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An Interview with Dr. Peter de Keizer
Dr. Jihane Mriouah, Josh Conway and Steve Hill July 16, 2018
We interviewed Dr. Peter de Keizer, a researcher who is engaged in studying senescent cells and designing therapies to destroy them in order to delay and prevent age-related diseases. Cleara Biotech is currently using his research to develop a senolytic peptide that accomplishes this via interfering with the interactions between p53 and FOXO4.
Senescent cells and aging
As your body ages, increasing amounts of your cells enter into a state of senescence. Senescent cells do not divide or support the tissues of which they are a part; instead, they emit a range of potentially harmful chemical signals that encourage other nearby cells to also enter the same senescent state.
Their presence causes many problems: they degrade tissue function, increase levels of chronic inflammation, and can even eventually raise the risk of cancer. Today, we will talk about what senescent cells are, how they contribute to age-related diseases, and perhaps most importantly, what science is hoping to do about the problem.
Senescent cells normally destroy themselves via a programmed process called apoptosis, and they are also removed by the immune system; however, the immune system weakens with age, and increasing numbers of these senescent cells escape this process and build up.
By the time people reach old age, significant numbers of these senescent cells have accumulated in the body and caused inflammation and damage to surrounding cells and tissue. These senescent cells are one of the hallmarks of aging and are thought to be a key process in the progression of aging.
In 2017, a research team led by Dr. de Keizer published a quite significant study on senescent cells [1]. The team discovered that the molecule FOXO4-DRI was able to cause these senescent cells to destroy themselves and was a candidate senolytic, a therapy designed to remove these problem cells.
We had the opportunity to speak with Dr. de Keizer and find out more about his research.
What impact did your publication in Cell have?
The most exciting aspect was that aging research as a whole gained a lot of attention. Even now, I notice that there is a lot of enthusiasm when discussing the various mini-revolutions in the lab. Many mainstream media outlets picked it up, and I think that this will be a boost for the field and our joint mission to raise awareness about targeting the negative aspects of aging.
It doesn't seem like as many people in Europe talk about aging as in the U.S. Is being in Europe instead of the U.S. better or worse for your research?
As usual, the U.S. innovates, China imitates, and Europe hesitates. I returned to Europe for personal reasons, but I have been talking to American investors who want to explore Europe a bit more, and there are possibilities. People here do acknowledge aging as a problem, and the Undoing Aging in Berlin was a success. The downside with Silicon Valley is that there are big budgets and a great spirit, but we also need a style of research, which is, in every city, a little bit different.
In Europe, the focus is very much molecular. I would like to combine the great vision and budget of Silicon Valley with European quality and maybe a bit of skepticism. We never publish anything unless we are really convinced. In that sense, I like Europe because people are interested in aging here; you just have to talk to the right people, and many people are skeptical. When I talk to scientists about what we do, they also get excited.
Are the regulations regarding trials more stringent than in the U.S.?
Yes, that's true, especially for animal work. There's a lot of societal pressure not to do animal work. We have to deal with these hurdles, but there's good money in science here, certainly in Western Europe, and we can make do quite well. This is generalizing, but we tend to talk less and do more.
Some researchers are worried about excessive lysis of cells, which might cause organ failure, particularly in the kidney, which contains more of these cells than other organs. How do you plan on addressing this issue?
This was found in fast-aging mice, which we used in our studies; they proved to have a lot of senescence in the kidneys. Natural aging, of course, is in virtually every organ, but the kidney is definitely susceptible.
Would you say that a potential side effect of the drug, if not used at the proper dose, could be excessive lysis?
The honest answer is "We don't know." I've seen in mice that you can go too far; if you look at the cell data, it's tenfold more potent against senescent cells. That sounds like a lot, but if you want to treat relatively healthy people with this, if one in ten cells [that will be destroyed] is basically a healthy cell, I find it very risky. So, you need to have a perfect dose or a perfect range.
With mice, we could scale it and we could say if it's too much or not, but for humans, it's more difficult. What we're doing now is trying to optimize this to make it tenfold more selective. This is version 4, and the published paper is on version 3; the first two were generated in the US in 2012, and they were not so effective. The first step was very short and had a very poor solubility, the second step lasted much longer, and the third peptide we made in D-amino acid is the one we published now.
Now, we're making the fourth one because we know where the critical amino acids and the non-important and important ones are in the interaction domain of the two proteins. We plan on giving number 4 to a team of drug development experts to get it to a hundredfold selectivity, and then it should be much safer for use.
Is there a good biomarker right now for senescent cells?
There are some aging biomarkers, such as the epigenetic clock, but that's not necessarily a marker for senescence. For senescence, the honest answer is that we've tried. We've looked for interleukins, and there's very poor correlation because you don't know which organ has been affected. We have to look for tissue-specific biomarkers to know what's going on; but it's very difficult to do.
Maybe we don't entirely need to; if we can get a rough aging score from the blood based on the methylome, phenotypical markers, and a frailty index, perhaps then we can suggest a treatment. This is something we have to think about as a field. I would, of course, love to have biomarkers. This is also part of our plan for part two; the first part is optimizing the drugs, and the second part is finding markers for senescent cells so that we can actually do antigen studies.
How long would you say it's going to be for this safe version four to be optimal?
That's the fun part. It took me ten years to come to this third version because in academia, we always have 20 other things that are also interesting. Now, we actually teamed up with a company, Cleara, that we founded just recently. The team has 20 people, with 10 structural experts, and they're going crazy on this. Every week, we have a meeting at which they have made some more progress, and it is super fast. We gave ourselves four months for a library screen on the first version, and then it's another ten rounds of optimizations.
Once we have a lead candidate, we will start doing all the things that academia never wants to look at, like a liver update and all the stuff that scientists aren't interested in but is important to have. I want to do ten rounds of that, and it's three weeks per round, then we'll know roughly where the weak spots are in our current version, and we can go back and add heavy metal toxicity, etc. We gave ourselves a year for optimization, but I hope sooner.
Once the peptide is optimized, that's when the real work begins. Which biomarker would you use to assess its efficacy?
We've known for a while now that some therapy-resistant cancer cells, such as melanoma and glioblastoma, also upregulate FOXO-p53 complex. It also goes up in therapy-surviving cancer cells. So, our lead indication would be to go for a lethal form of cancer. The benefit is that we'd only need to do Phase 2 trials, not Phase 3, before we get approval to progress to the market.
If we go with Phase 2 for cancer, we can go for an age-related disease, or for aging as a whole, much easier. The problem is that aging is not accepted as an endpoint. However it is now with the FDA, in Europe, we're fighting to get, first, frailty as an endpoint. There's currently no trial possible for simply treating aging.
With cancer, it's slightly easier; because you can just take biopsies from the tumor to actually show p21 or some interleukin marker; usually, it's a combination of things, and those are usually high in a target tumor. Then, after a month, with whatever's left, you can check for a reduction of those markers. You can do a blood base, or you can test the DNA. For tumors, it's relatively straightforward; you can just take biopsies every now and then. That's actually why we also go for cancer. If it's proven, you know how it works in humans, then it's much easier to go for osteoarthritis. Sarcopenia would also be something I'd be interested in seeing and then maybe aging as a whole.
How often do you think people would need senolytic treatments, will they be for older or younger people?
In mice, over a year; we did it once a month. It seemed to be enough, and I think we can actually reduce that frequency. But, I still have to do the experiment. If we do it once in a while, once every three months, once every half a year in mice, it might actually be sufficient. I don't think they accumulate that fast. Maybe later in life, you'll do it a bit faster. Early in life, there's really no reason to do it so often. It's like a car. If it's only a couple of years old, you don't go to the mechanic as often.
Do you expect to see the benefits of senolytics in people who are already showing signs of aging, or as more of a preventive treatment?
I think the first one. This was what we showed in the mouse study; we took mice that were already in bad shape and gave them senolytics. I think it could be like if you take a rusty car, and it's in very bad shape, and remove the rust, you may be removing too much at once. You should do it very carefully and very gently, in gradual stages. If you have a reasonably okay car, I think it's much safer to treat.
