I’m working on a startup to develop a new pharmaceutical drug, and I need a lab to help with some of the development and testing. I figure the Thinkgene community might be able to help me out. I’m going to be a little sparse on details in the post, but I can give more information to those who ask.

I’m essentially looking for a lab that can perform an assay to screen a range of compounds for their effectiveness at activating a g-protein coupled receptor, preferably a cell based assay that uses cultured cells.

I have a lab that will generate the compounds that I’m interested in testing, but I need a lab to measure their ability to activate various receptors in neurons. Simple assays that just measure the Kd for the compounds and these particular receptors tend to underestimate the actual effectiveness in the studies I’ve read, so I would prefer an assay that measures something downstream of the receptor; hence why I think a cell based assay would be best. I have a few ideas of different approaches to do this, but it would be complicated by the fact that not much seems to be known about the downstream pathway of these receptors.

If a cell based assay is infeasible or unpractical, simply measuring the Kd would probably be sufficient (I have a protocol for this).

Eventually I would need a lab that can do animal studies with mice to test the compounds after the initial screening. So it would be great if the lab has experience with animal testing.

If anyone has lab or knows someone with a lab that would be capable and willing to help with these tests, please either post a comment with your contact information or email me at josh@thinkgene.com

I just read a short, interesting piece at the Telegraph about an increasing population of jellyfish that can apparently reverse their aging. I’m not entirely sure how this is possible and will be reading through published papers to see if I can figure it out.

From what I gather from the mainstream article, the cells dedifferentiate. Perhaps some of the pathways used are still present in humans? This species most likely has modified pathways that wouldn’t be the same in humans, and if they are unused in us chances are they are no longer in tact due to no selection pressure to maintain them. It could give some interesting clues about which areas to focus on for human aging research. Perhaps once day we will also be able to grow “younger” instead of just older. I’m sure Malthus would not be pleased…

There have been plenty of other posts here on Think Gene foretelling the failure of the DTC market, such as free microarray tests. The consensus is that for these companies to survive, they must enter the medical market.  Critics will say that while companies such as 23andme, Navigenics, and deCODE are just waiting for the right time to enter the medical market, I think there is a different reason why they haven’t entered this market: malpractice.

Let’s first examine the issues in pharmacogenomics with genetic testing. There’s a very well written academic paper by Gary Marchant titled Legal Pressures and Incentives for Personalized Medicine. Additionally, at Redorbit, Olga Pierce writes:

Thus far, lawsuits based on a failure to offer genetic testing before prescribing a drug have mainly targeted drug manufacturers’ deep pockets. But drug companies have circumvented legal problems by including information on genetics and the potential danger of the drugs in package inserts given to consumers with their medication.

That means doctors have become the new targets, Marchant said. It’s a short matter of time before we see a new wave of these cases. Juries are going to say ‘you should’ve done something different.’

But doctors are faced with a catch-22, he said. Most health insurance plans do not cover such genetic tests. If patients cannot afford them, the doctor must decide whether to risk malpractice allegations or simply not prescribe a potentially helpful medication.

Doctors are in a very difficult position, Marchant said.

Doctors’ general lack of training in genetics makes matters worse, he added. Anybody practicing medicine in the country in the next ten years has to understand genetics — or go out of practice.

Institutions and professional organizations can help by establishing clear guidelines for when genetic testing is required, he said, and medical schools should offer new doctors more genetics training.

Nonetheless, there will be a dangerous period for doctors, he said. It’s doctors that are going to bear a lot of the risk during the transition period.

So doctors are liable if they do not give a genetic test when one is available and it may help with prescribing medication. An example is Wafarin/Coumadin, which Dr. Steve Murphy talks about often at his blog, where people can have extremely adverse side effects if they have a particular genotype.

If a doctor did have the genetic data and still prescribed the medication, then it would be pretty clear grounds for malpractice.

Now imagine if a doctor or institution had access to a full microarray of genomic data (including high penetrance mutations). On the one hand, it would be great because if a doctor is prescribing Warfarin, he can easily check the genetic data on file to see if Warfarin is an appropriate medication for the patient. On the other hand, what about mutations that aren’t widely known yet but can be used to determine adverse reactions to drugs such as Warfarin?  If the data is on file, regardless of whether the doctor knows about the mutation, then he may be held liable for malpractice. Negligence could be argued.

This poses quite a problem for the current SNP microarray testing companies. Why would doctors get a whole genome scan which could potentially put them at higher risk for malpractice when they could simply order individual tests? It costs more, but it keeps them safer.

I now propose a simple solution: involve a third party. Say a doctor at a hospital orders a test for Warfarin. The cost of doing a microarray is essentially the same as doing a single genetic test, but the hospital doesn’t want all that data on file. Instead, a third party can do the test and instead only give the hospital access to the specific region that request. In addition to malpractice issues, the other reason for doing it this way is to reduce the cost of licensing fees; why pay the license fee for a BRCA1/2 test if it’s not actually needed? If another doctor later requests a BRCA1/2 test, it can be made available immediately without having to perform another test, and the patient or the patient’s insurance is billed accordingly.

