrafish, the answer is partly due to convenience derived from the unique features and accelerated life cycle of zebrafish.

Zebrafish life cycle. Taken from en.wikipedia.com.

Zebrafish life cycle. Taken from en.wikipedia.com.

Seen right, these advantages include its small size, easy care, and rapid generation time. In addition—and very importantly—the embryos and growing zebrafish are transparent, allowing for continuous observation of developing organs under the light microscope.

Mutagenesis screens allow examination of defects in early organogenesis and late organ function. These many advantages of investigating zebrafish—and Zon’s huge facility comprising thousands of tanks—are nicely explained and shown in a video, which I found well worth viewing. The video also includes Zon’s specially bred, virtually transparent species of zebrafish named—humorously—Casper, after Casper the Friendly Ghost. Pictures below are (a) the transparent Casper zebrafish; (b) the non-transparent wild-type zebrafish; and transparent Casper the Friendly Ghost, which brings back my childhood memories. But again I digress…let’s get back to science!

(a) Casper, (b) wild type zebrafish. Taken from nature.com. Transparent Casper the Friendly Ghost. Taken from enchantedamerica.wordpress.com

(a) Casper, (b) wild type zebrafish. Taken from nature.com. Transparent Casper the Friendly Ghost. Taken from enchantedamerica.wordpress.com

Aided by the availability of DNA sequence information for the zebrafish genome, researchers have published ~2,000 (!) reports dealing with antisense gene “knockdown” using phosphorodiamidate oligonucleotides. By numerical coincidence, the first such report appeared in 2000, and was prophetically entitled Effective targeted gene ‘knockdown’ in zebrafish.

Taken from igtrcn.org.

Taken from igtrcn.org.

As shown below, these rather unusual oligonucleotides—dubbed “morpholinos” by resemblance of the 6-membered ring to morpholine—can be injected directly into zebrafish embryos. Interested readers can consult a detailed “how to” guide on use of morpholinos in zebrafish.

Going forward, however, I expect that uber-hot CRSPR/Cas9 gene editing will be widely adopted, based on the titles of these two pioneering publications in 2016:

Stem Cells and Beyond

Now that we know a bit about Zon’s zebrafish and how to knockdown or edit a gene for functional genomics (aka “gene functionation”), let’s zero in on what Zon studies and how he does that. In a nutshell, the overarching science in Zon’s lab deals with stem cells, which are undifferentiated cells that can differentiate into specialized cells, as well as divide to produce more stem cells, as depicted below.

Taken from nas-sites.org.

Taken from nas-sites.org.

According to Zon’s website, the hematopoietic system that forms various types of blood cells is an excellent model for understanding tissue stem cells. This conceptual relationship is very important because it provides insight to cell differentiation regulation, and involvement in aging, disease, and oncogenesis. In addition, better understandings of the regulation of hematopoietic stem cell biology and lineage differentiation improves diagnosis and treatment of human hematopoietic disorders (aka “blood cancers”) and bone marrow transplantation therapies.

Differentiation of different blood cells from hematopoietic stem cell to mature cells. Taken from wikipwedia.com.

Differentiation of different blood cells from hematopoietic stem cell to mature cells. Taken from wikipwedia.com.

From Zebrafish to Clinic

Scientific theory is nice, but success is best, and Leonard Zon’s theory of using zebrafish to manipulate human stem cells for discovering therapies seems indeed to be headed for success, according to an article in the Harvard Gazette.

Zon and others at the Harvard Stem Cell Institute (HSCI) have published initial results of a Phase Ib safety study wherein 12 adult patients undergoing umbilical cord blood transplantation received two umbilical cord blood units, one untreated and the other treated with the small molecule 16,16-dimethyl prostaglandin E2 (dmPGE2). This molecule had been found in Zon’s zebrafish screen, which I’ll outline below.

Fate Therapeutics, a San Diego-based biopharmaceutical company of which Zon is a co-founder, sponsored the investigational new drug (IND) application, under which the aforementioned clinical program was conducted, thus translating his research findings from the laboratory—dare I say tank—into the clinic.

Zon’s Zebrafish Yield New Approaches to Treat Muscular Dystrophies

According to NIH’s National Institute of Neurological Disorders and Stroke website, muscular dystrophies (MD) are a group of more than 30 genetic diseases characterized by progressive weakness and degeneration of the skeletal muscles that control movement. It adds that there is no specific treatment to stop or reverse any form of MD. Consequently, MD is a compelling target for new drug discovery, and Zon’s zebrafish are being used for such discovery in the following way.

Each zebrafish produces about 200 (!) eggs per week, so Zon’s lab collects and deposits a single egg into each well of a multi-well plate for individual but parallelized treatment with individual chemicals to screen for effects on differentiation, thus screening many compounds in a speedy manner.