If you can take a human at 60 who's starting to get senescent cells, it'll work nicely. If you take a 90 year old who's in very bad shape, I think you have to be very careful how much you take at once. But, the idea is, indeed, that you can do this. You might take a very old person and give him a few shots of an anti-senescence drug, and you would revitalize him.
My theory is that senescent cells, because they secrete all these inflammatory factors, they stop the neighboring cells from differentiating. You see a correlation of senescent cells and stem cells right next to them, at least in the kidney. This reprogramming is permanent, so if there's a need for rejuvenation, it malfunctions because the stem cells are unable to differentiate. This is called senescent stem lock theory. But, if you remove the senescent cells, it means the stem cells can differentiate again, supporting tissue rejuvenation.
So, just by removing the senescent cells, you could unlock the stem cells' potential?
Yes, that's the idea. I think that the senescent cells are a brake on rejuvenation, so they prevent proper rejuvenation from taking place. They do two things. First of all, they are annoying for the environment, and second of all, if you have lots of them and you get injured, we know that rejuvenation doesn't take place very well. But, if you remove senescent cells in mice, not just using my method but the genetic method used by Darren Baker, for instance, you see that the mice do better. There is a rejuvenation increase.
Arguably, you could do this with a very old person, that's my theory. In mice, it works. If you take a mouse that's 130 weeks old, which is really like 80, 90 years old in human years, you can restore the kidney function; that's what we showed.
There's a lot of heterogeneity in old mice, so it's not easy to study a lot of things, because there is a lot of variation between individuals. This is why we use fast-aging mice, but I think it's probably true for many organs, and that's why if we have a drug that's tenfold more potent, then I think we can treat for longer and higher doses.
The variation was always in the untreated group. The old mice always showed a lot of variation in aging. Some mice aged in better health and some mice were very sick. In the treated group, we could reduce the signs of aging, so this heterogeneity was not in the treatment group but in the control group.
To make a long story short, I think that if you have an old group of people and you don't know how sick they are, you take biomarkers to know who's in bad shape and who's in good shape, and then you could create a personalized therapy. Some people could get a lot, and some people could get less. In theory, it's all possible.
Can you tell me more about using FOXO4-DRI for people who have had chemotherapy?
Yes. There are many off-target effects of chemotherapy. What we have done a lot of work on, and you can look it up in publications, are chemotherapy-surviving cells. Breast, melanoma, and glioblastoma are usually the ones that we look at. They upregulate FOXO and active p53. That's essentially what we find in senescence, but when they become senescent cells, they just keep on dividing.
The idea is that you use chemotherapy or radiotherapy and kill 90 percent of the cells, whatever is left becomes senescent-like, then you give anti-senescence treatment, such as the FOXO4 drug, in order to kill the other 10 percent, or maybe they go back to the original state, and you go back and forth. Chemotherapy, senescence therapy, repeat. That's essentially what we are aiming for.
What would stem cells be doing in that situation? Would that be positive for cancer patients?
When you have chemotherapy-surviving cells, they become more stem-like. They have more pluripotency markers, and they become more migratory. They get epithelial mesenchymal transition. This is seen in patients, and it means that whatever you do not kill is more aggressive than the original and harder to treat. However, we now know their weak spot; we now know that they become senescent-like. This is why I am saying that if we do a combination therapy, with the chemo and anti-senescence, you may solve the problem to a large extent. This is, of course, still in the test phase. As soon as we have more information, I'll let you know, but in the lab, it worked.
So, you've tested this sequence of chemo and senescence therapy?
Yes, we have done it in melanoma, for instance. However, we have only done it for one cycle, not ten. We do the chemo first, and if we have cells that are growing continuously, the very resistant survivors, we give an anti-senescence drug. The parental line is not sensitive to this drug, but the chemo survivors are. We create our own target, basically. We want to go for cancer first. If that works, we can measure the biomarkers; p21, for instance, is a good biomarker that should be up after chemotherapy and radiotherapy, and it goes down with senescence treatment. That's the next biomarker assay we'd use, and it can be a test for age-related diseases.
If you wanted to change the way clinical trials are run, would that take years and require dealing with politicians?
The FDA is not known to be very progressive. The only thing we can argue for is that it should be easier for people to enroll. There are multiple compassionate care programs for terminal patients, but for volunteers, we don't have anything. For aging, it should be possible for people to participate in a trial after a good amount of preclinical work. Right now, it's not possible. I'm talking to a lot of politicians and am trying to convince them to do this, but it's going to take a long time. It doesn't mean we shouldn't do it. It helps a lot that we have a lot of media attention.
Would you say that being out there, showing your face, and talking to journalists have played a large role in your work recently?
The irony is that universities are a bit reluctant to share their science. It's a shame, because when I talk to people about aging, they're always excited, and they always have the wrong ideas too. When we start, they all think we are working on immortality, and if the discussion progresses, it's always about cryopreservation, crazy apps where you can exchange life hints, or unrealistic sci-fi. Then, I have to separate realistic science approaches from sci-fi.
Then, after doing that, the discussion is "Yeah, but if we are immortal, how would we deal with that? Are we psychologically not equipped for immortality?" It's not the discussion we should have, we should instead teach the masses about what's going on and what's realistic: for instance, the nicotinamide work, rapamycin, the stem cell replacement work, the Yamanaka factors from the Belmonte group, and then the senolytic drugs. Those are all realistic revolutions in the lab in the last two years.
I would like to promote the message everywhere that if we do a good job now, in twenty years, we can have something that's effective in humans. However, if we don't do anything, we'll only have old and frail humans. Society will be stuck with a lot of old people in bad shape, so we have to do something now.
Is anyone working on an immunotherapy approach to senolytics?
That's what everybody's been looking for. But, immunotherapy works because of mutation load; there's a lot of mutation in melanoma, and it's one of the most mutating type of cancer there is. Senescent cells are relatively genetically stable, so I think immunotherapy will be very difficult on senescent cells.
The T cells look for new antigens, and that's why for melanoma and other cancers, it's brilliant, and it's why I don't think classical immunotherapy using CAR-T will work. You would have to use natural killer cells or something like that.
What about the suggestion that the immune system is the best tool for finding senescent cells?
It's a paradox, right? The natural killer cells in vitro can do this very well. However, moles, for example, are all senescent. We're born with them, and, sometimes, we die with them 80 years later. We do not yet understand why.
So, it's not clear how the immune system works with senescent cells.
I think it's too easy to say that the natural killer cells destroy senescent cells. It's true, but there are so many exceptions to that. I think it may be the secretion profile. As a field, we need to identify subtypes of senescent cells, because there is no such thing as just a senescent cell; there are different kinds.
Our drug, the FOXO drug, works very well against IL-6 cells, but it doesn't work very well against MNP3-high cells. It definitely doesn't work very well against low-inflamed senescent cells. So, we need to identify homogeneity in subtypes of senescent cells, and maybe each subtype has a different immune response. Let's say that there are five or ten different senescent cell types.
In our lab, and you can look this up on my academic webpage, we've followed this goal for the last ten years and are now able to track individual cells in vivo. We track certain senescent cells and sort them, and then we see how they are different from other senescent cells at the same location in the body via single-cell sequencing. Then, you can quantify subgroups, which correspond differently to diseases. For cancer, IL-6 is a problem, but for aneurysms, MNP3 is a problem. So, different subtypes have different diseases and maybe different treatments.
Our peptide will not work against MNP3-high cells or IL-6 low cells, and it works well against IL-6 high cells. For immunotherapy, IL-6 is a decoy for the immune system. So, maybe if you have IL-6 senescent cells, they are not targeted by T cells, but the other ones are. It's a very new concept.
Do cells become senescent differently due to their tissues of origin?
That's probably true, because the kidney carries a lot of waste products, and there is a lot of oxidative stress in the kidney and the lung. The skin, liver, and kidney are heavily exposed to stress, although other organs are more shielded from oxidation. The skin can have damage-induced senescence, as UV rays can cause it. Let's identify the tissue subgroups and then do tissue studies.
There is a new technique called Cytof, and it can do up to 20, and maybe even 50 in the future, stainings at once on a tissue. With Cytof, we shoot a small pixel out of the tissue, then incubate it with heavy metal-labelled antibodies. Fifty metals mean fifty antibodies. For each pixel, we get a range of values with different proteins. If we have a big tissue sample, we can get a whole grid. For the whole tissue, we can get 50 markers at once. This is what we want to do for aging, and we're one of the first to do that.