This leaves the microarray DTC providers in quite a bind though. They spent significant resources to develop their genome browser, which is really what gives them their competitive advantage in the DTC market. However, this genome browser doesn’t help them in the medical arena, and in fact may even hurt them for the reasons stated above — information overload and malpractice liability from it.

Hospitals in Australia are stuck in a bad position when it comes to genetic testing. The Sidney Morning Herald has a piece discussing the patented gene SCN1A, which is used to diagnose a particular type of epilepsy in infants. The company that has the test patented, Genetic Technologies, won’t let hospitals do in house testing. Instead, they must resort to sending samples to Scotland to be tested…a process that takes a lot of time and costs much more than necessary. This results in worse care for the infants.

Babies with a severe form of epilepsy risk having their diagnosis delayed and their treatment compromised because of a company’s patent on a key gene.

It is the first evidence that private intellectual property rights over human DNA are adversely affecting medical care.

This is only the beginning of genetic testing. What role are patents going to play in this, especially considering that they seem to do more harm than good from the patent’s perspective. I wonder if there is some legal loophole that hospitals can use to get around this, at least in the United States. Perhaps it may work if the hospital conducted the test for internal research purposes only and then used the results after it had them, though I don’t know if this argument would hold up in court.

What do Think Gene readers think about this? Let’s hear your thoughts!

Update From Andrew:

I think that Fred Bart is personally accountable for his decision which was to defend his legal property and “maximize stakeholder wealth through a market dominant genetic testing business.” This is entirely within his legal rights to do. Let’s say hello to Fred Bart:

.
Hi, Fred. How’s the textile market lately? That’s great.

Fred, you have willfully chosen to enrich your company and yourself despite the full understanding that your decision will adversely affect the health of babies. That is perfectly within your legal right to do, and others have made and continue make similar decisions to a profitable effect.

However, rather than sucking up to you like every other sycophant because you’re rich and powerful, I instead choose to openly disrespect you. That is my prerogative as a free thinking citizen. F*ck you. That is all the civil recourse I have for you for now, but I am working to change that in the near future. The best of luck to you and your shareholders.

Josh: We’re going to see an increase in sites like this where researchers from various disciplines can help each other out. This site has contact information for experts in various fields, allowing labs to more easily collaborate to do interdisciplinary research. I foresee sites like this becoming more “social”, where there are forums or means for researchers in one discipline to ask questions to experts in another discipline. It’s actually surprising that this doesn’t already exist, but I suppose most Web 2.0 technologies haven’t really been applied to other areas yet.

A world-first network linking experts in two leading biotechnologies, proteomics and metabolomics, has been launched by The Hon Gavin Jennings at The University of Melbourne.

The portal website of Proteomics and Metabolomics Victoria (PMV) was activated during the opening of Metabolomics Australia’s node at the University, and is now publicly accessible at www.pmv.org.au.

“Nowhere else is there a cross-sector network of this nature, involving collaboration between academia, trade and industry,” said Professor Mike Hubbard of the University of Melbourne’s Department of Paediatrics, who spearheaded the initiative.

PMV aims to provide education about proteomics and metabolomics, to help scientists access these technologies, and to facilitate practitioners’ interactions with the numerous companies supplying this field.

“Education and workforce development is a central concern shared by academic and commercial members, and together we aim to establish training schemes tailored to our collective needs.”

The State Government of Victoria supported establishment of PMV through funding of a proposal made jointly by Prof Hubbard and Monash University’s Professor Ian Smith.

Simply put, ‘proteome’ means all the proteins in an individual and ‘proteomics’ is the study of as many of those proteins as practicable.

Proteomics provides scientists with a variety of key benefits including deeper understanding of biological processes, increased diagnostic power, and access to information not available from gene-based approaches.

Similarly ‘metabolomics’ is the study of numerous metabolites, which are small molecules such as breakdown products of food, hormones and drugs.

Metabolomics provides scientists with several benefits that are both powerful in themselves and complementary to those of proteomics.

Through its link with the varied and dynamic nature of metabolism, metabolomics offers a very sensitive fingerprint for the status of a biological system (e.g. whether it is healthy or diseased or laden with performance-enhancing drugs).

Proteomics and metabolomics are used in many different research scenarios from academic laboratories in search of hot discoveries through to commercial applications in biotechnology, agriculture and medicine.

In the laboratory, these technologies are typically used to unravel basic biological mechanisms, details of which could lead to new understanding and ideas. Such “nuts and bolts” advances might in turn be harnessed by applications scientists to guide development of new drugs or diagnostics, for example.

“We hope to improve scientists’ access to proteomics and metabolomics, and facilitate interactions between the supply companies and practitioners of these technologies.”

“We also hope to give students and the public a clear understanding about our field, and illustrate its successful practice in Victoria.”

“The website showcases the depth of information and services available in Victoria.”