Zon and coworkers concluded that “these studies reveal functionally conserved pathways regulating myogenesis across species [zebrafish, mouse, and human] and identify chemical compounds that…differentiate human iPSCs into engraftable muscle.”

Let’s hope that human clinical trials using this novel therapeutic approach enabled by Zon’s zebrafish soon prove successful for treatment of MD.

Zon’s Zebrafish Also Enable Elucidation of Melanoma Development

According to a fact page by the American Cancer Society, skin cancer is the most common of all cancers. About 3.5 million cases of basal and squamous cell skin cancer are diagnosed in this country each year. Melanoma, a more dangerous type of skin cancer, will account for more than 73,000 cases of skin cancer in 2015.

Zon and a large group of 18 coworkers have recently reported in venerable Science work that has been heralded in a New York Times article. This study is very comprehensive and involves lots of “heavy duty” molecular and cellular biology, which you can read in detail in the aforementioned linked article. Snippets of the key findings are as follows.

  • Benign melanocytic skin cells carry oncogenic BRAF-V600E mutations and can be considered a “cancerized” field of melanocytes, but they rarely convert to melanoma.
  • In an effort to define events that initiate cancer, they used a melanoma model in the zebrafish in which the human BRAF-V600E oncogene is driven by the melanocyte-specific mitfa
  • When bred into a p53 mutant background, these fish develop melanoma tumors over the course of many months.
  • The zebrafish crestin gene is expressed embryonically in neural crest progenitors (NCPs) and is specifically reexpressed only in melanoma tumors, making it an ideal candidate for tracking melanoma from initiation onward.
  • As show below, they developed a crestin:EGFP reporter that recapitulates the embryonic neural crest expression pattern of crestin and its expression in melanoma tumors.
  • They show through live imaging of transgenic zebrafish crestin reporters that within a cancerized field (BRAFV600E-mutant; p53-deficient), a single melanocyte reactivates the NCP state, and this establishes that a fate change occurs at melanoma initiation in this model.
Taken from Zon and coworkers Science 2016.

Taken from Zon and coworkers Science 2016.

Zon Interviews L. Zon

Dr. Zon and some of his 4,000 zebrafish tanks. Taken from bizjournals.com.

Dr. Zon and some of his 4,000 zebrafish tanks. Taken from bizjournals.com.

After researching Leonard Zon’s aforementioned unique—and promising—use of zebrafish to advance basic science and discover new therapies, I contacted him by email to “interview” him, regarding several points. My questions (JZ) and his answers (LZ) are as follows.

JZ: Aside from the cord blood clinical trial mentioned in the Harvard Gazette, are any other human clinical trials being carried out based on your zebrafish findings?

LZ: We have had two chemicals discovered in zebrafish, and ultimately went to a clinical trial. The first was a di-methyl form of PGE2 for cord blood transplantation for leukemia. The second was leflunomide, an arthritis drug that paused transcription in neural crest cells and is being evaluated for metastatic melanoma.

JZ: Is Fate Therapeutics your only startup company?

LZ: I started Scholar Rock about 3 years ago. This company is targeting the TGF-B family of ligands. Has about 25 employees, and is in Cambridge. I am about to start a third company.

JZ: Is your zebrafish method for screening chemicals patented?

LZ: We have patents on several screening methods, but in general we patent the chemicals we find.

JZ: Zebrafish offer many reported advantages for your kind of research, but what is a primary disadvantage?

LZ: The major disadvantage of the zebrafish is that the system occasionally lacks definition. For instance, in the blood system, we have one monoclonal antibody against one epitope. We really need to create reagents for the field that brings it in line with other systems such as mice and humans.

JZ: How many tanks and zebrafish are maintained in your two labs?

LZ: We have 4000 tanks and about 300,000 fish.

JZ: Did you name your transparent Casper zebrafish after Casper the Friendly Ghost?

LZ: Absolutely.

In closing, I should add that the huge amount of information on zebrafish as a model organism for human disease and drug discovery from many labs has been centralized and organized in a database that is available through The Zebrafish Information Network (ZFIN) for researchers to share at the ZFIN Community Wiki.

I hope that you found this blog interesting, and I welcome your comments.

Joe Zon with some of his famous guitars at NAMM Show 2015. Taken from ilan.me.

Joe Zon with some of his famous guitars at NAMM Show 2015. Taken from ilan.me.

Postscript

Truth be told, compared to being asked if I’m related to Leonard Zon, I’m more frequently asked if I’m related to Zon guitars, which apparently are quite well known, and are produced in Redwood City, CA by Joe Zon, who is pictured below. My reply to that frequent question is that I don’t know if I’m related, but will someday look into that, as well as whether I’m distantly related to Leonard Zon.