We're talking five or ten years from now. We'll be able to know whether a particular tissue has 5% senescent cell subtype A and 20% senescent cell subtype B. That's what I want to do: make an atlas of senescent subtypes.
Can the heterogeneity of cancer theory be applied to senescent cells?
Absolutely, except cancer goes faster because cancer mutates rapidly. This is not a genetic thing per se. We know that if we have a dish of senescent cells, they're completely homogenous, so it's a genomically stable cell line. If we synchronize the cell cycle and irradiate them so that they all get an equal amount of damage, there's still a massive amount of heterogeneity. Only 20% of the cells are IL-6 positive, so 80% is something else.
The field still considers "senescent cells" as if they are one thing, like cancer. There is not one cancer, and there is not one senescence. This puts us on the wrong track. It's something that I think more and more people realize, but now we actually have to identify the subgroups.
Would making senolytic drugs successful require finding the niche, focusing on the one type of senescent cells you're going to target?
Yes. There is no magic bullet. Our drug only targets IL-6 high, but Navitoclax targets the BCL pathway, and there are quercetin and dasatinib; no one is sure if or how they really work, but maybe they target another subtype, as they seem to work on adipocytes, which we have not tested. It may be cell type-specific and also molecular background dependent.
FOXO p53 is only active in a subset of senescent cells, not in everything. So, we will end up with a bunch of senolytics. I don't think anyone is going to say, "My senolytic is better than your senolytic." It'll be niche driven.
How well does this treatment compare to other treatment options, such as fasting?
With fasting, you don't kill, you just delay the secretions from senescent cells. It's like rapamycin and aspirin; it just blocks the secretion profile. Fasting offers a transient benefit for sure, but a week later, you eat again, and they're just there again. It's just making them dormant. We have not seen evidence that senescent cells are removed by fasting, in mice or in cells.
Fasting works well before exposure to damage. It increases chemosensitivity in patients if you fast the patient 24 hours in advance; it works really well because you prevent the build-up of senescence, that is my theory at least. If you do it right after, it's completely toxic. They've done it in mice as well. If you fast 24 hours in advance, great, every mouse survives; if you do it 24 hours after transplantation, all the mice die. With senescence, it's the same; we should not do it at the time of damage. There's a tangent benefit of senescence, of wound healing. If you do it after the huge stress is gone, it's fine.
Have you looked at other senolytics?
We tried a lot, and the BCL inhibitors look the most promising. We used navitoclax and ABT drugs 263 and 727. They identified the subgroups, and we could reproduce that in vitro, at least, not in humans. What we saw when comparing them to FOXO4 is that they are toxic at low levels and should not be given to healthy people. That's the downside of these drugs.
However, in vitro, if you do low-level navitoclax on healthy cells, you get 10, 20 percent cell death. That's relatively stable. That's a decrease in viability because you're affecting some cells that are apparently sensitive to BCL inhibition. We did not see that with FOXO4, and that's what's reported in our paper. You usually get a low level of toxicity with low-level navitoclax, so it's questionable if you want to do this in a healthy 80-year-old.
As for quercetin and dasatinib, I'm absolutely not a fan of those. We've tried a couple of experiments; we've never seen a good result. Campisi's lab has tried it extensively, and they said that quercetin actually prevents senescence. It upregulates stress responses through antioxidants and promoting DNA repair. But it's' still not clear, there is no known mechanism for quercetin.
Now there are Hsp90 inhibitors too, but we have not tested them.
What about gene therapies; could they be more powerful than senolytic drugs?
It depends on what gene you want to target. Maybe it relates to the Oisin work, with the p16 promoter. However, as we've seen with FOXO4, if you do something permanently, it's not a good idea. These genes are there for a reason. If you always block p53, you get cancer. If you always block p16, you get cancer. If you block FOXO4, the mice are apparently normal, but if we treat the mice with chemotherapy, they all die. We don't see that with the peptides, but we see with the p16 knockouts that we get a lot of other effects.
That's why I like peptides so much because peptides are very specific: you only break one interaction. However, kinase inhibitors block everything, and if you do a knockout, then the whole protein is absent. I don't think gene therapy will work for senescence.
What about a transient gene therapy?
Yes, that should probably work, such as with a temporary expression of the p16 promoter. The Oisin work seems plausible, and they're testing it now for prostate cancer.
Is it difficult to design studies in vivo to show proof of concept?
That's why I like fast-aging mice, where we know the driver of the aging phenotype, such as a DNA repair defect that causes senescence. We can also test late-stage cancer that upregulates the markers that we're interested in. We're different from all the other approaches that we focus on, and this direction is very niche-specific.
It's not like p16 or p53; we don't inhibit all p53, as every cell has p53. This is the only criticism I have with Oisin's approach: their p53 construct will be activated in all stressed cells. That's a risk. If you're in an acute state of damage, then you don't want to have that construct.
What stage is FOXO4-DRI currently at?
We are now trying to optimize the FOXO4-DRI peptide further so it will become truly potent, and especially safe, enough for human translation. FOXO4-DRI is the third therapeutic version in an evolutionary process of about a decade in research on FOXO4-p53. Right now, the selectivity of FOXO4-DRI for senescent cells is good enough for proof-of-concept experiments in experimental laboratory settings, but to truly allow for usage in humans, the safety profile needs to be even higher. Especially since it will take a long time and serious investments, we want to make sure translation happens with a version that is optimized to allow for this.
I recently become an assistant professor at the University Medical Center in Utrecht, the Netherlands, where there is great expertise on the molecular regulation of FOXO4 and when I started this journey so long ago, to make this a reality. Excitingly, we also teamed up with a group of drug development experts in our start-up company Cleara to really be able to make translation steps to the clinic.
What challenges are you facing in its development?
For one, the time and investment needed for a broadly applicable drug to make it to the market causes people to take matters into their own hands and resort to self experimentation. Darren Moore is an example hereof. I think Darren's vision of targeting aging is very exciting. I still advise against such approaches though, as, of course, it is dangerous and could be harmful to the real development program if unexpected side effects occur. Gene therapy is a hallmark example hereof; this field is only slowly recovering now after some bad cases in the early days.
Another issue is that "aging" itself is not a measurable end point that the FDA or EMA considers for clinical translation. This means that we need to focus on single (age-related) diseases first, even though there may be broad applicability.
Last, the system of clinical trials dates back to the pre-internet era when people did not have easy access to experimental compounds and tended to rely more on the expert opinion of clinicians and scientists. Nowadays, compounds are easier than ever to obtain through the internet, and people have become more convinced of their own opinion. When left ignored, this is a recipe for disaster, as we will see more self-experimentation with anti-aging drugs.
To overcome this, I argue for an update in the rules and regulations for clinical trials to allow easier access for (late-stage) patients and potentially even volunteers to enrol in trials with drugs that have been effectively tested in preclinical studies.
How do you think anti-aging research could provide proof of principle in humans without having to run lifetime studies?
A valid, but tough, question. For one, it would be best if we can study the effects in patients that are middle/late aged and not just measure a delay but an actual reversal of one or more features of aging, such as tissue function (using blood/urine samples or biopsies) or methylation status. Studies on the prevention/delay of aging will be much harder. While I agree that this needs to be done properly and with scientific rigor, it should be easier for people to enrol when preclinical tests are (reproducibly) positive and the treatment shows little negative side effects.
We would like to thank Dr. de Keizer for taking the time to do this interview.
[1] Baar, M. P., Brandt, R. M., Putavet, D. A., Klein, J. D., Derks, K. W., Bourgeois, B. R., … & van der Pluijm, I. (2017). Targeted apoptosis of senescent cells restores tissue homeostasis in response to chemotoxicity and aging. Cell, 169(1), 132-147.
CategoryNews
TagsCleara, FOXO4-DRI, Peter de Keizer, Senescent cells, Senolytics
Dr. Jihane Mriouah
Jihane's background is in cell biology, cancer and longevity research. She completed a PhD working on head and neck cancer then went on to a 5-year postdoctoral position during which she contributed to the development of a nanoparticle for gene therapy and drug delivery with a focus on prostate cancer and aging.
Josh Conway
Josh is a professional editor and is responsible for editing our articles before they become available to the public as well as moderating our Discord server. He is also a programmer, long-time supporter of rejuvenation biotechnology, and avid player of the strange game called "real life." Living in the center of the northern prairie, Josh enjoys long bike rides before the blizzards hit.
  
