Gene therapy gives patient a cure and a new lease on life

Brenden Whittaker (left), of Ohio, is a patient born with a rare genetic immune disease who was treated at the Dana-Farber/Boston Children’s Cancer and Blood Disorders Center in a CIRM funded gene therapy trial. Dr. David Williams (on right) is Brenden’s treating physician.
Photo courtesy of Rose Lincoln – Harvard Staff Photographer

Pursuing an education can be quite the challenge in itself without the added pressure of external factors. For Brenden Whittaker, a 25 year old from Ohio, the constant trips to the hospital and debilitating nature of an inherited genetic disease made this goal particularly challenging and, for most of his life, out of sight.

Brenden was born with chronic granulomatous disease (CGD), a rare genetic disorder that affects the proper function of neutrophils, a type of white blood cell that is an essential part of the body’s immune system. This leads to recurring bacterial and fungal infections and the formation of granulomas, which are clumps of infected tissue that arise as the body attempts to isolate infections it cannot combat. People with CGD are often hospitalized routinely and the granulomas themselves can obstruct digestive pathways and other pathways in the body. Antibiotics are used in an attempt to prevent infections from occurring, but eventually patients stop responding to them. One in two people with CGD do not live past the age of 40.

In Brenden’s case, when the antibiotics he relied on started failing, the doctors had to resort to surgery to cut out an infected lobe of his liver and half his right lung. Although the surgery was successful, it would only be a matter of time before a vital organ was infected and surgery would no longer be an option.

This ultimately lead to Brenden becoming the first patient in a CGD gene therapy trial at the Dana-Farber/Boston Children’s Cancer and Blood Disorders Center.  The trial, lead by UCLA’s Dr. Don Kohn thanks to a CIRM grant, combats the disease by correcting the dysfunctional gene inside a patient’s blood stem cells. The patient’s corrected blood stem cells are then reintroduced, allowing the body to produce properly functioning neutrophils, rebooting the immune system.

It’s been a little over three years since Brenden received this treatment in late 2015, and the results have been remarkable. Dr. David Williams, Brenden’s treating physician, expected Brenden’s body to produce at least 10 percent of the functional neutrophils, enough so that Brenden’s immune system would provide protection similar to somebody without CGD. The results were over 50 percent, greatly exceeding expectations.

Brenden Whittaker mowing the lawn in the backyard of his home in Columbus, Ohio. He is able to do many more things without the fear of infection since participating in the trial. Photo courtesy of Colin McGuire

In an article published by The Harvard Gazette, Becky Whittaker, Brendan’s mother, is quoted as saying, ““Each day that he’s free of infection, he’s able to go to class, he’s able to work at his part-time job, he’s able to mess around playing with the dog or hanging out with friends…[this] is a day I truly don’t believe he would have had beyond 2015 had something not been done.”

In addition to the changes to his immune system, the gene therapy has reinvigorated Brenden’s drive for the future. Living with CGD had caused Brenden to miss out on much of his schooling throughout the years, having to take constant pauses from his academics at a community college. Now, Brenden aims to graduate with an associate’s degree in health sciences in the spring and transfer to Ohio State in the fall for a bachelor’s degree program. In addition to this, Brenden now has dreams of attending medical school.

In The Harvard Gazette article, Brenden elaborates on why he wants to go to medical school saying, ” Just being the patient for so long, I want to give back. There are so many people who’ve been there for me — doctors, nurses who’ve been there for me [and] helped me for so long.”

In a press release dated February 25, 2019, Orchard Therapeutics, a biopharmaceutical company that is continuing the aforementioned approach for CGD, announced that six patients treated have shown adequate neutrophil function 12 months post treatment. Furthermore, these six patients no longer receive antibiotics related to CGD. Orchard Therapeutics also announced that they are in the process of designing a registrational trial for CGD.