Source: University of Melbourne

Josh: This is a really neat idea. I’m guessing they would take CD8 cells from the patient, modify them, perhaps grow them in culture, and re-introduce them? I don’t think this is really going to be that practical in reality, and would probably be more expensive that taking anti-retrovirals.

HIV is a master of disguise, able to rapidly change its identity and hide undetected in infected cells. But now, in a long-standing collaborative research effort partially-funded by the Wellcome Trust, scientists from Oxford-based Adaptimmune Limited, in partnership with the Universities of Cardiff and Pennsylvania have engineered immune cells to act as “bionic assassins” that see through HIV’s many disguises.

The findings of the study, published online today in the journal Nature Medicine, may have important implications for developing new treatments for HIV and slowing – or even preventing – the onset of AIDS. Over 33 million people were estimated to be living with HIV worldwide in 2007. Although anti-retroviral drugs have been successful in delaying the onset of AIDS for several years, the drugs are expensive, have serious side effects and must be taken for life. No vaccine or cure yet exists and drug resistance is increasingly becoming a problem.

When viruses enter our bodies, they hijack the machinery of host cells in order to replicate and spread infection. When our body’s cells are infected with a virus they expose small parts of the virus on their surface, offering a “molecular fingerprint” called an epitope for killer T-cells from the immune system to identify. This triggers an immune response, eliminating the virus and any cells involved in its production.

As with other viruses, HIV enters the body and replicates itself rapidly. However, it also has the ability to mutate quickly, swiftly disguising its fingerprints to allow it to hide from killer T-cells.

“When the body mounts a new killer T-cell response to HIV, the virus can alter the molecular fingerprint that these cells are searching for in just a few days,” explains Professor Andy Sewell from Cardiff University, co-lead author of the study and long-term collaborator with Adaptimmune. “It’s impossible to track and destroy something that can disguise itself so readily. As soon as we saw over a decade ago how quickly the virus can evade the immune system we knew there would never be a conventional vaccine for HIV.”

Now, Professor Sewell and colleagues from Adaptimmune Ltd and the University of Pennsylvania School of Medicine have engineered and tested a killer T-cell receptor that is able to recognise all of the different disguises that HIV is known to have used to evade detection. The researchers attached this receptor to the killer T-cells to create genetically engineered “bionic assassins” able to destroy HIV-infected cells in culture.

“The T-cell receptor is nature’s way of scanning and removing infected cells – it is uniquely designed for the job but probably fails in HIV because of the tremendous capability of the virus to mutate,” says Dr Bent Jakobsen, co-lead author and Chief Scientific Officer at Adaptimmune Ltd, the company which owns the technology. “Now we have managed to engineer a receptor that is able to detect HIV’s key fingerprints and is able to clear HIV infection in the laboratory. If we can translate those results in the clinic, we could at last have a very powerful therapy on our hands.”

The researchers believe that HIV’s chameleon-like ability may still prevent the virus from being completely flushed out of the body. It could mutate and change its fingerprint further, hiding behind these new disguises and evading detection. However, each time the virus is forced to mutate to avoid detection by killer T-cells, it appears to become less powerful.

“In the face of our engineered assassin cells, the virus will either die or be forced to change its disguises again, weakening itself along the way,” says Professor Sewell. “We’d prefer the first option but I suspect we’ll see the latter. Even if we do only cripple the virus, this will still be a good outcome as it is likely to become a much slower target and be easier to pick off. Forcing the virus to a weaker state would likely reduce its capacity to transmit within the population and may help slow or even prevent the onset of AIDS in individuals.”

Pending regulatory approval, Professor Carl June and Dr James Riley from the University of Pennsylvania in Philadelphia will shortly begin clinical trials using the engineered killer T-cells.

“We hope to begin testing the treatment on patients with advanced HIV infection next year,” says Professor June. “If the therapy in that group proves successful, we will treat patients with early stage well-controlled HIV infection. The goal of these studies is to establish whether the engineered killer T cells are safe, and to identify a range of doses of the cells that can be safely administered.”

“The AIDS virus evades human immunity in all it infects,” says Professor Rodney Phillips, from the University of Oxford, where the collaborative research effort first began in 2003. “Until now no-one has been able to clear the virus naturally. Immune cells modified in the laboratory in this way provide a test as to whether we can enhance the natural response in a useful and safe way to clear infected cells. If successful the technology could be applied to other infectious agents.”

The researchers are now exploring using engineered receptors on killer T-cells as a way of improving immune responses to cancer.

Source: Wellcome Trust

Control of HIV-1 immune escape by CD8 T cells expressing enhanced T-cell receptor. Angel Varela-Rohena, Peter E Molloy, Steven M Dunn, Yi Li, Megan M Suhoski, Richard G Carroll, Anita Milicic, Tara Mahon, Deborah H Sutton, Bruno Laugel, Ruth Moysey, Brian J Cameron, Annelise Vuidepot, Marco A Purbhoo, David K Cole, Rodney E Phillips, Carl H June, Bent K Jakobsen, Andrew K Sewell & James L Riley. Nature Medicine. 09 November 2008; | doi:10.1038/nm.1779