Steve serves on the LEAF Board of Directors and is the Editor in Chief, coordinating the daily news articles and social media content of the organization. He is an active journalist in the aging research and biotechnology field and has to date written over 500 articles on the topic as well as attending various medical industry conferences. In 2019 he was listed in the top 100 journalists covering biomedicine and longevity research in the industry report – Top-100 Journalists covering advanced biomedicine and longevity created by the Aging Analytics Agency. His work has been featured in H+ magazine, Psychology Today, Singularity Weblog, Standpoint Magazine, and, Keep me Prime, and New Economy Magazine. Steve has a background in project management and administration which has helped him to build a united team for effective fundraising and content creation, while his additional knowledge of biology and statistical data analysis allows him to carefully assess and coordinate the scientific groups involved in the project. In 2015 he led the Major Mouse Testing Program (MMTP) for the International Longevity Alliance and in 2016 helped the team of the SENS Research Foundation to reach their goal for the OncoSENS campaign for cancer research.
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and the infinite frontier that is my space.


USDA's National Institute of Food and Agriculture released the 2014 Request for Applications for the Beginning Farmer and Rancher Development Program. Applications are due June 12.
Organizations can apply for grants to provide education, training, technical assistance and outreach for U.S. farmers, ranchers, and managers of non-industrial private forest land. Priority will be given to projects that are partnerships and collaborations led by or including non-governmental organizations, community-based organizations, and school-based agricultural educational organizations with expertise in new agricultural producer training and outreach. Approximately $19.2 million is available for 2014 awards.
NIFA is hosting two webinars for interested applicants, on April 30 and May 6 at 2:00 p.m. EDT.