Targeted treatment for pediatric brain tumors shows promising results

Image of medulloblastoma

Imagine sitting in the doctor’s office and being told the heartbreaking news that your child has been diagnosed with a malignant brain tumor. As one might expect, the doctor states that the most effective treatment option is typically a combination of chemotherapy and radiation. However, the doctor reveals that there are additional risks to take into account that apply to children. Since children’s tiny bodies are still growing and developing, chemotherapy and radiation can cause long-term side effects such as intellectual disabilities. As a parent, it is painful enough to have to watch a child go through chemotherapy and radiation without adding permanent damage into the fold.

Sadly, this scenario is not unique. Medulloblastoma is the most prevalent form of a pediatric brain tumor with more than 350 children diagnosed with cancer each year. There are four distinct subtypes of medulloblastoma, with the deadliest being known as Group 3.

Researchers at Sanford Burnham Prebys Medical Discovery Institute (SBP) are trying to minimize the collateral damage by finding personalized treatments that reduce side effects while remaining effective. Scientists at SBP are working with an inhibitor known as LSD1 that specifically targets Group 3 medulloblastoma in a mouse model. The study, published in Nature Communications, showed that the drug dramatically decreased the size of tumors grown under the mouse’s skin by shrinking the cancer by more than 80 percent. This suggested that it could also be effective against patients’ tumors if it could be delivered to the brain. The LSD1 inhibitor has shown promise in clinical trials, where it has been tested for treating other types of cancer.

According to Robert Wechsler-Reya, Ph.D., senior author of the paper and director of the Tumor Initiation and Maintenance Program at SBP: “Our lab is working to understand the genetic pathways that drive medulloblastoma so we can find better ways to intervene and treat tumors. This study shows that a personalized treatment based upon a patient’s specific tumor type might be within our reach.”

Dr. Wechsler-Reya’s work on medulloblastoma was, in part, funded by the CIRM (LA1-01747) in the form of a Research Leadership Award for $5,226,049.

Budgeting for the future of the stem cell agency

ICOC_DEC17-24

The CIRM Board discusses the future of the Stem Cell Agency

Budgets are very rarely exciting things; but they are important. For example, it’s useful for a family to know when they go shopping exactly how much money they have so they know how much they can afford to spend. Stem cell agencies face the same constraints; you can’t spend more than you have. Last week the CIRM Board looked at what we have in the bank, and set us on a course to be able to do as many of the things we want to, with the money we have left.

First some context. Last year CIRM spent a shade over $306 million on a wide range of research from Discovery, the earliest stage, through Translational and into Clinical trials. We estimate that is going to leave us with approximately $335 million to spend in the coming years.

A couple of years ago our Board approved a 5 year Strategic Plan that laid out some pretty ambitious goals for us to achieve – such as funding 50 new clinical trials. At the time, that many clinical trials definitely felt like a stretch and we questioned if it would be possible. We’re proving that it is. In just two years we have funded 26 new clinical trials, so we are halfway to our goal, which is terrific. But it also means we are in danger of using up all our money faster than anticipated, and not having the time to meet all our goals.

Doing the math

So, for the last couple of months our Leadership Team has been crunching the numbers and looking for ways to use the money in the most effective and efficient way. Last week they presented their plan to the Board.

It boiled down to a few options.

  • Keep funding at the current rate and run out of money by 2019
  • Limit funding just to clinical trials, which would mean we could hit our 50 clinical trial goal by 2020 but would not have enough to fund Discovery and Translational level research
  • Place caps on how much we fund each clinical trial, enabling us to fund more clinical trials while having enough left over for Discovery and Translational awards

The Board went for the third option for some good reasons. The plan is consistent with the goals laid out in our Strategic Plan and it supports Discovery and Translational research, which are important elements in our drive to develop new therapies for patients.

Finding the right size cap

Here’s a look at the size of the caps on clinical trial funding. You’ll see that in the case of late stage pre-clinical work and Phase 1 clinical trials, the caps are still larger than the average amount we funded those stages last year. For Phase 2 the cap is almost the same as the average. For Phase 3 the cap is half the amount from last year, but we think at this stage Phase 3 trials should be better able to attract funding from other sources, such as industry or private investors.

cap awards

Another important reason why the Board chose option three – and here you’ll have to forgive me for being rather selfish – is that it means the Administration Budget (which pays the salaries of the CIRM team, including yours truly) will be enough to cover the cost of running this research plan until 2020.

The bottom line is that for 2018 we’ll be able to spend $130 million on clinical stage research, $30 million for Translational stage, and $10 million for Discovery. The impact the new funding caps will have on clinical stage projects is likely to be small (you can see the whole presentation and details of our plan here) but the freedom it gives us to support the broad range of our work is huge.

And here is where to go if you are interested in seeing the different funding opportunities at CIRM.

Helping patient’s fight back against deadliest form of skin cancer

Caladrius Biosciences has been funded by CIRM to conduct a Phase 3 clinical trial to treat the most severe form of skin cancer: metastatic melanoma. Metastatic melanoma is a disease with no effective treatment, only around 15 percent of people with it survive five years, and every year it claims an estimated 10,000 lives in the U.S.

The CIRM/Caladrius Clinical Advisory Panel meets to chart future of clinical trial

The CIRM/Caladrius Clinical Advisory Panel meets to chart future of clinical trial

The Caladrius team has developed an innovative cancer treatment that is designed to target the cells responsible for tumor growth and spread. These are called cancer stem cells or tumor-initiating cells. Cancer stem cells can spread in the body because they have the ability to evade the body’s immune defense and survive standard anti-cancer treatments such as chemotherapy. The aim of the Caladrius treatment is to train the body’s immune system to recognize the cancer stem cells and attack them.

Attacking the cancer

The treatment process involves taking a sample of a patient’s own tumor and, in a laboratory, isolating specific cells responsible for tumor growth . Cells from the patient’s blood, called “peripheral blood monocytes,” are also collected. The mononucleocytes are responsible for helping the body’s immune system fight disease. The tumor and blood cells (after maturation into dendritic cells) are then combined and incubated so that the patient’s immune cells become trained to recognize the cancer cells.

After the incubation period, the patient’s immune cells are injected back into their body where they generate an immune response to the cancer cells. The treatment is like a vaccine because it trains the body’s immune system to recognize and rapidly attack the source of disease.

Recruiting the patients

Caladrius has already dosed the first patient in the trial (which is double blinded so no one knows if the patient got the therapy or a placebo) and hopes to recruit 250 patients altogether.

This is the first Phase 3 trial that CIRM has funded so we’re obviously excited about its potential to help people battling this deadly disease.  In a recent news release David J. Mazzo, the CEO of Caladrius echoed this excitement, with a sense of cautious optimism:

“The dosing of the first patient in this Phase 3 trial is an important milestone for our Company and the timing underscores our focus on this program and our commitment to impeccable trial execution. We are delighted by the enthusiasm and productivity of the team at Jefferson University (where the patient was dosed) and other trial sites around the country and look forward to translating that into optimized patient enrollment and a rapid completion of the Phase 3 trial.”

And that’s the key now. They have the science. They have the funding. Now they need the patients. That’s why we are all working together to help Caladrius recruit patients as quickly as possible. Because their work perfectly reflects our mission of accelerating the development of stem cell therapies for patients with unmet medical needs.

You can learn more about what the study involves and who is eligible by clicking here.

Cell mate: the man who makes stem cells for clinical trials

When we announced that one of the researchers we fund – Dr. Henry Klassen at the University of California, Irvine – has begun his clinical trial to treat the vision-destroying disease retinitis pigmentosa, we celebrated the excitement felt by the researchers and the hope from people with the disease.

But we missed out one group. The people who make the cells that are being used in the treatment. That’s like praising a champion racecar driver for their skill and expertise, and forgetting to mention the people who built the car they drive.

Prof. Gerhard Bauer

Prof. Gerhard Bauer

In this case the “car” was built by the Good Manufacturing Practice (GMP) team, led by Prof. Gerhard Bauer, at the University of California Davis (UC Davis).

Turns out that Gerhard and his team have been involved in more than just one clinical trial and that the work they do is helping shape stem cell research around the U.S. So we decided to get the story behind this work straight from the horse’s mouth (and if you want to know why that’s a particularly appropriate phrase to use here read this previous blog about the origins of GMP)

When did the GMP facility start, what made you decide this was needed at UC Davis?