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(function() {
    'use strict';

    angular
        .module('app')
        .factory('animalsService', animalsService);

    function animalsService() {
        var service = {
            getAll: getAll
        };

        return service;

        function getAll() {
            return ['Perro', 'Gato', 'Tortuga', 'Delfin', 'Caballo'];
        }
    }
})();

redpajama_set_name: RedPajamaGithub


text:
Greatly Exaggerated Reports of Death
Sometimes obituaries have happy endings—like those in Wikipedia's List of Premature Obituaries. Most seem to fall into one of four categories:
Jumping the Gun — As when the aging Bob Hope was reported dead on the Associated Press website in 1998, and then eulogized in the U.S. House of Representatives.
Mixed Up Names — As when actor James Earl Jones was confused with recently deceased assassin James Earl Ray.
Hoax — As when Britney Spears was reported dead by two Texas DJs.
Technical Mistake — As when the CNN website killed off Fidel Castro, Dick Cheney, Bob Hope, Gerald Ford, Pope John Paul II, Nelson Mandela, and Ronald Reagan all on the same day.
The best sport was probably the perennially ancient Abe Vigoda, whose death was reported in People magazine in 1982. Abe "posed for a photograph showing him sitting up in a coffin, holding the magazine in question."
Filed under famous folks

redpajama_set_name: RedPajamaCommonCrawl


text:
G2 Ocean names Wallem - Sectors
G2 Ocean names Wallem
Wallem Ship Agency has been appointed to provide ship agency services to all of G2 Ocean's vessels calling at Southeast Asian ports.
Dickson Chin, managing director of Wallem Ship Agency, said: "Our teams are very experienced in handling multipurpose vessels and have completed extensive preparation work for these calls which commenced at the end of 2017."
The agreement with G2 Ocean includes Wallem's offices in Singapore, Malaysia, Thailand, the Philippines, Vietnam and Myanmar.
G2 Ocean, a joint venture between Gearbulk and Grieg Star, was formed in May 2017 and operates a pool of around 130 multipurpose vessels, ranging from open and semi-open hatch to conventional bulk carriers.
www.g2ocean.com
www.wallem.com