Gerhard: In 2006 the leadership of the UC Davis School of Medicine decided that it would be important for UC Davis to have a large enough manufacturing facility for cellular and gene therapy products, as this would be the only larger academic GMP facility in Northern CA, creating an important resource for academia and also industry. So, we started planning the UC Davis Institute for Regenerative Cures and large GMP facility with a team of facility planners, architects and scientists, and by 2007 we had our designs ready and applied for the CIRM major facilities grant, one of the first big grants CIRM offered. We were awarded the grant and started construction in 2008. We opened the Institute and GMP facility in April of 2010.

How does it work? Do you have a number of different cell lines you can manufacture or do people come to you with cell lines they want in large numbers?

Gerhard: We perform client driven manufacturing, which means the clients tell us what they need manufactured. We will, in conjunction with the client, obtain the starting product, for instance cells that need to undergo a manufacturing process to become the final product. These cells can be primary cells or also cell lines. Cell lines may perhaps be available commercially, but often it is necessary to derive the primary cell product here in the GMP facility; this can, for instance, be done from whole donor bone marrow, from apheresis peripheral blood cells, from skin cells, etc.

How many cells would a typical – if there is such a thing – order request?

Gerhard: This depends on the application and can range from 1 million cells to several billions of cells. For instance, for an eye clinical trial using autologous (from the patient themselves) hematopoietic stem and progenitor cells, a small number, such as a million cells may be sufficient. For allogeneic (from an unrelated donor) cell banks that are required to treat many patients in a clinical trial, several billion cells would be needed. We therefore need to be able to immediately and adequately adjust to the required manufacturing scale.

Why can’t researchers just make their own cells in their own lab or company?

Gerhard: For clinical trial products, there are different, higher, standards than apply for just research laboratory products. There are federal regulations that guide the manufacturing of products used in clinical trials, in this special case, cellular products. In order to produce such products, Good Manufacturing Practice (GMP) rules and regulations, and guidelines laid down by both the Food and Drug Administration (FDA) and the United States Pharmacopeia need to be followed.

The goal is to manufacture a safe, potent and non-contaminated product that can be safely used in people. If researchers would like to use the cells or cell lines they developed in a clinical trial they have to go to a GMP manufacturer so these products can actually be used clinically. If, however, they have their own GMP facility they can make those products in house, provided of course they adhere to the rules and regulations for product manufacturing under GMP conditions.

Besides the UC Irvine retinitis pigmentosa trial now underway what other kinds of clinical trials have you supplied cells for?

Gerhard: A UC Davis sponsored clinical trial in collaboration with our Eye Center for the treatment of blindness (NCT01736059), which showed remarkable vision recovery in two out of the six patients who have been treated to date (Park et al., PMID:25491299, ), and also an industry sponsored clinical gene therapy trial for severe kidney disease. Besides cellular therapy products, we also manufacture clinical grade gene therapy vectors and specialty drug formulations.

For several years we have been supplying clinicians with a UC Davis GMP facility developed formulation of the neuroactive steroid “allopregnanolone” that was shown to act on resident neuronal stem cells. We saved several lives of patients with intractable seizures, and the formulation is also applied in clinical trials for the treatment of traumatic brain injury, Fragile X syndrome and Alzheimer’s disease.

What kinds of differences are you seeing in the industry, in the kinds of requests you get now compared to when you started?

Gerhard: In addition, gene therapy vector manufacturing and formulation work is really needed by several clients. One of the UC Davis specialties is “next generation” gene-modified mesenchymal stem cells, and we are contacted often to develop those products.

Where will we be in five years?

Gerhard: Most likely, some of the Phase I/II clinical trials (these are early stage clinical trials with, usually, relatively small numbers of patients involved) will have produced encouraging results, and product manufacturing will need to be scaled up to provide enough cellular products for Phase III clinical trials (much larger trials with many more people) and later for a product that can be licensed and marketed.

We are already working with companies that anticipate such scale up work and transitioning into manufacturing for marketing; we are planning this upcoming process with them. We also believe that certain cellular products will replace currently available standard medical treatments as they may turn out to produce superior results.

What does the public not know about the work you do that you think they should know?

Gerhard: The public should know that UC Davis has the largest academic Good Manufacturing Practice Facility in Northern California, that its design was well received by the FDA, that we are manufacturing a wide variety of products – currently about 16 – that we are capable of manufacturing several products at one time without interfering with each other, and that we are happy to work with clients from both academia and private industry through both collaborative and Fee-for-Service arrangements.

We are also very proud to have, during the last 5 years, contributed to saving several lives with some of the novel products we manufactured. And, of course, we are extremely grateful to CIRM for building this state-of-the-art facility.

You can see a video about the building of the GMP facility at UC Davis here.

Researchers cool to idea of ice bath after exercise

Have you ever had a great workout, really pushed your body and muscles hard and thought “You know what would be good right now? A nice plunge into an ice bath.”

No. Me neither.

Weightlifter Karyn Marshall taking an ice bath: Photo courtesy Karyn Marshall

Weightlifter Karyn Marshall taking an ice bath: Photo courtesy Karyn Marshall

But some people apparently believe that taking an ice bath after a hard workout can help their muscles rebound and get stronger.

It’s a mistaken belief, at least according to a new study from researchers at the Queensland University of Technology (QUT) and the University of Queensland (UQ) in Australia. They are – pardon the pun – giving the cold shoulder to the idea that an ice bath can help hot muscles recover after a hard session of strength training.

The researchers got 21 men who exercise a lot to do strength training twice a week for 12 weeks. One group then agreed – and I’d love to know how they persuaded them to do this – to end the training session by jumping into a 50 degrees Fahrenheit (10 Celsius) ice bath. The other group – let’s label them the “sensible brigade” – ended by doing their cool down on an exercise bike.

Happily for the rest of us at the end of the 12 weeks the “sensible brigade” experienced more gains in muscle strength and muscle mass than the cool kids.

So what does this have to do with stem cells? Well the researchers say the reason for this result is because our bodies use so-called satellite cells – which are a kind of muscle stem cell – to help build stronger muscles. When you plunge those muscles into a cold bath you effectively blunt or block the ability of the muscle stem cells to work as well as they normally would.

But the researchers weren’t satisfied just putting that particular theory on ice, so in a second study they took muscle biopsies from men after they had done leg-strengthening exercises. Again, half did an active cool down, the others jumped in the ice bath.

In a news release accompanying the article in the The Journal of Physiology, Dr Llion Roberts, from UQ’s School of Human Movement and Nutrition Sciences, said the results were the same:

“We found that cold water immersion after training substantially attenuated, or reduced, long-term gains in muscle mass and strength. It is anticipated that athletes who use ice baths after workouts would see less long-term muscle gains than those who choose an active warm down.”

The bottom line; if you strain a muscle working out ice is your friend because it’s great for reducing inflammation. If you want to build stronger muscles ice is not your friend. Save it for that nice refreshing beverage you have earned after the workout.

Cheers!

Da Mayor and the clinical trial that could help save his vision

Former San Francisco Mayor and California State Assembly Speaker Willie Brown is many things, but shy is not one of them. A profile of him in the San Francisco Chronicle once described him as “Brash, smart, confident”. But for years Da Mayor – as he is fondly known in The City – said very little about a condition that is slowly destroying his vision. Mayor Brown has retinitis pigmentosa (RP).

RP is a degenerative disease that slowly destroys a person’s sight vision by attacking and destroying photoreceptors in the retina, the light-sensitive area at the back of the eye that is critical for vision. At a recent conference held by the Everylife Foundation for Rare Diseases, Mayor Brown gave the keynote speech and talked about his life with RP.

Willie Brown

He described how people thought he was being rude because he would walk by them on the streets and not say hello. The truth is, he couldn’t see them.