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Environmental Science, B.S.
Are you in love with nature and enjoy being outside as much as inside? Do you often rely on logic to solve complex problems or come up with original solutions? Could you see yourself helping businesses and organizations understand how decision-making processes impact the environment? If this sounds like you, then a Bachelor of Science in Environmental Science could lead to a fulfilling and meaningful career.
PLNU's Biology Department prepares environmental science majors to address the very serious need in our world today for people trained to advocate for the healing and restoration of creation — both land and people. To prepare you for environmental science careers, we offer an inter-departmental program where you'll have the chance to take core science classes in biology, chemistry, mathematics, and physics alongside electives in political science, economics, philosophy, or sociology. This broad range of academic disciplines will empower you to understand the connections and interactions across these areas of study, and ultimately how each affects the environment.
Mike Mooring, Ph.D.
Since 2009, PLNU's Department of Biology has led a biennial Neotropical Ecology field course in Costa Rica that has garnered rave reviews by students. In 2010, Dr. Mike Mooring, professor of biology, began leading his summer research students to Costa Rica to conduct field research.
This major also will require you to complete 8 units within an off-campus environmental program. The purpose behind having you study in an off-campus program is to encourage you to expand your learning beyond PLNU and allow you to take advantage of many specialized courses offered through study abroad programs or summer field courses. Other opportunities, like Chemistry or Biology undergraduate research allow you to study fascinating subjects in compelling settings and apply your passions in unique and deeper contexts.
PLNU also has a robust pre-health program to train and equip you for professions in medicine, dentistry, optometry, pharmacy, and veterinary medicine. Since 2004, Over 90 percent of PLNU students who have applied for health professions schools have been admitted. By offering rigorous courses alongside individualized support and guidance in the form of internships, pre-health advisors, seminars, and more, you can be confident and prepared moving onto graduate and medical schools.
Learn more about how students gain hands-on STEM experience through PLNU's summer research program.
For information about the courses required for the Environmental Science, B.S. program, view the PLNU Catalog.
Are you ready to take the next step to begin your PLNU journey? Whether you're a high school senior, college transfer student, or international student, find out what we're looking for in our applicants and how you can apply.
For most students, the transition into college life is one full of adjustments. There is the excitement of newfound freedoms, but also some uncertainty as you begin to make choices and take responsibility for your own future.
At PLNU, we're committed to supporting you — academically, professionally, spiritually, personally — so that you may be successful both in your time as a student and beyond. That's why we offer a holistic support system that focuses on your unique experiences, particular needs, and personal and professional goals — resulting from our deep concern for you, our student.
With a focus on authentic relationships and personalized attention, our goal is to help transform you so you can follow your calling in your own career and life.
Do you have a passion for hiking, exploring nature, and understanding its origin? Merge your love of the great outdoors with your studies through a degree in environmental science. Covering ecology, biology, and a wide range of other science topics, you'll learn not only how to better understand the inner workings of the environment around you, but also how you can be an advocate and innovator for conservation efforts.
Environmental science vs. environmental studies:
While environmental science focuses on the mechanisms behind the problems our environment faces, environmental studies give more of an overview of the challenges through the many social, political, and economic perspectives.
At PLNU, our Environmental Science B.S. program focuses on two goals:
Empowering you to understand the connections and interactions across areas of scientific study
Training you to advocate for the healing and restoration of creation
Job outlook for environmental science careers
Employment in careers related to a degree in environmental science is projected to remain steady given the current state of our climate and environment. For conservation scientists, (one of the careers pursued by graduates of the PLNU environmental science programs), employment is projected to grow 5% from 2019 to 2029, according to the U.S. Bureau of Labor Statistics.
Caleb Bryce, Ph.D.
In graduate school, Caleb M. Bryce, Ph.D. trained dogs how to run on a treadmill. It was cute he says, but it was to study the effects of domestication and intensive artificial selection on the running performance of various breeds in comparison to their shared wild cousin, the wolf.
What can you do with an environmental science degree?
Many graduates of the PLNU environmental science program have gone on to work at waste/recycling facilities, zoos and wildlife rehabilitation organizations, and even government departments such as the California Department of Fish and Wildlife. All graduates are equipped to work in many different and interesting places — in labs, in remote nature, and even in positions of government leadership.
Some of the positions PLNU graduates currently hold:
Conservation Scientist
2020 Median annual salary: $64,010
Conservation scientists manage the land quality of forests, parks, rangelands, and other natural resources. With research and funding, they are responsible for maintaining and supervising the overall well-being of their parks and protected areas. They often work for governments or social advocacy organizations advising them on the right plan of action to promote conservation and the safety of the environment.
Necessary skills and attributes:
Extensive knowledge of plant and animal species
Communication with landowners, governments, and farmers to improve land for forestry purposes
Organization of plans for managing forest lands and resources
Ability to negotiate terms and conditions for forest harvesting and for land-use contracts
Environmental scientists and specialists use their knowledge and experience in the natural sciences to promote the conservation and protection of the environment and human health. Most work in offices and laboratories while others may spend time in the field gathering data and monitoring environmental conditions firsthand. All this research is for formulating the best plan of action to protect the environment.
Knowledge of data collection methods for research projects, investigations, and surveys
Ability to interact and collect information on plant and animal species
Data and sample analysis
Ingenuity to create plans preventing and fixing environmental problems
Communicate information and guidance to government officials, businesses, and the general public
Prepare technical reports and presentations that explain their research and findings
Food Scientists and Technologists
Food scientists and technologists look into ways to improve the efficiency and safety of agricultural companies/establishments and their products. Most work in laboratories, offices, and in the field. They often experiment with genetically modified organisms (GMOs) such as vegetables and fruit. These scientists are important because they help expand and shed light on the nation's food supply. They work with both basic and applied research and development. Basic research explores the biological and chemical processes by which crops and livestock grow. Applied research tries to answer how to improve the quality, quantity, and safety of agricultural products.
Knowledge of how to conduct research and experiments
Problem-solving skills to improve the efficiency and productivity of field crops
Experiment with new food products
Creativity to develop new and better ways to process, package, and deliver them
Strong communication to share research findings
A clinical scientist conducts experiments, collects data, and uses high-tech equipment while screening and monitoring medical conditions in individuals. They may work in many settings such as hospitals, clinics, or pharmaceutical companies.
Necessary attributes and skills:
Creativity to design and conduct studies that investigate human diseases
Knowledge to prepare and analyze medical samples and data
Inventiveness to produce and head programs that improve health outcomes
Teamwork and partnership with health departments, industry personnel, and physicians
Strong writing for research grant proposals and applying for funding from government agencies
Bachelor's degree and a practicing license from an occupational board
Thorough understanding of procedures to maintain safety
Explore and uncover the unknowns of the environment with a degree in environmental science to promote sustainability.
The Environmental Science B.S. from PLNU prepares you with experience and knowledge to be an innovator in protecting and promoting the conservation of the environment. Whether you pursue field research or hands-on lab work, you'll be ready with the insight you gained on PLNU's campus.
Apply to PLNU today, or get connected with one of our counselors for additional support and to answer any questions you may have.
Dianne L. Anderson, Ph.D.
Program Director, Master of Science in General Biology
(619) 849-2705 dianneanderson@pointloma.edu
Laurance G. Beauvais, Ph.D.
Associate Professor of Chemistry
Chemistry Club Faculty Advisor
(619) 849-3251 laurancebeauvais@pointloma.edu
Walter W. Cho, Ph.D.
(619) 849-2398 waltercho@pointloma.edu
Yoojin J. Choi, Ph.D.
(619) 849-2654 ychoi@pointloma.edu
Sara Yu Choung, Ph.D.
Pre-Health Professions Advisor
(619) 849-2627 sarachoung@pointloma.edu
The Biology Club (TriBeta)
TriBeta is the national biology honors society comprised of biology, biology-chemistry, and environmental science majors and faculty from PLNU.
From synthesizing pharmaceutical drugs to discovering new materials, chemistry is everywhere. That's why PLNU's Chemistry Club is here to help you get involved.
Science and Religion Club
Join PLNU students and faculty to engage with each other and the community about the connections between the studies of modern science and Christian faith.
What type of student are you?
- Select -High SchoolInternationalTransferUS Citizens Living Abroad
Want to learn more about PLNU?
Email Me Information
Ready to start your PLNU journey?
Biology, B.A.Biology, B.S.Biology-Chemistry, B.S.Chemistry, B.S.Organismal Biology, minor
Visit the Department of Biology
Visit the Department of Chemistry


Hi Emma! Great to have you here for our readers! A stunning release of yours is dropping on Déepalma this month. Tell us a little bit about this track.
Well ..I am a child of the 80's ! I grew up listening to Donna Summer, Level 42, Hue & Cry, Five Star, Duran Duran etc.. and I still love to blast a bit of old school (but good!) 80's cheese! There's so many elements that fit so nicely with the nu disco sound that I absolutely adore right now! After listening to quite a lot of music that has that kinda 80's edge from labels like LouLou records, Bunny Tiger and of course Déepalma I really felt so inspired that making this track was so natural for me.
You are having KORT included in the release package with a truly amazing interpretation. On which other projects have you worked with him before and how did you meet eachother?
Ben Webb aka Kort had a track released on Copyright records called "No Fear" a couple of years ago ( which hit traxsource number 1). I absolutely fell in love with it after hearing it dropped by Sam Holt and Gavin Mils aka Copyright at a Defected in the house night at Ministry of Sound. I decided to do a little investigating and checked our Kort's previous releases and just loved his chunky, bouncy out & out house beats that I decided to contact him randomly and ask him if he'd like to collaborate on a track and luckily he liked my voice ! We made a track called "Gratitude" which was released on the legendary King Street Sounds. Last year Kort started his own label Tropical Velvet which has enjoyed a good amount of Traxsource and beatport success and recently enjoyed the jackin house chart traxsource number 1 slot with his own release. I also released a track called "History" on Tropical Velvet with Deeptrak which was remixed by Terence Parker and received support from Roger Sanchez. The label has also been putting on some amazing parties, showcasing the artists that release on it and I have been honoured to have been on the line up to perform my music at them! Kort and I are at present making a new track at the moment , I laid down the vocals last week ..so I await with excitement!
It's hard to pick but, these are the first ones that hit me!
Mark Ronson – why not aim high?!
Sandy Rivera – well he's produced some of the greatest vocal house of all time and is still on point ! Weiss – Wow this guy is just pure fire right now such solid production.
Josh Butler – I don't think this chap makes anything that I don't like! His production has blown me away multiple times. I can only have one more ?! ..mm may be .. MK – just purely because of his creativity with vocals and I love the way the vocals that he uses are spliced and vary so much with the artists he chooses to sample. DENNIS FERRER! Omg..you gotta let me have him too as a number 6?! Every track this guy makes sounds different and he never ceases to surprise me!
Your whole life obviously revolves around music. In those spare moments apart, what do you love the most? What hobbies do you have? What makes you happy besides your music life?
Well I'm a Mummy ! So I have to work around my children which is tricky but I'm lucky cos they are little house heads too. They obviously take up a huge amount of my time so I really don't get much time spare ! But if I do I love to head to the beach if it's a nice day and I do try to keep a bit fitter now and walk my dog as much as I can and hit the swimming pool as I love to swim !
Which place from around the world remains true in your heart as your favorite to date where you've performed at?
No doubt about it I performed to an awesome huge crowd of around 5000 at last year's world renowned Nottinghill carnival. I was so nervous my knees were trembling when I got on the stage and saw how big the crowd was! But it was electrifying ! A great reaction and a definite high point for me that I'll never forget.
Too hard !! So I'll try and stick to house !
Tell us a little bit about the House music scene in the UK. What could our readers expect if they went out in London with you? What places can you recommend?
House music is so exciting in London, it's played everywhere! so so many clubs but for me it's not just about the big boys, I love the smaller too! My favourite haunts in London are Egg, Lightbox and small yet perfectly formed down and dirty venue 'The Nest' .
What is the proudest moment of your career to date?
That's an easy one, my release with Flashmob for the mighty DFTD ! I've been a huge fan of Defected records for well over 10 years so to have had a release signed to their imprint label meant the world to me.
What are your plans for the next months? Any exciting releases or projects coming up?
Yes !! well…obviously some I can't tell you about as they are in progress and quite often tracks will change..but I can tell you that I have a release coming out with K&K (who really have been getting a lot of love on their music from some huge names atm) that's coming out on onefold digital. A tasty collaboration in the making with the deepshakerz is almost finished, and obviously my ongoing work with Deeptrak never stops..!
Thanks a lot for the interview, Emma!
Copyright © 2018 by Déepalma Records. All rights reserved.