He was famous for driving fancy cars like Bentleys, Maseratis and Ferraris. When he stopped doing that, he said, “people thought I was broke because I no longer had expensive cars.” The truth is his vision was too poor for him to drive.

Despite its impact on his life RP hasn’t slowed Da Mayor down, but now there’s a new clinical trial underway that might help him, and others like him, regain some of that lost vision.

The trial is the work of Dr. Henry Klassen at the University of California, Irvine (UCI). Dr. Klassen just announced the treatment of their first four patients, giving them stem cells that hopefully will slow down or even reverse the progression of RP.

“We are delighted to be moving into the clinic after many years of bench research,” Klassen said in a news release.

The patients were each given a single injection of retinal progenitor cells. It’s hoped these cells will help protect the photoreceptors in the retina that have not yet been damaged by RP, and even revive those that have become impaired but not yet destroyed by the disease.

The trial will enroll 16 patients in this Phase 1 trial. They will all get a single injection of retinal cells into the eye most affected by the disease. After that, they’ll be followed for 12 months to make sure that the therapy is safe and to see if it has any beneficial effects on vision in the treated eye, compared to the untreated one.

In a news release Jonathan Thomas, Ph.D., J.D., Chair of the CIRM Board said it’s always exciting when a therapy moves out of the lab and into people:

“This is an important step for Dr. Klassen and his team, and hopefully an even more important one for people battling this devastating disease. Our mission at CIRM is to accelerate the development of stem cell therapies for patients with unmet medical needs, and this certainly fits that bill. That’s why we have invested almost $19 million in helping this therapy reach this point.”

RP hasn’t defeated Da Mayor. Willie Brown is still known as a sharp dresser and an even sharper political mind. His message to the people at the Everylife Foundation conference was, “never give up, keep striving, keep pushing, keep hoping.”

To learn more about the study or to enroll contact the UCI Alpha Stem Cell Clinic at 949-824-3990 or by email at stemcell@uci.edu.

And visit our website to watch a presentation about the trial (link) by Dr. Klassen and to hear brief remarks from one of his patients.

Creativity sparks a bright future for science

When some people want to see the future they use a crystal ball. Others use tarot cards or runes. But when anyone at CIRM wants to see the future all we have to do is look into the faces of the students in our Creativity program.

Creativity students 2015 with program director Dr. Mani Vessal (front & center with tie)

Creativity students 2015 with program director Dr. Mani Vessal (front & center with tie)

Over the past three years the Creativity program has given some 220 California high school students a chance to spend the summer working in a world-class stem cell research facility. And when I say work, I mean work. They are required to attend lectures, grow their own stem cells, and do experiments. In short, they are expected to do what all the other scientists in the lab do. In return they get a great experience, and a modest stipend for their effort. At the end they produce papers on their work with titles like:

  • Notch Signaling as a Possible Regulator of Mesenchymal Stromal Cell Differentiation in the Hematopoietic Stem Cell Niche
  • RNA Splicing Factor ZRSR2 in Human Erythroleukemia and Stem Cells

We also ask the students to either write a blog or create a video about their experiences over the summer. Many do both. We’ll come back to the video portion later this week. The blogs make for a great read because they chart the students as they progress from knowing little if anything about stem cells, to being quite proficient at working with them. And all in just 8 weeks. One of the hardest parts of our job is choosing the best blog. For example Alice Lin, part of the City of Hope program, got an honorable mention for her blog that was a “diary” written by an embryonic stem cell. Here’s a small sample of her approach:

‘Also, this is NOT YOUR TYPICAL LAB JOURNAL ENTRY. It’s an autobiography chronicling my life. That way, when the stem cell controversy cools down, the general public can get a FIRST HAND ACCOUNT of what we do. This blog is going to rack up some serious views someday. Until then, I’m attached to my colony and the plate.’

Ryan Hale, part of the Scripps team, wrote about how the experience taught him to think like a scientist:

‘One day, after performing an experiment, our mentor asked us the reason behind our experiment. He wasn’t asking us about the experimental procedure or quizzing us on the pre-reading packet, he wanted us to understand the thought process a researcher would go through to actually think up such an experiment… Our mentor stressed how important it is to be creative, inquisitive, and critical if one wants to become a successful researcher.’

Selena Zhang

Selena Zhang

The winner was Selena Zhang, also part of the City of Hope team. She writes about her experiences in the lab, learning the ropes, getting to understand the technology and language of science. But it’s her closing paragraph that sealed the deal for us. In a few short sentences she manages to capture the romance, the mystery and the magic of science. And we’re also happy to say that this program is coming back next year, and the year after that, for five more years. Our Board has just approved renewed funding. The name of the program is changing, it will be called SPARK, but the essence will remain the same. Giving young students a glimpse at a future in science. You don’t need a crystal ball to know that with these students the future is bright. Here’s Selena’s winning blog:

My very own lab coat. It was a lot to live up to, my freshly laundered lab coat with the City of Hope logo. Looking around the lab, I was nervous and excited to start my very first day. There were papers to read and meetings with my mentor to hear about my project. I was starstruck, as I learned that I would be working with induced pluripotent stem cells, Alzheimer’s disease, and CRISPR. Terms that seemed to only exist in textbooks and science magazines that I lovingly read at the library were suddenly alive to me. Although, embarrassingly enough, the only thing that came to mind when my mentor mentioned CRISPR was a salad crisper. Fairly certain that she was a) speaking about something else and b) that I needed to eat more for breakfast, I asked her what that was. It turned out that CRISPR was a new genome editing tool we could use to create isogenic lines to study the independent effects of each allele of the APOE gene that is the most significant risk factor for Alzheimer’s. We would do this by converting a patient and wild-type fibroblast into induced pluripotent stem cells. From this, we would edit a normal allele into the patient’s cell for rescue and the mutated allele in the wild-type cell for insertion, respectively. We would eventually differentiate these cells into neurons and astrocytes to study how the change of this allele can impact neural interaction. This was real science in progress, not enshrined in a textbook, but free, fluid, and vibrant. I slowly grew into my own independence around the lab. I found myself more confident and emotionally invested with each experiment, every immunostaining and PCR. Science, for all of its realism, had always seemed like the unimaginable fantasy to me. Through this opportunity, science has become more tangible, grounded in unglamorous details: hard work and deadlines, mistakes and mishaps, long lab meetings and missed lunches. Yet, that has only made me more confident that I want to pursue science. Now, I’m embracing a reality, one that gives me something worth striving for. In fact, I am very fortunate that my project has encountered numerous obstacles. My initial response to these problems was and still is a lot less Zen and a lot more panic-driven. But I’ve slowly come to realize the beauty of the troubleshooting process for progress. My project has been an emotional rollercoaster, as our rescue cell line met success, but couldn’t advance to the next stage. Our insertion cell line appeared to have incorporated the mutation, but it turned out it only incorporated one allele. It’s been a process of finding the balance between defending our ideas and accepting new ones, the border between defending and defensiveness. My curiosity and drive to improve, to understand, to conquer the unknown is learning to coexist with the need for patience and flexibility No matter how solid our theory should have been, reality is fickle and all the more interesting for it. I thought science was all about doubt and skepticism, questioning everything. Through this internship, I’ve learned that there’s also a surprising amount of faith, the faith to accept any setbacks as part of the discovery process. I thought I loved science before because I loved how enough facts could help me make sense of things. But through this internship in the lab, I’m learning to love a larger part of science, which is not only loving knowledge, but also loving not knowing, loving discovery for all of its uncertainty and perfect imperfections. I’m learning to grow into my lab coat, and hopefully, to find my place in the field of science.

Bridging the gap: training scientists to speak everyday English

Getting a start in your chosen career is never easy. Without experience it’s hard to get a job. And without a job you can’t get experience. That’s why the CIRM Bridges program was created, to help give undergraduate and Master’s level students a chance to get the experience they need to start a career in stem cell research.

Last week our governing Board approved a new round of funding for this program, ensuring it will continue for another 5 years.

But we are not looking to train just any student; we are looking to recruit and retain students who reflect the diversity of California, students who might not otherwise have a chance to work in a world-class stem cell research facility.