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What is Hagley
The revolutions in mass production and mass consumption of the nineteenth and twentieth centuries transformed the material world of modern America. The industrial and commercial buildings of that era expressed, in architectural form, the new images of progress and efficiency that characterized Victorian America and then the Machine Age and modernism. The research collections of the Hagley Museum and Library on business and technology are a rich resource for the study of the iconography and the built environment of modern commercial and industrial America. We invite the attention of architectural historians to our collections, and to the grants available to assist visiting scholars.
View PDF version of the guide with images from our collections
Hagley's collections contain significant documentation on many of the commercial and industrial structures that defined modern America, such as the skyscraper, the industrial plant, the department store, the office building, the railroad station, and the airport. Many major industrial sites are described in our collections, as well as some of the best-known buildings in America, including the Empire State building, Penn Station, the Pentagon, and the Philadelphia Saving Fund Society (PSFS) building. The focus of the collection is on American topics, but there are also significant materials that permit comparison with European practice.
Building types represented in the Hagley collection include:
Aircraft factories
Automobile factories
Coal and ore processing plants
Coke ovens
Company towns
Defense plants
Electrical factories
Explosives factories
Exposition buildings
Gasoline service stations
Hydroelectric dams
Industrial research laboratories
Leather tanneries
Nylon factories
Prefabricated housing
Railroad shops
Rayon plants
Rubber and tire factories
Textile mills
Worker housing
World's Fairs
The imprints collection of approximately 200,000 volumes includes a wide range of material pertinent to the study of commercial and industrial architecture. Publications describe the planning and building of industrial and commercial structures and how they operated on a daily basis. There is considerable information on building materials, furniture, building systems, and design. Of particular note are two microfilmed collections of rare insurance drawings totaling more than 3,600 images, primarily from the 1840s to the 1930s. These collections include both site plans and axonometrics with notes. The E. Hexamer & Company plates primarily cover the Philadelphia region. The Associated Factory Mutual Fire Insurance Company's group of images is national in scope and has documentation on textile, aircraft, paper, automobile, tobacco, electrical equipment, and other factories.
Hagley possesses one of the nation's finest collections of trade catalogs, including ones that describe the full range of building types from industrial to domestic, and from component parts to prefabricated structures. The trade catalogs also contain specific information on mechanical equipment, hardware, furnishings, office equipment, and building materials.
Hagley has a distinguished collection of World's Fairs and exposition publications and ephemera. These include catalogs, guide books, pictorial volumes, pamphlets issued by exhibitors, and materials on the physical structures that housed exhibitions. Beginning with the London Crystal Palace of 1851, all the leading international expositions in Europe and North America are represented, along with numerous lesser ones. These collections are important sources of information on architectural history, including the exhibits and buildings of major corporations (often created by leading designers such as Raymond Loewy, Walter Dorwin Teague, and Norman Bel Geddes), and the expositions' ties to urban planning.
Hagley also has an extensive set of trade journals, ranging from the general to the specialized. They contain information on building types, building materials, design, fireproofing, refrigeration, and lighting and heating systems. Several journals directed towards builders and contractors are especially useful.
Hagley's extensive collection of specialized technical encyclopedias and period textbooks describe standard practices in building and construction. Regional histories, atlases, city directories, industrial directories, and monographs on individual building types can supplement research on industrial and commercial structures.
Imprints holds many publications issued by individual firms. They include firm histories, annual reports, company magazines, and promotional brochures, generally with illustrated views of industrial plants and offices. The imprints collection also contains many published materials that discuss specific features of industrial and commercial architecture. Among the subjects covered are: Building materials (asbestos, concrete, terra cotta, etc.)
Building systems (including electricity and plumbing)
Civil, mechanical, electrical, and nuclear engineering
Factory design and management
Interior design and office planning
Store fronts and window displays
Studies of individual builders, architects, and designers
ARCHIVAL AND PICTORIAL MATERIALS
Hagley holds the country's finest collection of business records and corporate archives (25,000 linear feet). Many of these organizations built significant structures, employed prominent architects and engineers, and sponsored innovations in building materials and construction practices.
Included in Hagley's holdings are some original materials relating to the work of architects such as Daniel Burnham, Frank Furness, Cass Gilbert, Vincent G. Kling, William Lescaze, Kenneth M. Murchison, Edward Durrell Stone, and Lester Tichy of Raymond Loewy Associates. The work of architectural firms Graham, Anderson, Anderson, Probst & White, and Howe & Lescaze also are represented, along with the archive of Victorine and Samuel Homsey, Inc., one of the first husband and wife architectural practices in the U.S.
The business records at Hagley generally have correspondence and other written materials on design and construction of industrial and commercial facilities. Many of the collections include building and site plans, and the PSFS and Phoenix Bridge Company records contain full drawing sets. Some original furnishings for the PSFS building, designed by William Lescaze are at Hagley. Some collections also contain material promoting construction-related products such as steel, concrete, and plastics.
Hagley's holdings include the archives of the following major corporations and trade associations:
American Iron and Steel Institute
Bethlehem Steel Corporation
Chamber of Commerce of the United States
E. I. du Pont de Nemours & Co. (explosives, nylon, rayon, plastics)
Joseph Bancroft & Sons Company (textiles)
J. E. Rhoads & Sons, Inc. (leather tanneries)
Lukens Steel Company
MCI Communications Corporation, Inc.
Maryland Steel Company
Pennsylvania Power & Light Company
Pennsylvania Railroad Company
Philadelphia Saving Fund Society (PSFS)
Phoenix Bridge Company
Radio Corporation of America (Camden, NJ)
Remington Rand (office interiors)
Seagram Company Ltd.
Sperry Corporation (computers, defense)
Strawbridge & Clothier (retail stores)
Sun Oil Company (oil refining, service stations)
Westinghouse Electric Corporation (Power Generation Divisions)
Westmoreland Coal Company
Many of the photographs in Hagley's extensive pictorial collection provide an especially rich source on commercial and industrial architecture. Firms routinely took pictures to document the engineering, design, and construction of buildings, and then photographed interiors, production processes, and employees in the work place.
Among Hagley's major holdings are more than 100,000 photographs from the Sperry Corporation, 70,000 photographs documenting the iron and steel industry, 60,000 views of the Westinghouse Electric Corporation's Power Generation Divisions plant, and more than 20,000 images from the Pennsylvania Railroad and the Reading Railroad. The 5,000 photographs from the PSFS archive show many of its bank buildings, including the construction of its Philadelphia headquarters and views of the interior.
Other commercial structures documented in Hagley's photographic collections range from gas stations to convenience stores. In addition to material from corporate archives, the Dallin Aerial Survey contains 15,000 aerial views of the Delaware Valley and adjacent areas, taken between 1925 and 1940.
Hagley also holds the papers of individual entrepreneurs, managers, and engineers. Some of these collections contain information on plant and building design. The records of general contractor John McShain are a particularly rich source. His extensive work included the Jefferson Memorial, the Pentagon, the Kennedy Center for the Performing Arts, and National Airport in Washington, D.C., as well as many churches, schools, and office buildings.
For general questions about using any of these materials, please use our Ask Hagley online form or call 302-658-2400 ext 227.
The Hagley Center for the History of Business, Technology and Society awards travel grants for visiting scholars. Some housing is available on the property. The Center also organizes conferences, research seminars, and academic programs. For more information emailclockman@Hagley.org.
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Insulated camp with wood stove & wall propane heater. Bunk beds sleep 6. Walk to beach. Spring on property. Year round access.
Large corner lot with many possibilities!
Large wooded lot with wildlife throughout. Close to public access to ocean at Sullivan Harbor. Acadia National Park & Schoodic close by.


Just as it happened with cars like Audi, Mercedes, etc., Toyota's Lexus will also have to go through the hostile probe by NDRC and CADA. According to the statement issued by Toyota, the regulatory board will be conducting a series of tests on the various parts of the car before allowing the Lexus models to hit the showrooms. This is not the first time that the National Development and Reforms Commission (NDRC) and various other regulatory bodies of China pushed car models to the brink of tests before allowing them into their markets.
As a part of the elaborated statement, the National Development and Reform Commission will conduct a series of probes taking a close look at the various parts of the Lexus model. The probe will be conducted by NDRC and China Automobile Dealers Association (CADA) in collaboration. CADA has been conducting tests on a variety of cars since the month of April.
As a part of the initial survey, the officials from CADA and NDRC inquired about the various parts of Lexus and the working technique for it. According to the major market analysts, this can easily be stated as a policy by the Chinese government to abolish the monopoly management for Global car companies. The Chinese Government enacted the anti-monopoly act back in the year 2008 and since then a variety of industries have been affected.
It was earlier this week when the Chinese Regulatory board issued a notice for car makers like Volkswagen and Fiat for practicing monopoly. According to the law under which the notice was served, the car maker can be fined up to 10% of their local annual revenue in China. The general perception is that since China is the world's largest car market, the government is using this opportunity to earn more from foreign investors.


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