Want to know what that kind of student looks like? What kind of work they do? Well, the Bridges program at City College of San Francisco recently got its latest group of Bridges students to record an “elevator pitch”; that’s a short video where they explain what they do and why it’s important, in language anyone can understand.

They do a great job of talking about their research in a way that’s engaging and informative; no easy matter when you are discussing things as complex as using stem cells to test whether everyday chemicals can have a toxic impact on the developing brain, or finding ways to turn off the chromosome that causes Down’s syndrome.

Regular readers of the CIRM blog know we are huge supporters of anything that encourages scientists to be better communicators. We feel that anyone who gets public funding for their work has an obligation to be able to explain that work in words the public can understand. This is not just about being responsive, there’s also a certain amount of self-interest here. The better the public understands the work that scientists do, and how that might impact their health, the more they’ll support that work.

That’s why one of the new elements we have added to the Bridges program is a requirement for the students to engage in community outreach and education. We want them to be actively involved in educating diverse communities around California about the importance of stem cell research and the potential benefits for everyone.

We have also added a requirement for the students to be directly engaged with patients. Too often in the past students studied solely in the lab, learning the skills they’ll need for a career in science. But we want them to also understand whom these skills will ultimately benefit; people battling deadly diseases and disorders. The best way to do that is for the students to meet these people face-to-face, at a bone marrow drive or at a health fair for example.

When you have seen the face of someone in need, when you know their story, you are more motivated to find a way to help them. The research, even if it is at a basic level, is no longer about an abstract idea, it’s about someone you know, someone you have met.

Even the early worm gets old: study unlocks a key to aging

A new study poses the question, ‘When does aging really begin?’ One glance in the mirror every morning is enough for me to know that regardless of where it begins I know where it’s going. And it’s not pretty.

But enough about me. Getting back to the question about aging, two researchers at Northwestern University have uncovered some clues that may give us a deeper understanding of aging and longevity, and even lead to new ways of improving quality of life as we get older.

The researchers were focused on C. elegans, a transparent roundworm. They initially thought that aging was a gradual process: that it began slowly and then picked up pace as the animal got older. Instead they found that in C. elegans aging begins just as soon as the animal reaches reproductive maturity. It hits its peak of fertility, and it is all downhill from there.

The researchers say that once C. elegans has finished producing eggs and sperm – ensuring its line will continue – a genetic switch is thrown by germline stem cells. This flipped switch begins the aging process by turning off the ‘heat shock response’; that’s a mechanism the body uses to protect cells from conditions that would normally pose a threat or even be deadly.

In a news release Richard Morimoto, the senior author of the study, says that without that protective mechanism in place the aging process begins:

C. elegans has told us that aging is not a continuum of various events, which a lot of people thought it was. In a system where we can actually do the experiments, we discover a switch that is very precise for aging. All these stress pathways that insure robustness of tissue function are essential for life, so it was unexpected that a genetic switch is literally thrown eight hours into adulthood, leading to the simultaneous repression of the heat shock response and other cell stress responses.”

You read that right. In the case of poor old C. elegans the aging process begins just eight hours into adulthood. Of course the lifespan of the worm is only about 3 weeks so it’s not surprising the aging process kicks in quite so quickly.

To further test their findings the researchers carried out an experiment where they blocked the genetic switch from flipping, and the worm’s protective mechanisms remained strong.

Now, taking findings from something as small as a worm and trying to extrapolate them to larger animals is never easy. Nonetheless understanding what triggers aging in C. elegans could help us figure out if a similar process was taking place at the cellular level in people.

Morimoto says that knowledge might help us develop ways to improve our cellular quality of life and delay the onset of many of the diseases of aging:

“Wouldn’t it be better for society if people could be healthy and productive for a longer period during their lifetime? I am very interested in keeping the quality control systems optimal as long as we can, and now we have a target. Our findings suggest there should be a way to turn this genetic switch back on and protect our aging cells by increasing their ability to resist stress.”

The study is published in the journal Molecular Cell.